This review of traumatic brain injury encompasses its impact on society, pathophysiology, and rehabilitative management. Topics include mild traumatic brain injury, outcomes, prognosis, cognitive rehabilitation, behavioral management, and neurologic and medical complications. Emphasis is placed on clinically relevant topics that have had recent developments or have been historically difficult to treat. Neurologic complications discussed include seizure, balance, visual dysfunction, and spasticity. Medical complications discussed include neuroendocrine and pain issues.
Epidemiology
Impact on society
Traumatic brain injury (TBI) is an important cause of disability in the United States, with estimates of direct and indirect costs exceeding $56 billion . Centers for Disease Control and Prevention (CDC) data estimate the annual incidence of TBI in the United States at 1.4 million people. Of these, 50,000 will not survive the acute injury, 235,000 will be hospitalized, and the remaining 1.1 million people will be treated and released from emergency departments. Data are lacking on patients who have TBI evaluated in nonhospital settings and those who do not receive medical care, but estimates show that primary care providers see 439,000 patients and another 89,000 are seen in other outpatient settings . These data do not include persons receiving care within the Veteran’s Administration or military hospital systems . Patients who have mild TBI, especially secondary to sports-related injuries, who do not seek medical attention may also add many thousands of unaccounted patients . Although infants, toddlers, and young adults are at highest risk for TBI, patients older than 75 years are more likely to be hospitalized or die from their injury . During the years 1995–2001, the average incidence of death from TBI was 18.1 per 100,000 , and average incidence of death from TBI in patients older than 75 years was estimated at 50.6 per 100,000 . Subgroups that have a higher incidence of TBI include men (1.5 times more common than women) and individuals who have certain behavioral or work characteristics, such as paratroopers .
Although new cases of TBI greatly impact the health care system, the chronic effects of TBI are equally important. CDC estimates indicate that at least 5.3 million people in America, approximately 2% of the population, require long-term assistance with activities of daily living secondary to impairments related to TBI . Each year, 80,000 to 90,000 people are added to the numbers of people who have TBI and experience permanent disability.
Mechanisms of injury
The most common causes of TBI are falls (28%), motor vehicle–traffic accidents (20%), being struck by objects (19%), assault (11%), and bicycle (non–motor vehicle) accidents (3%) ; approximately 9% of the time the mechanism of injury is unknown. Falls, the leading cause of TBI, occur most often in a bimodal distribution, with peaks in the ages of 0 to 4 years and 75 years and older . Although falls are most common overall, motor vehicle–traffic collisions cause the most TBI-related hospitalizations; for individuals aged 15 to 19 years, TBI is more commonly associated with motor vehicle accidents and assaults than with falls .
Prevention
CDC recommendations for primary prevention of head injury include wearing seat belts, abstaining from alcohol and drugs while driving, wearing a helmet during higher-risk activities, taking measures to avoid falls in the home, using shock-absorbing material on playgrounds, and keeping firearms unloaded and locked .
Mild traumatic brain injury
Accurate statistics on mild traumatic brain injury (MTBI) or concussion are difficult to find because most people with MTBI are never admitted to a hospital. In addition, an estimated 25% of people who sustain a TBI are never evaluated at injury . The CDC estimates that more than 300,000 sports-related concussions occur annually . TBI is also noted to be the signature injury of the Afghanistan and Iraq military conflicts; 28% of soldiers evacuated to Walter Reed Army Medical Center have TBI, with half considered mild .
The CDC defines MTBI as
“…an injury to the head as a result of blunt trauma or acceleration or deceleration forces that result in one or more of the following observed or self-reported conditions: 1) transient confusion, disorientation, or impaired consciousness, 2) dysfunction of memory around the time of injury, and 3) loss of consciousness lasting less than 30 minutes. In addition, there may be observed signs of neurological or neuropsychological dysfunction that, when identified soon after injury, can be used to support the diagnosis of MTBI. Such signs include: 1) seizures acutely following injury to the head, 2) infants and young children with irritability, lethargy, or vomiting following head injury, and 3) symptoms such as headache, dizziness, irritability, fatigue, or poor concentration” .
