Identification, Prevention, and Treatment Recommendations for Concussions

Release Date: January 1, 2013

Expiration Date: January 31, 2015

FACULTY:

Jennifer Confer, PharmD, BCPS
Critical Care Clinical Specialist, Cabell Huntington Hospital
Clinical Assistant Professor, West Virginia University School of Pharmacy
Huntington, West Virginia

Kimberly M. Tzintzun, BS in Nutritional Sciences Candidate
University of Arizona, College of
Agriculture and Life Sciences
Tucson, Arizona

FACULTY DISCLOSURE STATEMENTS:

Dr. Confer and Ms. Tzintzun have no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy acpe
Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-13-001-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

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TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To familiarize participants with the identification, prevention, and treatment of concussions and associated symptoms.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Discuss the pathophysiology and natural progression of a concussive injury.
  2. Recognize signs and symptoms associated with concussive injuries.
  3. Develop treatment options that prevent and/or lessen progression of symptoms associated with concussions.
  4. Identify preventive measures for concussion avoidance and for patients at risk for further sequelae.


ABSTRACT: Sports-related head injuries, although underreported, are quite common and are being increasingly discussed in an attempt to raise awareness of the severity of complications relating to concussions. The consequences of concussive injuries often remain undiagnosed and are not always inconsequential or self-limiting. Symptoms that arise from a concussive injury can impact patients emotionally, cognitively, physically, and socially. Although concussions frequently are associated with sports and recreational activities, published data regarding effective treatment are few, with most recommendations based on anecdotal evidence and reports. Pharmacologic treatment regimens focus on symptom management. Numerous evaluative techniques and resources are available to assist in the diagnosis of concussion and should be used in the management of concussive injuries.


Throughout the 20th century, measures were enacted to eliminate sports-related injuries. In the early 1900s, football was a brutal and lethal sport due to violent tackles and little protective equipment. In the wake of a vicious football season in 1905 in which 19 athletes were either killed or paralyzed while playing football, President Theodore Roosevelt called for broad reforms to minimize the danger to players. This led to the formation of the National Collegiate Athletic Association (NCAA), which established additional regulations to improve safety and reduce sports-related head injuries. Despite the NCAA's efforts to eliminate sports-related head injuries, football fatalities peaked in 1964, with a total of 30 players killed.1 Since this time, many changes have been made regarding rules and regulations, protective equipment, and coaching techniques. In recent years, sports-related injuries—including concussions—have begun to attract the attention of the media and the public, thanks to an increase in the number of athletes who are speaking out about these injuries and sharing their experiences.

Since 2001, international conferences on concussions and traumatic brain injuries (TBIs) associated with sports have been held in Vienna (2001), Prague (2004), and Zurich (2008). The aims of the conferences were to develop a better understanding of sports-related concussions and to formalize an approach to the treatment and management of affected players.2 Increased efforts have been made to educate players, parents, coaches, and the general public on the recognition, consequences, and prevention of concussions. The CDC has developed many publications and specialized tool kits to raise awareness about sports-related head injuries.3 Although concussion awareness has centered on football, many high-impact contact sports, including baseball, hockey, boxing, soccer, and swimming, increase the risk of head injuries.3 In January 2011, Congress reintroduced legislation to set minimum safety standards for concussion management in public schools. As of July 2011, 32 states have laws and regulations endorsing the use of protocols to guide identification and treatment of sports-related concussions.4,5 Although laws have been introduced into Congress, there are currently no federal laws or regulations preventing athletes from returning to practice or playing without expert evaluation.5

