Sleep Medicine 14 (2013) 1235–1246

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Sleep Medicine journal homepage: www.elsevier.com/locate/sleep

Review Article

Screening for sleep dysfunction after traumatic brain injury Tatyana Mollayeva a,b,⇑, Angela Colantonio a,b, Shirin Mollayeva b,c, Colin M. Shapiro b,d a

Toronto Rehabilitation Institute, University Health Network, Toronto, Ontario M5G 2A2, Canada University of Toronto, Toronto, Ontario M5G 1V7, Canada c University of Toronto, ABI Research Lab, Toronto, Ontario M5G 1V7, Canada d Toronto Western Hospital, University Health Network, Toronto, Ontario M5T 2S8, Canada b

a r t i c l e

i n f o

Article history: Received 12 February 2013 Received in revised form 12 July 2013 Accepted 16 July 2013 Available online 13 September 2013 Keywords: Traumatic brain injury Sleep disorders Screening Treatment Rehabilitation Neurotrauma Prevention

a b s t r a c t Numerous studies on the high prevalence of sleep disorders in individuals with traumatic brain injury (TBI) have been conducted in the past few decades. These disorders can accentuate other consequences of TBI, negatively impacting mood, exacerbating pain, heightening irritability, and diminishing cognitive abilities and the potential for recovery. Nevertheless, sleep is not routinely assessed in this population. In our review, we examined the selective screening criteria and the scientific evidence regarding screening for post-TBI sleep disorders to identify gaps in our knowledge that are in need of resolution. We retrieved papers written in the English-language literature before June 2012 pertinent to the discussion on sleep after TBI found through a PubMed search. Within our research, we found that sleep dysfunction is highly burdensome after TBI, treatment interventions for some sleep disorders result in favorable outcomes, sensitive and specific tests to detect sleep disorders are available, and the cost-effectiveness and sustainability of screening have been determined from other populations. The evidence we reviewed supports screening for post-TBI sleep dysfunction. This approach could improve the outcomes and reduce the risks for post-TBI adverse health and nonhealth effects (e.g., secondary injuries). A joint sleep and brain injury collaboration focusing on outcomes is needed to improve our knowledge. Ó 2013 Elsevier B.V. All rights reserved.

1. Introduction Traumatic brain injury (TBI) has been defined as ‘‘an alteration in brain function, or other evidence of brain pathology, caused by an external force,’’ [1] and is a leading cause of death and disability in adults and children in Canada and the United States [2]. The sleep and wakefulness cycles often become disturbed with brain injury, irrespective of the severity [3–5]. This disturbance occurs through various pathophysiologic mechanisms resulting from direct and indirect trauma to the brain areas responsible for sleepwake regulation regulation; conceivably, damage to these areas can lead to hypothalamus and neurotransmitter dysfunction. Furthermore, pain resulting from neck or back injury or other medical or psychiatric disorders caused by brain trauma and subsequent medications may affect sleep. Once sleeping problems develop they lead to additional confusion, frustration, and depression [6], further impairing the individual. A recent study of 29,640 US Navy and Marine Corps men with blast-related TBI found that sleep problems mediated the effect of a positive TBI screen on the development of posttraumatic stress disorder and depression [7], ⇑ Corresponding author at: Toronto Rehabilitation Institute, 550 University Avenue, Rm 11207, Toronto, Ontario M5G 2A2, Canada. Tel.: +1 416 597 3422x7848; fax: +1 416 946 8570. E-mail address: [email protected] (T. Mollayeva). 1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.07.009

highlighting the significance of early identification and treatment of sleep dysfunction following injury. Moreover, individuals with sleep complaints are more sensitive to pain and may increase their medication requests, increasing sleep disruption and establishing a pathologic reverberating loop [8,9]. High comorbidity of chronic pain with head and other trauma has been reported, with headaches as the primary complaint in postconcussive syndrome. The incidence of headaches is a whopping 90% in the immediate period following the accident [10], with 44% of patients experiencing ongoing problems 6 months after injury [11]. Moreover, seizures and epilepsy, important medical and neurologic TBI sequelae, have an established relationship with sleep dysfunction. Sleep deprivation is a seizure trigger [12] and recent studies on the relationship between sleep disturbances and epilepsy emphasize the significance of early diagnostic and therapeutic management of sleep dysfunction in individuals with TBI, given its influence in posttraumatic seizure development [13–15]. In the past two decades, numerous researchers have studied the relationship between TBI and sleep disturbance, with coinciding findings and conclusions: sleep dysfunction is prevalent in this population and is an integral component in health following injury. It is crucial that the evidence is acknowledged and that steps are taken to integrate the screening and management of sleep complaints and the associated wakefulness disturbances into TBI clinical programs.

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Presently, most individuals with TBI do not undergo sleep dysfunction screening or assessment during their treatment and rehabilitation phase. This constitutes a knowledge-to-practice gap that requires intervention to ensure an evidence-based approach to the evaluation and rehabilitation of individuals with TBI. Our review first aimed to appraise the selective screening criteria and examine the scientific evidence regarding sleep disorder screening following TBI; second, we aimed to identify gaps in our knowledge that are in need of resolution. 2. Search strategy and selection criteria We searched PubMed using exp sleep⁄ OR sleep disorders, AND exp brain injuries, craniocerebral trauma, coma, post-head injury, head injuries, penetrating, intracranial hemorrhage, traumatic, OR exp skull fractures. The appropriate truncations were included. Only papers written in the English-language literature published before June 2012 were used. The reference lists of relevant review articles were scanned for published studies that may have been overlooked during the electronic literature search. We emphasized experimental studies, prospective epidemiologic studies, and nonrandomized and randomized trials. An additional literature search was performed using the PubMed database for findings on cost-effectiveness from other study populations. 3. Screening as a secondary prevention tool Screening is a secondary prevention tool, the primary goal of which is to prolong life, decrease morbidity, and improve the outcome and quality of life—all using the available resources. According to the Canadian Task Force on Preventive Health Care [16,17], the selective screening criteria for the presence of existing disease in a specific population subgroup are: (1) the targeted disease must be sufficiently burdensome to the population that a screening program is warranted; (2) efficacious treatment for the target illness must be available; (3) early detection must improve disease outcome; (4) accurate (i.e., sensitive and specific) screening tests should be available; (5) diagnosis and treatment facilities should be available; and (6) cost, feasibility, and acceptability of screening and early treatment should be established. 4. Analysis 4.1. Nature of sleep (and wake) disorders following TBI: incidence, prevalence, and impact The International Classification of Sleep Disorders lists 84 sleep disorders under eight major categories, each possessing a well-understood history and a description of disorders that can be successfully treated [18]. Many of these disorders are sufficiently burdensome after TBI [19]. Specifically, this applies to insomnias [20,21], sleep-related breathing disorders (SRBD) [22], hypersomnia not due to breathing disorders [3,23], circadian rhythm sleep disorders (CRSD) [24–26], sleep-related movement disorders [27], and other sleep disorders [28]. 4.1.1. Insomnia Fichtenberg et al. [21] reported the increased insomnia incidence following acute TBI (e.g., 4 months after injury) relative to the general population. Thirty percent of TBI patients were found to have insomnia, with both sleep initiation difficulties and sleep duration limitation being more than three times as common compared to that in the general population [20]. The study also reported that TBI patients with insomnia had poorer vocational outcomes, more behavioral problems, cognitive and

