Handbook of Clinical Neurology, Vol. 128 (3rd series) Traumatic Brain Injury, Part II J. Grafman and A.M. Salazar, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 35

Sleep in traumatic brain injury NICOLE L. MAZWI1, HEIDI FUSCO2, AND ROSS ZAFONTE1,3* Department of Physical Medicine, Spaulding Rehabilitation Hospital, Boston, MA, USA

1 2

Department of Physical Medicine and Rehabilitation, Mount Sinai Hospital, New York, NY, USA

3

Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA, USA

INTRODUCTION

NORMAL SLEEP

Sleep disturbances after traumatic brain injury (TBI) are particularly common, affecting up to 75% of patients (Shekleton et al., 2010). A recent prospective study found that almost half of inpatients receiving TBI rehabilitation had abnormal polysomnograms (Castriotta et al., 2007) and there is a wide range of sleep-related complaints at all stages of recovery. Unfortunately, the mechanisms underlying impaired sleep remain unclear. It is likely a multifactorial phenomenon, involving physiologic as well as psychological, iatrogenic and environmental contributors. It has been reported that on neuropsychological tests, TBI patients with concomitant sleep disorders perform worse than their counterparts, particularly when sustained attention and short-term memory are tested (Wilde et al., 2007). In fact, in a study of a large group of post-TBI outpatients, sleep disturbance accounted for 14% of the variance in performance in cognitive measurements beyond that accounted for by gender and injury severity using the Trails B, COWAT (Controlled Oral Word Association Test), Digit Symbol, Digit Span, Block Design, and Grooved Pegboard tests (Mahmood et al., 2004). Additionally, patients with sleep disturbances may have a tendency toward increased levels of pain, poorer social function and behavioral control, impaired memory, fatigue, and psychological distress (Ouellet et al., 2006; Zeitzer et al., 2009). Sleep disturbances is also thought to impair neural remodeling that is key in recovery from brain injury and has been shown to hinder overall rehabilitation (Rutherford, 1977).

Sleep architecture In the 1960s a consensus committee first classified sleep into two states, rapid eye movement (REM) and nonrapid eye movement (NREM). The NREM state was further subdivided into four stages (1–4), each representing a progressively deeper phase of sleep. This classification remained static until the Academy of Sleep Medicine refined the classification, renaming stage 1 as N1, stage 2 as N2, slow wave sleep (formerly stages 3 and 4) as N3, and REM as R (Iber et al., 2007). The commonest practice involves the assessment of electroencephalography (EEG), electromyography (EMG), and electro-oculography (EOG) findings as physiologic measures of brain activity. The EEG waves found during the sleep–wake cycle are classified on the basis of the predominant frequency and amplitude of voltage oscillation. Most commonly observed are d (13 Hz, 3 months Excessive sleepiness or muscle weakness

+

Cataplexy

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Sleep paralysis, or Hypnagogic hallucinations, or Automatic behaviors, or Disrupted major sleep

REM, rapid eye movement; MSLT, multiple sleep latency test. (Adapted from American Academy of Sleep Medicine, 2005.)

+

Polysomnography demonstrates: Sleep latency less than 10 minutes, or REM latency less than 20 minutes, and MSLT that demonstrates mean sleep latency of less than 5 minutes and Two or more REM periods

+

No medical or mental condition to account for this

SLEEP IN TRAUMATIC BRAIN INJURY sleep apnea was measured and defined using a respirator disturbance index (RDI), or number of apneic episodes per hour of sleep. RDI of 5 was considered abnormal and RDI of 10 was considered severely abnormal (Webster et al., 2001). It was demonstrated that 36% of TBI patients had a RDI of 5 or more, and 11% of patients had a RDI or 10 or more, with a predominance of central apnea. SDB is associated with excessive daytime sleepiness and impairments in cognition, attention, judgment, and mood (Bresnitz et al., 1994, Wilde et al., 2007), and secondary cardiopulmonary morbidity (Hudgel, 1996). It has been shown that there is also greater impairment in memory and attention in people with TBI an SDB than in those with TBI and no SDB (Wilde et al., 2007). Although cause of SBD after brain injury is unclear, it is thought that damage to the medullary respiratory center accounts for some of the increased central and obstructive apnea and after a brain injury (Dyken and Im, 2009). A future direction could evaluate whether the presence of SDB is associated with the risk of obtaining a brain injury, which may also explain increased prevalence of SDB after brain injury. Insomnia is a condition that results in difficulty initiating or staying asleep with daytime sleepiness that also results in daytime impairment (American Academy of Sleep Medicine, 2005; Castriotta and Murthy, 2011). Insomnia is the most well documented sleep disorder after TBI, occurring in 30–50% of the TBI population (Ouellet et al., 2006; Orff et al., 2009). Specific diagnostic guidelines are outlined in Table 35.3. Insomnia has been attributed to damage to the central nervous system sleep onset centers or preoptic nuclei of the hypothalamus (Dyken et al., 2012) and extrinsic causes such Table 35.3 Diagnostic criteria of the insomnia syndrome* A. Difficulty sleeping characterized by one or both of the following: (i) Difficulty with sleep initiation (30 min to fall asleep) (ii) Difficulty with sleep maintenance (>30 min of nocturnal awakenings) B. Sleep disturbance occurs 3 nights per week C. Sleep disturbance results in significant distress or impairment of daytime functioning Duration parameters: ● Transient or situational: 6 months *

