INTRODUCTION — Sleep-wake disturbances are among the most prevalent and persistent sequelae of traumatic brain injury (TBI) [1-3]. Patients suffering from TBI of any severity, in both the acute and chronic phases, commonly report excessive daytime sleepiness, increased sleep need, insomnia, and sleep fragmentation [4-6].
Identification and treatment of sleep disorders in patients with TBI is important and can complement other efforts to promote maximum functional recovery.
The clinical features, evaluation, and treatment of sleep-wake disorders in patients with TBI are discussed here. The classification of TBI and management of other complications of head injury, including the postconcussion syndrome, are reviewed separately. (See "Traumatic brain injury: Epidemiology, classification, and pathophysiology" and "Acute mild traumatic brain injury (concussion) in adults" and "Postconcussion syndrome" and "Sequelae of mild traumatic brain injury".)
EPIDEMIOLOGY — TBI is a well-established risk factor for incident sleep disorders. In a cohort study of nearly 100,000 United States military veterans who sustained TBI and the same number of age-matched veterans without TBI, those with TBI were 41 percent more likely to develop a new sleep-wake disturbance over a mean follow-up of five years, after adjustment for multiple demographic variables and medical conditions [7].
The point prevalence of sleep-wake disturbances after TBI varies depending on the phase and severity of injury. TBI severity is most commonly classified according to the Glasgow Coma Scale (GCS) (table 1).
●Mild TBI – Sleep-wake complaints are reported by approximately one-third of adults within the first 10 days after mild TBI and up to 50 percent at six weeks post-injury [8-11]. Risk factors for persistent sleep disturbance may include female sex, poor pre-injury sleep quality, and symptoms of poor sleep or cognition within two weeks after injury [11]. A meta-analysis of 44 observational studies of sleep disturbances in children after mild TBI found a pooled prevalence of 51 percent within one week and 21 percent after three months [12].
●Severe TBI – The prevalence is even higher among individuals with severe TBI [13,14]. In a prospective study of 205 patients admitted to an acute rehabilitation hospital after severe TBI, 84 percent had sleep-wake disturbances upon admission, and 66 percent continued to have disturbances at one month post-injury [14].
●Chronic phase – In observational studies of survivors of TBI, the most common sleep disturbances reported in the chronic phase (>3 months after injury) are [15]:
•Insomnia (50 percent)
•Difficulty maintaining sleep (50 percent)
•Poor sleep efficiency on polysomnography (PSG) (49 percent)
•Early morning awakenings (38 percent)
•Nightmares (27 percent)
Of note, many studies evaluate the subjective experience of insomnia without objective sleep measurement using electrophysiologic testing [15]. This is relevant given that, in at least one study, brain-injured patients tended to overestimate insomnia when subjective and objective measures were compared [16].
Additional abnormalities on formal testing in survivors of TBI include excessive daytime sleepiness, increased sleep need, and sleep-related breathing disorders [5,15,17,18].
PATHOPHYSIOLOGY — The pathophysiology and neuropathology of sleep-wake disturbances after TBI are under investigation in both animal models and humans [3].
●Orexin (hypocretin) and the hypothalamus – Changes in the neuropeptide orexin (also known as hypocretin), which is deficient in human narcolepsy type 1, likely play a role in sleepiness and sleep fragmentation after TBI. Orexin neurons in the posterior hypothalamus excite several downstream wake-promoting monoaminergic and cholinergic systems and therefore possess a strong wake-promoting effect [19].
Studies in patients have identified low orexin levels in the cerebrospinal fluid (CSF) within the first four days of moderate to severe TBI as well as a reduction in the number of orexin neurons in the hypothalamus in autopsy specimens [20,21]. Mouse models of mild and moderate TBI show decreased brain orexin levels and decreased orexin neuron activation during wakefulness after brain injury [22-24].
●Other wake-promoting brain regions – Other wake-promoting areas of the brain, such as the ventral periaqueductal gray, locus coeruleus, basal forebrain, and tuberomammillary nucleus, could also play a role. Postmortem studies in patients with severe TBI have shown loss of histaminergic neurons in the tuberomammillary nucleus [25], loss of serotonergic dorsal raphe nuclei neurons, and loss of noradrenergic locus coeruleus neurons [26].