Although there is no universal definition, the term concussion was defined at Zurich's International Conference on Concussion in Sport as a complex pathophysiological process affecting the brain that is induced by traumatic biomechanical forces.2 These forces may be caused by a direct strike to the head, face, or neck or by an indirect force that is transmitted to the head. Several common features combining clinical, biomechanical, and pathological sequelae may help further define concussion: 1) neurologic impairments have a rapid onset and quickly and spontaneously resolve; 2) acute clinical symptoms primarily imitate a functional disturbance rather than a structural injury; 3) clinical symptoms resulting from concussion may or may not involve loss of consciousness; 4) symptom resolution normally follows a sequential pattern, yet specific postconcussive symptoms may be prolonged; and 5) traditional neuroimaging studies (e.g., CT scan, MRI) provide little insight, since structural findings are generally normal.2

The estimated prevalence of sports-related head injuries in the United States is 1.6 to 3.8 million cases annually, with approximately 80% classified as mild.6-8 Data on nonfatal TBIs related to sports and recreational activities in patients aged 19 years and younger who reported to an emergency department (ED) from 2001 to 2009 were analyzed by the CDC. The number of sports-related TBI visits to the ED increased approximately 62%, while the overall rate of TBI visits rose about 57%.3 The increase in ED visits suggests increased participation in sports and/or greater awareness of detection and evaluation. Despite these findings, the consequences of concussive injuries often remain undiagnosed and are not always inconsequential or self-limiting.1 This article will discuss measures to prevent, identify, and appropriately treat patients who have suffered a concussive injury.

Pathophysiology

Concussion is a type of TBI; therefore, the terms concussion and mild traumatic brain injury (mTBI) are often used interchangeably to describe patients with head injuries. While most patients diagnosed with concussion have self-limiting symptoms lasting just days to weeks, approximately 10% to 20% have persistent symptoms known as postconcussive syndrome (PCS).7,9 Patients with PCS have semipermanent brain damage and are therefore considered to have mTBI. In this phase, most patients experience associated sequelae and long-term signs and symptoms.7,10 Most research has focused on this postinjury phase, which has no definitive time frame but commonly is considered to be the 3 months postinjury.

Immediately following biomechanical trauma, neurotransmitters are released abruptly and spontaneous ionic flux occurs. When excitatory transmitters are bound, additional neuronal depolarization occurs because of an efflux of potassium and influx of calcium. As it attempts to restore ionic homeostasis, the sodium-potassium (Na+/K+) pump is forced into overdrive, rapidly increasing the influx and efflux of K+ and Na+, respectively.9 Increased functioning of the Na+/K+ pump initiates a surge in glucose metabolism.7 The lack of blood flow to the brain and the inability to restore a balance in cellular energy lead to diminished brain capacity, rendering the brain vulnerable to second injury. At this point, the body becomes hypometabolic. An abrupt increase in calcium may result in reduced mitochondrial oxidative metabolism and activate pathways leading to cell death. Calcium flux within the axon can ultimately result in a decline in neural connectivity.9

While research supports the hypothesis that one reason for the decrease in mitochondrial oxidative metabolism is the concurrent decline in the neuro-metabolite N-acetylaspartate (NAA), a study conducted by Henry et al suggested that other neurometabolites, including glutamate and myo-inositol, also may be affected.11 MRIs of 10 concussed athletes and 10 nonconcussed athletes were compared to identify neurometabolic derangements. All concussed athletes were scanned 1 to 6 days postconcus-sion, with negative MRI findings in all cases. Further effects of concussion on brain metabolism were examined using proton magnetic resonance spectroscopy. Concussed athletes displayed neu-rometabolic impairment in the acute phase, in which NAA levels remained low relative to levels in controls. Some recovery was noted in the chronic phase, in which glutamate returned to levels similar to those in controls; however, there was an increase in myo-inositol levels that occurred only in the chronic phase. These results confirmed the presence of neurometabolic changes in the acute postconcussive phase, as well as recovery and continued metabolic depression in the chronic phase. Results also indicated that pathophysiological functions differ depending upon the postinjury phase, and that neurometabolic homeostasis differs with each metabolite.11