The criteria combine those from the DSM-IV and the International Classification of Sleep Disorders and those regularly used in clinical research. (Adapted from Ouellet et al., 2004.)

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as medical, psychiatric, or environmental conditions including noise, lighting, administration of medications, tube feeds and intravenous fluids, roommate needs, and timing of stimulant medications (Ouellet et al., 2004; Castriotta and Murthy, 2011). Further studies define the difference between sleeponset insomnia, where the individual suffers from a pathological amount of time between going to bed and falling asleep, and sleep-maintenance insomnia, where the patient suffers from difficulties staying asleep. In one particular study of 50 postacute traumatic braininjured patients, sleep onset insomnia occurred twice as frequently as sleep maintenance insomnia (Fichtenberg et al., 2002). Psychogenic insomnia can also present as dyssomnia. Psychogenic insomnia is due to somatized tension and learned sleep prevention associations. In this disorder, the person complains of insomnia, has insomnia, and has decreased function during wakefulness. Somatized tension results in increased muscle tension, arterial vasoconstriction, and increased arousal and wakefulness at night. In addition, often, the bedroom, bed, and time of night is associated with tension and increased wakefulness. This disorder is associated with increased daytime fatigue, poor motivation, and decreased daytime alertness. No pathology is known to cause this, but it should be noted that 15% of patients presenting with complaints of insomnia have psychogenic insomnia (American Academy of Sleep Medicine, 2005). Incidence in the brain injury population is unknown. In circadian rhythm disorders (CRDS), there is persistent alteration of the endogenous circadian system with resultant poor sleep, excessive daytime sleepiness, and disruption of daytime functioning (American Academy of Sleep Medicine, 2005; Barion, 2011). Circadian rhythm disorders are often misinterpreted or mislabeled as insomnia (Ayalon et al., 2007), particularly when only the nocturnal portion of an abnormal sleep pattern is acknowledged. Because the normal circadian cycle is established by external cues which include timing of light, social, and physical activity, it is thought that causes of CRDS in brain injury include an iatrogenic loss of external cuing and day/night light cycles, or physiologic responses to these cues (Barion, 2011; Castriotta and Murthy, 2011). A subtype of circadian rhythm disorders is delayed sleep phase syndrome (DSPS), which is characterized by the chronic inability to fall asleep until a later time, followed by a waking up at a later time (Barion, 2011). It is thought to be due to an abnormal sensitivity to evening light which alters the circadian clock (Aoki et al., 2001). Post-traumatic DSPS was first reported in 1992 in a 13-year-old who fell off a bike, sustaining a mild TBI, and assumed a persistent sleep schedule from

