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Introduction: Defining Sports-Related Concussion

Sports-related concussion (SRC) is broadly defined as the immediate and transient symptoms of traumatic brain injury (TBI) [1]. The underlying issue with this definition is that it does not provide insight into the underlying processes causing brain impairment. This definition also does not distinguish between different grades of severity. The term mild traumatic brain injury (mTBI) is often used interchangeably with concussion. This term is also vague and lacks validated criteria in this context. Therefore, the term concussion with this usage is imprecise.

The most commonly recognized definition of concussion stems from the consensus statement from the 5th International Conference on Concussion in Sport, which states that sports-related concussion (SRC) is a traumatic brain injury (TBI) induced by biomechanical forces [1].

Several common features that may be utilized in clinically defining the nature of a concussive head injury include:

  • SRC may be caused either by a direct blow to the head, face, neck, or elsewhere on the body with an impulsive force transmitted to the head.

  • SRC typically results in the rapid onset of short-lived impairment of neurological function that resolves spontaneously. However, in some cases, signs and symptoms evolve over a number of minutes to hours.

  • SRC 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.

  • SRC results in a range of clinical signs and symptoms that may or may not involve loss of consciousness. Resolution of the clinical and cognitive features typically follows a sequential course. However, in some cases, symptoms may be prolonged.

  • The clinical signs and symptoms cannot be explained by drug, alcohol, or medication use, other injuries (such as cervical injuries, peripheral vestibular dysfunction, etc.) or other comorbidities (e.g., psychological factors or coexisting medical conditions).

Several definitions of mild traumatic brain injury (mTBI) have been used over the past decades [2]. Traumatic brain injury (TBI) is typically graded from mild to severe, with use of the clinical assessment of the Glasgow Coma Scale (GCS) . The GCS has a composite score ranging from 3 to 15. A numerical assignment is awarded according to the patient’s eye opening, motor responses to verbal and physical stimuli, and verbal responses to questions and commands. Based on this scale, mTBI refers to patients with a GCS score of 13 to 15. The World Health Organization (WHO) Collaborating Centre for Neurotrauma Prevention, Management and Rehabilitation Task Force on Mild Traumatic Brain Injury proposed the following mTBI definition [3]:

MTBI is an acute brain injury resulting from mechanical energy to the head from external physical forces. Operational criteria for clinical identification include: (i) 1 or more of the following: confusion or disorientation, loss of consciousness for 30 minutes or less, post-traumatic amnesia for less than 24 hours, and/or other transient neurological abnormalities such as focal signs, seizure, and intracranial lesion not requiring surgery; (ii) Glasgow Coma Scale score of 13–15 after 30 minutes post-injury or later upon presentation for health care. These manifestations of MTBI must not be due to drugs, alcohol, medications, caused by other injuries or treatment for other injuries (e.g. systemic injuries, facial injuries or intubation), caused by other problems (e.g. psychological trauma, language barrier or coexisting medical conditions) or caused by penetrating craniocerebral injury.

This definition set forth by the WHO was created as an attempt to standardize an operational definition of mTBI for research purposes.

MTBI may also apply to patients in whom structural lesions are found on standard neuroimaging, or those with focal neurological deficits. This is not consistent with the most commonly accepted definition of concussion. Such imaging findings may include epidural or subdural hematoma, subarachnoid hemorrhage, parenchymal contusion, skull fractures, etc. [4]. The focus of this chapter is traumatic brain injury as it relates to functional brain abnormalities, without the structural changes seen on standard neuroimaging. Please refer to Table 10.1, which provides descriptions of various levels of TBI severity according to GCS score.

Table 10.1 Classification of head injury severity
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Epidemiology

TBI is a global healthcare-related problem of paramount importance [5]. An estimated 1.7 million TBIs occur annually in the United States. A majority of these TBIs are mild [6]. TBI incidence in military personnel, commonly overshadowed by the focus on sports-related injuries, has gained increased attention in recent years. Mild TBI occurred in 20% of deployed personnel, and accounted for the majority of military-associated head injuries during the conflicts in Iraq and Afghanistan [7]. Blast injury caused by improvised explosive devices (IEDs) is an especially common cause of mTBI and concussion, contributing to as much as 79% of these injuries [8,9,10,11,12,13].

The number of American patients seeking care for traumatic brain injuries, most of which are mild in nature, has been on the rise. Marin and colleagues [14] estimated that there were 2,544,087 visits to emergency departments (EDs) for TBI in 2010. This represents a 29.1% increase when compared to the number of ED visits in 2006. This rate of increase is nearly eight times greater than the rate of increase of total ED visits over the same time frame; it is most likely attributed to a combination of factors such as increases in TBI awareness, exposure, and diagnoses. Children <3 years old, and adults >60 years old had the highest rates of ED visits, with falls serving as the leading mechanisms of injury [14].

The annual incidence of sports-related concussion in the United States is estimated to be approximately 3.8 million. This number likely underestimates the true incidence given that many concussions might go unreported or affected athletes might have no gateway to formal medical follow-up [15]. Clay and associates [16] performed a systematic review of the epidemiology of concussion in sport, and reported that the highest reported incidences of concussion, in descending order, are related to football, female and male soccer, wrestling, and female basketball. Between 2% and 15% of athletes participating in organized sports will suffer a concussion during one season (Table 10.2) [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35].

