Future Directions in Sports-Related Concussion Management

This article focuses on 3 concepts that continue to be investigated in the search for the holy grail of concussion—a valid diagnostic test. Imaging advances are discussed with optimism that functional MRI and diffusion tensor imaging may be available clinically. Biomarkers and the use of genetic tests are covered. Sideline accelerometer use may help steer discussions of head trauma risk once technology exists to accurately estimate acceleration of the brain. In the meantime, strategies including allowing athletes to be substituted out of games for an evaluation and video review in elite sports can improve recognition of sports-related concussion.

Key points

•

Despite continued efforts, there is no biomarker or imaging modality that can be used clinically to diagnose a sports-related concussion.
•

Genetic testing is not a clinically useful tool for evaluation of sports-related concussion risk.
•

Video review of mechanism of injury during elite sports performance has advantages for the team physician evaluating sports-related concussion on the sideline.
•

Measurement of head acceleration shows promise, but clinical usefulness has yet to be established.
•

Injury epidemiology should remain the backbone of changes in regulation and law enforcement, so that effects of interventions can be studied, and decisions can be based on data rather than expert opinion.

Introduction

Sports-related concussion (SRC) is an evolving field, and keeping abreast of the most recent literature and investigative findings remains a continual challenge. Some of the world’s sports governing bodies have embraced this challenge by helping to fund an international consensus every 4 years, entailing experts reviewing the previous 4 years of research and meeting in person before disseminating the results. The most recent meeting took place in Berlin in 2016, and the next event is scheduled for 2021 in Paris.

Future directions of SRC can perhaps be best gauged from the discussion at each of these consensus meetings. Some topics have been discussed at almost every meeting and remain an area for optimism, despite not quite being ready for “prime time.” Investigations exploring the use of imaging and biomarkers for SRC would fall into such categories and will be covered in this article. Alternative strategies ready for immediate implementation, such as the use of video review, change in regulation to allow proper field side evaluation, and law changes based on injury epidemiology and biomechanics are good examples.

Imaging in sports-related concussion

One of the major challenges of SRC management in current clinical practice is the lack of significant structural changes associated with concussion that can be identified with standard neuroimaging modalities. A defining feature of SRC highlighted at the 2016 Berlin Consensus underscores this point, namely that concussion “may result in neuropathological changes, but the acute clinical signs and symptoms largely reflect a functional disturbance rather than a structural injury and, as such, no abnormality is seen on standard structural neuroimaging studies.” To this end, there has been a general push to eschew obtaining unwarranted computed tomography images of the brain in closed head injuries in the emergency department per the Pediatric Emergency Care Applied Research Network. There are, however, several more advanced imaging modalities currently available that have a greater sensitivity for subtle structural and functional brain changes associated with sport related concussion. These modalities have become the source of a great deal of recent clinical research. The possibility of using neuroimaging for the diagnosis and management of concussion has therefore gained increasing interest among clinicians in recent years, although debate remains regarding the validity of these modalities and the feasibility of using these tools in everyday practice.

Arguably, the 2 imaging modalities of greatest interest currently are functional MRI (fMRI) and diffusion-weighted MRI (also known as diffusion tensor imaging [DTI]). The fMRI has the ability to measure brain activity by detecting differences in cerebral blood flow, because it is known that blood flow increases to parts of the brain that are in use. This phenomenon is of particular interest in what is known as the default mode network, which is a network of interacting brain regions that demonstrates increased activity in healthy controls during rest and deactivation during attention demanding tasks. Several studies have demonstrated reduced network connectivity among key regions of the default mode network in concussed patients immediately following concussion. Resting-state fMRI (rs-fMRI) is a further subset of fMRI that does not rely on task-based designs when obtaining imaging and has shown alterations in local connectivity acutely following SRC. Resolution of these imaging abnormalities seems to correlate with clinical recovery from SRC. ^, ^, In addition, there seems to be a negative association between default mode network connectivity and the number of concussions an individual sustains. ^, One could argue that this factor makes rs-fMRI the more clinically applicable imaging modality, because it has the potential to predict patient recovery or development of persistent post-traumatic symptoms after an SRC. Nevertheless, this modality remains challenging to apply to the clinical setting, because rs-fMRI studies generally reflect population-based functional changes as opposed to patient-specific alterations. The heterogenic nature of postconcussive symptoms also makes interpreting rs-fMRI a challenge, because there can be significant overlap between other psychological disorders including depression and post-traumatic stress disorder.