558 N.L. MAZWI ET AL. 5 a.m. to 3 p.m. for over 1 year, causing complete disrupand Arnulf, 2010). These disorders are most prevalent tion in social, academic, and family life (Patten and and considered normal in children (ISCD-2) but also Lauderdale, 1992). occur after administration of lithium, short-acting benSleep-related movement disorders include periodic zodiazepines, or nonbenzodiazepine benzodiazepine limb movements in sleep (PLMS) and restless leg synagonists such as zolpidem in the elderly, cognitively drome (Castriotta and Murthy, 2011). Periodic limb impaired, and in some cases, the general population movements in sleep are characterized by bilateral, small, (Leu-Semenescu and Arnulf, 2010). There is an unclear slow, rhythmic limb movements or twitches (American incidence in the brain injury population or association Academy of Sleep Medicine, 2005; Castriotta and with a particular injury. It is important to correctly diagMurthy, 2011). They can occur at least every 90 seconds nosis and treat these behaviors as they can lead to premaand are not perceived by the patients, but cause nonperture transition to a nursing care facility of an elderly or ceived arousal from sleep. Restless leg syndrome (RLS) cognitively impaired patient (Leu-Semenescu and occurs during wakefulness, or during the phase when an Arnulf, 2010). individual is falling to sleep and is described as a feeling Confusional arousal disorder is disorientation in of discomfort and sensation of needing to move the time and space, slow speech, slow mentation, and poor limbs (American Academy of Sleep Medicine, 2005; command following forced arousal from sleep. ConfuCastriotta and Murthy, 2011). Both PLMS and RLS sion can last several minutes to hours and is associated affect the legs more than the arms. Additionally, RLS with lesions to periventricular gray area, midbrain reticand PLMS are both thought to be due to lesions that ular areal and posterior hypothalamus. Confusional involve the lenticulostriate region (Sechi et al., 2008), arousal disorder is also associated with use of CNS dopamine or dopamine receptor dysfunction (Sechi depressants or metabolic derangements, sleep terrors, et al., 2008; Leschziner and Gringras, 2012). Iron defiand sleep walking (American Academy of Sleep ciency is also associated with RLS and PLMS, likely Medicine, 2005). because iron is a cofactor in dopamine synthesis REM sleep behavior disorder (RBD) is described as (Leschziner and Gringras, 2012). This is consistent with loss of normal REM motor inhibition paralysis, and subthe finding that RLS and PLMS are prevalent in sequent dream enactment (Castriotta and Murthy, 2011; Parkinson’s disease and conditions that cause iron defiDyken et al., 2012). In RBD, patients have been observed ciency anemia, such as pregnancy and renal disease to have jerky, often repeated limb movements, body (Sechi et al., 2008; Leschziner and Gringras, 2012), and jerks, and fights (Arnulf, 2012). RBD is hypothesized why symptoms are often ameliorated with Sinemet to be due to degeneration or damage in the brainstem, and iron repletion (Leschziner and Gringras, 2012). specifically, in the subcoeruleus area in cats (Dyken The prevalence of PLMS has been reported to be et al., 2012), a location that functions in causing atonia 7–25% in TBI patients (Masel et al., 2001; Castriotta during dreaming. RBD has been documented in MS, et al., 2007; Castriotta and Murthy, 2011). stroke, CNS tumors, and almost 50% of Parkinson’s disease patients with a sleep complaint (Dyken et al., 2012) in which there is brainstem injury. RBD is often a Parasomnias heralding sign of Parkinson’s disease (McCarter et al., Parasomnias are sleep disorders that occur during 2012). The prevalence of RBD has been reported to be arousal, partial arousal, and sleep stage transition 13% in TBI patients with sleep complaints (Verma (American Academy of Sleep Medicine, 2005). They et al., 2007). include sleepwalking, sleep talking, sleep terrors, nightREM sleep behavior disorder has also been associated mares, confusional arousal disorder, sleep-related eatwith sleep deprivation, hormonal fluctuations, and antiing disorder, REM sleep behavior disorders, and cholinergic and antidepressant medications (Winkelman bruxism. and James, 2004). Newer studies have found an associaIn sleepwalking (somnambulism), sleep talking (somtion between RBD and impaired glycine and GABA niloquy), sleep terrors, confusional arousal, and sleep(A) receptor function in mice (Brooks and Peever, 2011). related eating disorder, patients have been documented It is important to distinguish RBD from frontal lobe epito have a wide-eyed and confused expression, sitting up lepsy, periodic limb movements in sleep, and other parain bed or bolting out of bed, wandering into inapproprisomnias, as RBD is very responsive to treatment with ate locations, yelling, or eating edible or nonedible oral clonazepam and melatonin (Brooks and Peever, objects. The patients are often amnestic to the events 2011; Dyken et al., 2012; Leschziner and Gringras, 2012). during the episode and are at risk for severe environmenThe final sleep disorder discussed is bruxism, or noctal dangers, such as falling or poisoning (American turnal tooth grinding, which has a prevalence in the genAcademy of Sleep Medicine, 2005; Leu-Semenescu eral population of 21% (Ivanhoe et al., 1997) and an

SLEEP IN TRAUMATIC BRAIN INJURY unknown prevalence in the brain injury population. It has been observed in various levels of consciousness with the appearance of sleep–wake cycles, and is thought to disappear after significant improvement in the level of consciousness (Pratap-Chand and Gourie-Devi, 1985). Considering the variety and complexity of sleep disorders and their impact on health rehabilitation and recovery, it is paramount to thoroughly evaluate brain injury patients with difficulties sleeping. Assessment of sleep disorders is not uniform and should be tailored to each patient’s specific presentation in the context of his or her brain injury. A review of diagnostic tools and methodology is discussed below.