communicative dysfunctions, and a higher incidence of anxiety and depression. Insomnia with shortened sleep time was the most biologically severe phenotype of the disorder, associated with cognitive-emotional and cortical arousal; activation of the limbic and stress systems; and high risk for hypertension, diabetes mellitus, neurocognitive impairment, and mortality [29]. A sleep duration of less than 5 h also was shown to be associated with an increased risk for falls [30], lower grip strength, and slower walking speed in a population of elderly men [31]; poorer cognitive performance in the Nurses’ Health Study Cohort [32]; and obesity in individuals older [33] and younger than 65 years [34]. Other than these general insomnia patterns, some factors specifically related to TBI could explain the increased risk for insomnia. Although the presence of insomnia following injury has not been found to be related to time since injury, injury severity appears to play a role. Several studies have reported more insomnia complaints in individuals with milder TBI, possibly due to their greater awareness of changes to sleep since injury [35,36]. Another explanation is that mild TBI has been shown to increase cortical arousability, which could be due to hypocretin (orexin) neurotransmitter dysregulation because of the injury. This hyperarousability causes sleep fragmentation and increases the amount of lighter stages of sleep, leading to the feeling of being unrested or unrefreshed on awakening, and therefore feeling greater dissatisfaction with sleep [37]. It also could be from increased intracranial pressure during the night after the injury, which was shown to be associated with reduced sleep quality [38]. Lastly behavioral and psychosocial factors such as irregular sleep–wake pattern, consumption of caffeine and other substances, excessive worrying at night, and extended time in bed including naps, also may contribute to insomnia, which may be challenging but necessary to address.

4.1.2. SRBD Higher SRBD prevalence in TBI populations ranges from 25% to 35% [22,27] compared to 6% in the general population [39]. Recent systematic reviews have demonstrated an increased risk for serious adverse effects in patients with untreated SRBD [40]. Acute cardiovascular events have been associated with SRBD, and an extremely high odds ratio for myocardial infarction in patients with obstructive sleep apnea (OSA, a form of SRBD) has been observed [41], as well as axonal damage because of OSA [42]. A recent neuropsychologic study of TBI patients with OSA revealed cognitive domain deficits in executive functioning and attention [43]. It also has been reported that cognitive performance deterioration is significantly correlated with increased severity of nocturnal breathing irregularity, magnitude of nocturnal hypoxemia, and the extent of sleep disruption in patients with SRBD for decades in the general population [44,45]. The other effects of SRBD include exacerbation of epilepsy through sleep disruption and deprivation, hypoxia, and decreased cerebral blood flow [46]. Because head trauma also has been cited as a cause of epilepsy with the relative risk for being diagnosed with the seizure disorder increasing 2- and 7-fold after mild and severe head injury, respectively [47], it is difficult to dismiss these relationships as coincidental. Therefore, it would make sense to consider sleep factors in posttraumatic epileptogenesis. Seizures can also often cause repetitive periods of apnea, which can closely mimic the conditions of obstructive or central apneas [48]. Clinical differentiation between sleep disorders and epileptic events after TBI should be considered in any recurrent, stereotyped, and unusual events during sleep reported by a TBI patient. Recently, the effect of untreated OSA on cognitive decline in TBI patients was uncovered: TBI patients with OSA performed significantly worse on neuropsychologic testing than those without

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OSA; groups were comparable in age, education, injury severity, time since injury, and Glasgow Coma Scale scores [43]. Patients with SRBD also may complain of excessive daytime sleepiness (EDS) and fatigue, a primary complaint in the TBI population [49]. Guilleminault et al. [3] found that 30–40% of TBI survivors who complained of EDS had SRBD. The terms daytime sleepiness, fatigue, and impaired alertness have been used interchangeably, though fatigue is reportedly easier to perceive than any degree of sleepiness [50]. Additionally, prolonged sleep deprivation stemming from SRBD may result in adjustment to impairment and consequent failure to accurately report the symptom of sleepiness, with fatigue or tiredness being described instead. Currently, research directly linking SRBD with posttraumatic fatigue is insufficient; however, findings from other study populations have described such a relationship [51,52]. It also is possible that prior untreated SRBD was a proximate cause of brain injury itself, and evidence supporting an association between sleepiness, fatigue, and the probability of involvement in an accident is growing [53,54]. SRBD aggregation following TBI can occur with commonly prescribed muscle relaxants, sedatives, or hypnotics. Thus the excessive sleepiness and fatigue reported after TBI might be secondary to sleep dysfunction or a combination of disturbed sleep and direct sedative effects. Regardless, sleepiness and fatigue indicate the danger of participating in activities requiring sustained attention (e.g., operating a motor vehicle or heavy machinery). For healthcare providers assessing individuals with TBI, it also can indicate underlying sleep pathology. 4.1.3. Dementia following TBI and links to SRBD TBI has been implicated as a contributing factor in the development of Alzheimer disease (AD) and dementia [55]. In some individuals, axonal transport disruption following TBI can lead to the rapid accumulation of amyloid precursor proteins and other proteins associated with the neurodegenerative disease. The variation observed in the apolipoprotein (APOE) E4 allele in individuals with TBI prompted exploration of the role of genetic factors in modulating the risk for AD after TBI [56]. Coincidentally, O’Hara et al. [57] reported the relationship between sleep apnea and dementia through the APOE E4 allele, whose carriers may face an increased risk for dementia. Another possible link between TBI and dementia is related to increased oxygen demand required for cognition and decreased oxygen delivery after TBI due to blood vessel injury from mechanical displacement, hypotension in the presence of autoregulatory failure, inadequate availability of cholinergic neurotransmitters, and the potentiation of prostaglandin-induced vasoconstriction [58]. The presence of SRBD following TBI can intensify oxygen insufficiency and hasten cognitive decline. Masel et al. [59] reported that individuals with TBI who suffered from sleep apnea had worse cognitive outcomes (e.g., memory recall measures, number of lapses, retention) when compared to TBI participants without apnea. These findings and that of Ancoli-Israel et al. [60], who studied the relationship between SRBD and dementia in AD patients, are highly promising for the TBI population, demonstrating that sleep apnea may, with treatment, be a reversible cause of cognitive loss after TBI [60]. This finding reinforces the necessity of identifying and treating SRBD in individuals with TBI in the early stages of rehabilitation. 4.1.4. Hypersomnia not due to SRBD Hypersomnia disorders involve primary complaints of daytime sleepiness. Narcolepsy is included among them. Baumann et al. [61] reported the new onset of sleep–wake disorders in 72% of TBI patients: EDS, posttraumatic hypersomnia, and narcolepsy were present in 28%, 22%, and 3% of head-injured patients, respectively. The rate of narcolepsy is 0.05% in the general population

