Moderate to severe traumatic brain injury (TBI) is a leading cause of morbidity and mortality in the United States and worldwide, with an annual incidence of 60 to 100 per 100,000.1–4 In 2010, there were 715.7 per 100,000 emergency department (ED) visits related to TBI, with 91.7 per 100,000 TBI-related hospitalizations, and 17.1 per 100,000 TBI-related deaths.5 It is estimated that over 5 million people in the United States are living with TBI-related disability,6 and by 2020, TBI will be the third leading cause of disability in the world,7 with the annual cost of providing acute and rehabilitation care for individuals in North America projected to be in the billions of dollars.8 These statistics are especially troublesome because the incidence of TBI is highest among young males between the ages of 15 and 24,1,8,9 leading to decades of disability and lost productivity. Despite the improvement in mortality rate, many survivors are left with lifelong impairments in physical, cognitive, and psychosocial functioning. Management of these individuals is challenging, given the varying severity of illness and baseline comorbidities.
This chapter will focus on patient management in TBI; key points will be reviewed, and the reader is encouraged to review the references for a more detail examination of the topic.
PHARMACOLOGIC INTERVENTIONS FOR COMMON PROBLEMS IN PATIENTS WITH TRAUMATIC BRAIN INJURY
This section will review frequent problems associated with traumatic brain injury and their most common pharmacologic treatments. For many of these problems, limited or no high level evidence exists to support common management strategies often used by physicians. Despite the paucity of data, clinical recommendations regarding medication management are based on the best data available. Often, when no data exist, extrapolation of data from studies not specific to patients with brain injuries is utilized. When the decision to start a medication has been made, the old adage by many experts in the field of brain injury medicine, “start low and go slow” truly applies. “Go slow” takes into account dosing adjustments and timing of adjustments. Not waiting long enough to allow a medication to fully take effect and increasing dosing prior to this may lead to side effects or other adverse consequences. Patience and understanding the pharmacodynamics of the medication may lead to an adequate response to the symptom being treated at the lowest possible dose.
Antidepressant medications are frequently used in the management of brain-injured patients. The content of this section will focus on commonly used drug classes: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and benzodiazepines. They have been used in this patient population for depressive disorders, anxiety, and behavior disorders. This section is organized by drug class and their potential indications.
Depression incidence following head injury ranges quite a bit, mostly due to study design and diagnostic capture. The incidence of depression has been reported from 8% to 60% in the early postinjury time period. The prevalence of depression in these patients has been reported to be anywhere from 8.5% to 31%.10 The SSRIs—namely fluoxetine, citalopram, sertraline, fluvoxamine, escitalopram, and paroxetine—have been considered to be first-line treatment for depression in the brain-injured patient. This may be in part due to their favorable side effect profile when compared to the tricyclic antidepressants (of which anticholinergic side effects are most concerning). Most common side effects of SSRIs include gastrointestinal complaints, insomnia, decreased libido, and sexual dysfunction. The time to steady state in bloodstream is in the 7- to 14-day range for citalopram, sertraline, fluvoxamine, and paroxetine, while for fluoxetine, it is quite a bit longer at 30 to 60 days.
There have been studies that suggest sertraline to be helpful in the management of depression post-TBI. A prospective cohort study on patients in a rehabilitation unit demonstrated that patients improved clinically with the administration of sertraline and that they also improved when switched to sertraline from another SSRI.11 Similarly another study showed improvement in early depressive symptoms with sertraline; however, they noted that the timing of administration of the medication does not seem to offer protection from depressive symptoms once the drug is stopped.12
Citalopram, escitalopram, paroxetine, and fluvoxamine have limited or no data on treatment of depression in the brain injury population. Fluoxetine, the oldest of the SSRIs, has, however, been studied in brain-injured patients with depression. Like sertraline, there have been studies suggesting favorable findings when assessing improvement of depressive symptoms. One study suggested that fluoxetine administration not only improved mood but also improved cognitive function.13
As stated before, the SSRIs are considered first-line agents in the treatment of brain-injured patients with depressive symptoms. Tricyclic antidepressants (TCAs) predate the SSRI drug class. They act as monoamine reuptake inhibitors and inhibit reuptake of noradrenaline and serotonin. The most common side effects of these drug class include anticholinergic side effects, of which amitriptyline has the most. Symptoms such as sedation, impaired concentration, and memory, as well as urinary retention and constipation, are problematic in the recovering brain-injured patient. Nortriptyline, amitriptyline, and desipramine have some limited data with regard to their usage in brain-injured patients with depressive symptoms. One study, involving patients with severe TBI and long-standing depressive symptoms, showed that desipramine demonstrated a clinically significant effectiveness in treating long-standing depression.14 It should be noted that there were a significant number of patients reporting side effects with treatment (30%). Primarily, this is the reason why the SSRI drug class is favored over tricyclics in patients with head injury. In a comparison review of younger non-TBI patients, SSRI had better efficacy and fewer adverse effects as well as dropouts.15
As for anxiety following head injury, the same methodological issues cause the reported incidence to vary—one review showed an incidence of 4% to 28%.10 It should be noted that there is often overlap of both anxiety and depression in patients with brain injury. Approximately three-quarters of patients with depression had a coexistent anxiety disorder in one study of TBI patients.16 The commonly prescribed medications for this problem include the SSRIs, SNRIs, buspirone, and benzodiazepines.
As with depression, the SSRIs and SNRIs (duloxetine and venlafaxine) are the preferred treatment options, due mostly to efficacy and side effect profile. The effectiveness of this drug class has been demonstrated in the general population. Limited data exist as to which SSRI is most beneficial in the treatment of anxiety. The decision of which SSRI to use is based on side effect profile and clinician preference oftentimes.
Benzodiazepines and buspirone are considered second-line treatment for anxiety-related disorders. Buspirone is thought to affect the serotonergic system via blockade of 5HT1A autoreceptors. Benzodiazepines are used often to treat anxiety. They are not desirable in this population, however, because of side effects, which include sedation, impaired memory, and balance. When and if they are prescribed for patients, preference for benzodiazepines with shorter duration is recommended. Concerns over dependence and additional potential should also figure in the decision to treat.
Emotional dyscontrol in the brain-injured patient refers to affective lability, irritability, and pathological laughing and crying (PLC). Antidepressant medications are the preferred choice in the management of pathological laughing and crying and affective lability disorders in the brain injured population. Pathological laughing or crying is often referred to as pseudobulbar affect disorder. This condition may manifest itself early during the recovery period and can occur in mild to severely injured patients. The literature regarding this condition consistently demonstrates that serotonergically (SSRIs) and/or noradrenergically (SNRI) active antidepressants are effective treatments of PLC involving episodes of crying, laughing, or both.17 Sertraline, citalopram, and escitalopram are favored for this purpose in light of their relatively short half-lives, limited drug-drug and CYP450 interactions, and generally favorable side effect profiles.17 Affective lability characteristically involves crying or laughing but may also entail anxiety and/or irritability.18 Again SSRIs are the favored treatment medication when pharmacologic management for this problem is recommended.
Agitation can be a challenging part of care for patients with traumatic brain injury, and several issues exist. The agitation itself may serve as a source of disability for the patient, and it can be a great cause of stress on caregivers and families. The incidence of agitation has been estimated to range from 11% to 50%, depending on the source quoted.19–21 The difficulty in quantifying this problem is the operational definition of agitation that is used. One of the most commonly accepted definitions for agitation is “a subtype of delirium unique to survivors of a TBI in which the survivor is in the state of post-traumatic amnesia and there are excesses of behavior that include some combination of aggression, akathisia, disinhibition, and/or emotional lability.”22 There is limited information from well-controlled studies to definitively direct treatment on this problem. Clinical decisions to initiate a medication should take into account the failure of nonpharmacologic interventions, the specific symptoms that the medication is being started for, and the side effect profile of the medication.
The discussion in this text will focus on a subset of agitation: aggression. Aggression often poses the most problems to the patient, families, and caregivers. Aggression refers to verbal or physical behaviors, including disruptive or destructive behaviors, directed toward other persons or things in the patient’s environment. The most commonly used medication classes to treat aggression include antipsychotics, benzodiazepines, anticonvulsants, antidepressants, stimulants, and beta blockers.
The antipsychotic drug class encompasses both typical and atypical antipsychotics. Both typicals and atypicals block dopamine, with the typicals having more extrapyramidal side effects than the atypicals. In addition to dopamine blockade, the atypicals alter serotonin levels in the brain. The most commonly prescribed typical antipsychotic is haloperidol. One of the most quoted studies when discussing haloperidol as it pertains to motor recovery is Feeney’s study of rats administered haloperidol post-brain injury.23 In addition to motor recovery, concern over prolonging the time spent in posttraumatic amnesia has made haloperidol a less ideal choice in this drug class.24
There are a number of atypical antipsychotics, but the most commonly prescribed medications include risperidone, olanzapine, quetiapine, and aripiprazole. Extrapyramidal side effects are typically less with the atypicals but still can occur. They are more common with the use of risperidone and less common with quetiapine. Caution should still be used with treatment of agents in this group, as they may cause prolongation of the QT interval, drug interactions, and metabolic abnormalities. With regard to sedation, risperidone seems to offer relatively less than quetiapine or olanzapine. This can be particularly helpful when the goal is to allow the patient to participate in rehabilitation while addressing impeding behaviors.