ASSESSMENT OF SLEEP DISORDERS When assessing sleep disorders in the acute and subacute setting, it is important to rule out and treat medical, psychiatric, and environmental causes of sleep disorders after TBI. These include, but are not limited to, anxiety, chronic pain, alcoholism, parkinsonism, dementia/ delirium, depression, gastroesophageal reflux disease, chronic obstructive pulmonary disease, asthma, atherosclerotic cardiovascular disease, diabetes mellitus, and thyroid disease (Thaxton and Myers, 2002). Methods to assess sleep disorders after TBI include both objective and subjective measurements. Objective measurements are important, as many patients with traumatic brain injuries may be unable to give complete and accurate self-assessments. This may result in overor underestimation of symptoms leading to inaccurate diagnoses (Ayalon et al., 2007; Baumann et al., 2007). Subjective measurements are usually in questionnaire form, and have the advantage of data collection by

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anyone and at any location. A summary of methods used in assessment of sleep disorders can be found in Table 35.4. Actography requires the patient to wear a device that measures wrist movements. It is useful for detecting when the individual is sleeping and in assessing if there is a CRD or abnormal sleep–wake cycle (Kushida et al., 2001). In the past, actography has been helpful in monitoring sleep in special populations such as in nursing homes and nurseries, or among astronauts or children (Sadeh et al., 1995; Kushida et al., 2001). Electroencephalography (EEG) is a temporal recording of spontaneous neural electrical activity along the scalp. It is useful in quantifying and qualifying sleep and provides a topographic map of cortical activity (slow waves, spindles, oscillations) during sleep (Lustenberger and Huber, 2012). Most recently, high density EEG has been studied and found to provide superior spatial resolution by increasing the density of electrodes on the scalp (with placement of up to 256) and may be useful in evaluating patients with brain dysfunction by detecting more subtle changes in cortical activity (Lustenberger and Huber, 2012). Polysomnography (PSG) monitors the whole body during sleep with the combined use of EEG, EOG, EMG, nasal-oral airflow, pulse oximetry, electrocardiogram (EKG), and in some cases, video or infrared video (Verma et al., 2007). Polysomnography is indicated for the diagnosis of parasomnias, periodic limb movements in sleep, sleep disordered breathing (SDB), and in evaluating treatment for SDB (with continuous positive airway pressure (CPAP)), and in combination with the Multiple Sleep Latency Test for evaluation of narcolepsy (Kushida et al., 2005) but not for the routine evaluation of insomnia (Littner et al., 2005).

Table 35.4 Methods used in the assessment of sleep disorders Method

Description

Shortcomings

Actography

Wearable device on wrist that measures wrist movements

EEG PSG

Electrical recording of neural activity on scalp Evaluates sleep with EEG, EOG, EMG, airflow, pulse oximetry, EKG with or without video Evaluates five sleep cycles with PSG Self-administered test Self-administered test Self-administered test Self-administered test

False-positive if patient has movement disorder Specialized technician to apply Requires sleep laboratory

MSLT ESS MOS PSQI SDQ

Requires sleep laboratory Subjective Subjective Subjective, but validated in TBI Subjective

EEG, electroencephalography; EOG, electro-oculography; EMG, electromyography; EKG, electrocardiography; PSG, polysomnography; MSLT, multiple sleep latency test; ESS, Epworth Sleepiness Scale; MOS, Medical Outcome Scale for Sleep; PSQI, Pittsburgh Sleep Quality Index; SDQ, Sleep Disorders Questionnaire; TBI, traumatic brain injury.