The clinical definition of MTBI is an injury with a Glasgow Coma Score (GCS) of 13 to 15. In addition to the GCS, several concussion scales used in sports medicine further differentiate MTBI, most recently the scale released in the American Academy of Neurology practice parameter ( Table 1 ) . These concussion scales are associated with return-to-play recommendations. Generally, any loss of consciousness results in having players undergo a physician examination before they return to the game . Ideally, baseline cognitive testing should be obtained before the playing season. Sideline evaluation should consist of cognitive testing (eg, Standardized Assessment of Concussion) , balance testing (Balance Error Scoring System) , and a symptom checklist. When asymptomatic, athletes should be retested with the same battery of tests after exertion (eg, a set of sideline jogging, sit-ups, push-ups, and sport-specific noncontact activities) and remain asymptomatic.
| Grade | Description |
|---|---|
| 1 | Transient confusion; no LOC; concussion symptoms or mental status abnormalities on examination resolve in ≤15 minutes |
| 2 | Transient confusion; no LOC; concussion symptoms or mental status abnormalities on examination last >15 minutes |
| 3 | Any LOC, either brief (seconds) or prolonged (minutes) |
In general, recovery from MTBI occurs fairly rapidly, and most patients are asymptomatic within 3 weeks . Approximately 15% will continue to experience symptoms with functional impairment beyond 3 months, termed the postconcussion syndrome . Studies imply that factors relating to pain and psychological distress may impact recovery in this population . Several small studies indicate that early education about the expected course of recovery is helpful for individuals who have MTBI . Aggressive management of symptoms and remobilization after the first few days are important.
Recent studies using functional MRI (fMRI) have shed some light on recovery after MTBI. When tested a week after a concussion, athletes generally score at their baseline on neuropsychological testing; however, fMRI shows that their regional brain activation differs from noninjured athletes, with increased activation in the parietal, lateral frontal, and cerebellar regions . Essentially, the concussed athletes are able to perform at baseline, but must invest extra cognitive work to do so. In addition, postural destabilizations induced by movements in the visual field have recently been shown in individuals after MTBI who have apparently returned to baseline functioning . These types of studies have implications for both athletes and nonathletes who have MTBI who complain of fatigue, memory impairment, poor balance, or visual disturbances despite being able to perform their normal activities.
Mild traumatic brain injury
Accurate statistics on mild traumatic brain injury (MTBI) or concussion are difficult to find because most people with MTBI are never admitted to a hospital. In addition, an estimated 25% of people who sustain a TBI are never evaluated at injury . The CDC estimates that more than 300,000 sports-related concussions occur annually . TBI is also noted to be the signature injury of the Afghanistan and Iraq military conflicts; 28% of soldiers evacuated to Walter Reed Army Medical Center have TBI, with half considered mild .
The CDC defines MTBI as
“…an injury to the head as a result of blunt trauma or acceleration or deceleration forces that result in one or more of the following observed or self-reported conditions: 1) transient confusion, disorientation, or impaired consciousness, 2) dysfunction of memory around the time of injury, and 3) loss of consciousness lasting less than 30 minutes. In addition, there may be observed signs of neurological or neuropsychological dysfunction that, when identified soon after injury, can be used to support the diagnosis of MTBI. Such signs include: 1) seizures acutely following injury to the head, 2) infants and young children with irritability, lethargy, or vomiting following head injury, and 3) symptoms such as headache, dizziness, irritability, fatigue, or poor concentration” .
The clinical definition of MTBI is an injury with a Glasgow Coma Score (GCS) of 13 to 15. In addition to the GCS, several concussion scales used in sports medicine further differentiate MTBI, most recently the scale released in the American Academy of Neurology practice parameter ( Table 1 ) . These concussion scales are associated with return-to-play recommendations. Generally, any loss of consciousness results in having players undergo a physician examination before they return to the game . Ideally, baseline cognitive testing should be obtained before the playing season. Sideline evaluation should consist of cognitive testing (eg, Standardized Assessment of Concussion) , balance testing (Balance Error Scoring System) , and a symptom checklist. When asymptomatic, athletes should be retested with the same battery of tests after exertion (eg, a set of sideline jogging, sit-ups, push-ups, and sport-specific noncontact activities) and remain asymptomatic.