Benzodiazepines are used by some clinicians to sedate or calm patients with aggression following traumatic brain injury. There is no good evidence to date to advocate for their use in this patient population. Of particular concern is the potential to worsen memory and impair coordination and balance. If used, the preference of agent should be one with a short half-life and at the lowest possible dose to achieve the desired effect.
Anticonvulsants may also be used in the treatment of aggression associated with traumatic brain injury. The most commonly prescribed anticonvulsants for this problem include carbamazepine, valproic acid, and gabapentin. Carbamazepine has been shown to be beneficial with patients with Alzheimer’s dementia.25 Valproic acid has likewise shown some improvement with patients with post-traumatic aggression in small studies.26 Gabapentin showed some benefit in improving aggression in patients with an underlying diagnosis of dementia.27 Side effect profiles and need to check serum levels of the drug may play a role in the clinician’s decision to start an anticonvulsant on an agitated patient. Both carbamazepine and valproic acid can cause Stevens–Johnson syndrome and hyponatremia in patients, which can be potentially serious. Agranulocytosis is a known side effect when using carbamazepine. Carbamazepine used in conjunction with warfarin may also lower the international normalized ratio (INR), while valproic acid used in the same setting may increase the INR, making it difficult to achieve therapeutic levels of anticoagulation. Gabapentin has fewer serious side effects and no black box warnings when compared to the other two anticonvulsants discussed. It should be used with caution and dosing adjusted in the setting of renal impairment.
Antidepressant medications may also be used in the treatment of aggression related to traumatic brain injury. The most common agents used are amitriptyline (tricyclic antidepressant), trazodone (serotonin antagonist and reuptake inhibitor), and the SSRIs sertraline and fluoxetine. Limited data, mostly case reports, exist for amitriptyline and trazodone in the treatment of aggression. The side effect profile for trazodone is more favorable when compared to amitriptyline, mostly due to concern over amitriptyline’s anticholinergic side effects. The SSRIs, in particular, sertraline and fluoxetine, also have some evidence of improvement of symptoms of aggression in head-injured patients. An open-label study in TBI patients showed improvement in aggression scales with use of sertraline.28 In a double-blind, randomized, placebo-controlled trial, fluoxetine was shown to improve scores on the Overt Aggression Scale-Modified in patients with intermittent explosive disorder.29 This effect was noted as early as week 2.
The use of stimulant medications (amantadine and methylphenidate) to treat agitation and aggression may seem counterintuitive to some. Most of the stimulant medications are dopaminergic in nature; earlier in this section, medications that act by dopamine blockade were discussed. Dopaminergic agents may be most useful in those patients with an intact frontal cortex. It has been shown that methylphenidate and amantadine target receptors in this portion of the brain. The orbitofrontal cortex and adjacent areas, such as the dorsolateral prefrontal cortex and the anterior cingulate cortex, modulate the activity of the amygdala through inhibition.30 In a parallel-group, randomized, double-blind, placebo-controlled trial of amantadine versus placebo, the authors suggested that amantadine was an effective and safe means of reducing frequency and severity of irritability and aggression among individuals with TBI.31 Methylphenidate, a noradrenaline and dopamine stimulant, has been shown in two studies to reduce both anger and aggression in brain-injured patients.32,33
The last group we will discuss in the section is the beta adrenergic receptor antagonists. The most common indication for this class of medications is for hypertension and when heart rate control is desired for conditions such as atrial fibrillation. Arguably, the best data for use with the aggressive patient with TBI come from studies within this drug class. The most commonly investigated drugs in this class are propranolol, pindolol, and nadolol. Both propranolol and pindolol are lipid-soluble, which allows them to pass the blood–brain barrier with less difficulty and may confer some benefit over nadolol. A study performed by Brooke demonstrated that TBI patients using propranolol up to maximum dosage of 420 mg/day had reduced intensity and frequency of aggressive episodes. Caution should be used when prescribing propanolol in the setting of hypotension or bradycardia.34
The incidence of seizures related to traumatic brain injury has been estimated to be 6%.35 Early seizures are defined as seizures occurring in the first 7 days of trauma, while post-traumatic epilepsy (PTE) is defined as seizures occurring after this initial period.36 Prophylactic treatment with anti-epileptic drugs (AEDS) has been shown to reduce the incidence of seizures with the first 7 days following injury; however, treatment in this time period has not been shown to reduce late seizures.37
The most commonly used AEDS include phenytoin and levetiracetam. Phenytoin has been the most studied AED, with strong evidence that prophylactic treatment with phenytoin, beginning with an IV loading dose, should be initiated as soon as possible after injury to decrease the risk of post-traumatic seizures occurring within the first 7 days.37 Phenytoin does have concerns worth considering in brain-injured patients, including cognitive sedation and difficulty maintaining therapeutic levels.
Levetiracetam is a newer AED that is a potential alternative to phenytoin. No randomized, double-blind studies have been performed to compare the two AEDs. Several studies have been done to assess the benefit of levetiracetam over phenytoin; however, these studies are limited by design and power to allow for a definitive answer to the question. Some studies have suggested that levetiracetam can improve visual short-term memory,38 working memory, and motor functions.39 Other studies have suggested that when compared to phenytoin for prophylaxis in the 7 days following injury, patients receiving levetiracetam had an increased seizure tendency and epileptiform activity on electroencephalogram (EEG).40
Other AEDS include valproic acid and carbamazepine. The benefit of using valproic acid or carbamazepine for prophylaxis of early post-traumatic seizures is not supported by available data. There have been limited quality studies looking into their benefit. One such study suggested that valproic acid showed no benefit over phenytoin in the treatment of early seizures or PTE.41 Carbamazepine was suggested to significantly lower the probability of early and late post-traumatic seizures,42 but the results of this study were noted to be confounded by the fact that patients were treated initially with intravenous phenytoin until they were able to receive oral carbamazepine.43
The type of the AED utilized by the rehabilitation healthcare provider is dependent upon the type seizure which has been diagnosed. In absence, myoclonic, and generalized tonic–clonic seizures, experts chose valproic acid as a treatment of choice. Ethosuximide was also selected as a treatment of choice for absence seizures.44 Carbamazepine was chosen by an expert panel for first-line treatment for simple partial, complex partial, or secondarily generalized seizures.44
Newer AEDS are also available and include topiramate, gabapentin, lamotrigine, oxcarbazepine, zonisamide, and tiagabine. While limited data exist about their efficacy in treatment of seizures related to head trauma, their side effect profiles may offer some benefit over the older AEDS in patients with cognitive impairment. One double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy suggested significant benefits of greater tolerability and better health-related quality of life with lamotrigine when compared with carbamazepine.45
Patients who suffer a traumatic brain injury may be subject to pain, both acute and chronic. TBI patients have more pain complaints than non-TBI patients.46 Patients may suffer from pain related to direct force to the head or may suffer from injuries associated with the accident, such as bony fractures or soft tissue injuries. Their pain may be of central origin or peripheral. Brain-injured patients may have spasticity, contracture, nerve injury, or heterotopic ossification that could all be potential pain generators. Pain can be a significant problem at one year after injury for individuals with TBI, with 74% of patients reporting some level of pain and 55% reporting interference with daily activities from pain.47
Pain can broadly be broken into three categories: somatic, visceral, and neuropathic pain. Any or all of these may be present in a brain-injured patient. It is important to understand the goals of treatment with regard to pain. When deciding on treatment options for pain in the brain-injured patient, several things must be taken into account. The effect of pain complaints on the patient’s overall functioning and well-being should be noted. Pain has been noted to increase insomnia nearly twofold.46 The brain-injured patient may have a decreased level of arousal, in which case caution should be used when administering analgesics that may have some sedation as a side effect. In addition to sedation, other side effects such as constipation, urinary retention, nausea, vomiting, and dizziness must be understood, as these may have consequences in impeding rehabilitation efforts post-injury. If used appropriately side effects may be of benefit, for example, the tricyclic antidepressants may be used for neuropathic pain but if used at night may also benefit the patient’s sleep.
In the brain-injured patient who is able to provide details of their pain, location, character, and associated aggravating and alleviating factors all help the clinician determine which treatment option is best suited. The challenge often in this patient population is the inability to accurately describe and quantify their pain symptoms. This may be due to altered sensorium or inability to vocalize. Signs that a patient may be having pain include grimace, agitation, or increased muscle tension.48 Nonverbal TBI patients exhibited raised eyebrows, opening eyes, and weeping eyes.48 Vital signs have been used in brain-injured patients who have difficulty communicating their pain. Nonspecific findings of increases in blood pressure, heart rate, and respiratory rate may be associated with a response to pain.