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The Multiple Sleep Latency Test (MSLT) is an objective test that has been validated in the diagnosis of excessive daytime sleepiness, idiopathic hypersomnia, and narcolepsy (Carskadon et al., 1986; Littner et al., 2005) and in distinguishing narcolepsy from other dyssomnias (Masel et al., 2001; Castriotta and Murthy, 2011). The MSLT is not routinely used in the initial evaluation of OSA, insomnia, or circadian rhythm disorders (Littner et al., 2005). A MSLT occurs in a sleep laboratory during the day for at least 10 hours, during which an individual who has slept as usual on the previous night is video monitored in a dark room. During the test, the individual is allowed to take five 20 minute naps at 2 hour nap intervals. Sleep latency, or time required to fall asleep, as well as entrance into REM sleep, is recorded and measured by PSG. If average sleep latency is less than 5 minutes, the patient is diagnosed with pathologic sleepiness. Mean sleep latency of 5–10 minutes can be considered normal or indicate a diagnosis of excessive daytime sleepiness (EDS) (Carskadon et al., 1986; Littner et al., 2005). Narcolepsy is considered if entrance into REM sleep occurs during two or more naps, and is not due to secondary causes such as medication (Littner et al., 2005; Castriotta and Murthy, 2011). It is recommended that TBI patients with suspected sleep disorders undergo PSG and MSLT to evaluate for SDB, PTH, and narcolepsy (Castriotta and Murthy, 2011). Excessive daytime sleepiness can also be subjectively assessed using the Epworth Sleepiness Scale (ESS). The ESS is a self-administered eight item questionnaire where the patient rates from 0 to 3 the likelihood of falling asleep in specific situations (Johns, 1991). It has been shown to be both sensitive and specific to detecting sleep apnea, narcolepsy, and hypersomnia (Johns, 1992). The 12 item Medical Outcome Scale for Sleep (MOS) scores in six domains including sleep disturbance, snoring, awakening with shortness of breath or headache, sleep amount, sleep adequacy, and daytime somnolence. It then uses summation indexes with additional descriptions of sleep and wakeful states and has been used in assessing patients before and after brain injury, with higher scores (1–100) indicating poorer sleep (Hays et al., 2005; Rao et al., 2008). The Pittsburgh Sleep Quality Index (PSQI) is a 19 item questionnaire that assesses sleep quality and disturbance over 1 month (Fichtenberg et al., 2002). Information is collected from the patient regarding bed time, rising time, minutes to fall asleep, and hours of sleep each night. On a four point scale, the individual rates quality of sleep, use of medications, daytime alertness and mood, and sleep disturbances due to respiratory problems, nightmares, discomfort, and dreams. The PSQI is useful for identifying poor sleepers and dyssomnias

and has been demonstrated to be a valid and useful tool for assessing insomnia in postacute mild TBI patients (Fichtenberg et al., 2002). On the same time scale is the Sleep Disorders Questionnaire (SDQ). The SDQ is a validated 175 item questionnaire that assesses sleep disturbance, sleep habits and perception of symptoms during the past month among four clinical diagnostic subscales: sleep apnea, PLMS, insomnia, and narcolepsy. Categories evaluated include sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction (Douglass et al., 1994). Finally, given the neuropsychological disruption that can occur after TBI, it is also important to assess for mood, depression and pain disorders. The Personality Assessment Inventory (PAI) and Hamilton Anxiety and Depression Scale (HASD) assess severity of depression and anxiety (Parcell et al., 2006). The Beck Depression Inventory (BDI) is a 21 item questionnaire that provides information on cognitive, affective, and physiologic characteristics of depression. The Multidimensional Pain Inventory (MPI) and the West Haven-Yale Multidimensional Pain Inventory (WHYMPI) have strong psychometric properties and are useful for measuring pain intensity, effect of pain on daily activities and functioning (Kerns et al., 1985).

TREATMENT OF INSOMNIA Though there is debate about which approach to take, addressing sleep disturbances in patients with TBI is key in providing comprehensive quality care. From a practical perspective, treating these disorders in a timely fashion is important because we now know that impaired sleep is associated with significantly longer stays in the trauma and rehabilitation center irrespective of initial Glasgow Coma Scale score (GCS) or patient age and is directly related to increased healthcare cost and social disability (Castriotta et al., 2007; Shekleton et al., 2010). Many medications commonly used may not be efficacious, and most present the risk of unwanted side-effects. Goldstein (1995) found that 72% of hospitalized patients in this population were prescribed medications that could interfere with recovery (Goldstein, 1995). At this time, however, there are no clear guidelines that help clinicians determine which medications to use and when it is appropriate to begin therapy to enhance sleep. Prior to beginning treatment, is important that medical causes of insomnia are assessed and treated. A systems-based approach can be very helpful as endocrine, cardiac, pulmonary, and neurologic disorders are all commonly present in TBI patients and can lead to worse outcomes if overlooked. Treating a patient for