●Melatonin – Melatonin is produced by the pineal gland and regulates the sleep-wake cycle following a circadian pattern of release into the bloodstream. Several studies in TBI survivors have shown alterations in melatonin secretion compared with controls in both the acute and chronic phases after injury [27-30]. Despite this data, however, exogenous melatonin does not appear to be helpful after TBI. (See 'Insomnia' below.)
●Structural brain changes – Abnormal neuroimaging is found in only a minority of patients with mild TBI, although imaging is likely to miss more subtle brain damage such as diffuse axonal injury or microhemorrhages, which may affect sleep-wake and circadian circuits. In an electrophysiologic and imaging study, intracranial hemorrhage due to TBI was associated with increased sleep need, independent of the extent and location of the hemorrhage [31]. In a separate study, analysis of microbleed patterns in patients with coma due to severe TBI found a variety of affected arousal nuclei, rather than a single nucleus affected in all patients [32].
CLINICAL FEATURES
Symptom spectrum — The most common manifestations of sleep-wake disorders after TBI are excessive daytime sleepiness, increased sleep need, and insomnia [7]. Less commonly, patients experience circadian sleep-wake rhythm disturbances and abnormal movements or behaviors during sleep, such as sleep talking, bruxism, and dream enactment.
Excessive daytime sleepiness — Excessive daytime sleepiness, distinct from fatigue, is a prominent symptom after TBI. The reported frequency in patients with TBI ranges from approximately 50 to 80 percent, compared with an expected rate in the general population of 10 to 25 percent [33-36].
Excessive daytime sleepiness refers to the inability to maintain wakefulness and alertness during the major waking episodes of the day, with sleep occurring unintentionally or at inappropriate times [37]. Sleepiness manifests mainly during sedentary activities, in contrast with fatigue, which typically affects pursuit of more active goals. (See "Approach to the patient with excessive daytime sleepiness", section on 'Definitions'.)
Some individuals with excessive daytime sleepiness after TBI describe daytime sleep attacks, similar to those experienced by patients with narcolepsy. However, additional symptoms of narcolepsy, such as cataplexy and sleep paralysis, are uncommon and have been described only in rare case reports [38]. No patient has been reported with the complete syndrome of posttraumatic orexin-deficient narcolepsy with cataplexy.
Subjective excessive daytime sleepiness is often but not always accompanied by a short time to fall asleep on the multiple sleep latency test (MSLT). A mean sleep latency of ≤8 minutes is generally considered to be abnormal. In addition to a reduced mean sleep latency, some patients have two or more sleep-onset rapid eye movement (REM) periods (SOREMPs) during the MSLT, fulfilling electrophysiologic criteria for narcolepsy type 2 (narcolepsy without cataplexy). However, before diagnosing narcolepsy after TBI, insufficient sleep syndrome must be ruled out, as chronic sleep deprivation can produce increased REM sleep pressure. (See "Clinical features and diagnosis of narcolepsy in adults", section on 'Diagnosis'.)
In one prospective study of 65 patients six months after TBI, 28 percent had posttraumatic sleepiness and 3 percent met criteria for narcolepsy type 2 [17]. A similar study found that 6 percent of patients met MSLT criteria for narcolepsy type 2 at a mean of 64 months after TBI, a marked increase compared with the prevalence in the general population (<0.1 percent) [5,39]. Other studies have also found that sleepiness persists long term in many patients [40]. (See 'Natural history' below.)
Kleine-Levin syndrome, a recurrent and severe hypersomnia, may occur in response to precipitating events such as TBI. In one large series of 186 patients with Kleine-Levin syndrome, 9 percent reported symptoms starting shortly after TBI [41]. (See "Kleine-Levin syndrome (recurrent hypersomnia)".)
Increased sleep need (pleiosomnia) — Increased sleep need is common after TBI. Since the term hypersomnia is often used for both excessive daytime sleepiness and increased sleep need, the term pleiosomnia has been proposed to denote an increased need for sleep per 24 hours compared with the patient's pre-TBI baseline [42].