Headaches are the most common pain complaint in patients with traumatic brain injury.49 Post-traumatic headaches are defined as a secondary headache disorder that occurs within 7 days of a TBI.50 The most important aspect of management in patients with post-traumatic headache is to rule out any cause of pain that could lead to worsening neurologic compromise or even death, such as expanding intracranial bleeds, hydrocephalus, or infectious causes in penetrating head injuries. Often simple imaging studies such as computerized tomography (CT) or magnetic resonance imaging (MRI) can rule out these worrisome causes. Once this is done, treatments may vary based upon the types of headache complaints that the patient presents with. Within the TBI population, migraine and probable migraine type headaches were the most frequent headache type, occurring in up to 59% of participants who reported headaches, followed by tension type headache in up to 21%, then cervicogenic headache in up to 10%. An accurate diagnosis and classification of the primary headache disorder is critical, as it will facilitate appropriate management.51
Abortive and prophylactic pharmacologic management is available for post-traumatic headaches. Abortive may be tried for patients who have infrequent headaches. Medication classes for abortive agents include nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, and combination analgesic products. NSAIDs have been suggested to be beneficial in the management of migraine,52 tension,53 and cervicogenic54 headaches and therefore may be a good first-choice agent. The type of NSAID is not as important in terms of benefit, but naproxen may be a better option in terms of duration.51 Triptans are recommended for use in patients with migrainous phenotype headaches. Uncontrolled studies suggest their benefit as an abortive agent for post-traumatic headaches as well.55 Combination analgesic products do not have controlled studies to suggest efficacy in patients with post-traumatic headaches. Two of the more commonly used drugs are Fioricet (butalbital/acetaminophen/caffeine) and Excedrin.56 Expert opinions on this topic recommend (acetaminophen/aspirin/caffeine). Caffeine has been found to potentiate the analgesic components with which it is paired in headache medications and also allow them to absorb faster. However, caffeine may also cause rebound headaches, so prescribing physicians must be cautious about overprescribing these medications. Making the issue more problematic is that there are no clinical trials to guide treatment of post-traumatic headaches.
Prophylactic medications for post-traumatic headaches (and headaches in general) are reserved for those patients who suffer from an increased frequency of headache. In general, patients who experience two or more moderate–severe headache attacks per week or 3 or more days of impaired activities per month over a period of several months despite use of abortive medications are good candidates for headache-prophylactic medication.51 As with abortive medications, there are no randomized controlled trials of prophylactic medications for treatment of post-traumatic headache, and primary headache practice recommendations often guide treatment. Preferred treatments for migraine prevention include valproic acid, topiramate, amitriptyline, and propranolol.55 Other agents include carbamazepine, which is a first-line treatment for trigeminal neuralgia. Tricyclic antidepressant medications may also be used for migraine prevention.54 Gabapentin is commonly used for prevention of symptoms in patients with occipital neuralgia.
Injections have been noted to be of benefit for certain types of headaches. In particular, headaches related to occipital neuralgia, cervicogenic headaches, and migraines may be improved with injections. Botulinum toxin injections have been suggested to aid in improvement of headache-related symptoms in patients with chronic migraine and that a cumulative effect of injections has been observed.57 Occipital nerve blocks may be useful in the treatment of occipital neuralgia, and improvement in headache symptoms has been seen in patients with cervicogenic and migraine-type headaches.58
Somatic pain complaints may be managed with either narcotic or non-narcotic pain medications. Non-narcotic pain medications include acetaminophen, NSAIDs, and neuropathic pain medications. While these drugs may be milder in potency of analgesia, they must be used with caution in patients with impaired liver function (acetaminophen) and impaired renal function or potential for gastrointestinal (GI) bleed (NSAIDs). The benefit oftentimes in patients with brain injury and pain symptoms is that these medications are less likely to cause sedation when compared to narcotic medications. Narcotic medications (opioids) work by binding to opioid receptors in the brain, spinal cord, and other areas of the body, thereby providing analgesia by decreasing pain signals to the brain. They are considered more potent in terms of pain relief when compared to non-narcotic medications. While the potency of narcotic medications may be greater than that of non-narcotic pain medications, they are not without side effects, which include nausea, vomiting, constipation, urinary retention, and sedation. Some or all of these may factor in to a brain-injured patient’s ability to function while on narcotic pain medications.
Central pain syndromes can and do occur in the head-injured patient. Limited data exist in terms of the incidence; however, in the stroke population it has been estimated to develop in 8% of patients, with the incidence increasing with age.59,60 Opiates, tricyclic antidepressants, and certain AED such as gabapentin and lamotrigine have demonstrated some positive effects.60
Sleep disturbances after head injury are common. While sleep disturbances include insomnia and hypersomnia, this section will focus on insomnia. There has been variation in the reported incidence due to lack of consistent definition of insomnia and variable assessment methods.61 In a study by Fichtenberg et al,62 30% of the patients with head injury (mild to severe) were found to suffer from insomnia, and sleep initiation was a problem almost twice as often as sleep duration.
Obtaining a thorough history to determine the pattern of sleep disturbance, exacerbating and alleviating factors, and response, if any, to prior treatments will help in determining the best course of action for the problem. In addition, any physical or psychological factors that may contribute to the worsening of sleep should be addressed prior to focusing on the sleep impairment alone.
The sedative-hypnotic medications are the most commonly prescribed class of drugs for insomnia. These medications work on GABA receptors to decrease sleep latency, decrease nocturnal awakenings, and increase total sleep time. The hypnotics for sleep can be divided into benzodiazepine and nonbenzodiazepine medications. The benzodiazepine group includes medications such as temazepam, clonazepam, and diazepam. These medications may cause cognitive impairment, dizziness, and morning sedation. Therefore, caution should be used with this group of medications. They have the potential to cause physical dependence and tolerance.
The nonbenzodiazepine medications include zolpidem, zaleplon, zopiclone, and eszopiclone. These drugs have preferential binding to GABA type A receptor complexes. These medications have varying half-lives, with zaleplon having the shortest (1 hour), which may make it beneficial for sleep-onset insomnia. Conversely, eszopiclone, with a half-life of 6 to 9 hours, may be beneficial in sleep maintenance insomnia.63 Hypnotic medications are not recommended for long-term use in patients with insomnia.
Antipsychotics, in particular atypicals, have been used to treat patients with insomnia. While there exists no Food and Drug Administration (FDA) indication for insomnia, the effect of this class of medications, sedation, can be used to potentially help with sleep disturbance. The most often used medications in this class are quetiapine, olanzapine, and risperidone. Quetiapine and olanzapine cause more sedation in patients, relatively speaking. Side effects are associated with these medications, which include weight gain, dyslipidemia, type 2 diabetes, and extrapyramidal side effects (although these are less likely when compared to typical antipsychotics). Therefore, in patients with an indicated use, there may be some benefit, but in patients without indications, the risk-benefit ratio may be less favorable.64
The FDA has approved three over-the-counter antihistamines for the treatment of insomnia: diphenhydramine hydrochloride, diphenhydramine citrate, and doxylamine succinate. These medications work on histamine 1 receptors, causing decreased arousal.65 Side effects, which are largely attributed to the anticholinergic effects of the medication, may include dry mouth, dizziness, daytime sedation, and memory problems.65 It is for these reasons that their use in brain-injured patients is not advised, as there are other drug classes with more favorable side effect profiles.
Tricyclic antidepressants have been used in the treatment of insomnia, in particular, amitriptyline and doxepin. Doxepin has an FDA indication for insomnia. Tricyclic antidepressants have sedating properties due to side effects related to their anticholinergic properties, which include urinary retention, dry mouth, and constipation. They can also pose problems with memory and attention. They should be used with caution in the TBI population.
Trazodone has an FDA approval for the treatment of depression; however, its usage for this condition has been minimal, given the introduction of SSRIs. It does have some popularity in terms of its use in the treatment of insomnia. It is thought that its mechanism of action is by selectively inhibiting serotonin. In a large multicenter study in patients with insomnia, trazodone showed modest improvement in sleep duration compared with placebo.66 The side effect profile of trazodone may make it a better option to assist with insomnia in the brain-injured patient. Unlike the tricyclic antidepressants, it lacks any anticholinergic side effects. And unlike the benzodiazepines, it is not felt that trazodone likely contributes to significant cognitive compromise when used in brain-injured patients.
Fatigue is defined as a feeling of extreme tiredness or lack of energy. It can manifest itself on different levels: mental, physical, and psychological. One study estimates the rate of fatigue to be up to 45% in patients with mild-to-moderate head injury one year post-injury.67 Another study suggests that post-traumatic brain injury fatigue in patients with moderate-to-severe injury exists in 33% to 44% of individuals in the first 2 years.68 Other studies have suggested that fatigue increased in 68% of individuals at 2 years post-injury and 73% at 5 years post-injury.69
The data behind pharmacologic interventions for fatigue in the brain-injured population are far from robust. Most studies suffer from issues associated with quantifying fatigue. There are some standardized scales, such as the Visual Analogue Fatigue Scale (VAFS), Global Fatigue Scale (GFS), and the Fatigue Severity Scale (FSS). Since fatigue is not specific to head injury, other causes need to be ruled out such as anemia, mood disorders, sleep disorders, endocrine abnormalities, and medications associated with the head injury. The focus of this section is pharmacologic interventions that may help with this problem.