Another factor influencing posttraumatic neurologic pathophysiology is the increased production of lactate through glycolysis. Low levels of adenosine triphosphate inhibit utilization of the citric acid cycle. In turn, pyruvate, which is generated by glycolysis, is converted to lactate. These increased lactate levels can cause neuronal dysfunction by inducing acidosis, membrane damage, altered blood-brain barrier permeability, and cerebral edema. Elevated levels of lactate after concussion may leave neurons vulnerable to a secondary ischemic injury.9

Presentation and Evaluation

Concussion is classified as a functional injury, rather than a structural injury; therefore, overt injury may not be clearly seen. Concussive symptoms fall into four main categories: 1) cognitive, 2) emotional, 3) somatic, and 4) sleep disturbance (TABLE 1).6,12 Symptoms are relatively subjective and are likely to be impaired immediately following a concussion or mTBI. Immediate-response teams should be acutely aware of the physical signs of suspected concussion, including drowsiness, convulsions or seizures, confusion, restlessness, and agitation. Loss of consciousness is an urgent sign that emergency action must be taken.12


tbl1

When a sports-related injury occurs, the athlete should be evaluated immediately for any obvious external injuries. In addition, the athlete should be removed from play and measures should be initiated to prevent a cervical spine injury. While it is important to obtain a sideline assessment, the signs and symptoms of concussion may not be apparent for several hours or days; therefore, further evaluation by a medical professional in an ED or office should be undertaken.2 A complete medical history including information not only from the patient, but also from parents, friends, teammates, and coaches who witnessed the injury, should be taken. Screening tools and neuroimaging studies should be employed in order to identify the concussion's severity, determine how to manage the concussion, and decide when the athlete can return to play.1,6

Depending upon the severity of signs and symptoms, a patient may need a brief sideline assessment and/or postural-stability testing. Although postural-stability testing is essential for evaluating the athlete's balance, there is inadequate support for its use. Neuropsychological testing to identify cognitive deficits may be necessary in some cases, but cannot be performed acutely on the sideline. Patients with severe trauma and those experiencing second-impact syndrome (SIS) may need precise neuroimaging, including CT or MRI. Further descriptions of specific assessment tools are given in TABLE 2.


tbl2

Special Considerations

Return to Play: Athletes who return to practice or a competitive game immediately following a concussive injury, even without loss of consciousness, are at extreme risk for further injuries of increased severity, such as cerebral edema.7 The Zurich conference determined a stepwise method for physical exertion, with a progressive approach for the return of a player to a sport.2 In this approach, the patient proceeds through each increasing level of activity over a 24-hour period and, if postconcussive symptoms occur, regresses to the last step in which he or she was asymptomatic. In addition to progressing asymptomatically through each step, from no activity to full-contact practice, the patient must be asymptomatic upon cognitive exertion. This is deemed to be achieved when the patient's performance has returned to baseline. To appropriately evaluate baseline cognitive function, preseason neuropsychological assessment should be conducted to compare preinjury versus postinjury functioning, if needed.2,13 Another important consideration for returning to play is that the patient should not be taking any pharmacologic medications for symptom relief, as this could conceal or alter post-concussive symptoms.6,7

SIS: While proper management of the initial injury is vital to protect an athlete from returning to play prematurely, proper documentation is equally important to a further understanding of repeated head injury. Unquestionably, head trauma may lead to biomechanical upset and neurologic dysfunction, but it is unclear whether the severity and morbidity of a second injury positively correlate with recurrence of trauma.14 SIS has been defined as occurring when "an athlete who has sustained an initial head injury, most often a concussion, sustains a second head injury before symptoms associated with the first have fully cleared."15,16 The effects of SIS are believed to be catastrophic and usually lead to mortality.14

Kelly et al reviewed the case of a 17-year-old high school football player who died after sustaining two brain injuries within a 1-week period.17 It was hypothesized that delayed development of PCS may have led to premature return to play and that "repeated concussions can predispose the brain to vascular congestion from auto regulatory dysfunction; this congestion then leads to elevation that may be difficult, if not impossible, to control."17