In a prospective electrophysiologic study of 65 patients who were studied six months after TBI, 22 percent reported that they needed at least two more hours of sleep in a 24-hour period than before the injury [17]. This general pattern was confirmed in a prospective case control study that included 42 patients with TBI studied six months after injury, in which post-TBI patients slept 1.2 hours more than matched controls [31]. This pattern persisted at 18 months [40]. (See 'Natural history' below.)
In both of these studies, patients with TBI underestimated both excessive daytime sleepiness and pleiosomnia [17,31]. In addition, daytime sleepiness was more pronounced in TBI patients with shorter sleep duration, suggesting that sleepiness might constitute an epiphenomenon of insufficient sleep in subjects needing more sleep than usual.
Insomnia — Insomnia has been widely documented in the chronic phases after TBI. Symptoms may include difficulty initiating sleep, sleep fragmentation, and early morning awakenings, plus negative consequences on daytime performance, vigilance, and mood.
Insomnia tends to be more prevalent after mild TBI compared with moderate or severe TBI [43,44], affecting more than 70 percent of patients [45]. Repeated head injuries may also be a risk factor [46]. The 12-month course of insomnia after TBI is markedly heterogeneous; some patients have acute mild to severe insomnia that remits, some have stable/persistent insomnia, and others have delayed onset of insomnia [47].
Insomnia often persists long term in TBI survivors. In one study, insomnia was present in approximately one-quarter of patients five years after injury [43]. In studies of military service members with TBI, rates of insomnia are greater than 50 percent at 15 to 20 years after injury [48,49].
The presence of insomnia correlates with decreased satisfaction in life, anxiety, and depression [50]. (See "Risk factors, comorbidities, and consequences of insomnia in adults".)
Circadian sleep-wake rhythm disturbances — There is preliminary evidence that disorders of sleep-wake timing (circadian rhythm sleep-wake disorders), including delayed sleep-wake phase disorder, irregular sleep-wake rhythm disorder, and non-24-hour sleep-wake rhythm disorder, occur with increased frequency in patients with TBI.
In moderate to severe TBI, actigraphy recordings in 16 patients within the first 10 days post-injury revealed severe fragmentation of the rest-activity cycle, reflecting severe sleep-wake fragmentation and possibly consistent with an irregular sleep-wake rhythm disorder [51].
Symptoms of a circadian sleep-wake rhythm disorder are easy to overlook and are often misattributed to insomnia [52-54]. An assessment of circadian sleep-wake rhythm dysfunction is therefore particularly relevant in patients with a history of TBI who present with chronic insomnia symptoms [54]. The distinction is important, since treatment approaches differ. (See "Evaluation and diagnosis of insomnia in adults", section on 'Differential diagnosis'.)
Patients with delayed sleep-wake phase syndrome typically go to bed late and wake up late relative to the general population. They may complain of difficulty falling asleep at usual bed times, and difficulty getting up at standard wake times. This may be confused with insomnia, in which patients have difficulty falling asleep or staying asleep regardless of bed time. (See "Delayed sleep-wake phase disorder", section on 'Clinical features'.)
Patients with an irregular sleep-wake rhythm lack a clearly defined circadian rhythm of sleep and wakefulness, such that sleep and wake patterns appear somewhat random across days to weeks. They may complain of both difficulty sleeping at the desired time and excessive daytime sleepiness and naps. Although insomnia can be accompanied by complaints of excessive daytime sleepiness, it is more commonly associated with difficulty napping or sleeping during the day. (See "Overview of circadian rhythm sleep-wake disorders".)
Abnormal movements or behaviors during sleep — Parasomnias and sleep-related movement disorders may occur with increased frequency after TBI in both the acute and chronic phases.
Symptoms include dream reenactment behaviors characteristic of REM sleep behavior disorder (RBD), somniloquy (sleep talking), sleep-related enuresis, and sleep-related bruxism (teeth grinding) [55-57].
Posttraumatic stress disorder (PTSD) increases the risk of RBD beyond what is seen with TBI alone [57]. A parasomnia distinct from RBD, "trauma-associated sleep disorder," has been postulated, which encompasses the clinical triad of dream enactment, REM sleep without atonia (RSWA), and autonomic hyperarousal (eg, tachycardia). This parasomnia was first noted in military personnel, and TBI as a triggering event is thought to be a risk factor [58-60].