The most commonly used agents to treat fatigue are modafinil, methylphenidate, and amantadine. Modafinil has FDA indications for obstructive sleep apnea, narcolepsy, and shift work disorder. Its mechanism of action is not well understood but is felt to increase dopamine, noradrenaline, and serotonin and decrease GABA. In a randomized, single-center, double-blind, placebo-controlled study using modafinil up to 200 mg/day in patients with fatigue 1 to 3 years post-injury, there was no significant improvement in fatigue as measured by the Fatigue Severity Scale; however, it did improve excessive daytime sleepiness.70 Similarly, no significant improvement was noted with regard to fatigue in a single-center, double-blind, placebo-controlled cross-over trial, where 53 participants with TBI were given modafinil, up to 400 mg/day.71
Methylphenidate, as previously mentioned, increases dopamine and noradrenaline. It carries FDA indications for attention deficit hyperactivity disorder (ADHD) and narcolepsy. It has been used off-label to help with fatigue in patients following head injury. The data are limited in terms of its efficacy here, however. In an open-label, crossover study of the efficacy of methylphenidate in the treatment of mental fatigue, it was suggested that those patients receiving methylphenidate showed significant improvement with mental fatigue and that the response was dose dependent.72
Amantadine, like methylphenidate and modafinil, augments dopamine in the brain. In the brain injury population, limited studies have looked at amantadine’s benefit on fatigue. There is some literature, however, in the multiple sclerosis (MS) population to suggest some benefit of amantadine to help treat fatigue. In a randomized, double-blind, placebo-controlled study of 93 patients with MS, it was suggested that amantadine-treated patients showed a significantly greater reduction in fatigue compared to placebo as measured by the FSS.73
The cognitive impairment in the brain-injured patient can pose several challenges. In this section we will discuss problems with attention, arousal, and memory and the data behind studied pharmacologic interventions for these problems. The neurotransmitters most commonly implicated with these problems are dopamine, noradrenaline, serotonin, and acetylcholine. The drug classes most commonly used to help with these problems include stimulant dopaminergic agents, SSRIs, and cholinesterase inhibitors.
For attention deficits in the brain-injured patient, the best data lie with the use of methylphenidate. Several randomized controlled studies have shown that use of methylphenidate increased cognitive processing speed and attention on neuropsychological tests in brain-injured patients.74–77 Limited evidence exists for the use of amantadine to help with focus and attention. One study suggested that amantadine increases the rate of improvement in attention and other cognitive functions in the acute stages following TBI in a small group of patients.78 Modafinil is another drug that has been suggested by some to help with focus and attention issues in patients with head injury. While there have been no studies looking at this to date in this population, there have been studies in patients with ADHD; however, the results of the benefit of modafinil in these patients is mixed. Bromocriptine, a dopamine agonist, has also lacked results to suggest it helps with this particular problem in brain-injured patients. Dextroamphetamine has been proposed to be of benefit for attention issues, given its similarities to methylphenidate; however, to date, limited research (mostly case studies) has been published in the brain-injured population.
Consciousness has two key components: arousal, which refers to degree of wakefulness, and awareness, which refers to the content of consciousness. Arousal is maintained by activation of the ascending reticular activating system involving several neurotransmitters, including glutamate, acetylcholine, and the monoamines. Impairment with arousal can have a significant impact on recovery and improvement with function.
Perhaps the best data for arousal in the brain-injured patient lie with amantadine. Amantadine, a dopaminergic agent, has been used for multiple off-label uses in brain-injured patients. One target group is those patients with disorders of consciousness. In a randomized placebo-controlled study, amantadine administration was compared to placebo in severe TBI patients who were either in a vegetative state or minimally conscious state with an outcome measure of the Disability Rating Scale. Amantadine accelerated the pace of functional recovery during active treatment in patients with post-traumatic disorders of consciousness.79 In another prospective randomized double-blind trial, children and adolescents with Rancho Los Amigos scores of 3 or less received either amantadine or pramipexole (a dopamine agonist). Their outcomes were measured on the Coma Near Coma Scale, Western NeuroSensory Stimulation Profile, and Disability Rating Scale. The study contained no placebo group. Patients were started on either medication; dosing was increased and then eventually weaned and stopped. Findings of weekly rate of change were significantly better for all three measures on medication than off medication, and there was no significant difference between the two drugs.80 Another study reviewed amantadine and found it to safely improve arousal and cognition in patients with TBI, with dosing ranging from 200 to 400 mg/day.81 Other dopaminergic agents, bromocriptine and levodopa, have been reviewed82 and have limited data behind their use in underaroused brain-injured patients.
Memory, like other cognitive functions, is controlled and regulated by multiple regions in the brain. The hippocampus and frontal lobes play significant roles in the storage and retrieval of information. Coincidently these areas are the most common region to be affected by contusions due to their location next to rigid bony prominences. Cholinesterase inhibitors, such as donepezil, carry FDA approval for treatment of Alzheimer’s dementia. They have also been used to treat cognitive impairment in patients with traumatic brain injury off-label. In a meta-analysis review of the usage of donepezil in patients with brain injury, the results suggested a small to moderate improvement for several cognitive outcomes following treatment with donepezil, which seemed to be dose dependent.83 Other cholinesterase inhibitors studied include physostigmine and galantamine; however, they have not shown significant improvement with memory. In a double-blind, placebo-controlled, crossover trial, bromocriptine was not shown to provide significant improvement with working memory.84 The SSRIs, in particular, fluoxetine, have been investigated to determine effect on memory in brain-injured patients. One study in which five TBI patients were administered fluoxetine 20 to 60 mg/day for 8 months, demonstrated improvement in the letter-number sequencing subtest of the WAIS-III, a measure reflecting working memory.13 The effect of sertraline (placebo or sertraline 50 mg daily for 3 months post-injury) on cognition was analyzed in a randomized double blind, placebo controlled study involving moderate to severely injured patients with TBI; the study failed to show any benefit in cognitive functioning or memory.85
There is a great deal of interest in the use of exercise as an intervention for various symptoms and disorders associated with TBI, although studies remain scarce. The effect of exercise on symptoms after TBI is still unclear.86 An important caveat to the resumption of exercise after TBI relates to early evidence that a degree of autonomic instability may continue to persist after injury. Those with TBI often have reduced aerobic capacities.87,88
Aerobic exercise has been demonstrated to be an effective behavioral approach for reducing depressive symptoms and treating major depressive disorder in otherwise healthy adults.89,90 One meta-analysis that examined trials comparing exercise versus control interventions89 had a modest effect size in favor of exercise reducing depressive symptoms. Another meta-analysis90 of 17 trials with clinically depressed participants reported that the exercise groups had a 1-SD reduction in depression scores compared with control groups. There is additional evidence that exercise training is comparable with antidepressant medication (sertraline) in its effects on depression and depressive symptomology.91 Similarly, a Cochrane review89 of the effects of exercise training on depression reported no differential improvement in depressive symptoms for those receiving exercise and those receiving CBT. A difference can be predicted on the basis of intensity and duration of exercise (dose of intervention).92
Adamson et al conducted a meta-analysis of 26 studies of exercise for depression in patients with neurologic disorders; only 3 of these studies included persons with traumatic brain injury, all with varying types of exposure to exercise. There was a small but significant effect for depression reduction overall,93 but few studies included patients screened for a major depression. Many study interventions did not meet standard cardiovascular guidelines for physical activity.
Only a few studies specific to exercise in the TBI population have been completed. Most have been very small groups or retrospective in nature.94–96 Persons with TBI have been shown to be able to demonstrate good aerobic training effects with vigorous exercise.97 Bellon et al trialed a 12-week home walking program with pedometer use vs. an educational control group with improved perceived stress and level of depression.98 In another study, those subjects with TBI who maintained exercise levels over 90 minutes per week following standard guidelines had improved mood and maintained gains over a 6-month follow-up period.99,100
Human studies of noninjured persons show that even a single bout of exercise can improve cognition temporarily and that sustained exercise can sustain that effect.101 A recent animal TBI model demonstrated that miRNA changes in mice were associated with exercise-induced cognitive improvement.102 The few existing reported studies in persons with TBI have yielded insufficient evidence for cognitive improvement, with small groups and poorly described interventions.103,104 A recent study, however, related changes in attention and general cognition, which correlated with the gain in cardiorespiratory fitness.105
Of the 1.7 million patients diagnosed with TBI annually, over 250,000 require hospitalizations, resulting in over 53,000 deaths.8 Fortunately, outcome for TBI patients has improved, with mortality decreasing 8.2% over the past decade.106 Much of this improvement may be related to faster and more effective emergency care, quicker and safer transportation to specialized treatment facilities, and advances in acute medical management due to better understanding of the pathophysiology of TBI.
The basic sciences of TBI injury are discussed elsewhere in this text. In the average adult, the rigid skull encloses a volume of 1450 mL: 1300 mL of brain, 65 mL of cerebrospinal fluid (CSF), and 110 mL of blood.107 According to the Monroe–Kellie hypothesis, the sum of the intracranial volumes of blood, brain, CSF, and other components is constant, and an increase of any component must be accompanied by a decrease in another component to keep the pressure constant. Common to TBI management is the need to monitor intracranial pressure (ICP) because cerebral ischemia is the most important secondary factor that influences outcome after TBI.108 In a normal adult, the ICP is between 5 and 15 mm Hg for a supine adult,109 and ICP between 20 and 30 mm Hg represents mild intracranial hypertension (ICH), although herniation can occur when ICP is less than 20 mm Hg and temporal mass lesion is present.110 Among those with moderate-to-severe TBI, ICP monitoring is often used, as ICP greater than 20 mm Hg is associated with neurologic deterioration, disability, and mortality.111–113 Several studies found a strong correlation between medical outcome and the number of hours with an ICP above 20 mm Hg.114,115 Sustained ICP >40 mm Hg indicate severe, life-threatening ICH, often requiring immediate intervention.116 The Brain Trauma Foundation provides evidence-based guidelines for management of head-injured patients and recommends ICP monitoring in patients with a Glasgow Coma Score (GCS) <8 or a normal head CT with two or more of the following indications upon admission: age >40, unilateral or bilateral posturing, or systolic blood pressure <90 mm Hg.117 Interventions to address elevated ICP include elevating the head 30 degrees118; use of sedation, pain control, barbiturate coma, or hypothermia119–121; hyperosmolar therapy (mannitol)122; hypertonic saline123; CSF drainage124; or decompressive craniectomy.117 Although ICP monitoring has recently become controversial, with a randomized trial failing to show benefit for ICP monitoring for functional recovery or mortality,125 it nonetheless remains a standard of care among most medical centers.