Table 10.2 Seasonal risk of concussion in sports
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Football accounts for the highest proportion of sports-related concussion overall [16]. The incidence ranges from 0.48 to 1.03 per 1000 athletic exposures (AEs) at the high school level, 0.52 to 0.81 per 1000 AEs at the college level, and 4.56 per 1000 game AEs in the National Football League (NFL). This NFL data does not include concussions sustained during practice [16, 36,37,38,39,40] Linebackers are the most commonly concussed players in football in all levels of play overall. Quarterbacks are the most frequently concussed players in the NFL [16]. The majority of concussions are sustained during competition rather than practices, with high-speed player-to-player impact serving as the most common mechanism for concussive injury [41,42,43].

The majority of concussions are sustained during competition rather than practices, with high-speed player-to-player impact serving as the most common mechanism for concussive injury. This correlates with helmet accelerometer data collected in a study of a college football team. Data from this study demonstrated that impacts during football games are nearly three times higher than those during practice [44].

It is unclear why high school athletes report a higher incidence of concussion when compared to college and professional athletes. These findings are unexpected, given that increased high impact exposure and increased cumulative concussions are established risk factors for sustaining concussions in the future [16, 45]. Proposed explanations, which are not well established, have included the immature anatomy of younger athletes, style of play differences (more running plays vs. passing plays in high school football), injury reporting differences, and greater force per hit due to lack of experience [46]. In most sex-comparable sports (excluding lacrosse), concussion incidence is consistently higher in females than in males [17,18,19,20,21,22,23]. A study of the National College Athletic Association ice hockey found that in women’s hockey, which prohibits body checking, player contact was the source of 41% of concussions, compared with 72% in men’s hockey [47]. Additionally, women suffer fewer impacts and experience lower head acceleration than men. This suggests that these factors are not the direct cause of an overall higher incidence of concussion in female athletes [48]. Various studies have proposed that differences in incidence may relate to differences in reporting, as well as the differences in the size and strength of head and neck musculature between males and females [49].

Concussion Diagnosis

The diagnosis of concussion is based on assessment of a range of domains, which includes physical signs, cognitive impairment, clinical symptoms, neurobehavioral features, and sleep disturbance [1]. If even one of these signs is present, concussion should be suspected, and the proper management strategy should be implemented [1]. Diagnosis requires awareness of multiple symptoms that may be present with concussive injury paired with a focused clinical examination. On-site assessment tools may aid the provider in the diagnosis of concussion. Adjuncts to the clinical assessment, such as advanced neuropsychological testing, neuroimaging techniques, and blood-based biomarkers of injury, can also be used to aid in identifying injury and secure the diagnosis of concussion. Although these new technologies are not required or recommended for routine clinical care, they show promise as investigative tools to advance our understanding of the pathophysiology of concussion and recovery. Through advanced imaging techniques and analysis of biomarkers that are released following injury, research has conceded that considering concussion as only a functional entity is an inappropriate underestimate.

There is a wide range of variability in the quality of training and experience of health care professionals diagnosing and caring for concussed athletes. This contributes to uncertainty and inconsistency in the various aspects of concussion diagnosis, prognostication, and treatment in affected athletes. In 2013, The Guideline Development Subcommittee of the American Academy of Neurology (AAN) published the “Evidence-based Guideline Update: Evaluation and Management of Concussion in Sports.” [50] This comprehensive publication reviews evidence in children, adolescents, and adults from 1955 through 2012 in an attempt to bring consistency to this clinical entity.

Concussion: Signs and Symptoms

The clinical manifestations of concussion affect one or more of the domains of somatic, cognitive, behavioral, emotional, vestibular, cervical, autonomic, and sleep/wake symptoms. Common signs and symptoms of concussion are headache, fatigue, dizziness, amnesia, irritability, anxiety, poor concentration, photophobia/phonophobia, disorientation, and postural instability. See Table 10.3 for a summary of commonly reported signs and symptoms of injury.

Table 10.3 Common signs and symptoms of mild traumatic brain injury
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These signs and symptoms are sometimes associated with other conditions in athletes, including dehydration, exertional migraines, heat-related illness, and sleep disorders. Thus, it is important to establish a relationship between mechanism of injury and the onset or worsening of symptoms [51,52,53,54,55]. Physicians and others caring for athletes must remember that although symptoms typically begin immediately following the inciting trauma, some patients may not experience symptoms for several hours after the injury [56].

Headache is the most common reported symptom of concussion, present in 83–86% of patients with concussion [57, 58]. The headache characteristics experienced after concussion or mTBI may include tension-type, cluster-like, migraine-type, and mixed. The mechanism for headache following head injury is not well understood. Both migraine and mTBI have common pathophysiologic effects, including increases in intracellular sodium, calcium, chloride, and extracellular potassium. Both conditions have been linked to increased release of excitatory amino acids, such as glutamate [59].