SLEEP IN TRAUMATIC BRAIN INJURY 561 insomnia in the presence of an untreated medical condisedative-hypnotic agents developed as alternatives to tion may lead to nothing more than sedation. benzodiazepines. They are more selective than benzodiazThere have been very few clinical studies on pharmaepines for the gamma-aminobutyric acid (GABA-A) cologic treatment of disordered sleep in TBI patients; receptor 1 subtype and therefore thought to be better tolthose published do not establish a consensus, which would erated. Though the newer agents have shorter half-lives, be helpful in developing an algorithm for treatment. which decreases the risk of the “hangover” effect, the type Benzodiazepines, nonbenzodiazepine-benzodiazepine 1 receptor has also been associated with amnestic effects agonists, tricyclic antidepressants, and antihistamines (Flanagan et al., 2007; Larson and Zollman, 2010). are all commonly used to treat sleep disturbance and Zolpidem (Ambien) is a popular choice, effective in many have unwanted side-effects including cholinergic decreasing sleep latency, increasing total sleep time, activity that may interfere with neural remodeling and and decreasing nocturnal awakenings. While welllowering the seizure threshold. Additionally, there is reatolerated in healthy populations, patients should be son to be concerned about the possibility of interactions warned of amnestic, hallucinatory, and motor effects with other medications prescribed to these individuals including somnambulism (Flanagan et al., 2007). The (Mahmood et al., 2004). onset of action is 30 minutes with a half-life of up to 4.5 hours. Studies also found that reaction time and memory were affected at peak plasma concentration Benzodiazepines and could last as long as 24 hours after administration A retrospective study found that 67% of patients with (Larson and Zollman, 2010). However this agent has also TBI in an inpatient rehabilitation unit received benzodibeen reported to have a beneficial effect on those with azepines (Ouellet et al., 2006). Drugs such as diazepam, disorders of consciousness, potentially via its gating flurazepam, clonazepam, and temazepam are known to mechanism at the globus pallidus internus (Schiff and decrease sleep latency, increase total sleep time, and Posner, 2007). decrease the number of nocturnal awakenings in the genZaleplon (Sonata) has anxiolytic, myorelaxant, and eral population. However, in patients with TBI the wellanticonvulsant properties similar to benzodiazepines known next day residual or “hangover” effects of these (Allen et al., 1993). It has a half-life of 1 hour, making medications including altered psychomotor skills, it useful for sleep initiation and limiting the duration decreased alertness and memory, and the risk of dizziof adverse effects such as impaired free recall and psyness and falls can adversely impact function and signifchomotor slowing at peak plasma concentrations icantly prolong hospital stay (Zeitzer et al., 2009). The (Larson and Zollman, 2010). The short action, however, paradoxical effect of agitation with the use of benzodilimits its efficacy in maintaining sleep. On discontinuaazepines has also been well described. Multiple studies tion there is no clinically significant rebound insomnia or have documented persistent adverse cognitive effects withdrawal symptoms (Walsh and Erwin, 1998). in neurologically normal long-term benzodiazepine Zopiclone (Lunesta) is the only sedative-hypnotic users (Larson and Zollman, 2010), and animal studies approved for long-term use with efficacy maintained have reported that benzodiazepines interfere with neural at 1 year and without evidence of tolerance (Roth plasticity and might slow or decrease functional recovet al., 2005). It has the longest half-life of the three at ery (Schallert et al., 1986; Larson and Zollman, 2010). 6 hours. In young, healthy patients it has been found Benzodiazepines are also known to have considerable to decrease sleep latency, increase total sleep time, abuse potential, with reports indicating that prolonged and improve quality and depth of sleep (Najib, 2006). use may lead to physical dependence, tolerance, and Side-effects include a bitter taste, dizziness, dry mouth, rebound insomnia (Holbrook et al., 2000). As a and somnolence. As with zaleplon, psychomotor speed result they are typically not routinely used following was also decreased in normal patients at the time of peak TBI. Newer agents demonstrate equal efficacy with plasma concentration (Billiard et al., 1987). regard to sleep latency, nocturnal awakenings, and In a randomized, crossover, double-blind trial, Li Pi sleep efficiency, but with a more favorable side-effect Shan and colleagues examined zopiclone and lorazepam profile, and represent safer choices (Li Pi Shan and and found them to be equally efficacious in treating Ashworth, 2004). insomnia in patients with TBI (Li Pi Shan and Ashworth, 2004). However, research on the short- and long-term effects of nonbenzodiazepine-benzodiazeNonbenzodiazepine-benzodiazepine pine agonists has primarily been performed in patients agonists without TBI and labels include warnings related to halA newer class of drugs, now commonly referred to as lucinations, disinhibition, somnambulation, and engagthe “z-drugs” (zopiclone, zaleplon, and zolpidem), are ing in activities without later memory of the events.