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[62]; it is 60 times higher in the TBI population. Its impact on a patient’s life is significant-according to a recent German study, 59% of individuals with narcolepsy are unemployed and 43% blame the disorder for their unemployment [63]. More pronounced cognitive impairments have been reported in the narcolepsy population in individuals older than 40 years, as well as a significant reduction in health-related quality of life, indicating the severity of the burden of narcolepsy [64]. Hypocretin-1, a hypothalamic neuropeptide involved in sleep– wake regulation, is characteristically reduced in individuals with idiopathic narcolepsy [65]. Researchers have also reported significantly reduced hypocretin-1 secretion in TBI survivors: 95% of patients with moderate to severe TBI presented with neurotransmitter deficiency [66]. Despite Baumann et al. [61] reporting that hypocretin-1 levels revert to the normal range of 6 to 12 months after injury, the association is a possible explanation for the manifestation of narcoleptic activity after TBI and its link to posttraumatic EDS. 4.1.5. CRSD Ayalon et al. [24] reported on the relationship between mild TBI and CRSDs, concluding that mild TBI may contribute to their emergence. The authors reported that 36% of individuals with complaints of insomnia following mild TBI were diagnosed with CRSDs. The frequency of CRSDs in their sample was considerably higher than that among the general population (6.6%) as reported by Weitzman et al. [67]. Although evidence is limited in the TBI population, testing for CRSDs is desirable due to existing effective solutions, as seen in the general population. However, posttraumatic psychiatric and behavioral disorders and shift work, which can lead to sleep–wake timing alteration after TBI, should be factored into the testing. 4.1.6. Other sleep disorders Other sleep disorders include sleep-related movement disorders, among others. Masel et al. [59] reported periodic limb movement disorder in 17% of TBI patients [59]; prevalence in population-based studies was estimated to range between 4% and 11% in adults [68,69]. Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by dramatic REM motor activation resulting in dream enactment, often with violent or injurious results. A population-based survey indicated an overall 2% prevalence of violent behavior during sleep, one-quarter of which was likely to be RBD, putting the prevalence of RBD at 0.5% [70]. Verma et al. [71] examined the spectrum of sleep disorders in chronic TBI patients and reported complaints of parasomnia in 25% of participants, with RBD being the most frequently reported parasomnia (13%). It has been proposed that the increased RBD incidence relative to that of the general population is attributed to damage to brainstem mechanisms mediating descending motor inhibition during REM sleep [71]. 4.1.7. Effects of comorbid psychopathology on sleep following TBI Major psychosocial stressors (e.g., physical and cognitive impairments and, disturbed social, family, productivity roles) accompany the TBI recovery process. They can trigger anxiety, depression, somatized tension, and excessive worrying. The literature documents a high prevalence of Axis I disorders after TBI; major depressive disorder and generalized anxiety disorder are the most commonly reported [72–75]. Major depression in between 14% and 77% of the TBI population [72,75] is significantly higher than the 6.6% reported in US adults [76]. Approximately 75% of adults with major depression reported sleep problems, including difficulty falling asleep, frequent nocturnal awakening, early morning awakening, nonrestorative sleep, decreased or increased total

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sleep time, and disturbing dreams [77]. In a preexisting condition, neurotransmitter imbalance stemming from head trauma will further disrupt serotonin, norepinephrine, and dopamine levels, exacerbating the effects seen in depression including sleep-related effects [78,79]. In significant TBI-associated tissue damage, altered serotonin levels are evident up to 1 year after injury [70–82]. In the acute stage following TBI, norepinephrine neurons release large amounts of norepinephrine linked to arousal, wakefulness, and sleep at levels associated with increased neuronal cell death [83]. It also has been established that dopamine levels associated with motor movement and arousal increase after brain injury, and similar to norepinephrine, they are associated with increased cell death in the regions of action. Sleep deficits (e.g., excitability, agitation) caused by increased dopamine have been observed in the long-term post-TBI [84]. Theoretical links exist between generalized anxiety following TBI and sleep difficulties. Although sleep is a restorative state of diminished cortical arousability, anxiety and fear manifest with heightened cortical arousability. This feeling can result in difficulty falling asleep and maintaining sleep (e.g., insomnias) [4]. Through a structural clinical interview, Rao et al. [28] found that the presence of insomnia in the acute period following TBI was related to heightened anxiety. Post-TBI posttraumatic stress disorder can manifest as panic attacks and nightmares [4,75]. Another relationship relevant in the discussion of comorbid psychopathology and sleep after TBI is between undiagnosed or untreated primary sleep disorders and mood disorders. A nearly 2-fold increase in the risk for major depressive disorders has been reported in individuals with sleep apnea [85]. Chaput et al. [86] found that depression and irritability in acute mild TBI patients were more frequent in those with sleep complaints. Recognizing the cumulative evidence for the intertwined mood, sleep, and neuroplasticity processes after TBI may have important implications for rehabilitation. 4.1.8. Pain in TBI and sleep Pain is an ‘‘unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage’’ [87]. A recent systematic review by Nampiaparampil [88] featuring 23 studies and 4206 TBI patients found that 51.5% of patients experienced chronic pain, the prevalence of which was greater in mild TBI patients [88]. As anticipated, this prevalence was significantly higher than the 11% and 29% reported for the general population [89]. The interaction between pain and poor sleep can be partly attributed to sleep fragmentation and reduced slow-wave sleep caused by chemical or mechanical stimulation and sensory nerve stimulation producing spinal reflexes or cortical responses with arousal awakenings [90,91]. Other evidence linking chronic pain and poor sleep is related to hypothalamic orexinergic or hypocretinergic system involvement in pain and headaches [92]. This association is supported by the work of Baumann et al. [61], who reported low hypocretin-1 levels in the cerebrospinal fluid in over 90% of 27 patients analyzed in the early days following TBI and in 19% of 21 patients analyzed 6 months following injury. Hypothalamic dysfunction resulting from brain injury and consequent autonomic and endocrine abnormalities characteristic of many primary pain disorders can be implicated as contributors to sleep dysfunction. Pain is more difficult to manage in individuals with TBI [93]. The current efforts in chronic pain management after TBI aim toward desensitization of the central nervous system, utilizing peripheral procedures, such as electromyography and temperature biofeedback, transcutaneous electrical nerve stimulation, relaxation and imagery procedures, behavioral activity programs, and psychotherapeutic and neurophysiologic procedures. Desensitizing drugs used to treat chronic pain after TBI include antiepileptic