Post-concussion headache may be associated with slowed reaction time, memory impairment, on-field anterograde amnesia, and increased overall symptoms [60]. Patients with migrainous headache after concussion scored lower on several neurocognitive measures (processing speed, verbal and visual memory, and reaction time) than those with nonmigrainous headaches or no headache after concussion [61]. Patients with migrainous headache also reported more or worse symptoms relative to the other two groups [61].

Mental status changes and subtle neurocognitive deficits are also quite common with concussion. Confusion has been a longstanding hallmark of concussion [62]. Confusion may also include a disturbance of vigilance with heightened distractibility, inability to maintain a coherent stream of thought, or the inability to carry out a sequence of goal-directed movements. Although disorientation may be present during a concussion, more subtle changes, as described previously, are more common and should be sought during examination of the patient or athlete [63]. One study highlighted that concussed athletes exhibiting “fogginess” have demonstrated poor performance on memory, reaction time, and processing speed measures, and an overall higher total symptom score [64].

Loss of consciousness (LOC) was previously viewed as a requisite for concussion, whereas the literature shows that more than 90% of concussions occur without LOC. Concussions of higher severity with corresponding signs and symptoms may occur with no LOC [65]. LOC occurs in 8–19% of sports-related concussions, with most LOC lasting less than one minute [66, 67]. The duration of LOC is not correlated to injury severity in concussion studies [68, 69]. This is contrary to what is reported in moderate and severe TBI studies [68, 69].

Posttraumatic amnesia can occur immediately, or several minutes after concussive injury in athletes [70,71,72]. Both retrograde and anterograde amnesia may be associated with neurocognitive deficits, and more reported symptoms in the days immediately following concussion [73]. The presence or absence of post-concussive amnesia as a predictor of long-term outcome is not currently established in the literature [1].

Decreased postural control after concussion is well established [74]. Assessing for this may be carried out by having the patient stand upright with the eyes closed. Eliminating visual referencing with eye closure accentuates postural control deficit that is associated with an inability to process altered sensory information [74]. Decreased postural stability symptoms typically persist up to 3 days following injury [75].

It is important to recognize that a variety of immediate post-concussive motor phenomena, such as convulsive movements and tonic posturing, may accompany a concussion [1]. These clinical features are typically benign and do not require specific management [1].

Acute Concussion: On-Field Assessment and Sideline Assessment Tools

The Consensus Statement on Concussion in Sport from the International Conference on Concussion in Sport states [1]:

When a player shows any symptoms or signs of an SRC:

  1. (a)

    The player should be evaluated by a physician or other licensed healthcare provider on site using standard emergency management principles, and particular attention should be given to excluding a cervical spine injury.

  2. (b)

    The appropriate disposition of the player must be determined by the treating healthcare provider in a timely manner. If no healthcare provider is available, the player should be safely removed from practice or play and urgent referral to a physician arranged.

  3. (c)

    Once the first aid issues are addressed, an assessment of the concussive injury should be made using the SCAT5 or other sideline assessment tools.

  4. (d)

    The player should not be left alone after the injury, and serial monitoring for deterioration is essential over the initial few hours after injury.

  5. (e)

    A player with diagnosed SRC should not be allowed to return to play on the day of injury.

Signs and symptoms which are of particular concern include severe or progressively worsening headaches, positive findings on neurological examination, emesis, or rapid decline in mental status that may indicate a more life-threatening injury (e.g., epidural or subdural hematoma, intraparenchymal hemorrhage) and necessitates immediate transfer to the emergency department.

There are a variety of sideline assessment tools that gauge concussion-related symptoms, neuropsychologic function, and balance [1, 76,77,78,79]. The most commonly used sideline assessment tool is the Sports Concussion Assessment Tool, fifth edition (SCAT5). This assessment includes a standardized evaluation of signs and symptoms, neurologic function, cognition, and balance [1]. The original SCAT was developed by the second International Conference on Concussion in Sport [1]. The SCAT5 is designed for use in athletes age 13 years or older, and combines aspects of several previously published concussion tools into multiple components (Fig. 10.1) [1]. In order to eliminate the possible confounding effects of fatigue from competitive play when testing for concussive symptoms, the athlete should be removed from play and be “in a resting state” before testing is performed [1]. This usually requires at least ten minutes or more, which gives time for the athlete’s heart rate to return to the resting state. Therefore, it is important to recognize that the SCAT5 cannot be performed correctly if less than 10 minutes have passed since time of suspected concussion. A preseason baseline evaluation can provide tremendous benefit. Possession of a baseline “scorecard” for reference facilitates serial tracking of a concussion over time, should injury occur during competitive regular season events. This may be helpful given reports regarding the variability in baseline testing, as well as test reliability for earlier SCAT versions. One study reported baseline values for 260 collegiate athletes utilizing the original SCAT [80]. This study demonstrated gender differences in baseline values. A history of previous concussion in athletes also accounted for differences in baseline scores. Another study investigating representative baseline values on the SCAT2 reported differences in scores associated with age, gender, and self-reported concussion. This further highlights the benefit of baseline testing of athletes before initiation of competitive events during the regular season [81]. It should be noted that scores for the SCAT5 are not “pass/fail” scores, but rather, the tool is used by the healthcare professional to assist in the diagnosis of concussion, to determine overall injury severity, and management of concussion.