| Grade | Description |
|---|---|
| 1 | Transient confusion; no LOC; concussion symptoms or mental status abnormalities on examination resolve in ≤15 minutes |
| 2 | Transient confusion; no LOC; concussion symptoms or mental status abnormalities on examination last >15 minutes |
| 3 | Any LOC, either brief (seconds) or prolonged (minutes) |
In general, recovery from MTBI occurs fairly rapidly, and most patients are asymptomatic within 3 weeks . Approximately 15% will continue to experience symptoms with functional impairment beyond 3 months, termed the postconcussion syndrome . Studies imply that factors relating to pain and psychological distress may impact recovery in this population . Several small studies indicate that early education about the expected course of recovery is helpful for individuals who have MTBI . Aggressive management of symptoms and remobilization after the first few days are important.
Recent studies using functional MRI (fMRI) have shed some light on recovery after MTBI. When tested a week after a concussion, athletes generally score at their baseline on neuropsychological testing; however, fMRI shows that their regional brain activation differs from noninjured athletes, with increased activation in the parietal, lateral frontal, and cerebellar regions . Essentially, the concussed athletes are able to perform at baseline, but must invest extra cognitive work to do so. In addition, postural destabilizations induced by movements in the visual field have recently been shown in individuals after MTBI who have apparently returned to baseline functioning . These types of studies have implications for both athletes and nonathletes who have MTBI who complain of fatigue, memory impairment, poor balance, or visual disturbances despite being able to perform their normal activities.
Pathophysiology
The term traumatic brain injury encompasses a wide variety of lesions. Injuries are classified as primary or secondary. Primary injuries result directly from the traumatic event, whereas secondary injuries result from delayed processes associated with the trauma. Primary injuries include contusions, lacerations, axonal shear injury, diffuse vascular injury, tearing of the pituitary stalk, and shearing of cranial nerves. Secondary injuries include intracranial hemorrhage, cerebral edema, increased intracranial pressure, hypoxic injuries, intracranial infections, hydrocephalus, metabolic changes, and responses to an outpouring of excitatory neurochemicals.
Diffuse axonal injury, first identified by Rosenblath and Strich in 1899 and 1956, respectively, has become the hallmark lesion in TBIs. However, TBI caused by blunt trauma or missiles may not involve axonal injuries, and the primary and secondary lesions associated with these injuries are not discussed here. The neurochemical cascade that follows the primary axonal injury exacerbates secondary injuries, including edema and neuronal cell death . Therefore, this neurochemical cascade is being increasingly studied with quantitative structural and functional neuroimaging in hopes of finding preventative treatments .
The term diffuse axonal injury may be misleading, because these axonal injuries are primarily focal . The axonal injury results from deceleration and acceleration forces, most often associated with rotational forces, causing axonal shear-strain and resulting in cytoskeletal malalignment and axolemmal permeability changes. This shear-strain is more likely to develop in areas between tissues of different densities and viscosities, where differential movements create shearing strain on the axons . The microscopic extent of injury always exceeds the macroscopic abnormalities. Most diffuse axonal injury cannot be seen on CT or MRI, but petechial hemorrhages in the cortex or corpus callosum indicates the presence of underlying diffuse axonal injury. The most frequent location of diffuse axonal injury is at the gray–white matter junction in the frontal and temporal lobes . Because higher-level functioning occurs here, diffuse axonal injury has been postulated to be responsible for some of the cognitive deficits after mild TBI .
Prognosis and outcome measurement
Prognostic information is needed by families making medical and legal decisions, caregivers considering treatment and placement options, and patients looking at potential return to community and work activities. However, the prediction of outcome for a specific individual is not reliable in the early stages after TBI. Multiple factors have been associated with long-term outcomes, including injury severity as measured by the GCS, duration of coma, time to follow commands, duration of posttraumatic amnesia, early pupillary response, increased intracranial pressures, lesion burden on neuroimaging, age, serum protein S100b, genetic presence of E4 allele, and evoked potentials . Few of these factors, however, have proven useful for prognosis, because the outcomes associated with the factors remain broad, ranging from good recovery to severe disability . This section reviews the outcome measurements and useful prognostic tools for clinicians.
