What are the most promising point-of-care treatment options for sport-related concussions, specifically those in ice hockey?
In this narrative review, the most promising point-of-care pharmacologic, transcranial light, and nutritional supplement treatment options for concussion that warrant further preclinical and clinical investigation include: dimethyl fumarate, memantine, thioredoxin-mimetic peptides, transcranial photobiomodulation as well as several nutritional supplements (berberine, creatine, curcumin, melatonin, omega-3 fatty acids, resveratrol and vitamins).
The prevalence of concussions in collision sports, such as ice hockey is well established (1–4). Players routinely sustain both direct head contact and indirect force transmission to the brain as a result of body checking, incidental or illegal collisions, and fighting (5). This narrative review focuses on current potential point-of-care treatment options for sport-related concussions (SRC).
Prevalence of Concussions in Hockey
Studies have focused on the incidence of SRC in professional and youth hockey with the potential for generalizability. A prospective case series of concussions over seven National Hockey League (NHL) regular seasons (1997 to 2004) reported 559 concussed players with an incidence of 1.8 concussions per 1000 player-hours (6). More recently, Kontos et al. (7) conducted a prospective cohort study of 31 youth hockey teams. The study found 37 of the 397 participants incurred a medically diagnosed concussion, with a combined concussion incidence rate for games and practices of 1.58 concussions per 1000 exposures.
Critical Demand for Management
The incidence of SRC coupled with a doubling in the participation rate in youth hockey over the past two decades (8) provided the impetus to review the most promising concussion treatment options. The 2017 Ice Hockey Summit III: Action on Concussion reaffirmed the sport's commitment to identifying new treatment methods (9). A review of Ovid Medline and Embase from 2010 to 2019 identified 1568 articles on concussion management. The following is a narrative review based upon relevance to the primary focus of elucidating SRC point-of-care treatment options.
Pathophysiology of Concussion
The pathogenesis of concussion has yet to be fully elucidated, but it is becoming increasingly clear that biomechanical forces lead to an energy crisis, neuroinflammation, cerebral blood flow changes, and pathological cascades (Fig.).
Biomechanical forces from collisions, checking, and fighting in hockey generate disruptions of neuronal cell membranes and axonal stretching, triggering indiscriminate flux of ions through previously regulated ion channels (10). This imbalance of K+, Na+, and Ca2+ (K+ efflux, Na+, and Ca2+ influx) causes neuronal depolarization. The resultant disruption in the ionic equilibrium across cell membranes leads to spreading depolarization, near-complete loss of electrochemical energy, and neuronal swelling (11).
The adenosine triphosphate (ATP)-dependent Na+/K+ pumps attempt to restore ionic homeostasis, and hyperglycolysis rapidly depletes energy stores, resulting in lactic acid buildup, and ultimately, the development of cerebral edema (10). Neuroinflammation has been detected in humans up to 17 years postconcussion (12), suggesting progressive, long-term pathological consequences and the potential for progressive neurodegeneration. In addition to the ionic flux, there is a hyperacute release of glutamate, the brain's primary excitatory neurotransmitter. Excessive glutamate receptor binding can activate calcium-dependent proteases and phospholipases, uncouple mitochondrial ATP synthesis, promote oxidative stress, produce reactive oxygen species, deplete glutathione (GSH) levels, and increase cellular energy demands (13).
Concussion-induced disruption of the blood-brain barrier (BBB) exacerbates the neuroinflammatory response mediated by immune cells, microglia, cytokines, and other inflammatory mediators. BBB dysfunction contributes to oxidative stress, inflammation, brain swelling, increased intracranial pressure, and ischemia. BBB dysfunction may affect the effectiveness of therapies (14).
Shearing forces from a direct blow to the head or acceleration-deceleration transmitted through the neck interrupt axonal transport resulting in accumulation of transported materials in injured regions (15). Axonal dysregulation and accumulation of transport products lead to axonal swelling, secondary disconnection, and Wallerian degeneration (an active, cell-autonomous death pathway as a consequence of the axonal transport system's inability to deliver essential biosynthetic enzymes) (16).