Fig. 10.1
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Developed by the concussion in sport group, SCAT5 is a standardized tool used by Medical professionals and qualified health care professionals to aid in evaluation of athletes suspected of having sustained a concussion [1]. SCAT 5 can also be used to obtain baseline data among health athletes for future reference

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For children aged 5–12 years, the Child SCAT5 was developed, and contains modifications from the SCAT5 that are more appropriate to children [82]. Some of the differences between the Child SCAT5 and the SCAT5 include a child-specific symptoms list, which includes both child and parent reported symptoms, simpler concentration questions for children, removal of orientation questions for children, and simplified balance testing for younger children. A large body of evidence supports balance testing (which includes balance assessed with tandem gait.), particularly in the first few days, as a sensitive component of the diagnosis of concussion [83,84,85]. This influenced the inclusion of the Balance Error Scoring System (BESS) that was included in the SCAT5.

The examiner should follow this with a more detailed evaluation of cervical range of motion (ROM). Range of motion testing should assess flexion, extension, and rotation in all directions, both passively and actively [86]. This should be followed with formal assessment of motor strength testing in all muscle groups. The athlete should be withheld from participation (even in the absence of deficits on previous portions of the concussion assessment) for further evaluation, because limitations in these areas may place the athlete at risk for further injury by restricting the athlete’s ability to protect the head and anticipate impacts from oncoming opponents [87]. For athletes who have performed at or above baseline for all other aspects of the assessment, functional testing marks the final step in the concussion evaluation.

The goal of functional testing is to elicit symptoms that may be exhibited with the physical and cognitive demands the athlete may experience upon return to play [87]. Simple tasks such as push-ups, and sit-ups, and Valsalva maneuver should be performed first [87].

Next, physical activity may be advanced by having the athlete jog. This may be followed by more strenuous aerobic activity such as interval sprinting exercises. Successful completion of the progression culminates with sport-specific activities (e.g., dribbling/shooting a basketball, passing drills with a soccer ball, throwing/catching a football, shooting a hockey puck, etc.) performed at a similar intensity level necessary for safe return to play [86]. With each step, the practitioner should ask the athlete whether any concussion-related symptoms have been elicited before moving on to an increase in activity level. If at any time, an athlete reports symptoms that result from the exertion, the player should not be permitted to return to play (or progressed to the next step). If no symptoms are elicited through these functional tests and all other assessments demonstrate normal findings, the athlete has not likely sustained a concussion and may be considered for return to play.

Although standardized sideline assessment tools may be useful in the evaluation of concussion, several points must be kept in mind. These tools are designed for rapid screening of concussion by the wider spectrum of practitioner types and should not be used to replace comprehensive neuropsychologic testing by a trained neuropsychologist [1]. Furthermore, no sideline assessment tool should be used for the ongoing management of sports-related concussions [1]. A standardized clinical evaluation of concussion is useful, but should not substitute for clinician’s judgment [87].

Adjuncts to the Clinical Assessment for Concussion

Neuropsychologic Testing

Neuropsychologists have contributed greatly to our knowledge of the effects of concussion on cognition and emotional functioning. The application of neuropsychologic testing has been long recognized in the evaluation and treatment of individuals with concussive injuries [88] Well-known sequelae of concussion include deficits in attention, processing speed, reaction time, and learning [89,90,91]. If a neuropsychological assessment is deemed necessary by the treating physician, it should be performed by a trained neuropsychologist [1]. Neuropsychological assessment can be especially helpful in the cognitive assessment of athletes when distinction between true cognitive impairment secondary to a concussion versus other factors are difficult to determine.

Multiple studies have demonstrated the usefulness of neuropsychologic assessment with concussed patients and in return-to-play (RTP) protocols [1, 92,93,94,95,96,97,98]. Neuropsychologists employ computerized measures to examine cognitive functions such as attention, memory, language, visual abilities, and executive functioning as well as affective functioning. Computerized tests offer the advantage of decreased administration time, availability of multiple alternative forms for serial testing, and more precise measurements [99, 100]. Perhaps the most widely-used computerized test is the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) program [101]. This is a 20-minute assessment that contains a symptom checklist, and measures visual and verbal memory, reaction time, and information processing time [102, 103]. Validity measures with computerized tests such as the ImPACT program reduce the risk of intentionally poor performance reporting on baseline testing without reaching threshold on the test validity indicators, which alert the administrator to an invalid test [104]. These validity measures may be used with or without baseline data, in which case normative data may be applied.

Various studies have demonstrated the utility of the ImPACT program in concussion [95, 103, 105,106,107,108,109,110,111]. Although the use of computerized instruments in concussion has become widely accepted, there are still legitimate concerns regarding this assessment method. Among some of the concerns raised are: privacy and data security, test reliability and validity, cultural, experiential, and disability effects, and checks on effort validity [112].

One study reported low reliability scores with ImPACT and other tests [113]. This study demonstrated that, even with alternative forms, practice effects can be seen on ImPACT, particularly with processing speed scores. Broglio and colleagues reported lack of test-retest reliability of three computerized tests (ImPACT, CogSport, and Headminders) in an often-cited study as argument against the validity of computerized testing [114].