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They should therefore be used with caution in TBI patients, particularly in those still in post-traumatic amnesia (Dolder and Nelson, 2008). Of interest, zopiclone has recently been shown to have potential efficacy regarding sleep disturbance in those with PTSD (Simon and VonKorff, 1997) and thus may warrant evaluation in those persons with the dual diagnosis of TBI and PTSD. The body of literature regarding these agents in healthy subjects is convincing, but there is a paucity of such studies in the TBI population. Given their known idiosyncratic effects in subpopulations, particularly those with cognitive deficits, the uncertainty about their effect in TBI patients is a real one and the need for clinical trials is pressing.

Antidepressants Tricyclic and nontricyclic antidepressants have both been used to treat sleep disorders in patients with and without TBI. Traditionally, the sedating properties of tricyclic antidepressants made them attractive for facilitating sleep. However, they have significant anticholinergic side-effects (xerostomia, blurred vision, dizziness, hypotension), risk of arrhythmia and EKG changes, a negative impact on attention and memory, and can lower the seizure threshold. As such, caution should be utilized in employing these drugs for sleep TBI patients. In spite of limited evidence for its use in the TBI population, trazodone, a nontricyclic antidepressant, is one of the most commonly used sleep aids. The mechanism of action in humans is poorly understood but its sedating qualities are potent as it decreases sleep latency and increases total sleep time in depressed patients. Besides the typical anticholinergic side-effect profile, trazodone carries the risk of rebound insomnia (Mendelson, 2005; Rosenberg, 2006). Its cardiac side-effect profile, however, is better than that of tricyclics, though discretion is advised in patients with pre-existing cardiac dysfunction. While several studies have found trazodone efficacious in improving sleep in depressed patients there are no clinical trials investigating trazodone’s effect on insomnia in patients with TBI. Further, results related to the drug’s impact on cognition are mixed (Larson and Zollman, 2010). Mirtazapine (Remeron) is a tetracyclic antidepressant that inhibits presynaptic a2, 5HT2, and 5HT3 receptors to increase central noradrenergic and serotonergic activity. In the context of use in depression, sleep latency and total sleep time were improved. However, its long half-life of up to 40 hours may cause excessive daytime somnolence (Wingen et al., 2005), and there is limited study regarding its effect on sleep in the nondepressed population.

Melatonin and melatonin agonists An endogenous hormone synthesized primarily in the pineal gland, melatonin has properties that are thought to induce sleep and shift circadian rhythms (Kemp et al., 2004). Melatonin is a neurohumeral agent derived from L-Tryptophan (the rate-limiting enzyme in serotonin synthesis); its production is triggered by darkness. Melatonin levels have been found to be temporally associated with the circadian system, which regulates REM sleep. Studies have found that in healthy subjects and patients with subnormal REM sleep duration, exogenous melatonin increases time spent in the REM phase. In a group of TBI patients, Shekleton et al. found a significant association between evening melatonin production and percentage of REM sleep. He hypothesized that the tendency for TBI patients to have less REM sleep was due to these lower hormone levels (Shekleton et al., 2010). As REM sleep is thought to be important in facilitating learning and memory consolidation, research on agents effective in this stage of sleep may benefit TBI patients significantly. A recent pilot study supported the hypothesis that melatonin levels are decreased in TBI patients (Paparrigopoulos et al., 2006); however, an earlier randomized trial found melatonin was unsuccessful in treating insomnia, though there were slight improvements from baseline (Kemp et al., 2004). Melatonin is also thought to have a neuroprotective role as an antioxidant in damaged cerebral tissue, particularly in the early post-TBI period (Seifman et al., 2008). Studies have shown that treatment with melatonin decreases sleep latency and may improve sleep duration and quality in conditions where the hormone concentration is reduced or circadian rhythms are disrupted (Kemp et al., 2004; Larson and Zollman, 2010). As with the other medications discussed in this chapter, there has been little study of melatonin in TBI patients specifically. Ramelteon (Rozerem) is a melatonin MT1 and MT2 receptor agonist developed following increased interest in melatonin agonists as a treatment for insomnia. Studies, though limited, have shown that ramelteon decreases sleep latency and increases total sleep time. It has a side-effect profile superior to sedative-hypnotics that may be secondary to its limited affinity for benzodiazepine, dopamine, and opiate receptors. To date, the literature has not reported any adverse performance-related effects (Flanagan et al., 2007; Larson and Zollman, 2010).

Atypical antipsychotics Quetiapine is an atypical antipsychotic that works via antagonism at the histamine type 1 (H1) and serotonin

SLEEP IN TRAUMATIC BRAIN INJURY type 2A (5-HT2) receptors. There are no data regarding the use of this drug for sleep disturbances in patients with TBI; however, it has been extensively studied in those with primary insomnia and is used off-label in this and many other populations, including patients with TBI. Insomnia treatment guidelines do not endorse routine use of atypical antipsychotics in the absence of psychiatric disorders, and in fact, recent data are inconclusive regarding the efficacy of the drug for primary insomnia alone. A recent review of several large studies and case reports concluded that quetiapine cannot be recommended for the treatment of insomnia in light of limited data and safety concerns (Coe and Hong, 2012).