Acute post-traumatic brain swelling is one of the pathological conditions that needs emergent treatment following traumatic brain injury because high ICP is the most frequent cause of death and disability after a severe TBI. Surgical interventions are indicated for certain causes of elevated ICP: removal of intracranial masses, drainage of brain abscess, and evacuation of pneumocephalus/epidural/subdural hematoma. However, surgical management of spontaneous intracerebral bleeding is controversial.126 In nonurgent cases, treatments such as positioning, sedation, hypertonic saline, and mannitol are tried first. When these measures fail to control high ICP, secondary measures include barbiturates, hyperventilation, moderate hypothermia, or decompressive craniectomy (DC). There is controversy about the effects of craniotomy on acute post-TBI. Randomized controlled trials suggest that standard trauma craniectomy is more effective than limited craniectomy in lowering elevated ICP, reducing mortality rate, and improving neurological outcomes (GCS at 6 months) over unilateral routine temporoparietal craniectomy.127,128 Some studies suggest unfavorable outcomes following early DC in adults with severe diffuse TBI and refractory hypertension,129 or delayed neurologic recovery after decompressive craniectomy.130 Other studies suggest no clear benefit in early DC,131 including a Cochrane Database Review that concluded there was “no evidence to support the routine use of secondary DC to reduce unfavorable outcome in adults with severe TBI and refractory high ICP.”132 However, results of nonrandomized trials and controlled trials with historical controls involving adults suggest that DC may be a useful option when maximal medical treatment has failed to control ICP. There are ongoing or recently completed international multicenter randomized controlled trials of DC in patients with severe TBI (Rescue ICP-Randomised Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intra-Cranial Pressure and DECRA-Decompressive Craniectomy in Patients with Severe Traumatic Brain Injury)133 that may allow further conclusions on the efficacy of this procedure in adults.
Sensorimotor reorganization within the human cortex occurs throughout life, during early childhood development,134 and even after brain damage.135–137 Reorganization of neuronal connections and the associated changes in their excitability is an example of cortical plasticity, leading to lasting morphological or functional change in cortical properties.138 While plasticity may be beneficial for normal function and for compensatory recovery after injury,139–141 it may be deleterious and is linked to a number of pathological conditions.141 There has been considerable interest in modulating plasticity in the adult human brain as a way to improve recovery of human function following brain injury.142 In TBI animal models and clinical stroke trials, neurostimulation has resulted in both behavioral enhancements and biological evidence of recovery in both motor and cognitive deficits after brain injury,143,144 which includes expansion of forelimb representation of the cortical representational maps,145 and induces greater neuronal activity as visualized by greater c-Fos immunoreactivity.146 These studies suggest cortical stimulation to be a safe and effective modulator of post-TBI behavioral and cortical function in animals and provide compelling evidence that cortical stimulation can alter brain plasticity (Fig. 23–1).
Neuromodulation is a method where an implanted medical device delivers a therapeutic alteration of activity either through stimulation or inhibition of various nerves in the central nervous system (CNS), peripheral nervous system (PNS), or autonomic nervous system (ANS), or by modulating the activity of the brain’s deep cell nuclei. Advantages of neuromodulation include the reversible nature of the treatments and the ability to be turned off. Targets for stimulation include the brain, spinal cord, and peripheral as well as the autonomic nerves. Examples of neuromodulation include cortical stimulation, repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS), spinal cord stimulation (SCS), and peripheral nerve stimulation (PNS)/vagal nerve stimulation (VNS). Although there are currently no FDA-approved therapeutic modalities for mitigating the consequences of TBI, neurostimulation using various forms of electrical stimulation to treat functional deficits using animal models and in clinical stroke trials suggests that neurostimulation may augment improvements in both motor and cognitive deficits after brain injury.
Introduced in 1989, rTMS is a noninvasive method used to stimulate small regions of the cerebral cortex by a train of magnetic pulses. In rTMS, a magnetic field generator/coil is placed near the head of the person, where the coil produces electromagnetic induction to stimulate the brain (Fig. 23–2). Repeated application of rTMS can influence brain plasticity and cortical reorganization through stimulation-induced alterations in neuronal excitability. As rTMS requires delivery of repeated pulses, which may induce the spread of synchronized neuronal activity causing seizure,147 and TBI can cause increased neural excitability and seizure risk,148 rTMS had been considered a relative contraindication for those with TBI.147 However, a recent Safety of TMS Consensus Group noted that the occurrence of seizures in those treated with rTMS was “extremely rare,” with most new cases occurring in patients undergoing treatment with drugs that potentially lower the seizure threshold. As rTMS has been shown to have a favorable outcome in patients with motor disorders,149 neurobehavioral gain during coma recovery,150 and chronic aphasia,151 it may be a promising treatment option for patients with TBI (Fig. 23–3). Due to the interest in the use of rTMS within the TBI rehabilitation community, guidelines now exist for safe and effective use of rTMS for those with moderate-to-severe TBI.152
DBS works by delivering electrical currents to the deep structures of the brain (subthalamic nucleus, globus pallidus, thalamus) to treat movement disorders such as Parkinson’s disease, tremor, and dystonia, as well as epilepsy (Fig. 23–4). A review by Villamar et al suggested that there is theoretical evidence from animal and human studies of the potential benefit of neurostimulation in decreasing the extent of injury and enhancing plastic changes to facilitate learning and recovery of function in lesioned neural tissue.153 DBS also has been reported to have a role in patients in a vegetative state (VS) or minimally conscious state (MCS), as 8 of the 21 patients emerging from the VS became able to obey verbal commands after they were treated with DBS therapy.154 Another study looked at central thalamic deep brain stimulation (CT-DBS) in patients with chronic post-traumatic MCS. CT-DBS was shown to significantly increase functional communication, motor performance, feeding, and object naming, with some domains remaining above baseline even after DBS was turned off.155 However the study acknowledges the challenges encountered, including difficulties of obtaining informed consent from patients in MCS and the experimental nature of the treatment, and concluded that “a more robust scientifically rooted ethical framework is needed to [pursue] this line of work.” Although the evidence from animal and human studies demonstrates the potential benefit of neurostimulation in decreasing the extent of injury and enhancing plastic changes to facilitate learning and recovery of function in lesioned neural tissue, it remains theoretical at this point and more studies are needed for validation.
SCS works by delivering therapeutic doses of electrical currents to the spinal cord (Fig. 23–5) to treat neuropathic pain in post-laminectomy syndrome, complex regional pain syndrome (CRPS), ischemic limb pain, and angina. In TBI, SCS has been used to treat heterotopic ossification (HO), which occurs in 11% of TBI patients.156 An ongoing study postulates that physiological conditions associated with TBI such as pain (head, neck, shoulders, upper extremities, low back pain), headache, sleep dysfunction, chronic fatigue, behavioral issues, impaired memory, attention, and information process may benefit from electrical stimulation of the spinal nervous tissue associated with a C1, C2, or C3 cervical vertebral segment.157 There is limited evidence supporting the use of SCS in brain injury at this time.
PNS is used in the treatment of headaches,158 neuropathic pain,159 and local pain. In a study by Lei et al, repetitive median nerve stimulations (RMNS) were carried out on 437 comatose patients 2 weeks after their injury.160 After a 2-week treatment, the patients demonstrated a more rapid increase in the mean GCS score, and at 6 months showed a significantly higher proportion who regained consciousness; the authors suggested RMNS may have a role in promoting the recovery of traumatic coma in the early phase. Other examples of PNS include studies/case series suggesting median nerve stimulation help hastens awakening from deep coma, either by increasing the dopamine level161 or through activation of the ascending reticular activating system to arouse the moderate to severely comatose patient.162 A recently completed clinical trial titled “A Feasibility Study to Examine the Efficacy of C2-C3 Dermatomal Peripheral Nerve Stimulation in Cognitive Improvements Following Persistent Impairment after Traumatic Brain Injury” looked at patients with mild traumatic brain injury (GCS 13 to 15), with persistent cognitive impairments lasting longer than one year. As the study was just completed, the results are not available at this time163 (ClinicalTrials.gov Identifier: NCT01588691).