Measurement tools
Functionally, outcomes after TBI are typically reported using the functional independence measure , Glasgow Outcome Scale, disability rating scale, Ranchos Los Amigos Level of Cognitive Functioning Scale , or Community Integration Questionnaire . The functional independence measure is widely used in rehabilitation and includes a cognitive subscale. The disability rating scale was designed specifically for use after TBI, and also includes multiple subscales. However, the overall usefulness of the functional independence measure and disability rating scale measurements for prognosis after TBI is limited . The Community Integration Questionnaire may be most useful to help differentiate outcomes among the individuals who gained the ability to live independently, but it does not provide prognostic information.
The Glasgow Outcome Scale ( Table 2 ) may be the most widely used outcome scale. Although it provides only generalized information on outcomes, these can be easily understood by family members of patients in the subacute stages of recovery . Using the Glasgow Outcome Scale, a rating of 3 or lower (severe disability) corresponds with an inability to live independently at home, which is a prognostic factor important to family members planning future care. A Glasgow Outcome Scale rating of 5 (good recovery) corresponds with resumption of prior occupational and social activities, another valuable prognostic factor to the patient and family. Between these ratings, moderate disability implies independence within a supported environment.
| Score | Classification | Description |
|---|---|---|
| 1 | Dead | Self-evident |
| 2 | Vegetative | Unable to interact with environment |
| 3 | Severe disability | Unable to live independently |
| 4 | Moderate disability | Able to live independently, but requires supported environment such as public transportation, assistance with medications/finances, or sheltered workshop |
| 5 | Good recovery | Able to live independently and resume normal job and social activities, but mild deficits may persist |
Disability prognosis
After severe TBI, most survivors are disabled to some degree, but many obtain the ability to live independently and often return to the workforce. A recent review of outcomes data analyzed the results to find threshold values consistent for useful prognosis after severe traumatic injury . Three factors were found to be useful: age , posttraumatic amnesia , and time to follow commands . Summarizing these guidelines, (1) a Glasgow Outcome Scale rating of greater than 3, implying independent living possible (although perhaps within a supported environment), will be likely when time to follow commands occurs in less than 2 weeks or duration of posttraumatic amnesia is less than 2 months; and (2) a Glasgow Outcome Scale rating of less than 5, implying the need for a supported environment and possible assistance at home, is likely if time to follow commands is longer than 1 month, duration of posttraumatic amnesia is greater than 3 months, or age is older than 65 years .
After experiencing moderate TBI, most people (>90%) are able to live independently but may need a supportive environment, which may provide assistance for medications or financial management, intermittent supervision for behavioral disturbances, accommodation for minor physical impairments, or assisted employment. After mild TBI, virtually all individuals are able to live independently and maintain preinjury occupations, but they may have minor residual impairments in the cognitive and psychosocial domains . Well-validated predictors of long-term outcome after moderate or mild TBI do not exist. With TBI of any initial severity, the best short-term prognostic factor is the patient’s recent rate of improvement .
Psychosocial outcomes
Good quality of life is possible even with residual severe disability . Although outcome studies largely show that most physical and psychosocial recovery occurs within the first 6 to 12 months after injury , improvements may continue for many years . Participation in activities and interpersonal relationships have been shown to be significant indicators of life satisfaction , although these may be limited by social stigmas, cultural acceptance, or structural barriers. The 1998 National Institutes of Health Consensus Statement on Rehabilitation of Persons with Traumatic Brain Injury emphasized the negative impact of cognitive deficits, behavioral issues, and emotional disturbances as limiting factors in achieving good psychosocial outcomes .
Depression and anxiety are common after TBI, with prevalence estimated at 30% to 40% . Among patients who have similar traumatic severity, the prevalence of major depressive disorder is greater in those who have TBI than in those who do not; however, the prevalence of minor depressive symptoms may be similar between the groups . Because most persons who have TBI who develop major depressive disorder do so after the first 3 months , depression often occurs after they have left the inpatient rehabilitation setting. Risks associated with developing major depressive disorder after TBI include a premorbid personal history of mood disorder or anxiety, but studies still suggest neuropathologic associations that have not been fully identified . Several measures have been found to be valid for screening for depression among persons who have TBI, including the Neurobehavioral Function Inventory, the Center for Epidemiologic Studies Depression Scale, and the Patient Health Questionnaire-9 .
