376 FIGURE 20–3 TEXTBOOK OF TRAUMATIC BRAIN INJURY Epworth Sleepiness Scale Source From Johns MW: “A New Method for Measuring Daytime Sleepiness: The Epworth Sleepiness Scale.” Sleep 14:540–545, 1991 Revised 1997 Used with permission of M.W Johns Copyright M.W Johns 1991–1997 complaints and diagnosed posttraumatic narcolepsy using formal sleep studies such as the polysomnogram (PSG) and MSLT We recommend that clinical diagnosis of narcolepsy should always be accompanied by formal sleep studies and HLA typing However, even if a patient is confirmed to have the appropriate HLA haplotype, the question always exists whether TBI was the causative factor or a precipitating event Post-TBI hypersomnia is an understudied area The prevalence, varieties, associated psychiatric disturbances, and effect on rehabilitation and physical, cognitive, and social level of functioning are yet to be identified Such identification is important because effective management of treatable disorders can have far-reaching results for the rehabilitative process Sleep-wake cycle disturbances Sleep-wake cycle distur- bance, or circadian rhythm sleep disorder, is defined as inability to go to sleep or stay awake at a desired clock time Both the duration and pattern of sleep are normal when patients with this disorder do fall asleep (Kryger et al 2000) There are several varieties of sleep-wake cycle disturbances, including the delayed, advanced, and disorganized types The pathogenesis remains unclear, although dysfunction of the suprachiasmatic nucleus has 377 Fatigue and Sleep Problems been postulated (Okawa et al 1987) Other factors often associated with this disorder in the general population include shift work and travel through different time zones (Patten and Lauderdale 1992) There is little literature available on the prevalence of this disorder in the TBI population Schreiber et al (1998) described circadian rhythm and sleep-wake cycle abnormalities in all 15 individuals evaluated after mild TBI using actigraphy (described in the section Evaluation of Fatigue and Sleep Disturbances in TBI) and PSG recordings None had past history of neurological illness, psychiatric history, or sleep apnea syndrome More than one-half of the patients were diagnosed with delayedphase type and the rest disorganized-type sleep-wake cycle disturbance Quinto et al (2000) described the case of a 48-yearold man who presented with sleep-onset insomnia after a severe closed head injury His complaints included difficulty in initiating sleep, being able to finally fall asleep around 3:00–5:00 A.M., and waking up around noon His attempts to wake up earlier resulted in poor functioning Before the injury, he was reportedly high functioning and denied problems with sleep A diagnosis of delayed sleep phase syndrome was confirmed by sleep logs and actigraphy Patten and Lauderdale (1992) also reported delayed sleep phase disorder in a 13-year-old boy after mild closed head injury Complaints of sleep disturbance in TBI patients are common, and therefore awareness and diagnosis of this disorder are important; some patients may respond to simple therapies such as adjusting the time of sleep (described in the section Chronotherapy) or exposure to bright light (described in the section Phototherapy) Parasomnias Parasomnias are undesirable motor or behavioral events that occur during sleep that can result in physical injuries to the patient and mental agony to the caregivers (Mahowald and Mahowald 1996) Sleepwalking, sleep terrors, REM sleep behavior disorders, and nocturnal seizures are some of the varieties of parasomnias Other than occasional case studies (Drake 1986), there is no literature available on the prevalence and clinical presentation of this condition after TBI Evaluation of Fatigue and Sleep Disturbances in TBI Evaluation of a brain-injured individual with fatigue or sleep disturbances should be complete and comprehensive (Table 20–3) It is important to differentiate between fatigue and sleep disturbance if possible and determine if these symptoms are occurring in isolation or are secondary to other TABLE 20–3 Evaluation of fatigue and sleep disturbances in traumatic brain injury Detailed history from patient and collateral informants Key questions: Level of physical and mental functioning pre- and postinjury Sleep pattern and duration pre- and postinjury Type and severity of brain injury Various treatments received since injury Alcohol and substance abuse history Medical history, including chronic pain, dizziness Current medications and dosages Past psychiatric history Duration and description of current problems Neuropsychiatric evaluation Includes physical, neurological, and mental status examination Neuropsychological tests in subjects with cognitive deficits Laboratory