Nonpharmacologic treatment options The development of post-traumatic insomnia is likely more complex than simply pathophysiologic processes alone. Psychological and environmental precipitating influences may produce sleep disturbances in the context of increased physiologic vulnerability after TBI (Morin, 1993; Morin et al., 2002). In addition to structural lesions in cerebral networks controlling sleep, these physiologic and environmental factors likely play an important role in sleep disturbance after TBI and are therefore a promising therapeutic target. Environmental factors in a rehabilitation facility can significantly affect sleep. Taking vitals, administering tube feeds or medications, and addressing the needs of a patient’s roommate during the night should all be considered in evaluating sleep difficulties. At home, there may be substantially different, but equally important issues and distractions preventing proper and timely sleep. Any modifiable environmental problem should be addressed prior to discussing physician-initiated interventions in these patients. Research in nonpharmacologic treatment of insomnia has primarily been focused on evaluating factors that contribute to insomnia such as maladaptive sleep habits and hygiene and sleep-related attitudes and beliefs. Meta-analyses from studies of the general population have found that nonpharmacologic treatments can be efficacious and even superior to current traditional pharmacologic options for treating chronic insomnia (Ouellet et al., 2004; NIH, 2005). Primary insomnia has been the focus of the majority of the research on these interventions, but more recent work has demonstrated efficacy in medical and psychiatric conditions causing insomnia. In primary chronic insomnia treatments including sleep hygiene education, sleep restriction, relaxation training, stimulus control, and cognitive/cognitive behavioral therapy (CBT) have been evaluated and found to be efficacious (Zeitzer et al., 2009).

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Sleep hygiene involves teaching patients how to change daily behaviors and control environmental influences to improve sleep. It includes eliminating nicotine and evening caffeine, avoiding exercise and heavy meals just prior to bedtime, sleeping in a dark, quiet environment, and having a regular sleep–wake schedule. Sleep restriction therapy is designed to increase sleep efficiency through initially creating a mild sleepdeprived state theoretically promoting more rapid sleep onset and restorative sleep. It is accomplished by setting a fixed rising time and slowly adjusting bedtime to maintain a normal sleep–wake cycle. For example, if someone must wake at 7 a.m. daily but is only sleeping 4 hours at night they should not get in bed until 3 a.m. This bedtime should be gradually made earlier (in 15 minute increments, for example) until the desired total sleep duration is achieved (National Heart, Lung, and Blood Institute Working Group on Insomnia, 1999). Relaxation training involves various methods (progressive muscle relaxation, imagery training) to decrease anxiety and inappropriate arousal levels to improve sleep onset and maintenance. Stimulus control therapy is used to establish cues for sleeping and reduce associations with activities disruptive to sleep. Use of the bed is limited only to sleeping or sexual activities and the bedroom is therefore reassociated with those activities, thereby promoting a consistent sleep–wake pattern. Cognitive therapy focuses on identifying and changing maladaptive beliefs and attitudes about sleep and helping the patient to realize their ability to develop healthy coping skills to facilitate proper sleep. CBT combines cognitive therapy with one or more of the behavioral therapies discusses above (National Heart, Lung, and Blood Institute Working Group on Insomnia, 1999; Zeitzer et al., 2009). CBT has been the most thoroughly studied method among the aforementioned, though as with other interventions, data in the TBI population are limited. A comparative study suggested that CBT alone was superior to pharmacotherapy alone or in combination with CBT in providing long-term improvements in sleep (Wu et al., 2006). Recent work in the TBI population found that after 2 months of participation in CBT there was an increase of at least 10% in sleep efficiency. For most of the patients, the benefits began to appear within 2 weeks of therapy and were sustained over the 3 month period of evaluation with reductions in fatigue (Ouellet and Morin, 2007).

On the horizon There appears to be promise in certain areas of drug development for insomnia in the TBI population. For example, hypocretin-1 levels are low immediately

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postinjury and return to normal over a 6 month period. The role of this compound as a neuropeptide promoting wakefulness makes it an appealing target for drug development. However, the diversity of injury that occurs in the context of TBI makes monotherapy with any agent unlikely to be appropriate in all circumstances (Zeitzer et al., 2009). More vigorous study of clinically active therapies is warranted.

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