There are multiple studies looking at VNS as a way to modulate brain neural plasticity to improve memory, learning, cognitive processing, motor/perceptual skills, and recovery from TBI and to treat persistent impairment of consciousness in patients (Fig. 23–5). VNS has been shown to activate several parts of the brain that are specifically involved in cognitive processing, memory, learning, and sensory and motor processing, and affects regions of the brain that are prone to developing epilepsy or that regulate the development of epilepsy.164 Studies show that VNS activates the amygdala and cingulate cortex (involved in learning and cognitive processing), the thalamic nuclei (serve as relay functions), and the sensory nuclei (auditory, visual, and somatic sensory systems). VNS also activates monoaminergic nuclei (locus ceruleus and A5 groups) to increase cerebral norepinephrine to the brain,165 which may have a positive effect on the recovery of function following TBI.166 In rat models, VNS appears to exert positive effects by protecting glutamic acid decarboxylase positive (GAD) neurons and increasing GAD neuronal count in the hippocampus.167 It also enhances the GABAA receptor density (which is often reduced after epilepsy); the normalization of the receptor density may contribute to the clinical efficacy of VNS.168 An ongoing prospective pilot clinical trial hypothesizing that stimulation of the vagus nerve results in increased cerebral blood flow and metabolism in the forebrain, thalamus, and reticular formation to promote arousal and improved consciousness to improve outcome after TBI is ongoing.169,170 A recent study by Pruitt et al showed that VNS paired with rehabilitation enhances functional recovery after TBI in rats.171
Introduced by Penn and Kroin in 1984,172 intrathecal baclofen (ITB) (Fig. 23–6) was approved by the FDA in June 1996 to treat spasticity of cerebral origin, with more than 300,000 ITB pumps implanted to date,173 including patients with brain injury and stroke. The relationship of intrathecal or intracerebral baclofen and the CNS is not completely understood, although recent findings support its involvement in the globus pallidus and subthalamic nucleus and its involvement in plasticity.174 Baclofen can stimulate retinal ganglion cell neurites’ outgrowth in animal models175 and may have an inhibitory influence by reducing neurite outgrowth of olfactory axons.176 Among patients in a persistent vegetative state (PVS) who underwent ITB implantation to treat their spasticity, there have been multiple case reports or case series (5 to 13 patients) of awakening from PVS worldwide, some as long as 19 months from their injury date.177–181 The mechanism for such remarkable recovery is unclear, although it has been postulated that in cases of diffuse axonal injury, axonal conduction may be improved with baclofen, based on animal studies showing baclofen improves conduction of demyelinated axon.182 Other hypotheses on how ITB improves arousal include modulation confined to spinal cord segmental activities and to neuronal centripetal outputs reaching the cortex, or through modulation of sleep-wake cycles that may be dysregulated and interfere with alertness and awareness.177 Despite representing a superior and effective management option in patients with severe spasticity refractive to other treatments, as demonstrated by patients’ and caregivers’ satisfaction,183,184 it is not without adverse effects, as potential complications from ITB are well documented.185–189
According to the National Institutes of Health (NIH) (2013), over 5 million people living with brain injury require continuous support and assistance in the areas of cognition, memory, loss of communication skills, loss of vocational skills, and mobility.190 Some may never fully recover and often require continued support to address these deficits. Treatment goals for individuals with TBI can be restorative or compensatory. In some cases, the compensatory goals may bring about restorative benefits, such as using an electronic device to remind them of their appointments or tasks, as frequent use of these types of compensatory devices may result in improved memory.191 Assistive technology (AT) has been used to assist TBI survivors in the domain of cognition, communication, leisure skills, and vocational skills, and allows an individual with brain injury to regain some of the independence, self-determination, and autonomy lost.192,193
One of the primary cognitive areas affected by TBI is memory and executive functioning, leading to difficulty with storing and retrieving relevant information about themselves, others, and events/tasks. AT can range from low-tech (pocket calendar, memory notebook) to hi-tech (portable electronic devices to assist memory, microswitches to allow individuals to interact with the environment,194 or speech-generating devices to assist with communication and social interactions).195 On the other hand, high-tech AT provides “active reminders” to users by alerting them to the device or to the task to be completed,196 with several randomized controlled trials supporting the use of AT/high-tech external aids as a compensatory strategy for memory impairments.196–198 These daily tasks include taking medications, preparing meals/going out to eat, and taking a walk, including navigation instructions. Other potential tools include the use of an electronic calendar such as Google Calendar196 or Microsoft Outlook,199 which were found to be more effective in improving performance on planning and organizational skills than the paper diary. Current literature supports the use of both low-tech and hi-tech AT for cognitive impairments in individuals with TBI, with the type of device depending on the individual’s skills, preferences, and needs.200–202
Individuals with TBI can experience a vast array of communication impairments that present significant barriers to full participation in life. This often presents challenges for community reintegration, family and social interactions, and academic and vocational success.203 The communication deficits range from poorly organized speech to loss of speech (temporary or permanent), or may be exacerbated by deficits from the TBI, making it difficult for individuals with TBI to successfully use new communication strategies.192 Both low-tech and hi-tech AT has been shown to be useful to augment or provide an alternative way of communication in individuals with communication deficits following TBI. AT for communication includes augmentative and alternative communication (AAC), which involves the use of external materials (pictures, electronic devices, books, boards with text) to assist the person to express their wants, needs, and opinions (Fig. 23–7). It may be used in cases where speech is no longer present, minimal, or unintelligible204 and help to compensate for loss of communication skills, as well as address impairment in receptive language skills, expressive language skills, or pragmatic language skills. An example is an AT speech-generating device (SGD), a portable device that produces a pre-recorded digitized or synthesized verbal message when activated, ranging from a simple device with a single button to more complex devices with dynamic displays requiring the user to scan the menu to pick the message they want to communicate (Fig. 23–8).205 For individuals with limited motor movements, the SGC can be paired with microswitches or an eye-controlled device (Fig. 23–9) to allow them to communicate their wants and needs.206 The important role that AT played in helping individuals with disabilities led to the passage of the Assistive Technology Act of 1998,207 which was amended in 2004. This legislation provides states with financial assistance to support programs designed to maximize the ability of individuals with disabilities and their family members/guardians to obtain AT devices/services to improve or maintain an individual’s independence and/or functioning.
Personality changes and social and behavioral disorders are common after TBI, and often affect all domains of a patient’s psychosocial network. Challenges faced by TBI survivors include problems with disinhibition, irritability, aggression, sexual inappropriateness, social awkwardness, and impaired social perception, often leading to social withdrawal. Among adults, aggressive behavior was present in about 25% of TBI survivors at 6, 24, and 60 months post-injury.208 Aggression was linked to depression, concurrent traumatic complaints, younger age, and low life satisfaction, while loss of emotional control (impulsiveness, aggression, irritability, frequent mood changes) was a critical predictor of poor community integration.209,210 Poorly controlled behavior and challenging social interactions have been linked to difficulty in family reintegration and educational, vocational, avocational, and social pursuits.211–213 These behaviors may worsen over time,210,214 and the persistence and frequency of social and behavioral problems following TBI point to the importance of finding effective treatments/interventions to address these difficulties faced by those affected by TBI.
Irritability, aggression, and other externalizing symptoms have been associated with brain systems vulnerable in closed head injury: orbitofrontal cortex, medial prefrontal cortex, anterior temporal lobe cortex, limbic structures, and their interconnections.215–217 When frontal control mechanisms are unavailable to regulate limbic impulses, minor everyday provocation can cause aggressive or otherwise socially unacceptable responses. Baguley and colleagues looked at 228 patients with moderate-to-severe TBI and found that 25% of the participants were classified as aggressive, where aggression was associated with depression, concurrent traumatic complaints, younger age at injury, and low satisfaction with life at 6, 24, and 60 months post-injury.208 The authors concluded that aggression is a common, fluctuating, and long-term problem following TBI, and an underlying association between aggression and psychosocial factors suggests psychological and behavioral interventions to be beneficial for all affected TBI survivors. Another study209 looked at 77 community-dwelling TBI survivors with a diagnosis of depression. Participants were randomized into either cognitive-behavioral therapy (CBT) or supportive psychotherapy (SPT) to treat post-TBI depression. This study found that both forms of psychotherapy were efficacious in improving diagnoses of depression and anxiety, suggesting that both CBT and SPT were effective in treating depression after TBI. Although CBT often requires a level of abstraction, making it difficult for those with TBI, at least one small randomized controlled trial210 and several uncontrolled studies211,212 noted that anger management principles can be adapted and taught to those with cognitive impairment due to brain injury. To determine the effectiveness of behavioral interventions in individuals with behavior disorders after TBI, Ylvisaker et al213 reviewed 65 studies with 172 experimental participants who had undergone interventions consisting of (1) traditional contingency management, (2) positive behavior interventions and supports, and (3) intervention combining both. In this review, 35% of participants were identified as having problems with physical aggression; 32% had problems with verbal aggression; and 19% had problems with general impulsiveness, disinhibition, or disruptiveness. The authors conclude that behavior interventions can be considered a treatment guideline for children and adults with behavior disorders for both the acute and subacute stage of recovery after TBI.