tests Blood count, comprehensive metabolic panel, vitamin B12 and folate levels, thyroid function test, and erythrocyte sedimentation rate Brain scans Computed tomography and/or magnetic resonance imaging Specific sleep studies Polysomnography Multiple sleep latency test neuropsychiatric disturbances such as mood disorder, anxiety disorder, substance abuse, chronic pain, or dizziness Patients with cognitive deficits, especially pertaining to attention and concentration, often complain of fatigue Medical illnesses such as idiopathic sleep disorders, chronic viral illness, malignancies, and medication side effects should always be ruled out The key elements include obtaining a detailed history from the patient and collateral information from family members with the patient’s consent, reviewing old medical records, and performing medical, neurological, and psychiatric examinations If the sleep disturbance is not considered to be secondary to another clinical syndrome, sleep studies should be performed These studies not only help in identifying the type of sleep disturbance but also may be helpful in differentiating fatigue (normal sleep studies) from sleep disturbances The most commonly used objective tests include the PSG and the MSLT (described in the section Multiple Sleep Latency Test) Actigraphy is a recently developed 378 measure to obtain objective data regarding activity during sleep and wakeful state and helps supplement the subjective sleep log An actigraph is a small device worn around the wrist or ankle that quantifies and records movements and thus detects activity during wakefulness and sleep Detailed information on these tests can be found in comprehensive texts on sleep disorders (Kryger et al 2000) TEXTBOOK OF TRAUMATIC BRAIN INJURY TABLE 20–4 Management of fatigue Pharmacological measures Psychostimulants Dopamine agonists Amantadine Modafanil Polysomnography The PSG is the standard tool for measurement of sleep disturbances and includes assessment of breathing, respiratory muscle effort, muscle tone, REM sleep, and the four stages of NREM sleep (Castriotta and Lai 2001) Standard electrophysiologic recording systems are used in polysomnography Polysomnography includes at least one channel of electroencephalography, electrocardiography, submental and anterior tibialis electromyography, and continuous monitoring of eye movements If clinically indicated, multiple respiratory parameters are monitored to evaluate breathing problems during sleep, extensive electroencephalography is monitored for parasomnias, esophageal pH is monitored for gastroesophageal reflux, and penile tumescence is monitored for erectile functions An all-night PSG will help to accurately quantify sleep and its different stages In addition, other abnormalities such as disruption of sleep architecture, motor activity, or any other abnormality associated with sleep and cardiopulmonary irregularities can also be determined (Mahowald and Mahowald 1996) Polysomnography aids in the diagnosis of sleep disorders such as obstructive sleep apnea, central sleep apnea, upper airway resistance syndrome, nocturnal seizures, and periodic limb movements Multiple Sleep Latency Test The MSLT is a well-validated measure of physiological sleep and provides objective measurement of daytime sleepiness It is a useful tool to quantify daytime sleepiness and differentiate pathological sleep abnormalities from subjective complaints of sleepiness and fatigue (Mahowald and Mahowald 1996) It consists of four or five 20-minute naps at two hourly intervals and quantifies sleepiness by measuring how quickly one falls asleep during the day and also identifies abnormal occurrence of REM during the nap A mean sleep latency of 5 minutes or less indicates abnormality The diagnosis of narcolepsy is based on an MSLT score of less than 5 minutes, with REM sleep during at least two of the naps Posttraumatic hypersomnia is diagnosed on the basis of a history of trauma, exclusion of other sleep disorders, excessive daytime sleepiness, MSLT of less than 10 minutes without sleep-onset REM periods, and a relatively normal PSG (Castriotta and Lai 2001) Nonpharmacological measures Balanced diet and lifestyle Sleep hygiene Regular exercise Psychotherapy Always treat underlying medical and psychiatric disorders Treatment Treatment of fatigue and sleep disturbances includes pharmacological and nonpharmacological measures Knowledge regarding pharmacotherapy in brain-injured patients is derived mainly from our experience in taking care of patients with primary psychiatric disorders and from case reports or small case series Pharmacological interventions should target the observable symptom and any other coexisting psychiatric disorder, if present If fatigue or sleep disturbance, or