DTI is another application of MRI that uses MRI sequences coupled with software that can estimate the directional diffusion patterns of water to generate contrast in MR images. This process provides an indirect pathway for measuring white matter axonal and myelin microstructure. White matter changes have been observed in portions of the frontal, temporal, and parietal lobes of the brain in the initial postconcussion phase with additional evidence to suggest that these white matter changes can persist beyond the medical clearance required for a return-to-play protocol, even up to 1 year after an injury. ^, The strength of DTI, however, may preferentially lie with its ability to detect chronic white matter changes associated with chronically concussed patients with persistent postconcussion symptoms. There is a sizable body of evidence that demonstrates white matter changes in younger patients, those with multiple prior traumatic brain injuries, and those with protracted post-traumatic symptoms. ^, It is important to note, however, that there has also been recent evidence to suggest that postconcussion symptom reporting was not associated with white matter integrity in the subacute to chronic phase of recovery after a concussion. This factor calls into question the validity of using DTI for diagnosis of concussion. A more practical challenge for the clinical application of DTI is the fact that this is a very high-cost modality. Coupled with the fact that, like fMRI studies, the majority of DTI studies are reflective of population-based structural changes (given the high variability of DTI findings on an individual level), ^, DTI remains a research tool and does not seem to be a clinically relevant imaging modality for the diagnosis of concussion at the present time. According to the American Medical Society for Sports Medicine position statement, additional research will be required to determine the clinical usefulness of advanced neuroimaging in the setting of SRC.

Biomarkers in sports-related concussion

An exciting and evolving area of research in SRC is the role of fluid biomarkers in its diagnosis and prognosis. Multiple definitions of the term “biomarker” exist, including this one from the National Institutes of Health Biomarkers Definitions Working Group. A biomarker is “a characteristic that is, objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.” SRC is a disease state with a vast spectrum of presenting signs and symptoms and long-term outcomes that have previously been outlined in detail. The potential exists for devastating consequences as a result of premature return to play. There would be great usefulness, then in identifying biomarkers that can accurately and reliably diagnose and prognosticate SRC.

Proposed mechanisms exist in which neuronal axonal injury occurs releasing various proteins into the interstitial space within the central nervous system and subsequently the cerebrospinal fluid (CSF). A reasonable first place to attempt to obtain a sample, then, is the CSF via a lumbar puncture. However, because obtaining a lumbar puncture comes with a potential for injury and adverse events including, but not limited to infection, hematoma and prolonged CSF leak requiring further procedures, alternate sources of tissue are prudent. Because the normally highly selective blood–brain barrier seems to become more permeable during the SRC disease state, there are proteins released during axonal injury that cross into the peripheral circulation. A second proposed mechanism of central nervous system injury markers being present in the periphery is via the glymphatic system. This mechanism, reported by Plog and colleagues and Brinker and colleagues and summarized by Anto-Ocrah and colleagues, describes proteins from axonal injury entering the brain’s lymphatic system from the interstitial space, which then empties in to the peripheral circulation. An important consideration is that just as the peripheral lymphatic system may become occluded, so may the glymphatic system especially after an injury.

A peripheral venous blood sample is a reasonable method of obtaining tissue for sampling for the purposes of SRC biomarker research. A consideration in the use of peripheral blood are the many potential confounding factors. The presence of normally circulating proteins, including albumin, immunoglobulins, and proteases can interfere with accurate detection, as can hepatic and renal clearance of biomarkers. Furthermore, to truly realize the benefit of sideline evaluation, Anto-Ocrah and colleagues propose that technology must be in place for a point-of-care analysis using capillary blood from a finger stick sample. This process would negate the necessity of having a phlebotomist on site for each practice, game, or other team activity. Until this is developed and perfected, however, a peripheral venous blood sample will remain the research standard.

According to a systematic review by McCrea and colleagues published in 2017, there have been significant alterations found in 10 blood biomarkers with a correlation to SRC. These included α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor peptide, S100 calcium-binding protein B (s100B), total tau, marinobufagenin, plasma soluble cellular prion protein, glial fibrillary acidic protein, neuron-specific enolase, calpain-derived αII-spectrin N-terminal fragment, tau-C79, and metabolomics profiling. Metabolomics, as defined by Klassen and colleagues, is a method of identifying and comparing a set of specific metabolites found in biologic samples under both normal and altered states. In their review, they did identify moderate to high risk of bias, mostly owing to study design translating to poor generalizability.

In another systematic review performed by O’Connell and colleagues, 5 blood biomarkers were investigated from a total of 26 papers that were ultimately included in their review. In the words of the authors, the findings must be interpreted with caution because they identified limitations in the studies included. Like other studies in this growing pool of literature, sample size among other factors, was partly responsible for this.

S100B has been identified as having the most promising data for use as a biomarker of SRC. S100B is a calcium-binding protein found mainly in astroglia and Schwann cells that help to regulate intracellular calcium concentration. It may also be found peripherally in adipocytes, melanocytes, bone, and injured muscle tissue. Its concentration in both the CSF and serum increases after injury, but also after physical activity. ^, Tau protein and neuron-specific aldolase have been highly sought after targets of investigation. Tau protein is found both in the central nervous system and systemically, and neuron-specific aldolase can be found in smooth muscle and adipose tissue. Again, this raises a challenge to prove that the elevated serum marker has a neuronal etiology.