drugs, muscle relaxants, selective serotonin reuptake inhibitors, and neuroimmunomodulators. Other prescribed pain medicines include nonsteroidal anti-inflammatory drugs for mild and moderate pain and narcotics, such as morphine, mixed agonists and antagonists, and partial agonist narcotics in more severe cases, some of which are controversial with regard to serious adverse effects (e.g., sleep-related effects) [93]. 4.1.9. Medication effects in TBI and sleep Although unstudied in the TBI population, highlighting the impact of TBI treatment medications, including corticosteroids, sedatives, analgesics, anticonvulsants, muscle relaxants, and antidepressants, is important. These drugs cross the blood–brain barrier and enter the central nervous system pathways, and therefore could interact with endogenous neurotransmitters to influence brain processes including those that regulate the sleep– wake cycle [94]. Inadequate timing when administering different pharmacologic agents also may cause sleep–wake problems [95]. Antiarrhythmic medications have been linked to fatigue, insomnia, and other sleep difficulties (e.g., vivid dreams) [96]. Some a adrenergic blockers such as prazosin have a sedating effect and are used for therapeutic purposes, including reducing insomnia and nightmares [97]. Severe rebound insomnia can result from acute withdrawal from benzodiazepines, especially those with a short half-life [97]. Antidepressant medications can result in weight gain, which can increase SRBD occurrence and induce sleep fragmentation if substantial [98]. Sympathomimetic stimulants (e.g., dextroamphetamine) modulate brain neurotransmitters (i.e., dopamine, serotonin, norepinephrine), increasing alertness and causing difficulty falling asleep. Withdrawal symptoms, mainly mental fatigue, depression, and increased appetite may last for days with occasional use and for months with long-term use. Excessive sleepiness, vivid dreams, REM rebound, and suicidal ideations also have been reported on withdrawal [99,100]. As reported by up to 70% of users, corticosteroids have many side effects including those affecting sleep that generally are related to insomnia [101]. Nonsteroidal anti-inflammatory drugs relieve pain by inhibiting prostaglandins and can affect sleep architecture by causing frequent awakenings and sleep fragmentation. Opioid-induced respiratory depression is a combination of decreased respiratory drive, reduced consciousness, and upper airway obstruction [102–104]. Given the evidence regarding the effects of medication on the nervous system and their potential proximity to areas responsible for sleep–wake cycle regulation, the medicines taken by TBI patients should be carefully considered, as this consideration would provide invaluable insight for proper differential diagnosis and treatment of sleep dysfunction following injury. We reviewed the prevalence of categories of the most clinically important sleep disorders following TBI and the effects of comorbid conditions on sleep. The burden is measured through indicators that include prevalence, financial costs, morbidity and mortality rates, disability, and long-term outcomes of the disease. We have reported the effects of untreated sleep disorders, many of which considerably affect daily functioning, and therefore are factors that influence disability rates and overall long-term outcomes in the TBI population. We feel that these effects and the high prevalence of sleep disorders in the TBI population satisfy the burden condition for implementation of screening. The next important issue to address is whether efficacious treatment exists for the target disease. 4.2. Treatment considerations To satisfy the principles of screening, adequate treatment should be available to the patient. Several approaches to treating post-TBI sleep disorders have been tested based on the understanding of their underlying mechanisms. Insomnia can be man-

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aged with medications or cognitive behavioral therapy (CBT) and other nonpharmacologic interventions [105–108]. Li et al. [107] compared benzodiazepine and nonbenzodiazepine hypnotics and found no difference between the two drug classes in sleep duration and sleep continuity in individuals with TBI. However, the medications were administered for 1 week, and whether or not they were effective in reducing insomnia in the pre- to posttreatment periods was not reported. Flanagan et al. [108] advised against use of benzodiazepines after TBI, due to their effect on sleep architecture; potential for abuse; and side effects, including memory impairment, dizziness, and altered psychomotor skills. Although short-term benzodiazepine use may be appropriate after due consideration [108], Worthington and Melia [109] found that the usage duration exceeded recommended UK guidelines in 20% of their TBI sample. Kemp et al. [110] conducted a trial with melatonin and amitriptyline involving seven TBI patients who complained of difficulty initiating and maintaining sleep 3 years after injury. They reported no improvement in sleep duration or reduced sleep onset with either drug; however, the effect size revealed encouraging changes: patients on melatonin reported improved daytime alertness, and those on amitriptyline had increased sleep duration compared to baseline [110]. Ouellet and Morin [105] studied the effectiveness of CBT in 11 participants with mild to severe TBI and insomnia, and it was found to result in clinically and statistically significant reductions in total wake time for 73% of the participants following 8 weeks of CBT, including stimulus control, sleep restriction, cognitive restructuring, sleep hygiene education, and fatigue management. Progress generally was sufficiently maintained at the 1- and 3-month follow-ups. Sleep improvements were accompanied by a reduction in general and physical fatigue symptoms. Acupuncture is another promising and relatively understudied instrument for treating post-TBI insomnia, which was found to be effective in a pilot randomized controlled trial (RCT) that compared it to an as-usual control condition [111]. Patients treated with acupuncture had significantly higher perceived sleep quality, cognitive function improvement as measured by the Paced Auditory Serial Addition Test and the Repeatable Battery for the Assessment of Neuropsychological Status, and the ability to taper sleep medication use [111]. The milder forms of SRBD often can be effectively managed by weight reduction, alcohol avoidance, nasal patency improvement, oral appliance use, and avoiding sleep in the supine position [112]. In more severe SRBDs, nasal continuous positive airway pressure (CPAP), delivering positive pressure through a nasal or full-face mask to maintain opening of the upper airway during sleep, is widely used and has been proven to be effective [113]. CPAP machine prices vary from approximately $700 to over $5000 [114]. The more expensive models usually incorporate alarms, medical data recording, and adjustable ventilator settings suitable for a wide range of disorders. In TBI patients, CPAP treatment significantly decreased apnea–hypopnea indices and improved sleep quality 3 months after administration, but it did not affect EDS [115]. However, that study did not report CPAP compliance and Epworth Sleepiness Scale (ESS) scores and Multiple Sleep Latency Test (MSLT) results were not adjusted for medication effects, which could explain the effect observed. Moreover, the main CPAP treatment target in several TBI patients may not be daytime sleepiness but cardiovascular complications stemming from intermittent hypoxia due to SRBD. Thus the proven apnea–hypopnea index reduction can be considered beneficial in preventing a cascade of adverse inflammatory and metabolic effects capable of initiating or exacerbating postinjury cardiovascular disease. Bright light therapy can advance the phase of circadian rhythms in delayed phase sleep disorder [116]. Its application following TBI demonstrated effectiveness in addressing fatigue and EDS [117]; however, published peer-reviewed papers discussing its efficacy