An analysis of published cases of SIS by McCrory and Berkovic systematically describes four diagnostic criteria for efficiently diagnosing SIS: 1) medical review after a witnessed first impact; 2) documentation of ongoing symptoms following initial impact up to time of second impact; 3) a witnessed second head impact with subsequent rapid cerebral deterioration; and 4) neuropathologic or neuroimaging evidence of cerebral swelling without significant intracranial hematoma or other cause for cerebral edema (e.g., encephalitis).15 The patient may be further classified as having definite, probable, or possible or no SIS based on the number of diagnostic criteria.15

Treatment and Management

Published data regarding effective treatment of concussions are limited; most recommendations are based on anecdotal evidence and reports.2,10 Moreover, pharmacologic treatment regimens focus on symptom management. While the majority of athletes who sustain concussive injuries will improve spontaneously, quantitative deficits in cognition can occur and therefore require complete physical and cognitive rest until symptoms resolve. Activities that require concentration and focused attention, such as video games, text messaging, and schoolwork, may worsen symptoms and delay overall recovery if initiated too soon.2

Pharmacologic therapy may be considered in patients who have developed and sustained prolonged symptoms that are negatively affecting recovery and quality of life. Initiation of such therapy should be considered only by a clinician who is proficient in the proper assessment and management of concussive injuries. Several management guidelines have incorporated concussion symptom scales and checklists to assess for the presence of postconcussive symptoms. See TABLE 3 for further details of pharmacologic treatment options for managing concussive symptoms, arranged by the four key symptom groups (cognitive, emotional, somatic, and sleep disturbance).


tbl3

Cognitive Symptoms: Various hypotheses exist regarding the cognitive changes that occur after TBI, including calcium dysregulation, free-radical injury, neurotransmitter toxicity, dopaminergic dysregulation, and cortical cholinergic dysfunction. Numerous medications have been investigated for their utility in treating cognitive changes postinjury.18 Although currently no drugs are approved for the treatment of cognitive impairment, psychostimulants, cholinesterase inhibitors (CIs), and dopamine agonists have all proven efficacious.

The role of methylphenidate in treating neurobehavioral changes occurring in patients with a concussion or TBI has been extensively investigated.10 A literature review conducted in 2005 concluded that despite variability in study design, methodology, and measured outcomes, methylphenidate has demonstrated a positive impact on memory, attention, concentration, and mental processing.19 Although randomized, placebo-controlled studies have identified a common dosing recommendation, larger studies are warranted to further identify the appropriate length of treatment and long-term effects in patients with TBI.

Masanic et al conducted a 16-week, open-label study to determine whether donepezil, a CI, would improve memory, behavior, and global function after chronic TBI.20 The four patients received donepezil 5 mg daily for 8 weeks, followed by 10 mg daily for 4 weeks. Memory, behavior, and global function were evaluated with standardized assessment tools before and after donepezil intervention. The nonsignificant increase in memory and behavior scores likely was due to the small sample size. Although this study demonstrated positive results for donepezil in chronic TBI, further clinical trials should be conducted.20

It has been suggested that dopaminergic agents such as amantadine and bromocriptine improve agitation, aggression, and decreased motivation by reversing central dopaminergic dysfunction.10,18 As with all of the medications discussed, careful dosing, monitoring, and assessment of side effects are recommended to ensure that the patient is on the lowest required dose and that the medication can be discontinued as soon as possible to allow the patient to return to play.