both, is secondary to any other psychiatric or medical disorder, the underlying disease should be treated Because individuals with TBI may be sensitive to medications, it is important to start at the lowest dose and gradually increase, if necessary Although there is overlap both pharmacologically and nonpharmacologically between fatigue and sleep disorders, we describe each of them separately (Tables 20–4 through 20–6) TABLE 20–5 Sleep hygiene Keep a regular sleep schedule of going to bed and awakening around the same time every day, including holidays and weekends Avoid lengthy naps during the day If unable to fall asleep within 10 minutes of lying in bed, get up and stay awake Avoid coffee, sodas, alcohol, and strenuous exercise late in the day, as they may be too stimulating and delay sleep Avoid bright lights and loud noise in the bedroom, especially before bedtime Maintain a sleep log, noting duration and quality of sleep Fatigue and Sleep Problems TABLE 20–6 Management of sleep disturbances Pharmacological measures Benzodiazepine sedative-hypnotics Nonbenzodiazepine sedative-hypnotics Modafinil Melatonin Nonpharmacological measures 379 trial of psychostimulants such as methylphenidate and pemoline for the treatment of fatigue associated with human immunodeficiency virus infection, both of the psychostimulants were found to be equally effective and superior to placebo in decreasing fatigue severity and improving quality of life (Breitbart et al 2001) Studies of MS patients have not favored pemoline over placebo for the treatment of fatigue (Branas et al 2000) Treatment of Fatigue Dopaminergic agonists Carbidopa/levodopa (10/100 mg to 25/100 mg qid) and bromocriptine (2.5–10.0 mg/ day) are both dopamine agonists that have been studied in small uncontrolled case studies for the treatment of mood, cognition, and behavior problems in TBI patients (Dobkin and Hanlon 1993; Lal et al 1988) Bruno et al (1996), in a study of five postpolio patients with history of moderate to severe fatigue, noted significant improvement in fatigue and cognitive tests of attention and information processing in three patients when treated with bromocriptine up to a maximum of 12.5 mg/day Pharmacological Measures Amantadine Amantadine was first used in the treat- There are only a few studies available on the treatment of fatigue specifically after TBI Psychostimulants, amantadine, and dopamine agonists have been used to treat impaired arousal, fatigue, inattention, and hypersomnia after brain injury (Gualtieri and Evans 1988; Neppe 1988) However, there are no studies available specifically for the treatment of fatigue in the TBI population ment of influenza in the 1960s and was later found to have antiparkinsonian effects It enhances release of dopamine, inhibits reuptake, and increases dopamine activity at the postsynaptic receptors (Nickels et al 1994) Case reports have found amantadine to be useful in the treatment of mutism, apathy, inattention, and impulsivity The usual doses are 100–400 mg/day Confusion, hallucinations, pedal edema, and hypotension are common side effects Krupp et al (1995) conducted a double-blind, randomized parallel trial of amantadine, pemoline, and placebo in 93 patients with MS who complained of fatigue Amantadinetreated patients improved significantly (both by verbal report and on the MS-specific Fatigue Severity Scale) compared with pemoline and placebo The benefit was not due to changes in sleep, depression, or physical disability Studies on the efficacy of amantadine for the treatment of fatigue in TBI patients are warranted Balanced diet and lifestyle Sleep hygiene Phototherapy Chronotherapy Psychotherapy Always treat underlying medical and psychiatric disorders Psychostimulants Psychostimulants exert their effect by augmenting the release of catecholamines into the synapses Methylphenidate (10–60 mg/day) and dextroamphetamine (5–40 mg/day) are the commonly used stimulants Pemoline (18.75–75.0 mg/day), which is another stimulant, is less commonly used because of its potential for hepatotoxicity as well as its long half-life that prevents rapid clearance from the body in the event of an adverse reaction (Gualtieri and Evans 1988) Psychostimulants are usually taken twice a day, with the second dose taken approximately 6–8 hours before sleep to prevent initial insomnia Treatment is usually begun at the lowest dose and gradually increased if necessary Possible side effects include paranoia, dysphoria, agitation, dyskinesia, anorexia, and irritability There is a potential for abuse, and, hence, patients taking these drugs should be closely monitored The efficacy of psychostimulants in the treatment of cancer, human immunodeficiency virus infection, and MS has been studied In a prospective, open-label pilot