Advanced Neuroimaging

Conventional neuroimaging findings seen in computed tomography (CT) and magnetic resonance imaging (MRI) are typically normal in concussion. CT and MRI of the brain are utilized when there is concern for intracerebral hemorrhage or a structural lesion is suspected in the setting of focal neurological deficit, prolonged loss of consciousness, or progressive worsening of symptoms. Several advanced neuroimaging techniques, such as diffusion tensor imaging (DTI), functional MRI (fMRI), magnetic resonance spectroscopy (MRS), and high-definition fiber tracking (HDFT), and positron emission tomography (PET), might possibly increase the sensitivity of neuroimaging to detect both structural and functional abnormalities associated with concussion—both in the acute setting and subsequently in the subacute and chronic phases of recovery.

Several studies have used advanced MRI techniques to assess for acute concussion. These studies demonstrate acute changes in brain function and structure following concussion. These acute changes were shown to gradually revert back to a normal pre-concussive state, which is comparable to non-concussed control patients. These acute MRI findings include changes in white matter integrity on diffusion imaging, changes in cerebral blood flow on arterial spin labeling (ASL), altered functional connectivity on resting state functional MRI (rs-fMRI), and appearance of microhemmorhage on perfusion imaging.

Several studies have evaluated and discussed fMRI findings in sports-related concussion [84, 115,116,117,118,119,120,121,122,123]. One study examined performance of memory and sensory tasks in a group of college football players, some of whom had suffered concussion. Brain activation was found to be more widespread following concussion than before injury (baseline fMRI used for comparison). This cohort was compared to un-injured control subjects [124]. The mid-dorsolateral prefrontal cortex (DLPC) is an area associated with working memory. Less task-related activation in the DLPC was observed in subjects with persistent post-concussion symptoms 1–14 months following concussion. These findings were present in the absence of abnormalities seen on structural MRI. Of particular interest was one subject who demonstrated resolution of symptoms with associated normalization of the observed widespread activation pattern. Some studies have also demonstrated a correlation between fMRI abnormalities and cognitive test results. Athletes with post-injury fMRI findings that demonstrated hyperactivation experienced a longer clinical recovery when compared to those without hyperactivation [125].

PET measures certain components of cerebral metabolism, including blood flow and the cerebral metabolic oxygen consumption. Some limitations of PET include expense, exposure to radiolabeled tracers, and the time required to complete the study. Despite these limitations, studies have demonstrated interesting findings when PET is performed after mTBI. Umile et al. observed adults after mTBI who exhibited persistent post-concussion symptoms. This study found the subjects to have significantly reduced metabolism in the medial temporal lobe [126]. Chen et al. demonstrated differences in cerebral metabolism during a visual-spatial working memory task in adult subjects with persistent symptoms following mTBI [127].

MRS measures concentrations of compounds in the brain within a sampled region. It is a useful tool that is commonly used in the evaluation of brain lesions [119]. TBI is associated with specific metabolites, which may include choline, a marker of membrane damage and turnover; lactate, an indirect marker for ischemia and hypoxia; N-acetyl aspartate (NAA), a marker of neuronal integrity; creatine (Cr), a cellular energy marker for adenosine triphosphate (ATP) resynthesis; and myoinositol, a glial marker [117, 128].

In a study of 14 patients with sports-related concussion, reduced NAA:Cr ratios were observed 3 days after concussion, with normalization of the NAA:Cr ratio 30 days post injury [129]. This reduced ratio persisted despite resolution of symptoms which occurred, on average, after 3 days. This suggests that metabolic normalization may be different than symptom recovery. Reduction in NAA and other metabolic derangements in post-concussion patients is supported by various studies comparing athletes with and without concussion [130, 131].

HDFT and DTI, both techniques that are capable of providing information regarding fiber tract integrity and white matter microstructure, have been increasingly utilized following mTBI and concussion. Many DTI studies have shown correlation between mTBI and widespread structural changes in cortical white matter tracts [132,133,134,135,136,137,138,139,140,141,142,143,144,145,146].

These studies report abnormalities in various regions of the brain. These areas include the corona radiate, corpus callosum, uncinate fasciculus, inferior and superior longitudinal fasciculus, cingulum bundle, inferior fronto-occipital fasciculus, internal capsule, as well as the acoustic and posterior thalamic radiations [135]. Studies have demonstrated a correlation between DTI and injury severity with symptoms [145] as well as functional deficits measured by neuropsychologic testing and other behavioral measures [138, 141, 147, 148].

HDFT provides high-resolution details of axonal pathways and projection fields that allow detection of the specific location and degree of damage [149, 150]. HDFT was used in one study to identify a specific lesion of the corona radiata corticospinal pathway that was associated with left-sided weakness in a patient 4 months after injury [149].

HDFT may overcome some of the shortcomings of DTI, but routine use of either modality for concussion is premature [149]. The results of initial studies using HDFT are preliminary and must be validated in larger studies, but emerging data is encouraging.