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remain scarce. This therapy and melatonin treatment appears to be efficacious in sleep (e.g., delayed sleep phase syndrome) when applied to individuals with TBI [118] and beneficial to mood, as reported in another study population [119]. Nagtegaal et al. [120] described a case of delayed sleep phase syndrome successfully treated with melatonin. TBI patients with narcolepsy and EDS have been reported to respond well to neurostimulant agents such as methylphenidate [121,122]. Kaiser et al. [123] recently reported the positive effect of modafinil in alleviating EDS after TBI. Concerning posttraumatic fatigue, Ouellet and Morin [105] proposed normalization of the sleep–wake schedule as an effective management method. It is debatable if all 84 sleep disorders in the core categories actually meet the chief criterion in the availability of an effective treatment that would benefit TBI patients who are positive for the condition. Presently scientific evidence supports the idea that a variety of sleep disorders can be effectively treated after TBI and that treatment positively affects outcomes (Table 1). 4.3. Screening and formal evaluation Screening tools and diagnosis and follow-up treatment facilities are necessary to detect a medical disorder or condition. In developed countries, clinicians analyze sleep using both subjective and objective tools. The former generally are questionnaires completed by subjects, and the latter are techniques, such as polysomnography (PSG), actigraphy, MSLT, and the maintenance of wakefulness test (MWT). Self-reported sleep measures are considered suitable for screening due to their cost-effectiveness and ready application; however, they may not be completely reliable, especially when self-insight (e.g., ability to recognize aspects of one’s own condition) may be affected, which is a principal concern in the TBI population [124]. Various sleep-related self-report measures have been used in TBI research and clinical practice to date. A recent systematic review identified 16 measures used to study sleep after TBI from more than 100 measures currently available in the field of sleep medicine [125]. Two self-report measures, the Pittsburgh Sleep Quality Index (PSQI) and the ESS, have been partially validated in the TBI population. The PSQI is a brief clinical tool encompassing multiple sleep domains (e.g., sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, sleep medication use, daytime dysfunction); it also is one of the few measures incorporating questions regarding daytime sleepiness. Fichtenberg et al. [36] reported on its validity in a subacute TBI sample of 50 consecutive patients, distinguished with respect to insomnia according to the Diagnostic and Statistical Manual of Mental Disorders criteria, fourth edition (DSM-IV) [126]. The overall agreement rate of the PSQI with the DSM-IV diagnosis was 94%, with 100% sensitivity and 96% specificity. When the PSQI-derived sleep-onset latency, sleep duration, and sleep efficiency calculations were compared using a sleep diary, the mean paired differences were small and the Pearson product moment correlation coefficient ranged from 0.633 to 0.796 (P < .05). The proposed global PSQI cutoff score of eight was found to be appropriate for correctly discriminating 96% of insomnia cases and a cutoff score of nine accurately established the sleep dysfunction in 98% of cases. Masel et al. [59] also reported the concurrent validity of the PSQI and ESS in 2001. They investigated ESS and PSQI scores and their relation to the mean MSLT scores in 71 TBI patients ages 3–27 years after injury. They found no significant correlation between the self-report scores and mean MSLT sleep latency. Sleep diaries frequently are used to evaluate individuals after TBI, enabling sleep quality and quantity assessment [20,35,61,127]. The findings from the diaries generally are applied toward a clinical diagnosis of insomnia and quantification of sleep and waking

Reference

Insomnia Li et al. (2004) [107]

Study design

 Randomized  Double-blind  Crossover trial

Kaiser et al. (2010) [123]

Prospective Randomized Double-blind Placebocontrolled  Pilot

   

Delayed sleep phase syndrome  Case report Nagtegaal et al. (1997) [120]  Randomized Kemp et al.  Double-blind (2004)  Controlled [110]  Crossover trial

Nonpharmacologic treatment options  Single-case Ouellet and design Morin  Multiple base(2007) lines across [105] participants Castriotta et al. (2009) [115]

 Prospective  Cross-sectional

Zollman et al. (2012) [111]

 Randomized  Controlled

Treatment

Participants who completed trial (n)/participants who were enrolled (N)

Treatment period

Drug:  Lorazepam-benzodiazepine hypnotic (0.5– 1 mg/d)  Zopiclone–nonbenzodiazepine hypnotic (3.75–7.5 mg/d)

6/6

1 wk/drug

Neurostimulant:  Modafinil (2  100 mg/ d)

51/51

Neurostimulant:  Modafinil (200 mg/d)

5/5 (3 narcolepsy, 2 PTH)

3 mo

 ESS  PSG  MSLT

Neurostimulant:  Modafinil (100–200 mg/ d)

20/20 (10 neurostimulant, 10 placebo)

6 wks

     

ESS FSS Actigraphy PSG MWT PVT

 Melatonin (5 mg/d)

1/1

4 wks

Drug:  Melatonin (5 mg/d)  Amitriptyline (25 mg)

7/7

1 mo/drug, 2-wk washout between

    

Plasma melatonin Body temperature Wrist activity EEG Sleep diary

CBT for insomnia:  Stimulus control  Sleep restriction  Cognitive restructuring  Sleep hygiene education  Fatigue management CPAP for OSA

11/11

8 wks

 Sleep diary

13/13

3 mo

24/24

5 wks, biweekly appointments

       

Acupuncture for insomnia:  Randomized to acupuncture  Randomized to control arms

Outcome measures

 Total sleep time  Questionnaire for nurses (scale 1–4 on alertness (feeling refreshed))  Self-report assessment (scale 1–10 on quality of sleep, depth of sleep, feeling refreshed, alert, tired)

 FSS  ESS  MOS Sleep Scale

ESS PSG AHI MSLT ISI Actigraphy RBANS PASAT

Treatment outcomes

 No difference in measures (exception: self-reported tiredness [P=.042])  No report on effectiveness of agent in reducing insomnia symptoms

 FSS, improvement not statistically significant (wk 4);  ESS, improvement at wk 4 but no improvement at wk 10;  Insomnia more severe with modafinil  MSLT and ESS, improvement not statistically significant;  1/3 Narcolepsy subjects and ½ PTH subjects, clinical improvement in MSLT Modafinil:  EDS, significant improvement;  MWT, improvement;  PTF, no improvement;  No clinically relevant side effects observed

 All measures returned to normal with treatment

Both drugs:  Sleep latency, duration, quality, daytime alertness, no improved. Effect size:Melatonin  Daytime alertness, improved. Amitriptyline:  Sleep duration, increased  73% of participants, statistically significant clinical improvement

CPAP:  AHI, significant improvement;  ESS and MSLT, no improvement Acupuncture:  Total sleep time, no significant change  ISI (sleep perception, improvement sustained)  RBANS and PASAT, significant improvement

Abbreviations: d, day; wks, weeks; FSS, fatigue severity scale; ESS, Epworth sleepiness scale; MOS, medical outcomes study; PTH, posttraumatic hypersomnia; mo, months; PSG, polysomnography; MSLT, multiple sleep latency test; EDS, excessive daytime sleepiness; MWT, maintenance of wakefulness test; PVT, psychomotor vigilance test; EEG, electroencephalography; CBT, cognitive behavioral therapy; CPAP, continuous positive airway pressure; OSA, obstructive sleep apnea; AHI, apnea–hypopnea index; ISI, insomnia severity index; RBANS, repeatable battery for the assessment of neuropsychological status; PASAT, paced auditory serial addition test.