Siman and colleagues compared serum levels of calpain-derived αII-spectrin N -terminal fragment after concussion to preseason levels and found a significant increase after concussion. There did not seem to be an increase in levels after exertion alone without injury. This finding lends itself to the possibility of αII-spectrin N -terminal fragment being used to confirm the diagnosis of SRC with greater specificity after a positive screening test with another biomarker such as S100B, which is perhaps not as specific to neuronal tissue, but more sensitive.

There are multiple fluid biomarkers that are being used in the setting of trauma to the brain. In Europe, S100B has been used clinically. In the United States, the Food and Drug Administration has approved a 2-protein brain trauma indicator-glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1. Both of these biomarkers have been shown to decrease frequency of computed tomography scan of the head in the emergency department.

Much of the current literature is limited in its application to a broad population of athletes. Small sample sizes, sport-specific studies, or those limited to a particular level of competition or gender have predominated. The time to sampling is also a factor that makes generalizability challenging. Many of the current studies obtain samples no less than 1 hour after injury. To create an applicable diagnostic test, it would ideally be conducted immediately at the point of care. Although researchers are working diligently, fluid biomarkers do not yet have a practical role in the diagnosis or management of SRC.

For athletes at all levels of competition, an accurate diagnosis and prognosis are important. With the growing foundation of knowledge regarding the lag between clinical and physiologic recovery from SRC, they become even more critical. Having objective data in the form of a fluid biomarker that can not only aid the clinical presentation in forming an accurate diagnosis, but to be able to trend that objective data along with the clinical course to inform physiologic recovery would be invaluable. It would help to ensure safe return to play for our youth and elite athletes and all levels in between.

Genetic testing

Genetic testing is an important research tool but requires further validation to determine clinical usefulness in evaluation of SRC. There is interest in genetics’ influence on the prediction of the risk the of initial injury, prolonged recovery, and long-term neurologic health problems associated with traumatic brain injury, and repetitive head impact exposure in athletes. However, there is currently no scientific support for genetic testing in the evaluation and management of athletes with SRC, and additional research is needed to determine how genetic factors influence risk of injury and recovery after SRC.

Video review

It has been established that SRC can be difficult to diagnose owing to the often subtle presentation, lack of uniformity, and vague symptoms. This difficulty can be magnified in professional sports, when medical staff are often expected to recognize athletes that may have sustained an injury and implement immediate management under the scrutiny of the watching public and the sport’s governing body. Of course, it can be even more easily accomplished if you have multiple camera views, the option of watching the event repeatedly, and an opportunity to slow the movements. The Fifth International Concussion in Sport Group consensus incorporated the use of video review in recommendations for elite sport that may be being broadcast live, often allowing sideline physicians this opportunity. World Rugby has included video review in the sports head injury assessment of potential concussion in elite-level matches for several years. A number of authors have suggested that video analysis can supplement the sideline evaluation of a rugby player and has the potential to decrease the incidence of missing head injuries. Video review studies have also been conducted in other contact/collision sports such as rugby league, ice hockey, and Australian rules football. ^,

Gardner and colleagues reviewed head impact events in more than 70 Australian rugby league matches. When there was no video review available, an unnoticed head impact events occurred once every 2 matches. With video review, this was reduced to an unnoticed head impact events every 4 matches, although the interobserver variability was weak (κ = 0.49; 95% confidence interval, 0.38–0.59). Gardner and associates cautioned that further investigations are warranted to determine the reliability of identifying the objective signs of concussion when using video review.

Patricios and colleagues identified 3 important components of video review:

1.

Identification: video can help the clinician to identify suspicious events and evaluate the athlete’s response immediately after the event.
2.

Confirmation: video can support the confirmation of mandatory versus discretionary signs of SRC.
3.

Management: video can support return to sport decisions if the off-field concussion screening is normal.

Accelerometers and head impact systems

It has long been recognized that the biomechanical characteristic of head trauma closest associated with brain injury is the acceleration of the brain tissue. This kinetic variable has a close relationship with force of impact and the masses of the objects colliding (F = ma). Acceleration can be measured and is described as linear acceleration in a straight direction (meters/s/s) or angular/rotational acceleration (radians/s/s), which occurs around an axis of rotation. ^, Rotational acceleration has been more closely associated with traumatic brain injury.

Athletes participating in helmeted contact sports have been investigated using techniques to try and establish and quantify the acceleration inside the helmet during collisions. Harmon and colleagues published a statement on helmeted and nonhelmeted impact monitors indicating that current impact sensor systems may not consistently record head impacts or forces transmitted to the brain. No device measuring angular acceleration can yet be used to diagnose concussion, and given the variability in threshold causing concussions, this modality may remain unlikely in the future. ^, Current impact measures are poor predictors of SRC, and it may take better quantification of the number, location, density, and individual thresholds of head impacts to improve this process.

Rule changes

Beaudouin and colleagues claim a 29% lower incidence (incident rate ratio, 0.71; 95% confidence interval, 0.57–0.86; P = .002) in head injuries in male professional soccer since FIFA implemented a rule change in 2006 to consider that an intentional elbow–head contact result in a red card for the offending player ( Fig. 1 ).