study, methylphenidate was used successfully to treat cancer fatigue in seven of the nine patients (Sarhill et al 2001) In another randomized, double-blind, placebo-controlled Modafinil Modafinil is a new agent with unclear mechanism of action but appears to activate the brain in a pattern different from that of the classic psychostimulants (Elovic 2000) Lin et al (1996), in studies of cats given equivalent doses of modafinil, amphetamines, and methylphenidate, noted that although the latter two drugs brought about widespread increase in activation of the cerebral cortex and dopamine-rich areas such as the striatum and mediofrontal cortex, modafinil was associated with activity in the anterior hypothalamus, hippocampus, and amygdala Modafinil’s effect was supposed to be more selective on the pathways that regulate sleep With 380 regards to the neurotransmitter activity, modafinil has been shown to inhibit γ-aminobutyric acid levels and increase glutamate levels (Ferraro et al 1999) It has been found to have little activity on the catecholamine system, cortisol, melatonin, and growth hormone (Brun et al 1998; Elovic 2000) The addictive potential of modafinil is much less than the classic stimulants Currently, there are no specific data on the use of modafinil for the treatment of fatigue in TBI patients Teitelman (2001) conducted an open-label study in 10 individuals with closed head injury who complained of excessive daytime sleepiness and in two individuals with somnolence secondary to sedating psychiatric drugs Modafinil was well tolerated at a dose of 100–400 mg given once a day All patients reported improvement in daytime sleepiness No adverse effects were encountered Modafinil has been studied for the treatment of fatigue in MS Rammohan (2002) conducted a single-blind Phase II study in MS patients and found that modafinil effectively treated fatigue Similar results were found by Zifko et al (2002) in an open-label study of modafinil and fatigue in MS patients Side effects were minimal in both studies Nonpharmacological Measures Education Patient and family members should be edu- cated about the frequent occurrence of fatigue in TBI as an isolated problem or secondary to other psychiatric disturbances, or both Often, it enhances the patient’s selfesteem to be told that the “feeling of tiredness” is not a sign of laziness but a symptom of the brain injury Diet and lifestyle Good nutrition and a balance between regular exercise and adequate rest are important measures to combat fatigue Patients should be encouraged to have three well-balanced meals a day Regular exercise is important because it prevents deconditioning and promotes normalization of physical efficiency and performance, both physically and mentally The exercise protocol should be individualized because too much or too little exercise can be detrimental In addition, adequate rest is also important, and patients should be encouraged to practice good sleep hygiene measures (see Table 20–5) Lezak (1978) has suggested that individuals who have difficulty with fatigue should be encouraged to perform most important activities in the morning or at a time when they feel best TEXTBOOK OF TRAUMATIC BRAIN INJURY ioral therapy was found to be significantly more effective than control conditions both for fatigue improvement and functional performance Studies of this approach are lacking for the treatment of fatigue after brain injury Treatment of Sleep Disturbances The general guidelines for the management of sleep disturbances are similar to those for fatigue Establishing a diagnosis is crucial Recognition and treatment of other coexisting psychiatric and medical disorders are important because they could be contributing to or exacerbating the sleep disturbance Management includes pharmacological interventions and an array of nonpharmacological measures such as sleep hygiene techniques, phototherapy, chronotherapy, and psychotherapy Pharmacological Measures Even though sleep disturbances are commonly seen in TBI patients, there are only a few drug trial studies available in the TBI literature Medications are mentioned here based on our knowledge of treatment of primary psychiatric disorders and sleep disturbances in the general population Benzodiazepine sedative-hypnotics The mechanism of action of benzodiazepines in the treatment of insomnia is unclear, although there is subjective and objective evidence of improvement in sleep (Chokroverty 2000) However, animal studies reveal impairment of neuronal recovery with the administration of benzodiazepines after laboratory-induced brain injury (Schallert et al 1986; Simantov 1990) Similarly, studies in humans have shown poorer sensorimotor functioning in stroke patients who received benzodiazepines compared with those who did