Cerebrospinal Fluid and Serum-Based Biomarkers of Injury

There has been a drastic increase in research in both cerebrospinal fluid (CSF) and serum biomarkers of neuronal, axonal, and astroglial injury with a goal of improving diagnosis and helping predict the clinical course after concussion and mTBI. Despite these efforts, there remains a lack of sufficient evidence to justify their routine clinical use [1, 151].

Recent studies have demonstrated changes in common TBI biomarkers after SRC, suggesting evidence of neuronal cell body damage, axonal injury, and neuroinflammatory response to injury. Serum may seem to be an attractive biofluid for analysis given its lower cost and lower associated risk of acquisition, but extensive studies with sampling of both biofluids suggest otherwise. Trauma to areas outside of the brain, as well as non-trauma-related athletic exertion, is associated with increased levels of certain biomarkers that may give a false representation of levels in the brain. For example, S100 calcium-binding protein (S100B) and glial fibrillary acidic protein (GFAP), both markers of astroglial injury, have been shown to be elevated in the serum of mTBI patients [152,153,154].

Other biomarkers, such as myelin basic protein (MBP), tau protein, and neuron-specific enolase (NSE) are being actively studied. Immunoassay technique sensitivity, validity, clinical assays for quantification, and the amount of longitudinal data in concussion need to improve before these biomarkers can be routinely used [151].

Concussion Management

The mainstays in concussion management have previously been both physical and cognitive rest. The Berlin consensus statement states [1]:

There is currently insufficient evidence that prescribing complete rest achieves these objectives. After a brief period of rest during the acute phase (24–48 hours) after injury, patients can be encouraged to become gradually and progressively more active while staying below their cognitive and physical symptom-exacerbation thresholds (ie, activity level should not bring on or worsen their symptoms). It is reasonable for athletes to avoid vigorous exertion while they are recovering. The exact amount and duration of rest is not yet well defined in the literature and requires further study.

Fortunately, most symptoms resolve relatively shortly over the course of several days following injury, thus allowing the patient to gradually return to social and academic activities.

A stepwise program is generally accepted with regard to return to athletic play [1]. This program begins with a period of no activity. This is followed by light aerobic exercise, followed by sport-specific exercise, noncontact training drills, full-contact practice, and finally return to play. Each of these levels is performed over a 24-hour period. The program may be initiated when the athlete is asymptomatic at rest. If the athlete exhibits any post-concussion symptoms at any of these steps, another 24-hour period of rest is completed, and the athlete reverts back to the previous step in the program. Same-day RTP should not be permitted on the day of injury. This is due to evidence that RTP on the day of injury may be associated with prolonged neuropsychological deficits with delayed onset.

It is uncommon for post-concussion symptoms to persist beyond 10 days, but it is possible in a subset of patients. This may prompt clinicians to consider pharmacologic treatments for management of symptoms. If this option is to be employed, the patient and clinician should come to a mutual agreement that that benefit of treatment outweighs any possible adverse effect of a medication under consideration [155, 156]. There are no clinically validated treatments that have demonstrated benefit with regards to expedited recovery or amelioration of deficits attributed to TBI [157]. However, athletes with post-concussion syndrome or prolonged post-concussion syndrome may experience some benefit from symptomatic medical treatment during the recovery phase [157,158,159,160].

Several factors must be considered by a physician considering use of medication for the treatment of post-concussion symptoms. Medications that lower seizure threshold, or those that contribute to fatigue, cognitive slowing, or daytime drowsiness should be avoided. Medical therapies should be initiated at the lowest effective dose, with a slow dose titration according to patient tolerability, clinical response, and side effects. In order to prevent adverse interactions, special care should be taken to review all medications and over-the counter supplements the patient is currently using [155, 156, 161].

The treatment of concussion should be specific to patient symptoms, which are grouped into the following four categories: cognitive, emotional, somatic complaints, and sleep disturbance [155, 160]. However, it should be noted that alleviating one symptom may improve upon others. A concise review of selected agents studied in mTBI or concussion for the management of various symptoms is provided below.

The most common symptom reported after concussion is post-traumatic headache, which occurs in more than 90% of patients [162,163,164]. Patients with persistent post-concussion headaches most commonly develop migraine-like or tension-type headaches [165,166,167]. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are typically avoided in the acute period following concussion. Therefore, acetaminophen is a reasonable choice for post-concussion headache treatment in the acute period. A majority of patients experience spontaneous resolution of the headache; patients with persistent headaches may require further treatment. Amitriptyline (an antidepressant) has shown efficacy in the treatment of post-concussion headaches [161, 168, 169]. Data is currently limited regarding other treatments, such as triptans, dihydroergotamine (DHE), anticonvulsants (valproic acid, gabapentin, and topiramate), calcium channel blockers, and beta clockers [155, 166, 167, 170].

Neurostimulants are often used for moderate or severe TBI with associated fatigue, but data on their usage in mTBI is sparse. Methylphenidate (a norepinephrine–dopamine reuptake inhibitor), modafinil (an atypical, selective, and weak dopamine reuptake inhibitor), and amantadine (a weak antagonist of the NMDA-type glutamate receptor) are pharmacologic agents that have been studied in randomized trials for use in mTBI, and shown variable success [155, 171, 172].