Community reintegration and return to work
Outcomes regarding community re-entry and return to work are less predictable than determining more basic levels of function. Evidence supporting any individual intervention remains limited, and comparing studies is often difficult because the study populations and interventions vary significantly . In addition, individual outcomes may depend partly on the relationship between individuals and their environment. Each individual’s setting and circumstances present a unique ability, or inability, to alter the environment and accommodate individual needs. Therefore, measures to assess community re-entry and return to work after TBI remain individualized .
Cognitive, behavioral, and emotional issues often impede community activity participation and return to work . The major obstacles encountered during community re-entry and return to work are behaviors consistent with frontal syndrome, an inability to arrange transportation, poor self-awareness or executive functioning, and limited resources. To improve community integration outcomes, the rehabilitation team should include coordinated efforts among family, teachers, neighbors, and employers . Potential supports to optimize return to work include participation in job trials, assistance in locating appropriate employment, and activities aimed at successfully maintaining employment (eg, job coaching, coworker support). Cognitive impairments may interfere with the successful use of typical classroom instruction aimed at employment, and more hands-on training may be necessary .
Cognitive and behavioral rehabilitation
The role of neuropsychological evaluations in traumatic brain injury
Neuropsychological evaluations consist of a battery of standardized measures that quantify various aspects of cognitive function. Testing of emotional functioning is typically included to evaluate its role in the patient’s functional status and cognitive presentation. The selection of tests for any individual may differ depending on the purpose of the evaluation, the experience and preference of the neuropsychologist, and the characteristics of the individual to be tested ( Table 3 ). In TBI rehabilitation, the neuropsychological evaluation is used to (1) predict outcome, (2) plan for appropriate rehabilitation strategies, (3) explain behaviors, (4) assist with vocational and educational planning, and (5) evaluate the extent of injury in conjunction with radiologic imaging.
| Area of function to be evaluated | Measure |
|---|---|
| Attention and concentration |
|
| Memory, verbal |
|
| Memory, visual |
|
| Executive function |
|
| Language |
|
| Motor function |
|
| Neurobehavioral function |
|
| Tests of validity |
|
Clinicians will often obtain brief neuropsychological testing for severely injured persons during hospitalization to gain an initial impression of cognitive difficulties and help guide treatment, supervision recommendations, and patient and family education. More comprehensive testing is typically conducted later in the course of injury (3–6 months after injury) to more specifically predict functional outcome for community-based activities, such as return to school or work. In milder injuries, routine imaging techniques may not be sufficiently sensitive to show lesions, and in more severe injuries, the extent of injury and its effect on function may be under- or overestimated because of reliance on imaging. Therefore, the neuropsychological evaluation adds an independent source of information about how the injury manifests functionally in terms of cognitive abilities. Definitive guidelines for using neuropsychological evaluation in prognostication are lacking because of the complexity and variability of brain injury and the desired levels of functioning. However, evidence shows that measures of executive function can predict functional outcome indexed by global scales, such as the disability rating scale and the Community Integration Questionnaire . Early cognitive testing has been shown to predict productivity status at 1 year after injury . However, specific thresholds for individual tests or test batteries have not been established for predicting clinical practice .
The neuropsychological evaluation is useful in targeting areas for cognitive rehabilitation and identifying intervention strategies to optimize treatment outcomes. For instance, through repetition, one can show improvement in memory performance even in the presence of retrieval difficulties. Testing can also help guide treatments through differentiating cognitive, personality, or emotional factors that may contribute to undesirable behaviors. For example, the tendency to not complete tasks may be secondary to memory impairment, impersistence, or depression. Careful analysis of neuropsychological findings is needed, because the cause of abnormal cognitive function, especially mild abnormalities, can often be multifactorial, involving the effects of the injury and emotional functioning, normal variation, secondary gain, and effort exerted during the assessment.
Cognitive rehabilitation
Cognitive therapy methods have long been a controversial part of the rehabilitation for patients who have TBI. Cognitive rehabilitation can be defined as a set of interventions that target specific intellectual, perceptual, psychomotor, or behavior skills for improvement. These methods are difficult to study effectively, and few large, adequately structured studies have been performed . Problems in research have included defining outcomes, using theory to guide study, and expanding on initial pilot efforts. Clinic-specific and specific neuropsychological measures have shown positive outcomes ; however, the “real-world” outcomes are not equally improved or even accounted for in many studies. Despite these research problems, more evidence is accumulating that cognitive efficiency and memory can be favorably impacted through targeted therapies. Animal studies also support that enriching the environment can help improve cognitive outcome .