Therapeutic interventions include insight-oriented psychotherapy, cognitive-behavioral therapy, and behavior therapy. Insight-oriented therapy represents a process to gain more awareness and insight into one’s thoughts, feelings, and behaviors where greater awareness allows the individual to change behavioral patterns.214 As this form of therapy requires an individual to attend to task, to maintain the thought process, to recall what occurred during therapy, to use reason, and to develop insight, it is limited to individuals who have suffered mild or moderate debilitating effects.215 The goal of psychotherapy for TBI survivors should be to increase understanding of what happened and its effects, to help the individuals develop strategies to accept the injury, have realistic expectations, and adjust to role and relationship changes that often follow the injuries.216 Cognitive behavioral therapy concerns with how people’s behavior is shaped by their interpretation and perception of their experience217 and aims at assisting the individual in understanding the relationship between beliefs (realistic and/or adaptive), thoughts, feelings, and behavior, which allows the individual to alter their behavior based on their analysis of the maladaptive behavior. It requires the person to take an active role in the application of techniques, including the ability to self-monitor, making this form of intervention dependent on an individual’s level of cognitive functioning usually found in those with mild or moderate debilitating effects. Behavior therapy is for those unable to participate in insight or cognitive behavioral therapy. The goal of behavior therapy is to change the person’s environmental antecedents and consequences to decrease the likelihood of maladaptive behaviors while increasing more positive adaptive behaviors.218 It can be an effective intervention for modifying behavior after TBI, as well as to help individuals to relearn other lost skills such as self-care and budgeting.
Psychotherapy describes the interactive/relational process between the therapist and the client with the intent of providing palliative or curative effects on any mental, emotional, or behavioral disorder. It accomplishes this by reducing the level of stress by changing an individual’s thoughts, feelings, or behaviors. A long-standing presumption is that brain injury survivors are unable to benefit from psychotherapy due to impairments of cognitive, emotional, and linguistic functions that often accompany their injury.219 The focus of psychotherapy with brain injury survivors is to help them improve their levels of awareness, acceptance, and realism.220 This can be difficult due to the survivors’ inability to accept their limitations, their impaired cognitive flexibility, and their limited capacity for empathy, leading to an adversarial alliance characterized by a sense of hostility and aggression between the therapist and the brain injury survivor and their family.221 A clinical review looked at the usefulness of psychotherapy for the treatment of psychiatric symptoms in the TBI population and found that psychotherapy for treatment of psychiatric symptoms in this population, though challenging and frustrating at times, can be very rewarding for both the survivor and therapist alike.222 As each brain damage is unique and survivors have varying ranges of abilities, deficits, and needs, psychotherapy must be tailored to the brain-injured survivor’s circumstances.223 The authors concluded that due to a lack of research looking at the challenges to form a working alliance with brain injury survivors, future research needs to adopt a more phenomenological approach, including a more focused exploration of the therapeutic process.
Family life often changes dramatically after brain injury, with the changes persisting for months to years. Because there is such a great focus on the patient, family members often lose sight of their own well-being and how their lives have changed. Family members who serve as caregivers commonly face many difficulties after injury: feeling overwhelmed and frustrated, upset by their loved one’s suffering, loss of abilities, and need for complex medical care. Besides financial concerns, caregivers worry about their ability to provide quality care, whether family life will ever return to “normal,” and feeling worn out by their increasing number of responsibilities. Lezak’s seminal paper titled “Brain Damage Is a Family Affair” acknowledges the stresses the whole family faces following their family member’s TBI,224 where family members experience emotional distress as early as 3 months after the TBI, and it may persist for up to 7 years.225 Cognitive problems may include impaired memory, deficits in attention, difficulty with learning, and problems with communication/expressing their wants. Psychosocial changes following TBI include decreased life satisfaction, decreased perceived social support, and decreased perceived self-efficiency. The emotional impact of TBI may lead to depression, anxiety, or substance abuse. Economic impact from TBI includes underemployment to unemployment among TBI survivors, as well as to their caregivers due to the increase in caregiver burden. Survivors find it difficult to talk to other people, to understand what others are saying, and find it difficult to express their thoughts and feelings. They may also feel self-conscious; become more irritable; and experience fatigue, low energy, pain, other physical problems, and mobility-related issues, all contributing to social isolation and decreased societal integration. Ineffective problem solving by caregivers contributed to depression, with an incidence as high as 60% among caregivers.226 Those whose approach to problem solving was negative, avoidant, or careless/impulsive were more likely to be depressed, regardless of the time they spent in their role as a caregiver.227 Satisfaction with the caregiving relationship was better among caregivers who relied on task-oriented coping and minimized emotion-focused coping, as an emotion-focused coping style was related to an increase in perceived burden.227 The amount of behavioral control within the family unit and the amount of social support perceived were important predictors of caregivers’ perceived burden, and those caregivers who reported high social support also reported more positive experience of their caregiver roles, greater satisfaction, and a better mastery experience in caregiving.227,228 This implies the importance of providing families of survivors with skills to deal with the behavioral problems, encouraging active problem-solving strategies for coping, providing emotional and social support, and educating the caregivers and their families to facilitate realistic expectations about their caregiving.
The goal of cognitive rehabilitation therapy (CRT) is to help individuals with brain injury enhance their ability to move through daily life by recovering or compensating for damaged cognitive functions.229 Besides variations in treatment as well as an individual’s response, treatment strategies may evolve, and different treatments may be required at different points in time. There are no standards in CRT, as it is practiced by a wide range of professionals in rehabilitation medicine. Some of the cognitive rehabilitation interventions include cognitive or academic exercises, computer-assisted training, compensatory technique training, use of external aids, communication skill training, psychotherapy, behavior modification, comprehensive interdisciplinary models, vocational rehabilitation, pharmacotherapy, physical exercise, therapy, aerobic training, art and music therapy, nutrition, spirituality, and alternative or nontraditional therapy.230 One randomized controlled trial (RCT) found that cognitive behavioral therapy reduces anxiety post-TBI and that these treatment gains were maintained at one-month follow-up.231 Cicerone et al in 2011 used PubMed and Infotrieve to review the literature using the terms attention, awareness, cognition, communication, executive, language, memory, perception, problem solving, and/or reasoning combined with each of the terms rehabilitation, remediation, and training for articles published between 2003 and 2008. Of the 112 articles scored for their level of evidence, 14 were rated as class I evidence (well-designed, prospective RCT); 5 as class Ia (prospective design with quasi-randomized assignment to treat conditions); 11 as class II (prospective, nonrandomized cohort studies; retrospective, nonrandomized case-controlled studies, or multiple baseline studies that permitted a direct comparison of treatment conditions); 82 as class III (studies designed as comparative effectiveness studies but did not include a direct statistical comparison of treatment condition). The studies were reviewed for remediation of attention, remediation of vision and visuospatial functioning, remediation of language and communication skills, remediation of memory, remediation of executive functioning, and comprehensive-integrated neuropsychological rehabilitation. The paper concluded “there is now sufficient information to support evidence-based clinical protocols, and to design and implement a comprehensive program of empirically-supported treatments for the treatment of cognitive disability after TBI and stroke.”232
Because no national brain injury rehabilitation licensure and credentialing exist and there are variations in standards among rehabilitation professionals, the Institute of Medicine in 2013 formulated guidelines on how to apply CRT in practice. It concluded that CRT interventions “are promising approaches, but further development and assessment of this therapy is required” and that it “supports the ongoing use of CRT for people suffering from a TBI.”229 Likewise, an international panel of experts in cognitive rehabilitation after TBI (INCOG) in 2014 came up with guidelines to provide evidence-based recommendations for the cognitive rehabilitations for those with moderate-to-severe TBI.233 INCOG concluded that cognitive rehabilitation should be tailored to the individual’s cognitive profile and premorbid activities and goals, ranging from restorative treatments to compensatory strategies to caregiver training, and should focus on meaningful activities. It includes interventions in the person’s own environment, and more importantly, it needs to have a role for reassessment of cognition on a regular basis to determine the effectiveness of interventions.