Acutely following a concussion, difficulty falling asleep is a common source of significant morbidity. This is especially true for student athletes [155, 164]. Trazodone is an antidepressant which antagonizes serotonin 2A (5-HT2A) receptors and inhibits serotonin reuptake, and is commonly used to treat sleep disturbance in post-concussion patients [155, 173]. Prazosin, zolpidem, and melatonin are other agents that have shown varied results for treatment of mTBI and concussion [173,174,175,176,177,178,179,180,181].

Antidepressants have been generally used for most emotional symptoms following concussion [155, 156]. Most evidence for use of selective serotonin reuptake inhibitors (SSRIs) in concussion comes from small, uncontrolled studies and case reports, thus efficacy is not well validated at this time. Despite this, SSRIs have become the primary treatment for TBI-associated depression due to their perceived clinical efficacy and relatively few side effects. A subset of patients may continue to experience cognitive deficits, as evidenced by neuropsychologic testing for a prolonged period following mTBI or concussion. Amantadine acts through several pharmacologic mechanisms and is a weak antagonist of the NMDA-type glutamate receptor, increases dopamine and norepinephrine release from free nerve endings, and blocks dopamine reuptake; it has been used to improve post-concussion neurocognitive recovery with varied success [182,183,184,185].

Recommendations for Concussion Management

The AAN makes several recommendations for health care providers regarding management of suspected concussion [50]. All athletes with suspected concussion should be removed from play immediately to avoid further injury. This should be followed by an evaluation by a provider experienced in diagnosis of concussion, and more severe TBI. Any athlete with concussion should be restricted from return to contact sports play until he or she is asymptomatic without medication use, and the concussion is resolved.

Licensed providers may use neurocognitive testing or other tools to determine concussion resolution.

The development of graded plans for return to cognitive and physical activity, in a monitored clinical setting, may help providers minimize exacerbation of early post-concussion impairments. Cognitive restructuring is a form of psychologic counseling focused on reassurance, education, and reattribution of symptoms that may help decrease the likelihood of the development of chronic post-concussion syndrome.

Post-concussion Syndrome

Symptoms associated with concussion typically resolve several days following injury. Symptoms that persist beyond 10 days occur in up to 10–15% of patients [1].

Post-concussion complications include acute symptoms, post-concussion syndrome (PCS), persistent or prolonged PCS (PPCS), mild cognitive impairment, chronic traumatic encephalopathy (CTE), and dementia pugilistica. The WHO’s International Statistical Classification of Diseases and Related Health Problems, tenth revision (ICD-10) defines diagnosis of PCS requiring the presence of three or more of the following symptoms: headache, dizziness, fatigue, irritability, insomnia, concentration difficulty, and memory difficulty. There is no universally agreed upon time frame for symptom duration that constitutes the aforementioned syndromes; however, the persistence of symptoms for between 6 weeks and 3 months is generally consistent with PCS, and the presence of any symptom for longer than 3 months is consistent with PPCS [156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186].

There is also some controversy regarding the pathophysiology of these phenomena, with some authorities suggesting that the symptoms associated with PCS are a direct consequence of brain injury, while others propose that the symptoms are functional and represent the emotional or psychologic sequelae of the brain injury [187,188,189].

It is important to note that symptoms associated with concussion may also be associated with various other conditions. Differentiating among etiologies can prove to be difficult. For example, comparison of the diagnostic criteria for post-traumatic stress disorder (PTSD), major depressive disorder, acute stress disorder, anxiety disorders, and PCS shows considerable overlap [190]. The differential diagnosis also can include vestibular dysfunction, visual dysfunction, cervical injury, somatization, chronic fatigue and pain, or a combination of these in some form [191, 192]. When clinical recovery extends outside the expected window, management by a multidisciplinary team with experience in concussion management should be undertaken [1].

It is unclear which patients will continue to experience PCS spectrum symptoms far beyond their injury, but certain variables may increase the risk. These clinical variables may include prior concussions, female sex, a history of cognitive dysfunction, and the presence of affective disorders, such as depression and anxiety [192,193,194,195,196,197,198]. The average time to normalization to pre-concussion baseline on neurocognitive testing has been reported as 10–14 days in high school students, 5–7 days in collegiate athletes, and 2–5 days in professional athletes [199,200,201].

Children may experience more severe, prolonged, and more widespread cerebral edema after brain injury [202,203,204]. The reasons for this are unclear, but may be due to differences in glutamate receptor expression and/or sensitivity, or weakened neck musculature that may result in greater rotational acceleration on impact when compared to that seen in adults [205,206,207,208].

There is no widely accepted explanation for the higher risk of PCS and PPCS in patients with underlying cognitive dysfunction. Patients with lower IQ scores have been found to be more likely to experience persistent post-concussion symptoms and to be diagnosed with PCS after brain injury [197, 209]. Several studies suggest that specific premorbid emotional and personality characteristics potentially put some people at increased risk for poor outcome following concussion [198, 210]. Post-concussion symptoms may be mediated by an interaction of psychologic and neurological factors after TBI. Psychiatric disease preceding or following brain injury, including PTSD, anxiety, depression, acute stress disorder, has been associated with increased risk of poor outcome following concussion [197, 209, 211].