Emotional Symptoms: Emotional symptoms are commonly reported after TBI, and depression has been demonstrated in up to 60% of patients.10,21 In addition to restrictions on the patient's activities, symptoms such as anxiety, sleep disturbances, fatigue, and lethargy can affect a patient's mood. No clear evidence exists for the optimal treatment of depressive symp toms in patients with concussive TBIs, but numerous studies have suggested the use of selective serotonin reuptake inhibitors.22 For tricyclic antidepressants (TCAs), treatment results are unfavorable for depressive symptoms, but are favorable for posttraumatic headaches.22,23

Sertraline has achieved improvements in depressive symptoms and cognition in TBI, as well as reductions in somatic-type symptoms.10,21 Fann et al conducted an 8-week, nonrandomized, single-blind, placebo run-in trial of sertraline in 15 patients diagnosed with major depressive disorder (MDD) who had sustained an mTBI within the past 3 to 24 months.24 The Hamilton Rating Scale for Depression (HAM-D), which was used to evaluate depressive symptoms, revealed a treatment response in 87% of patients. Remission by week 8 of sertraline was seen in 67% of participants. This study suggests that sertraline may be effective for treating MDD in patients with mTBI in the previous 2 years. Agitation and aggression also significantly improved with sertraline (P <.05), as assessed by an anger and aggression questionnaire.24

A systematic literature review by Comper et al identified four studies that investigated amitriptyline for the treatment of specific somatic, cognitive, and/ or psychological symptoms.23 Of these, two studies that evaluated amitriptyline used solely for depressive symptoms found that significantly more controls had improvements in depression compared with treated patients, based on HAM-D scores (P <.01 and P <.001, respectively).23,25,26

Somatic Symptoms: Posttraumatic headache, which develops within 7 days of head injury or after regaining consciousness postinjury, is the most commonly reported symptom following a concussion; these headaches are generally categorized as either tension-type or migraine-type.10,27 A prospective study by Faux and Sheedy compared 100 patients with defined mTBI and 100 patients with low-impact injuries such as falls with fractures and/or soft-tissue injuries (minor-injury group).27 In mTBI patients, the incidence of headache was 100% at the time of injury, 30.4% at 1 month postinjury, and 15.35% at 3 months. Significantly lower results were identified in minor-injury patients, with a 2.12% incidence of headache at 1 month postinjury and 2.25% at 3 months.27

Analgesics such as acetaminophen or ibuprofen may be helpful for acute headaches following injury, but rebound headaches may occur and there is an increased risk of intracranial bleeding, so frequent use is not recommended. The prognosis for posttraumatic headache is favorable, with 70% to 85% of patients recovering without significant complications.28 Numerous medication classes have been identified as beneficial for posttraumatic headaches, including antidepressants, beta-blockers (BBs), calcium channel blockers (CCBs), anticonvulsants, triptans, and dihydroergotamine.10 Nonrandomized, placebo-controlled studies of TCAs— specifically, amitriptyline—demonstrated improvement in up to 90% of patients treated for chronic posttraumatic headache. Although TCAs should be used with caution in patients with concomitant cognitive impairments because of symptom exacerbation, they may be beneficial in patients with both posttraumatic headaches and insomnia.28

CCBs and BBs have been well studied and found useful for migraine prevention. The mechanism by which these medications prevent migraine-type headaches remains to be elucidated, but it is thought that central neuronal hyperexcitability exhibited by a migraine caused by a calcium channelopathy could be inhibited through calcium channel blockade.28 Placebo-controlled trials of CCBs, although limited, have identified verapamil and nicardipine as effective agents. CCBs should be avoided in patients with left ventricular dysfunction, symptoms of cardiac failure, or atrioven-tricular conduction defects.28-30 As for BBs, although their mechanism of migraine prevention is poorly understood, evidence supports use of a nonselective BB, such as propranolol or nadolol.

Miscellaneous agents, such as anticonvulsants, triptans, and dihydroergotamine, have been explored as options for persistent headaches and for patients unresponsive to the conventional therapies noted above.10,28 Similarly to CCBs, anticonvulsants such as divalproex sodium and gabapentin are believed to prevent migraines through central neuronal hyperexcitability inhibition by directly or indirectly increasing the availability of gamma-aminobutyric acid (GABA), an inhibitory neuron, and through binding to sites present on calcium channels.28 Triptans (e.g., sumatriptan) are 5-hydroxy-tryptamine (5HT)1B and 5HT1D serotonin receptor agonists that cause vasoconstriction and reduce neurogenic inflammation. Dihydroergotamine, which is structurally similar to serotonin, dopamine, and alpha-adrenergic receptors, stimulates vascular smooth muscle, causing vasoconstriction and inhibition of trigeminal neurotransmission both peripherally and centrally. Finally, although not currently indicated for posttraumatic headaches, onabotulinumtoxinA (Botox) is indicated for both tension-type and migraine-type headaches and may be an emerging treatment for chronic posttraumatic headaches.28