not (Goldstein and Davies 1990) Therefore, benzodiazepines should be used with caution in individuals with brain injury because they theoretically may impair neuronal recovery Benzodiazepines commonly used as hypnotics include lorazepam (0.5–2.0 mg at bedtime), temazepam (7.5–30.0 mg at bedtime), and clonazepam (0.25–2.0 mg at bedtime) The main indication is for the treatment of transient insomnia or insomnia of short duration Benzodiazepines should not be used for more than a few days to a couple of weeks because of the risk of dependence Nonbenzodiazepine sedative-hypnotics Zolpidem (5– Psychotherapy and behavioral therapy Cognitive-behav- ioral therapy has been found to be useful in patients with chronic fatigue syndrome (Prins et al 2001) In a large multicenter randomized, controlled trial, cognitive-behav- 10 mg at bedtime) and zaleplon (5–10 mg at bedtime) are two nonbenzodiazepines also used in the treatment of transient insomnia They are structurally different from the benzodiazepines but act on the benzodiazepine recep- 381 Fatigue and Sleep Problems tor complex with more selectivity to the type 1 receptors that are involved in the mediation of sleep (Damgen and Luddens 1999; Wagner et al 1998) Because of nonbenzodiazepines’ selectivity, they are less likely to produce cognitive side effects They also have short half-lives and are less likely to cause daytime drowsiness Common side effects include anxiety, nausea, and dysphoric reactions, although rebound insomnia and anterograde amnesia have also been reported In a randomized, placebo-controlled, double-blind study comparing a 10-mg dose of zolpidem with a 10-mg dose of zaleplon given 5, 4, 3, and 2 hours before awakening in the morning to 36 healthy subjects, zaleplon was found to be free of hypnotic or sedative effects when administered as late as 2 hours before awakening (Danjou et al 1999) Zaleplon was found to be indistinguishable from placebo in terms of subjective and objective assessment of memory and even adverse reactions Zolpidem, in contrast, produced results different from that of placebo Memory problems (immediate and delayed recall) were detected up to 5 hours after nocturnal administration The differences between the two drugs are more likely to be due to their pharmacokinetic profiles than to their pharmacology (Danjou et al 1999) Vermeeren et al (2002), in their study of 30 healthy volunteers, demonstrated that zaleplon, 10–20 mg, could be taken at bedtime or even later (up to 5 hours before driving) with no serious risk of impairment No studies are currently available on the use of zaleplon or zolpidem in TBI subjects Modafinil Modafinil has been found to be both safe and efficacious in the treatment of narcolepsy at a dosage of 200–400 mg/day However, in patients with liver dysfunction, one-half of the recommended dose should be provided because there is a rare chance it can cause liver toxicity (Elovic 2000) Beusterien et al (1999) performed a double-blind, placebo-controlled study and looked at quality-of-life issues in patients with narcolepsy The treatment group reported improvement in energy level and in overall social functioning, increased productivity, and improved psychological well-being Headache was the only common side effect in clinically therapeutic doses of 200–400 mg/day Although modafinil appears to be useful in the treatment of hypersomnia, controlled studies need to be conducted to determine efficacy and side effects after brain injury in individuals with complicated and uncomplicated sleep disorders taining the body’s biological rhythm and synchronizing the sleep-wake cycle with the environment The suprachiasmatic nucleus, which mediates the circadian rhythm, has several melatonin receptors, suggesting the importance of melatonin in maintaining the body’s internal clock (Reppet et al 1988) Studies in the general population have shown that exogenous melatonin may be useful in improving duration and quality of sleep and altering the biological rhythm (Lewy et al 1992) Information on this drug is limited Although some people report improvement in sleep while taking a dose of 1.5 mg, the actual therapeutic dose is unknown Its manufacture is not regulated by government agencies Because of its vascular constriction property, melatonin should be avoided in patients with atherosclerosis, heart disease, and stroke Drowsiness is a common side effect of melatonin Herbal supplements Herbs and natural remedies have been widely used to treat numerous ailments, including sleep disturbances (Tariq 2004) A number of these natural remedies have been purported to be effective in the treatment of insomnia However, there is a paucity of studies in this area (Sateia et al 2004) Valerian is one of the traditional herbal sleep remedies that has