There are studies that do not show superiority of inpatient cognitive rehabilitation over in-home program. Salazar looked at 120 active-duty military personnel who had sustained a moderate-to-severe closed head injury (GCS 13 or less) and were randomly assigned to an intensive, standardized, 8-week, in-hospital cognitive rehabilitation program or a limited home rehabilitation program with weekly telephone support from a psychiatric nurse.234 In this study, the overall benefit of in-hospital cognitive rehabilitation for patients with moderate-to-severe TBI at one-year follow-up was similar to that of home rehabilitation. A Cochrane Database Review in 2013 looked at the effectiveness of cognitive rehabilitation for executive dysfunction in adults with stroke or other nonprogressive acquired brain damage. The search yielded 19 relevant studies involving 907 participants, and elimination of nonqualified studies left 660 participants, 395 (59.8%) of whom sustained a TBI. The review found no evidence that cognitive rehabilitation interventions were helpful for people with executive dysfunction for any other outcomes and that more research is needed to determine if cognitive rehabilitation can improve outcome after stroke or brain injury.235
Biofeedback uses sensitive instruments to measure physical responses in the body, allowing the individuals to alter their body’s responses by observing the feedback on a computer screen or listening to sound feedback. Neurofeedback allows a patient to control measurements of brain activity such as those recorded by an electroencephalogram. Biofeedback and EEG neurofeedback have been documented as successful treatment modalities for mild traumatic brain injury (mTBI) obsessive-compulsive disorder236 and reducing heart rate variability in chronic severe TBI.237 Neurofeedback training is brainwave biofeedback and allows for an individual to influence the activity to modulate the efficiency of the feedback. Different brain-wave frequencies are associated with various states and pathologies, and by allowing individuals to move in and out of certain brain-wave states, it may lead to improved performance, either by suppressing certain waves or enhancing certain wave forms. Neurofeedback has been shown to result in microstructural changes in white and gray matter in healthy individuals238 and increasing cortical gray matter and thalamocortical connection in patients with moderate TBI.239 May et al, did a Google Scholar search using the words neurofeedback and TBI yielding 999 search results, 22 of which were examples of primary research. All published data reported positive effects of neurofeedback in the improvement of both subjective reports and objective measures of neuropsychiatric symptoms of mild-to-moderate TBI. The authors concluded that neurofeedback remains a promising yet unproven treatment for traumatic brain injury but that randomized, double-blind, placebo-controlled studies are needed before this therapy can be unequivocally recommended.240
Individuals with a TBI may be left with significant cognitive-sensory-motor deficits preventing them from returning to their pre-injury levels of activity and participation.241,242 More worrisome, there is growing evidence that a subset of TBI survivors show cognitive deterioration across domains of cognitive functioning,243–245 with some studies showing evidence of decrease in cerebral blood flow,246 declines in whole brain volume,247–249 atrophy of gray and white matter structures,247,250 or reduced white matter integrity as measured by diffusion tensor imaging.250,251 The progressive cognitive and functional decline in some individuals with TBI months or years following their injury241,243,244 suggests that TBI is not a stable condition.243,248 Correlations between brain and behavior decline have also been observed, with increased brain atrophy at 8 weeks and 12 months post-injury negatively correlated with outcomes on the Glasgow Coma Scale.252
With evidence suggesting post-acute neural and cognitive decline among TBI survivors, questions were raised if environmental enrichment (EE) has a role in improving long-term outcomes for the survivors. EE refers to enhanced stimulation associated with environments that provide access to cognitive, physical, and social stimulation in conditions that encourage maximum participation resulting in improvement in cognitive and neuronal status.129,253 Lack of an EE has been shown to play a role in post-injury cognitive decline243 and greater hippocampal volume loss in chronic TBI.254 Exposure to EE has been associated with increases in cognitive functioning; improvement in learning ability, spatial/problem-solving skills, memory, and processing255–257; reduction in boredom258; less frustration259; and a decrease in repetitive preservation.260 The benefits of EE are also observed at the cellular and molecular levels, such as an increase in neurogenesis, synaptogenesis, and dendritic spine density in parts of the brain associated with learning and memory, and an increase in brain weight and cortical thickness. Other changes include an increase in the amount of nerve growth factor, brain-derived neurotropic factor, myelination of nerve fibers, acetylcholinesterase activity, neurotransmitter, glial proliferation, blood vessel number and size, and protein synthesis, with changes associated with improvement in functional performance.255,257,261–268 Taken together, these studies suggest that EE may protect against chronic-state atrophy in moderate-to-severe TBI.264,269,270 A review by Frasca et al concluded that a lack of EE may play a role in post-acute cognitive and neural decline and that maximizing EE in the post-acute state of TBI may improve long-term outcomes for TBI survivors, their family, and society.271 The most direct evidence of the benefits of EE in the post-acute stages of recovery from TBI can be shown where participation in activities involving cognitive, physical, and social demands correlates with less hippocampal volume loss.254 Engaging the TBI survivors in meaningful activities, tailored to the individual’s specific impairments to facilitate participation, has the potential to offset post-acute deterioration following TBI.
After TBI, changes in brain structure and function, including neurochemical and neuroendocrine changes, can lead to disruption of physical intimacy, affecting the processing of sexual stimuli, changes in sexual behavior, limited expression and communication of affect, and interference with intercourse.272 As sexuality is an integral part of one’s personality and an aspect of human beings that cannot be separated from other aspects of life, it needs to be addressed as part of the rehabilitation process with both the survivor and the significant other to prevent development of sexual dysfunction.273 Sexuality in the context of TBI is important because studies regarding marital stability showed a divorce or separation rate ranging from 15% to 78%.274,275 Another study looked at 120 married individuals who sustained a mild, moderate, or severe traumatic brain injury, which showed a separation rate of only 8% and a divorce rate of 17%.276 Those who were married longer before the injury, victims of nonviolent injuries, older persons, and those who had less severe injuries were more likely to remain married. Factors perceived as helping relationships remain strong included unconditional commitment, spending time together, open communication, a strong pre-injury relationship, bonding through surviving the injury together, social support, family bonds, spirituality, experience with overcoming hardship, and coping skills.277 Factors perceived as barriers to intimacy included injury-related changes, emotional reactions to changes, sexual difficulties, role conflict and strain, family issues, social isolation, and communication issues.277 A critical review of sexuality after TBI concluded that sexual difficulties are common in TBI survivors, and sexual changes after TBI can be attributable to physical and psychological variables.273 It reflects the diffuse pathophysiological processes in TBI, as well as the individual’s ability to cope with the resulting changes. For optimal outcome, it is necessary to address the component of sexuality and to start intervention as early as possible in the rehabilitation process to prevent sexual dysfunctions down the road. Difficulties in sexual intimacy are common in TBI survivors, and as such, education on intimacy should be integrated into rehabilitation.
Reintegration following TBI is a complex and lifelong process that includes vocational, avocational, educational, resource allocation, family system/caregiver burden, return to driving, and life satisfaction issues. Significant numbers of persons with TBI experienced low levels of community integration (CI),278 especially among older adults, as they have poorer outcomes compared to their younger counterparts due to injury severity or comorbidities common in older age, which affect their ability to travel in the community. Evidence suggests that CI should be the primary goal of people after TBI,279 as those who have difficulty with community integration tend to require assistance in community activities, while those with community participation are associated with a better quality of life.280 Factors found to be predictive of community integration include severity of injury, age at the time of injury, violent mechanism of injury, premorbid psychiatric history, prior alcohol and drug use, level of disability, and challenging behavior.281 Significant improvements in functional independence during rehabilitation predicted better community integration, while poor community integration was associated with more severe injury (longer acute care and PTA) and more functional disability at discharge.278 Randomized controlled trials suggest community reintegration following TBI can be improved through the role of mentoring or working with a resource facilitator,282 social peer mentoring programs to improve perceived social support,283 or hospital-based or community-based rehabilitation,284 and these effects were maintained 1 to 3 years later.285,286 Additionally, lesion location may play a role in successful reintegration, as frontal and frontotemporal groups tend to have more difficulty in executive functioning than those with frontal lobe dysfunction.287,288 Those with frontal lobe pathology have been shown to incur more perseverative errors,289 have more difficulty completing tasks requiring multiple activities,290 and are less efficient in strategy application.291
There is conflicting research regarding the success of individuals’ ability to return to work (RTW) following their brain injury. According to Vuadens et al, only 30% of moderately brain-injured individuals and 80% of those with mild brain injury are able to return to work, with 10% of brain-injured clients getting fired, and only 2% employed one year post-trauma.292 This is similar to the 22% of individuals with TBI able to RTW at one year after their injury, as published by the National Institute on Disability and Rehabilitation Research (NIDRR) Traumatic Brain Injury Model System (TBIMS).293 There are several case series supporting vocational rehabilitation following TBI, with vocational rehab resulting in greater total taxpayer benefits and the majority of TBI survivors having fair or good adjusted outcome even at 11 years post-discharge; 83.5% of patients were productive, and 67.1% were engaged in work or school and no decline in productivity was seen294 Not all individuals are able to resume any type of vocational activities after their TBI. Many are left with a reduced level of functioning, making vocational reintegration challenging, resulting in only a small number able to return to comparable premorbid vocational activities.295,296 For those with a severe TBI, this presents even a greater dilemma due to accompanying severe motor and cognitive disabilities as well as a high level of dependence, which prevents them from any kind of productive and competitive employment.297 Nonetheless even individuals with the most significant cognitive deficits benefit the most from vocational rehabilitation services,298 and individuals with severe head injury do benefit from supported employment services,299 with some able to resume high re-employment rates with proper support and treatment. It is difficult to predict which patients with a TBI will make a successful transition back to work, as this may be due to a complex interaction between premorbid characteristics, injury factors, post-injury impairments, and personal and environmental factors, with RTW rates ranging from 12% to 70%.295 A study by Walker et al used the TBI Model System to look at consecutive sample of 1,341 patients hospitalized with a TBI diagnosis who received both acute neurotrauma services and inpatient rehabilitation services. This study found that the type of occupation influences RTW outcome: people who had professional or managerial jobs have the best prospect for successful RTW, with the rate highest in professional/managerial jobs (56%), and lowest for manual labor (32%).296 Better vocational/school outcomes were associated with younger age, male gender, and more favorable working alliance ratings among the staff, patients, and their families.300 Return to work also has multiple beneficial effects, such as reducing depression and anxiety,301,302 and the use of cognitive strategies increases an individual’s chance to return successfully to full-time vocational activities after TBI. A recent systematic review of the literature from 1980 to 2005 focusing on acquired brain injury (ABI) rehabilitation looked at major aspects of community reintegration, including independence and social integration, caregiver burden, satisfaction with quality of life, productivity, and return to driving. In this review, the majority of interventions are supported by only limited evidence, with only 1 RCT found among the 38 studies reviewed, and it concluded that “further research, using an interventional approach, is required to advance the evidence base of reintegration into the community following brain injury.”303
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