Commonly observed symptoms of concussion include headache, photophobia, phonophobia, dizziness, emotional lability, and cognitive dysfunction. Symptoms may persist for more than 3 months (postconcussion syndrome) in up to 15% of individuals. Case series of contact sport athletes who have sustained repetitive head impacts have shown both gross and microscopic pathology and unique deposition of aggregated tau protein in the depths of the cortical sulci, the reported pathological hallmark of chronic traumatic encephalopathy (CTE) (17). Autopsy series in individuals who had participated in contact sport compared with controls have shown pathological changes consistent with CTE in up to one third of the cases (18). Further investigation into the direct causal relationship between contact sports and CTE is required, as the risk is likely multifactorial, including genetic predisposition and epigenetic influence.
Objective Diagnostic Tools
The heterogeneous pathophysiology of concussion, combined with subjective diagnoses and severity assessment, obfuscates the evaluation of critical therapies, creating significant barriers to demonstrating clinical efficacy in concussion therapies (19,20).
Symptom assessment, sign observation, and cognitive and balance testing have been used to diagnose concussions. These measures are largely subjective and inconsistent with a wide array of confounding covariates, such as the potential for overlapping behavioral maladies and desire to return to play (RTP) (21). The development of genetic risk factor assessments (22,23), blood-based biomarkers (24,25), and imaging modalities (26,27) are promising, but their invasive nature, costs, and inherent delays limit point-of-care applicability. The prevalence of SRC is believed to be significantly understated due to the lack of objective diagnostic tests used at higher levels of participation. Moreover, the numerous subconcussive hits sustained by athletes at all levels and the corresponding lack of objective testing of athletes with no observed or reported signs/symptoms also may contribute to a significant underestimation of the number of SRC. There is often considerable pressure for an athlete to RTP, which influences symptom denial. The current lack of promptly available objective diagnostic tests places the medical practitioner in a difficult situation. If athletes RTP while still recovering from an SRC, they are at higher risk for another concussion or second impact syndrome (SIS). While there remains some controversy surrounding the risk factors and outcomes of SIS, it is a rare, but serious, potentially fatal condition that is thought to occur when an athlete receives a second head injury before completely recovering from the first (28,29).
The most commonly used rink side diagnostic tool is the Sport Concussion Assessment Tool 5 (SCAT5) which assesses symptoms, cognitive status, and gross neurological functioning (30).
King Devick Test
In addition to the SCAT5, the King Devick (KD) test is increasingly being used to assist in rink side assessment of suspected concussions. The KD tests saccadic eye movements comparing an individual's baseline time taken to rapidly name numbers to the same timed test after a suspected concussion. The KD test demonstrated 86% sensitivity and 90% specificity, with a relative risk from meta-analysis of 4.92, indicating that an athlete is approximately five times more likely to have suffered a concussion, relative to a control participant, if the KD test scored worsened from baseline (31).
The SCAT5 and KD test are currently used for rink side assessment, but the opportunity exists to increase the objectivity, accuracy, and severity quantification of the diagnostic process.
There are several promising U.S. Food and Drug Administration-approved tools, currently in their infancy, which may be used in the future to verify SRC detection, scale severity, or assess prognosis, using the following measures:
Quantified electroencephalogram (qEEG) has been used to develop indices of brain dysfunction associated with concussion. The qEEG is thought to be able to detect the physiological effects of SRC, including decreased power of fast frequencies in the dendritic system, and a reduction in the effectiveness of synchronization of distributed cell assemblies throughout the cerebral cortex, an essential component of cognitive processing (32). FDA-approved qEEG based measures of brain function have been developed to assess the presence and severity of functional impairment in concussed patients (33). A sport-specific qEEG was performed in a repeated measure design of (i) preseason, (ii) postconcussion, (iii) prior to RTP, and (iv) postseason on 47 concussed hockey players. Three brain vital signs, auditory sensation, basic attention, and cognitive processing, each with two reported dimensions, amplitude, and latency were measured (34). Once a concussion is suspected, the test can be administered rink side, in a quiet area, requiring approximately 3 min to 4 min of setup and approximately 4 min of recording time. Feedback is then immediately available to medical personnel.
Oculomotor, Vestibular, and Reaction Time
It is thought that coordinated sensory motor function requires the integration of cortical and subcortical pathways of the central nervous system. As such, even subtle impairments of these pathways, such as those following an SRC, are likely to result in abnormal patterns of movement control, including eye tracking abilities and the ability to react to environmental stimuli (35). Several FDA-approved devices have been developed which detect eye convergence and accommodative abnormalities (36,37) as well as vestibular orientation (38).