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Excessive sleepiness or fatigue  Single-center Jha et al.  Double-blind (2008)  Placebo[118] controlled  Crossover trial  Prospective Castriotta  Cross-sectional et al. (2009) [115]

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Table 1 Treatments utilized in clinical trials sleep disorders on outcomes in the traumatic brain injury population.

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behavior over a certain period, usually 2–4 weeks. The instrument’s strength lies in its ability to prospectively depict sleep and daytime functioning over a particular duration. However, low diary return rates, response burden, possible impaired judgment, and common sleep state misperception in the TBI population warrants careful interpretation of the results. Several researchers have mentioned TBI patients under- or overreporting sleep disturbances and have recommended that self-reported sleep measures be utilized alongside objective instruments when assessing post-TBI sleep [20,21,59]. Currently, PSG is a reference standard for diagnosing specific sleep disorders, such as SRBD, narcolepsy, periodic limb movement disorder, and nocturnal seizures, among others, providing information on sleep continuity, sleep efficiency, sleep architecture, and physiologic parameters during sleep (e.g., heart activity and rate, breathing pattern, blood oxygen saturation, muscle movements) and allowing extensive study of electroencephalography (EEG) activity and arousability. It also provides an opportunity for continuous video and audio recording and monitoring of a patient’s sleep, which is particularly relevant for clinical differentiation between sleep disorders and epileptic phenomena after TBI. Although awakened and sleep-deprived EEG commonly is utilized for individuals with epilepsy, it may not reveal the diagnosis and full EEG PSG recordings can capture infrequent events and aid differential diagnoses [128]. The MSLT is a validated objective measure that quantifies daytime sleepiness. It has been proven useful in differentiating pathologic sleep abnormalities from self-reported sleepiness and post-TBI fatigue [38]. To diagnose narcolepsy, a patient falls asleep within 10 min and presents with at least two sleep-onset REM periods across 4–5 nap opportunities at 2-h intervals. The MWT evaluates an individual’s ability to remain alert. It is particularly relevant to individuals with TBI, as results can be linked to daytime vigilance or cognitive functioning variations [115]. Unfortunately, these tests are costly and currently require a specialized hospital or sleep clinic setting. Additionally, they may not adequately capture the fluctuating nature of sleep disorders such as insomnia and CRSDs. Furthermore, PSG results might be influenced by the first-night effect, the alteration of the sleep structure stemming from being in an unfamiliar environment as well as agitation and confusion in some TBI patients. Ambulatory PSG and other newly introduced medical devices [129] can measure sleep parameters in a less expensive and more natural manner. Actigraphy is an objective and less costly method of studying sleep–wake patterns and can conveniently record a patient’s activity during the entire day over long periods (e.g., weeks or months). It records sleep–wake parameters based on the absence or presence of motor activity (either limb or head) and has demonstrated promising application in individuals whose self-report is in question (e.g., dementia). Actigraphy has been used for individuals with acquired brain injury and was reported to have aided the study of circadian rhythm disorders. Zollman et al. [130] used actigraphy in a TBI sample and expressed caution regarding its application for TBI patients with spasticity, paresis, agitation, and impulsivity. A recent study by Nardone et al. [37] proposed transcranial magnetic stimulation as a useful complementary approach in the study of sleep pathophysiology after TBI. The authors found that posttraumatic sleep–wake disturbances were associated with changes in cerebral cortex excitability. Because these findings are similar to those reported in individuals with narcolepsy, cortical hypoexcitability might reflect a hypocretin (orexin) neurotransmitter system deficit. These observations may provide fresh insight into the causes of chronic sleepiness in TBI patients, which can manifest as loss of vigilance (e.g., attention). The psychomotor vigilance test is a visual signal detection test that correlates with the Stanford Sleepiness Scale and MSLT for convergent validity; it is reported to be a useful tool in TBI research

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[28,43,123]. A recent study [131] proposed that the psychomotor vigilance test might have clinical utility in quantifying impaired attention following TBI; the patients with TBI who reported fatigue or sleep disturbance had significantly greater attention outcome impairment compared to uninjured age- and sex-matched controls. The Profile of Mood States, designed to assess mood includes sleepiness items in vigor, confusion, fatigue, depression, and anger scales, indicating that sleepiness is not a unitary item [132]. In addition to the Functional Outcome of Sleep Questionnaire, which assesses the impact of excessive sleepiness on functional outcomes with respect to daily behaviors, this instrument has been utilized in the TBI population [27,115]. Researchers found both measures to be beneficial for evaluating sleepiness and wakefulness and for capturing the extra cognitive burden produced by sleep disorders in TBI patients. There are numerous instruments for detecting sleep dysfunction after TBI, which can assist in sleep functioning evaluation both in the acute and rehabilitation stages. As a first step, self-report measures (i.e., the PSQI enabling the differentiation of good and poor sleepers) can be utilized. For those suspected of having a sleep disorder or whose self-report data are not considered reliable, self-report should be followed by a more costly approach. Family member or caregiver involvement can enhance the validity of the responses and accuracy in reporting issues, such as snoring, bruxism, periodic leg movements, sleep talking, and other features the patient would not observe. The goal is to determine which sleep domain is impaired and to apply proper intervention accordingly. Due to the number of confounders associated with poor sleep following TBI and differentiating between primary and secondary sleep disturbances, it is important to consider the inclusion of additional measurements of common comorbidities, such as anxiety, depression, pain, and medication side effects alongside the initial assessment of sleep functioning [110]. Fig. 1 illustrates the proposed algorithm for structural screening for sleep dysfunction following TBI. Table 2 summarizes the symptoms and sleep features as well as the possible associated sleep diagnoses. 4.4. Cost of screening and intervention: how addressing sleep problems can reduce long-term costs The principles of cost, feasibility, and acceptability of screening and early treatment require further examination, and the value of screening for early disease detection in this particular situation should be emphasized. The first aim is related to the medical costs of undetected or untreated disorders and the other is related to economic costs [133]. Although the cost of undiagnosed sleep dysfunction has not been evaluated in the TBI setting, population-based research on the medical costs and economic burden of untreated sleep disorders as an indicator of the burden to society is striking. The total annual cost of insomnia in one Canadian province was estimated to be 6.6 billion Canadian dollars, with direct costs (e.g., healthcare consultations, transportation to consultation, prescription medications, alcohol as a sleeping aid, over-the-counter products) constituting $585.2 million and indirect costs (e.g., insomnia-related absenteeism, productivity losses) constituting approximately $6 billion. The average annual per-individual cost was $5010.00 for insomniacs and $421 for good sleepers—a 12-fold difference! The cost of untreated insomnia was significantly greater than that associated with its treatment [134]. Research on the costeffectiveness of using CPAP to treat severe OSA or hypopnea syndrome in the United Kingdom [135] by utilizing a Markov model, a method of representing a changing set of health states over time in which there is a known probability or transition rate from one health state to another [136], found that it was clinically more effective than no treatment. From the UK National Health Service perspective, this established CPAP as a cost-effective treatment [137].