Sleep Disturbance: As with other sequelae, sleep disturbances—including both insomnia and hypersomnia (excessive somnolence)—are common, occurring in 36% to 70% of patients.31 Disturbances may be caused by direct injury or by management of other TBI symptoms with pharmacologic agents that have associated sleep-disturbance side effects, or may occur secondary to neuropsychiatric circumstances associated with TBI. Prior to initiating medication therapy for sleep disturbances, it is imperative to obtain a complete history of the patient's sleep patterns before and after the head injury, any concomitant conditions that affected sleep before the injury, and current medications (including prescribed medications, OTC medications, and substances such as caffeine, nicotine, and alcohol).10

Several drug classes may be used to treat sleep disorders, including benzodiazepines, TCAs, serotonin receptor antagonists, stimulants for hypersomnia, and natural products such as melatonin. Data on pharmacologic treatment for sleep disorders are limited; most recommendations are derived from anecdotal experiences and small, nonrandomized studies. Regardless of the medication selected, it is essential to follow several general principles: 1) treat the underlying condition causing sleep disturbances; 2) consider lower dosages for patients with head injuries; 3) promote normal sleep-wake cycles; and 4) advise patients to eliminate distractions affecting the sleep process.10,31

While patients may initially complain of hypersomnia, symptoms of insomnia tend to develop several weeks postinjury, and natural sleep-wake cycles can become dysregulated. For patients whose hypersomnia continues, psychostimulants such as methylphenidate have been utilized; these agents also have been used to treat inattention and cognition problems. Benzodiazepines should be administered for insomnia, but because addiction, dependence, and decreased cognition may occur, they should be used short term, not for chronic sleeping difficulties. TCAs are helpful for insomnia because of their anticholinergic and antihistaminic properties. Based on favorable results in the treatment of posttraumatic headache and depression, amitriptyline may be a good option for patients experiencing numerous symptoms postinjury. Trazodone, a serotonin receptor antagonist, is effective for treating posttraumatic depression and insomnia.31

Although melatonin as therapy for sleep and circadian normalcy is represented in the literature, its use in postconcussion syndrome and TBI has been little explored. Melatonin, an endogenous hormone produced by the pineal gland from the amino acid tryptophan, functions as an antioxidant and free-radical scavenger and has anti-inflammatory effects. Samantaray et al investigated the use of melatonin in traumatic central nervous system injury and concluded that, because of the oxidative stress and disruption of sleep-wake cycles occurring after a TBI, melatonin would assist with the inhibition of proinflammatory cytokines and assist with resetting the natural circadian rhythm.32 Although it is not FDA approved, melatonin is available OTC and has been associated with few side effects, most notably stomach discomfort and excessive sleepiness.32

Conclusion

It is unrealistic to assume that concussions can be entirely prevented in sports and recreational activities; thus, it is imperative to use available resources and evaluation techniques to attempt to avoid severe and repeat injuries. Although there is no evidence that the use of personal protective equipment such as helmets, mouth guards, and padding is beneficial in preventing concussions, these items can greatly reduce the risk of skull fractures, dental fractures, and other facial injuries. Further prevention of concussions and long-term consequences begins with adequate education and legislative initiatives. Concussion treatment should focus on the management of postconcussive symptoms, and medications should be prescribed at the lowest necessary dose to avoid unwanted side effects. Finally, efforts to implement state laws and policies to ensure that further harm is minimized and guidelines are implemented are of utmost importance to protect athletes from long-term effects of concussions.

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