Repetitive Mild Traumatic Brain Injury: Cumulative Effects

The short- and long-term sequela of repetitive concussion has gained increased focus in the media and medical community over the last several years. The biggest short-term fear regarding repetitive head injury is that of “second impact syndrome.” This is defined as the quick deterioration and death of an athlete who experiences a second mild head injury following return to play subsequent to the first injury. Most case reports pertaining to this syndrome are not associated with space occupying lesions. Death was associated with severe and rapid cerebral edema [212]. This condition has been reported primarily in adolescent and young adult athletes. Proponents of this syndrome believe that following initial mild TBI in younger patients, there exists an increased underlying risk for development of autoregulation and catecholamine release that may result in diffuse cerebral edema and possibly death after even a mild secondary impact [213,214,215]. The pathophysiology leading to the severe edema and small hematomas that are often encountered is not fully understood. Furthermore, it remains unclear whether the edema or hematomas are the result of one of the individual blows to the head rather than the proposed pathophysiologic mechanisms leading to severe disability or death [215,216,217].

Suffering multiple concussions has been associated with increased risk for future concussion, cognitive deficit, delayed mild cognitive deficit, and sleep disruption. The association with CTE and suffering multiple concussions has gained increased attention in the media, and the mainstream public [218, 219]. First defined by Omalu et al. in 2005, CTE is defined as a progressive neurodegenerative syndrome caused by repetitive and episodic blunt force impact to the head that cause acceleration-deceleration forces to the brain [220]. A systematic review by Manley et al. examined potential long-term sequelae of concussion by examining cognitive, mental health, neuroimaging, and neuropathological features of CTE. This review demonstrated that despite reports with a small number of retired athletes who exhibited some mental health and cognitive problems, the majority of studies demonstrated these changes to be similar to the incidence in the general population [221]. These authors concluded that while multiple concussions appear to be a risk factor for mental health problems and cognitive impairment in some individuals, more research is needed to better understand the prevalence of CTE and other neurological conditions, and the degree to which they are related to concussions and sports-related repetitive neurotrauma.

A systematic review examining potential long term sequelae of concussion studied the neuroimaging, cognitive, mental health, and neuropathological features of CTE, and identified that whilst a very small number of retired athletes have some mental health and cognitive problems, the majority of studies demonstrate these changes to be similar to the incidence in the general population and the Berlin consensus paper stated that: [1, 221]

However, there is much more to learn about the potential cause-and-effect relationships of repetitive head-impact exposure and concussions. The potential for developing chronic traumatic encephalopathy (CTE) must be a consideration, as this condition appears to represent a distinct tauopathy with an unknown incidence in athletic populations.

A cause-and-effect relationship has not yet been demonstrated between CTE and SRCs or exposure to contact sports. As such, the notion that repeated concussion or sub-concussive impacts cause CTE remains unknown.

There is significant debate regarding both the clinical and pathological diagnostic criteria for CTE. There is also debate over the theory around a causal and exclusive link between exposure to repetitive head impact and risk for CTE. While case studies have received a great deal of attention, several studies have failed to find a link [222]. Tauopathy changes in the brain that meet the pathological criteria of CTE have been identified in multiple cases with a notable absence of history of head trauma [223, 224]. Therefore, the causal association between the pathological findings of CTE and the clinical condition requires continuing study.

The clinical features of CTE involve a prolonged latency period prior to a composite syndrome of neuropsychiatric disturbance, mood disorder, and cognitive impairment [225, 226]. Insidious onset of poor attention, loss of recent memory, frequent headaches, and bouts of confusion and disorientation are common early in the syndrome [226]. There is often a progression of effects referable to poor prefrontal cortex executive function and limbic system dysfunction, including worsening disorientation and confusion, poor insight and judgment, and the onset of antisocial behaviors [226]. The pathophysiologic mechanisms responsible for the clinical sequelae associated with repetitive brain injury are not entirely understood, but microvascular changes, blood-brain barrier (BBB) breakdown, diffuse axonal injury (DAI), and immunoexcitotoxicity have been implicated [227]. Currently, the diagnosis of CTE relies on autopsy and subsequent neuropathologic examination, with the defining feature of CTE being that of tauopathy, which may be seen in the form of neuropil threads (NT), glial tangles (GTs), or neurofibrillary tangles (NFTs), in an irregular, superficial cortical distribution [226, 228]. The development of tau-binding radiolabeled ligands will likely enhance the ability to diagnose CTE in living patients [218, 229]. Limited cases have demonstrated the ability to identify an increased tau burden within the brains of retired professional football players subjected to repetitive neurotrauma [229]. This work represents the first effort to clearly show the potential of premortem CTE diagnosis [219, 229].

Conclusion

The definition of concussion continues to evolve. Concussion epidemiology, signs and symptoms, and on-field assessment are important for the sports neurosurgeon. Concussion clinical assessment can be supported by neuropsychological testing, advanced neuroimaging, and cerebrospinal fluid and serum-based biomarkers. The American Academy of Neurology Guideline Recommendations for Concussion Management should be heeded by the sports neurosurgeon.