Emerging Concussion Treatments
Currently, there are no FDA-approved drugs for the treatment of concussion.
Symptoms are managed with a brief period of rest, followed by graded exercise and time. There is growing evidence that a prompt return to subsymptom threshold aerobic exercise is associated with faster recovery following SRC. Leddy et al. (39), in a random control trial of 103 athletes aged 13 to 18 years presenting within 10 d of injury, showed reduced time to symptom resolution following a prescribed aerobic exercise program.
The following point-of-care pharmacologic and transcranial light treatments warrant further preclinical and clinical examination.
Dimethyl fumarate (DMF) is an immunomodulatory compound indicated for patients with relapsing multiple sclerosis. The mechanism of action of DMF is not well understood, but it is thought to upregulate the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and trigger antioxidant gene expression. DMF binds transiently to GSH, an endogenous antioxidant with a ubiquitous role in host immune defenses. This results in temporary depletion of GSH levels, nuclear translocation of Nrf2, and eventual increased levels of cellular GSH. Kramer et al. (40) found concussed mice treated with DMF showed decreased neurological severity scores of motor ability, alertness, balance and general behavior as well as reduced brain damage.
Memantine is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that inhibits calcium influx into cells normally caused by chronic NMDA receptor activation by glutamate (41). Memantine is FDA-approved for the treatment of Alzheimer's disease. Memantine was found to significantly reduce cell death, loss of long-term potentiation, and astrogliosis in an in vitro model of organotypical hippocampal slice cultures (42). Mice treated with memantine after repetitive concussions (4 injuries in 4 days) showed a reduction in tau phosphorylation, glial activation, and long-term potentiation deficiency. However, no corresponding protection in behavioral outcomes was observed (43).
N-acetylcysteine (NAC) or N-acetylcysteine amide (NACA) have historically been two of the most promising concussion treatment options (44–46). However, with the addition of a CxxC motif to NACA, the novel thioredoxin-mimetic (TXM) peptides are more potent than NAC or NACA, demonstrating improved cognitive performance in mouse models (47). These peptides act as reactive oxygen scavengers and GSH precursors to effectively attenuate mitogen-activated protein kinase phosphorylation/activation and reverse nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) translocation to the nucleus under conditions of oxidative stress (48).
Transcranial photobiomodulation (tPBM) delivers red (600 nm to 700 nm) or near infrared (760 nm to 940 nm) light to the scalp with penetration to subjacent cortical brain regions (49). Nitric oxide, a byproduct of hypoxia or cellular damage, can inhibit the enzymatic activity of Complex IV of the electron transport chain. Dissociation of nitrous oxide by photons in red and near infrared regions from complex IV may increase mitochondrial membrane potential, increasing oxygen consumption, glucose metabolism, and ATP production (50). Wu et al. (51), in a mouse concussion model, tested a 665 nm and 810 nm laser. Both showed significant improvement in neurological severity scores. Human trials are limited to case reports of patients treated for postconcussion syndrome (52).
There are several nutritional supplements currently under investigation in controlled trials that have shown preclinical promise for the treatment of concussion including:
Berberine acts to suppress neuroinflammatory responses in microglial cells, and attenuate the production of inflammatory mediators through the suppression of toll-like receptor 4 (TLR4)-Nf-kB signaling. Berberine supplementation was found to significantly attenuate functional deficits, neuronal damage, apoptosis, and inflammation in a postconcussion mouse model (53).
Creatine is a naturally occurring nitrogenous organic acid, stored predominantly in skeletal muscles, but also is present in the liver, kidneys, testes, and brain. Creatine is thought to increase oxygen availability for oxidative phosphorylation, increase mitochondrial efficiency, and ultimately reduce lactic acid production (54). Animal models have shown a reduction in lactic acid accumulation, as well as a reduction in reactive oxygen intermediate production with creatine supplementation (55).
Tetrahydrocurcumin is believed to exhibit neuroprotection by enhancing autophagy activation, modulating mitochondrial apoptosis, and reducing oxidative stress. Treatment with tetrahydrocurcumin was found to improve neurological function and ameliorate cerebral edema in a murine model of concussion (56).
Melatonin, most commonly recognized for its regulation of sleep disturbances, also exhibits therapeutic potential as a free radical scavenger. Melatonin was found to regulate the mitochondrial system, amyloidogenic pathway activation and cognitive function in a mouse model of repetitive mild traumatic brain injury (57).