Cicerone describes three general areas of focus for cognitive rehabilitation: process-specific remediation, functional skills training, and metacognitive remediation. In a broad sense, neuropharmacologic interventions for improving memory or attention may be included under the umbrella of cognitive rehabilitation. Prolonged repetition is often needed to show memory improvement or even the successful use of memory aides . Several pilot studies have shown promise in using self-cuing techniques, problem-solving with emotional self-regulation, and training in cognitive strategies . Newer technology, such as portable organizers and virtual reality, may prove helpful in providing external cues for persons who have memory and other cognitive impairments . Self-regulation and executive functioning, such as problem-solving and working memory, have been investigated with mixed results .
A few larger randomized studies have examined the effects of a broad cognitive approach to rehabilitation in TBI. Comparing structured cognitive rehabilitation to psychosocial support, Ruff and Niemann found that improvements in both groups were likely caused by nonspecific effects of treatment. In a study comparing a cognitive rehabilitation program for military personnel with home-based education and encouragement from nursing staff, those who had more severe injuries showed greater improvement after the cognitive program . Bell and colleagues reported that a telephone-based trial of counseling and education for patients who had moderate to severe TBI resulted in improved overall outcome, including functional status and quality of life. When a program providing education through in-person counseling and a booklet was compared with usual treatment for children who had mild TBI, the former was found to be effective in reducing anxiety and symptoms . Another study on intervention in mild TBI reported that an 11-week program of individual cognitive–behavioral psychotherapy and cognitive remediation improved attention and emotional distress but not community integration .
Behavioral issues in traumatic brain injury and therapeutic interventions
Alterations in behavior are often the most distressing to caregivers, families, and friends of individuals who have TBI. Behavioral disorder encompasses a wide spectrum of display, including apathy, aggression, irritability, impulsivity, poor social skills, substance abuse, and several psychiatric diagnoses. However, behavioral manifestations of TBI can be linked tightly to neuropathology, depression, social stressors, medication, or cognitive disorders and cannot be assessed or treated accurately without a comprehensive analysis of the patient.
Agitation and aggression are problematic behaviors typically associated with TBI, but in practice these behaviors adversely affect few patients. Agitation in the early stages after injury is related to the degree of attentional impairment and should be distinguished from episodic dyscontrol disorders, which are seen later during recovery . Environmental controls and the behavior of individuals surrounding the agitated patient are essential for reducing the antecedents to agitation. Treating pain and encouraging adequate sleep are also important. Several medications have been used to treat agitation. Benzodiazepines should be used cautiously, because they can contribute to disinhibition. Episodic dyscontrol is related to impulsivity and can be addressed through cognitive–behavioral techniques, emphasizing the early recognition of distressing situations or physical responses to stress. Rarely, episodic dyscontrol can be associated with temporal lobe seizures. Pharmacologic therapies can be extremely helpful in more chronic syndromes of dyscontrol and irritability ( Table 4 ). Aggressive behavior is less frequent, correlated with injuries to the frontal ventromedial cortex, and most commonly verbal rather than physical in nature . Aggression has been associated with depression, poor premorbid social functioning, and a history of drug and alcohol abuse .
| Desired effect | Typical drug treatments |
|---|---|
| Arousal and alertness |
|
| Cognition |
|
| Agitation |
|
| Depression/anxiety | Antidepressants |
| Mood stabilization, emotional lability |
|
Apathy, a disorder of neurologically based motivation, is often misinterpreted as laziness, and is perhaps more disturbing than irritability . Apathy is a disorder associated with bifrontal injuries, including injury to the anterior cingulate gyrus, and can be associated with episodic dyscontrol, presenting a treatment challenge . Few studies of treatment address apathy; one of the most recent is a case series in which selegiline was successful in ameliorating apathy . Studies examining the use of cognitive-enhancing drugs, such as cholinergic medications, in other patient populations (eg, those who have Alzheimer’s disease) have noted improved behavioral profiles as a secondary benefit to improved cognition .