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EDS/fatigue/impaired alertness (Tool: ESS8, FSS9, THAT10, etc.)

Screen for

Poor sleep hygiene (Tool: STQ3)

SRBD (Tool: STOP-BANG11)

Onset before TBI

Anxiety, depression (Tool: HADS5, PHQ6, etc.)

Narcolepsy or posttraumatic hypersomnia (Tool: UNS12, SNS13, etc.)

Evaluation (Tool: PSG and video recording)

Evaluation (Tool: PSG, MSLT14, MWT15)

Evaluation (Tool: Nocturnal EEG, full EEG, PSG and video recording)

Evaluation (Tool: PSG)

Screen for

Screen for

Screen for

Circadian rhythm sleep disorders (Tool: STQ, MEQ4, etc.)

Onset after TBI

Sleep behavior changes (Tool: self/partner report of parasomnia, movement, etc.)

Screen for

Difficulty falling asleep or maintaining sleep (Tool: ISI1, DII2, etc.)

Violent behavior (RBD)

nREM parasomnias

Seizures

Diagnosis

Other medical disorders, including pain (Tool: impact scales, pain scale7, etc.)

Treatment

Evaluation (Tool: PSG and video recording)

PLMD, RLS

Medication effects, substance use, etc.

Fig. 1. Algorithm for screening for sleep dysfunction following TBI including examples of screening tools. Abbreviations: DII, diagnostic interview for insomnia; EEG, electroencephalogram; ESS, Epworth sleepiness scale; FSS, fatigue severity scale; HADS, hospital anxiety and depression scale; ISI, insomnia severity index; MWT, maintenance of wakefulness test; MEQ, morningness–eveningness questionnaire; MSLT, multiple sleep latency test; PQH, patient health questionnaire; PLMD, periodic limb movement disorder; PSG, polysomnography; RBD, rapid eye movement sleep behavior disorder; RLS, restless legs syndrome; STQ, sleep timing questionnaire; SNS, Swiss narcolepsy scale; THAT, Toronto hospital alertness test; UNS, Ullanlinna narcolepsy scale. References: 1Morin CM, Belleville G, Belanger L, Ivers H. The insomnia severity index: psychometric indicators to detect insomnia cases and evaluate treatment response. Sleep 2011;34:601–8. 2Morin CM. Insomnia: Psychological Assessment and Management. New York, NY: Guilford Press; 1993. 3Monk TH, Buysse DJ, Kennedy KS, Pods JM, DeGrazia JM, Miewald JM. Measuring sleep habits without using a diary: the sleep timing questionnaire. Sleep 2003;26:208–12. 4Horne JA, Ostberg A. A Self Assessment Questionnaire to Determine Morningness-Eveningness in Human Circadian Rhythms. Int J Chronobiol 1976;4:97–110. 5Zigmond AS, Snaith RP. The HADS: Hospital Anxiety and Depression Scale. Windsor: NFER Nelson; 1983. 6Fann JR, Bombardier CH, Dikmen S, Esselman P, Warms CA, Pelzer E, et al. Validity of the patient health questionnaire-9 in assessing depression following traumatic brain injury. J Head Trauma Rehabil 2005;20:501–11. 7Dobscha SK, Clark ME, Morasco BJ, Freeman M, Campbell R, Helfand M. Systematic review of the literature on pain in patients with polytrauma including traumatic brain injury. Pain Med 2009;10:1200–17. 8Johns MW. Daytime sleepiness, snoring, and obstructive sleep apnea. The Epworth Sleepiness Scale. Chest 1993;103:30– 6. 9Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:1121–3. 10Shahid A, Wilkinson K, Marcu S, Shapiro CM. STOP-THAT-100 Rating Scales on Sleepiness. Toronto: Springer Publisher; 2011. 11Adams RJ, Piantadosi C, Appleton SL, Hill CL, Visvanathan R, Wilson DH, et al. Investigating obstructive sleep apnea: will the health system have the capacity to cope? a population study. Aust Health Rev 2012;36:424–9. 12Hublin C, Kaprio J, Partinen M, Koskenvuo M, Heikkila K. The Ullanlinna Narcolepsy Scale: validation of a measure of symptoms in the narcoleptic syndrome. J Sleep Res 1994;3:52–9. 13Sturzenegger C, Bassetti CL. The clinical spectrum of narcolepsy with cataplexy: a reappraisal. J Sleep Res 2004;13:395–406. 14 Carskadon MA, Dement WC, Mitler MM, Roth T, Westbrook PR, Keenan S. Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. Sleep 1986;9:519–24. 15Castriotta RJ, Atanasov S, Wilde MC, Masel BE, Lai JM, Kuna ST. Treatment of sleep disorders after traumatic brain injury. J Clin Sleep Med 2009;5:137–44.

Table 2 Evaluation and diagnosis of possible sleep disorders in the traumatic brain injury population. Symptom

Additional sleep features

Possible sleep diagnosis

Method of evaluation

EDS

Nonspecific

Any

Snoring REM sleep abnormalities Restlessness

SRBD Narcolepsy PLMD

Self-report measures, report of significant other, sleep diary PSG PSG and MSLT, MWT Actigraphy, PSG

Insomnia

Nonspecific DSPS, ASPD Neurologic symptoms

Any CRSD Any or none (neurologic disorder)

Self-report measures, actigraphy Self-report measures, diary, actigraphy PSG, head MRI

Sleep-disordered breathing

Snoring, gasping in sleep, dry mouth on awakening

SRBD

Self-report measures, significant other report and PSG

Sleep behavior changes

Complex movements Violence Dream-related

Epilepsy, parasomnia, RBD RBD, PTSD

PSG, nocturnal EEG PSG Self-report and PSG

Abbreviations: EDS, excessive daytime sleepiness; REM, rapid eye movement; SRBD, sleep-related breathing disorder; PLMD, periodic limb movements in sleep; PSG, polysomnography; MSLT, multiple sleep latency test; MWT, maintenance of wakefulness test; DSPS, delayed sleep phase syndrome; ASPD, advanced sleep phase disorder; CRSD, circadian rhythm sleep disorder; MRI, magnetic resonance imaging; RBD, REM sleep behavior disorder; PTSD, posttraumatic stress disorder.