Omega-3 fatty acids
Omega-3 fatty acids increase levels of brain derived neurotrophic factor (BDNF) levels, decrease oxidative stress, and prevent synaptic degradation. Omega-3 fatty acids also act as anti-inflammatory agents by reducing pro-inflammatory cytokines and promoting the clearance of neutrophils (58). Omega-3 fatty acid docohexaenoic acid (DHA) in the brain supports membrane integrity and fluidity, regulates structural components of synaptic membranes, and contributes to neurite outgrowth and membrane expansion (59). DHA supplementation has been shown to protect against impaired cognitive processing and locomotion while also protecting against reduced neuronal plasticity and oxidative stress in murine models (60).
Resveratrol is thought to exert neuroprotection by modulating neuronal autophagy and acute neuroinflammation, through mediation of the hippocampal TLR4-NF-kB signaling pathway. Resveratrol was found to significantly reduce brain edema, neuromotor deficiency, and neuronal loss while improving spatial cognitive function in a rat model of concussion (61).
Vitamin E supplementation subsequent to concussion was shown to decrease functional neurological deficits, microscopic brain damage, oxidative stress, and amyloid accumulation in a rodent model of concussion. With the addition of vitamin C supplementation to complement vitamin E, there was a greater reduction in oxidative stress than with either supplement alone in a rat model of concussion (62).
Limitations of Animal Study Design
An estimated US $1.1 billion has been spent on unsuccessful traumatic brain injury clinical trials (63). However, there are limitations in the applicability of animal studies to human point-of-care treatment.
Murine models are most commonly used to evaluate potential concussion therapies. However, rodents have lissencephalic brains, whereas humans have gyrencephalic brains. Brain types influence the degree of brain deformation caused by a mechanical insult to the head. Brain size is critical because smaller lissencephalic rodent brains tolerate greater angular acceleration forces than larger gyrencephalic brains. Shearing forces and inertial loading directly relate to brain mass (64).
Most rodent models are limited by the number of repetitive blows that can be applied, which is typically less than five concussion impacts. In addition, there are several commonly occurring compounding, adverse, pathological events including intracerebral bleeding, skull fractures, severe axonal injury, neuronal cell death, and increased mortality (65). The recent development of animal models that more closely resemble human concussion, however, hold promise for preclinical research and testing of novel therapies (66,67).
Assessment — Motor and Cognitive Function
Concussions in humans often present as a complex combination of symptoms, including headache, dizziness, balance problems, and sleep disturbances. More subtle cognitive symptoms also occur, such as impaired planning, diminished memory and learning, reduced attention and ability to process information, slowed reaction time, and increased variability in response (68). This spectrum of signs and symptoms is difficult to replicate in a preclinical model. A variety of behavioral outcome tests are used in murine models, including the Rotarod, Morris water task, and the forced swim test. However, accurate concussion appraisal and treatment comparison requires translatable outcome measures.
Human brains are poorly prepared to withstand traumatic damage from the rapid acceleration/deceleration of the head, resulting in dynamic shear, tensile, and compressive brain tissue strain (69). Contact and collision sports, such as hockey, place athletes at risk for functional and structural axonal damage. Identification and testing of pharmacologic, transcranial light, and nutritional supplement treatment options to enhance recovery and prevent secondary injury from activated and persistent pathological cascades is paramount. Management must begin with an objective diagnosis of concussion. DMF, memantine, TXM peptides, and tPBM, along with several nutritional supplements (berberine, creatine, curcumin, omega-3 fatty acids, melatonin, resveratrol, and vitamins), warrant further preclinical and clinical examination to advance SRC treatment.
The authors would like to thank Dr. Hugh C. Smith, Dr. David Dodick, and Dr. John H. Noseworthy for their incredible guidance and invaluable insight. This research was supported partially by the USA Hockey Foundation and the Johansson-Gund Endowment.
Jonathan Finnoff, DO is on medical advisory boards for COVR Medical, Aim Specialty Health, Sanofi; and receives royalties from Demos Publishing and UpToDate. John Huston III MD stock options Resoundant Inc. and NaviNetics as well as research support: NIH and Batterman Family Foundation. Michael J. Stuart MD — consultant and royalties: Arthrex, research support: Stryker, Arthrex, USA Hockey Foundation.
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