been studied Ziegler et al (2002) conducted a randomized, double-blind, comparative clinical study in which insomnia patients (ages 18–65 years) took either 600 mg/day valerian extract LI 156 or 10 mg/day oxazepam for 6 weeks The results found that valerian was as safe and efficacious as oxazepam However, Glass et al (2003) conducted a placebo-controlled, double-blind, crossover study comparing single doses of temazepam (15 mg and 30 mg), diphenhydramine (50 mg and 75 mg), and valerian (400 mg and 800 mg) in 14 healthy elderly volunteers (mean age, 71.6 years; range, 65–89 years) Valerian was comparable to placebo in measures of both sedation and psychomotor performance Nonpharmacological Measures Diet and lifestyle Diet, rest, exercise, and sleep hygiene programs, as mentioned in the section Treatment of Fatigue, should be recommended to patients with sleep disturbance Patients and their families should also be educated about their symptoms and the treatment options available Phototherapy Circadian rhythm disorders may respond Melatonin Melatonin is a hormone secreted by the pineal gland It is a metabolite of serotonin Darkness augments the production of melatonin, and light suppresses its secretion It plays an important role in main- to phototherapy The actual mechanism of action is unknown, but exposure to bright light at strategic times of the sleep-wake cycle produces a shift of the underlying biological rhythm (Mahowald and Mahowald 1996) The tim- 21 Headaches Thomas N Ward, M.D Morris Levin, M.D POSTTRAUMATIC HEADACHE (PTH) affects millions of people annually It is the most common presenting complaint of postconcussion syndrome (see Chapter 15, Mild Brain Injury and the Postconcussion Syndrome) PTH is defined as a new headache beginning after brain injury Headache associated with brain or neck injury usually is short-lived; when it persists for months to years after the event, it is termed chronic Awareness of this phenomenon allows proper evaluation, diagnosis, treatment, and ascertainment of prognosis Prevalence Estimates of PTH after injury to the brain or neck vary from 30% to 90% (Gfeller et al 1994; Rimel et al 1981) However, definitions are inconsistent, making comparisons of reports problematic For example, the current International Headache Society (IHS) criteria for PTH do not recognize late-onset headaches (headaches beginning more than 7 days after the injury or after regaining consciousness therefrom) (International Headache Society 2004) However, such headaches are described Brain injury may also occur as part of “whiplash” injuries Just as headache is the most frequent symptom of postconcussion syndrome, occurring in up to 90% of patients, more than 90% of patients evaluated medically after whiplash events complain of headaches (Machado et al 1988) Precise numbers are elusive because most whiplash events are not reported Given the common co-occurrence of brain injury and whiplash, an estimate of 4 million cases of PTH annually in the United States is conservative PTH seems to occur more frequently in milder brain injuries There appears to be no clear relationship between the severity or duration of PTH and gender, age, intelligence, occupation, or conditions under which the injury occurred (Guttman 1943) Definitions The IHS criteria defines acute PTH as beginning within 7 days of the trauma (or of awakening therefrom) and resolving within 3 months Chronic PTH is defined as persisting beyond 3 months (International Headache Society 2004) In that the majority of PTH resolves within 6 months, it has been proposed that persistence beyond 6 months is a more practical definition of chronic PTH (Packard and Ham 1993) The IHS criteria additionally specify two subtypes of acute PTH First is acute PTH with significant head trauma (having at least one of the following: loss of consciousness; posttraumatic amnesia lasting longer than 10 minutes; and at least two abnormalities among the clinical neurological examination, including skull X ray, neuroimaging, evoked potentials, and cerebrospinal fluid [CSF], vestibular function, and neuropsychological tests) Acute PTH after minor head trauma and no confirmatory signs is the other subtype Whiplash injuries refer to flexion-extension and lateral motions of the neck related to acceleration-deceleration injuries Because these movements also affect the head and brain, it is not surprising that both are injured concomitantly and that there is great overlap between postconcussion syndrome and whiplash syndrome Pathophysiological Changes The mechanism(s) of PTH are not fully understood Most cases of PTH clinically resemble tension-type 385 386 TABLE 21–1 International Headache Society criteria for episodic tension-type headache A At least 10 previous episodes occurring