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Cost savings associated with an educational campaign on the diagnosis and management of sleep-disordered breathing in the not-for-profit US-based Union Health Plan substantiated its efficacy; overall medical costs decreased considerably, saving $4.9 million over 2 years, excluding the decreased inpatient hospital costs and number of hospital admissions [138]. Data from a stroke rehabilitation unit revealed that the presence of sleep apnea in stroke patients undergoing rehabilitation was associated with more severe functional impairment and a longer hospitalization and rehabilitation period [139]. Sleep problems also were reported as being strongly and independently associated with subsequent retirement due to disability [140]. This finding is a serious challenge to social security. To prevent the reported negative outcomes observed in other study populations and to acknowledge the economic impact of undetected or untreated sleep dysfunction, it is apparent that early detection of sleep problems by screening may not only improve the health outcomes of those affected, but also may be economically beneficial in a TBI population. This benefit is promising for the proper allocation of resources during the rehabilitation phase after TBI, which could translate to long-term economic gain, e.g., by preventing secondary injuries, improving rehabilitation outcomes, and enhancing the potential to return to a productive life after injury. In view of the absence of screening cost-effectiveness in the TBI population, awareness and interpretation of relevant information from studies of other populations is essential. 5. Clinical and research agenda The cost of delivering proper medical care is high. Clinicians and policymakers search for a care delivery method to achieve the best outcome with reasonable costs without compromising patient health. Over the past decade, there has been a remarkable increase in acknowledgment of the importance of sleep and the need to diagnose and treat sleep disorders following TBI. Unfortunately there appears to be little if any change in the sleep functioning investigation methods in this population. Kennedy et al. [141] surveyed healthcare providers about their evaluation and treatment of mild TBI in adults. They presented two models describing mild TBI cases to staff in an emergency department and a primary care clinic, enquiring how they would evaluate and treat them. They found that the majority of staff would assess visual changes, nausea or vomiting, headache, and neck pain, and that emergency department personnel were more likely to make referrals to different specialties. Neither group mentioned assessing common postconcussive symptoms of fatigue, emotional changes, and problems sleeping [141]. The study highlights the need to include sleep in the education of healthcare professionals dealing with individuals with TBI and for the review of published research on sleep functioning after TBI regarding the development of guideline recommendations. The current argument for sleep dysfunction screening in the TBI population is that (1) TBI is a major health problem; (2) sleep dysfunction is highly prevalent after TBI; (3) little evidence exists for the relative benefits of sleep disorder treatment in the TBI population, though substantial research exists for other populations; (4) evidence on the drawbacks of screening is limited; and (5) the education provided to date on sleep and sleep disorders generally is significantly limited, particularly in TBI care, despite the numerous specialties and areas of expertise involved in TBI care and the differing screening-related values and preferences [142,143]. 5.1. Areas and unresolved issues in which further efforts should be applied 5.1.1. Education We should implement policy provision to educate treatment providers, clinical staff, and other healthcare professionals who

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deal with individuals with TBI concerning sleep dysfunction after injury and its effects on health, recovery, daytime performance, and quality of life after injury. 5.1.2. Policy We should implement structural screening (e.g., Fig. 1 sample) of sleep function in all individuals with TBI in the early stage of treatment and rehabilitation, first using the simpler techniques of self-report instruments (e.g., questionnaires completed by the individual with help from a significant other). This screening may be followed by more costly evaluation, such as PSG, actigraphy, MSLT, and MWT of those suspected of sleep dysfunction on the self-report or those whose self-report data are unreliable. 5.1.3. Treatment and cost-effectiveness: unresolved issues We must investigate if screening and treatment decrease the risk for poor long-term injury outcomes and determine if they are cost-effective. 5.1.4. Research: unresolved issues All but two (PSQI and ESS) standardized self-report sleep measures contain no data on psychometric properties in the TBI population. Therefore, do self-report instruments have the potential to directly promote TBI patient–centered care and to be a cost-effective screening tool for sleep dysfunction after injury once psychometrically evaluated? If randomized trials (e.g., on the value of sleep disorder screening tests) are to be performed, how should the issue of performing numerous adjustments for covariates and implementing a multidimensional approach to the assessment of outcomes be addressed? To elaborate, the baseline characteristics of the TBI population are heterogeneous (e.g., sex, age at injury, time since injury, injury severity [Glasgow Coma Scale] and localization, mechanism of injury, medication regimens at assessment, comorbid conditions [anxiety, depression, pain, cognitive level]), as is the prognostic risk (e.g., morbidity and mortality). The greater the population heterogeneity, the larger the RCTs required to detect differences in interventions. To address this issue in the TBI population in both the trial design and analysis phases, Turner et al. [144] recommended using strict study enrollment criteria (e.g., strict selection) or selecting participants with a specified risk level for the outcome of interest (e.g., prognostic targeting). Thus only individuals who would derive the most benefit from treatment would be enrolled in a trial. Another recommendation was adjustment for baseline characteristics (e.g., covariate adjustment) to account for interindividual differences in important prognostic outcome factors [144]. With regard to sleep disorders after TBI, both approaches including strict inclusion criteria and prognostic targeting, require well-established risk factors, which are not always known. Additionally, if a trial is planned based on restrictive inclusion criteria, the results cannot be generalized to a broader TBI population. Similarly, although covariate adjustment can be used to attain the same level of power with a reduced sample size, it cannot be advocated for the planning of smaller trials. 6. Conclusions We have summarized the status of the evidence for screening and outlined the key direction for identifying sleep disorders after TBI with the aim of improving the diagnosis, treatment, and rehabilitation of individuals with brain injury. In view of the relative scarcity of evidence from well-designed RCTs, it may appear that the findings from the past few decades regarding sleep and TBI research contain insufficient scientific evidence to merit the imple-

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mentation of sleep dysfunction screening in a TBI population; however, other factors may be used as evidence to influence decision making. First, conducting RCTs in a TBI population poses significant challenges. Issues with characterizing and properly grouping patients according to sex, age, injury localization and severity, confounding factors, difference in medication regimen, genetic makeup, ethical concerns, difficulty obtaining proper resources, and multidimensional outcome considerations are challenges that render a well-designed RCT in a TBI population hardly feasible [145]. Second, Sackett et al. [146] defined evidence-based medicine in 2000 as ‘‘the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients’’ [146]. This best evidence is available and its implementation into practice could enhance clinical care and ensure that priorities for the health and rehabilitation of individuals with TBI are met, focusing on the diverse factors that contribute to the experienced disability, including other health conditions, impairments, and capacity restrictions [147]. Lastly, due to issues regarding selfinsight and awareness, some TBI patients cannot or will not report sleep difficulties. Accordingly, there remains an unmet need for sleep disorder screening in the TBI population. Funding sources This manuscript had no external funding source. The first author was supported by a 2012/13 Toronto Rehabilitation Institute Scholarship, 2012/13 Ontario Graduate Scholarship, and 2013/15 Frederick Banting and Charles Best Canada Graduate Scholarships-Doctoral Awards from the Canadian Institutes of Health Research. We also recognize the support of the Canadian Institute of Health Research – Institute of Gender and Health #CGW-126580. Support also was provided by the Ontario Work Study Program. Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2013.07.009.

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Screening for sleep dysfunction after traumatic brain injury.

Numerous studies on the high prevalence of sleep disorders in individuals with traumatic brain injury (TBI) have been conducted in the past few decade...
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