Neuropharmacology
Neuropharmacology can be categorized into treatments for three general areas of effect: cognitive, behavioral, and psychiatric . Cognitive treatments may address alertness, attention, memory, or executive functioning. Behavioral treatments typically focus on management of aggression, agitation, or social inappropriateness. Most commonly, psychiatric treatments focus on depression, anxiety, mood stabilization, and emotional lability.
Pharmacologic interventions often have broad applications with variable effects reported in patients who have TBI . In practice, patients experience tremendous individual variability in response to these medications, probably because of the difference in brain lesion, pretraumatic brain function, and posttraumatic emotional reactivity . Also, considerable genetic variation exists in response to psychoactive drugs. Although evidence for pharmacologic interventions with the posttraumatic population is limited and often ambiguous, most experts agree that neuropharmacology can be effective in practice if the principle “start low and go slow” is followed in clinical use .
Neuropharmacologic effects may differ in the acute, subacute, and chronic stages of post-TBI. No specific treatments have been found effective in phase 3 trials , but greater support exists for rehabilitative neuropharmacology in the postacute and chronic periods. Generally, drugs that increase dopaminergic, cholinergic, adrenergic, and serotonergic activities have been found to be effective in varying degrees for cognitive recovery after TBI in the postacute periods . Assessing outcomes can be challenging; cognitive functional boundaries often overlap, making measurements of arousal, attention, perception, recognition, memory, and executive functioning complex . The fact that spontaneous recovery occurs after TBI also emphasizes the need for randomized, controlled trials for drug efficacy. Table 4 outlines general treatments.
Arousal and alertness
Medications used to encourage arousal and alertness in the postacute phase generally include those that increase dopaminergic effects . Amantadine and bromocriptine may be the most commonly used drugs for arousal and alertness. If motor restlessness becomes apparent after amantadine trial, bromocriptine and carbidopa/levodopa may be tried . Second-line pharmacotherapy for arousal and alertness may include selective serotonin reuptake inhibitors (SSRIs) . Alternatively, modafinil may ameliorate fatigue and somnolence and improve alertness and attention, although measures showing cognitive improvements have not been robust . Medications with little support of their effectiveness for alertness also include the psychostimulants .
Attention
Methylphenidate, a nonamphetamine central nervous system stimulant with dopaminergic properties, has been used to improve attention, reaction times, and processing speeds. Although attention to single tasks may typically improve after treatment with methylphenidate, divided attention, sustained attention, and distractibility remain essentially unaffected . Although methylphenidate has also been found effective for controlling agitation in some cases , adverse reactions of nervousness, psychosis, and dyskinesia should be monitored.
Memory and learning
The cholinergic medications, such as donepezil and rivastigmine, may have more a focused effect on cognitive improvements in memory, divided and sustained attention, learning, and processing speed in the postacute and chronic periods . However, they have not been shown to expedite emergence from posttraumatic amnesia . A new norepinephrine reuptake inhibitor, atomoxetine, has also been shown to have positive effects on memory, concentration, fatigue, and executive functioning . In addition, cognitive improvements in attention, concentration, processing speed, and functional independence measure or disability rating scale measurements may also be seen with amantadine or bromocriptine . A recent randomized controlled trial of rivastigmine for memory enhancement and learning showed promising results for persons who have moderate to severe TBI .
Depression and emotional lability
SSRIs are first-line treatment for depression after TBI. Some evidence shows that sertraline may be preferred in treating posttraumatic brain injuries , and venlafaxine is often chosen when the SSRIs are ineffective. For resistant cases of depression, adjunctive treatment with a second antidepressant of a different class or with methylphenidate may be useful. Many antidepressants are also effective for anxiety control or emotional lability. SSRIs are generally believed to be neutral with respect to cognitive functioning.
Antiepileptic drugs (AEDs) have been used after TBI to manage episodic dyscontrol disorders and neuropathic pain, as headache prophylaxis, and to treat emotional lability. Valproic acid has been most widely documented for use in posttraumatic patients to manage destructive and aggressive behavior, lability, and impulsivity . Overall, the newer AEDs, such as gabapentin, lamotrigine, levetiracetam, tiagabine, vigabatrin, topiramate, and oxcarbazepine, may have fewer negative psychiatric and cognitive side effects than the older AEDs. However, levetiracetam and tiagabine may have greater tendency to produce behavioral or psychiatric side effects .
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