Of note, it is not yet clear whether trauma-associated sleep disorder and/or RBD after TBI are associated with future risk of neurodegenerative synucleinopathy, as is the case in idiopathic RBD [61,62]. Since TBI and PTSD are risk factors for Parkinson disease, the association of RBD with TBI/PTSD could reflect an early clinical manifestation of posttraumatic neurodegeneration [63]. (See "Rapid eye movement sleep behavior disorder", section on 'Etiology'.)
Sleep-disordered breathing — Sleep-related breathing disorders, including obstructive sleep apnea (OSA) and central sleep apnea (CSA), may occur with increased frequency after TBI [5,64,65]. The reported prevalence of OSA varies widely across studies, ranging from 11 to 77 percent [15,17,66,67]. The highest rates have been in studies that enrolled military personnel with sleep complaints from a sleep clinic, a population known to be enriched for sleep problems [33,66,68].
Many symptoms of OSA overlap with those of TBI as well as other sleep-wake disorders. The most common symptoms of OSA in the general population are daytime sleepiness and loud snoring. Additional symptoms include waking up gasping or choking, morning headaches, nocturia, moodiness or irritability, lack of concentration, and memory impairment. On physical examination, patients are often obese and may have evidence of a crowded oropharynx and increased neck circumference. Clinical features of CSA are similar, except that obesity is less likely to be present. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults", section on 'Clinical features'.)
Important comorbidities — Psychiatric disorders and chronic pain commonly co-occur in patients with TBI. These comorbidities are important to recognize, since they may cause or exacerbate a wide range of sleep-wake disturbances.
●Depression and anxiety – Patients with TBI have high rates of depression and anxiety. In some, depression and anxiety are premorbid conditions that may be exacerbated after TBI; in others, depression or anxiety emerges after TBI [69,70].
Nearly 75 percent of adults with depression report sleep difficulties, including insomnia, excessive daytime sleepiness, increased sleep need, early morning awakenings, and sleep fragmentation [71]. TBI may exacerbate sleep-wake disturbances in patients with comorbid depression and anxiety [72,73]. Conversely, untreated depression or anxiety may prevent successful treatment of sleep disturbances in patients with TBI.
●Posttraumatic stress disorder – TBI and PTSD commonly co-occur, especially in the military population, rendering a much higher incidence of PTSD-related nightmare disorder and dream enactment compared with the non-TBI population [74,75]. TBI may increase vulnerability to PTSD by damaging autonomic networks in the central nervous system [76].
●Chronic pain – Patients with TBI report more difficulty managing pain [77]. In a systematic review of 23 studies and over 4000 patients with TBI, chronic pain affected 52 percent of patients [78]. Chronic pain affects sleep quality by fragmenting sleep and reducing slow-wave sleep [79].
Electrophysiologic changes — Electrophysiologic changes in sleep are apparent in both the acute and chronic stages of TBI and vary according to the severity of the injury.
In the acute stage after mild TBI, patients may show longer sleep latency and lower sleep efficiency, along with lower delta power (but higher alpha and beta power) during non-REM (NREM) sleep [80,81]. This electroencephalogram (EEG) pattern of fast frequencies intruding into deep NREM sleep has been described in insomnia patients and may represent a deficit in turning off arousal [82].
EEG patterns in the acute stage after severe TBI may have prognostic implications. Slow-wave sleep, sleep spindle density, and other markers of sleep quality on EEG in the acute phase have been associated with improved modified Rankin Scale scores, rates of discharge to home or acute rehabilitation after hospitalization, and long-term cognitive outcomes [83,84]. Conversely, poor sleep after TBI has been associated with impeded recovery [85].
Chronic changes in sleep architecture have also been described after TBI across of range of severities. In a meta-analysis of 14 observational studies, chronic TBI (>6 months after injury) was associated with increased slow wave sleep (SWS), and moderate to severe TBI was associated with reduced stage 2 sleep and reduced sleep efficiency [86].
Natural history — Many of the sleep-wake disturbances described above appear to persist long term after TBI and have a chronic impact on well-being [87]. This was illustrated by a prospective case-control study in which 31 out of 60 patients with TBI of any severity were evaluated at 18 months after injury [40]. Key findings included the following:
●Pleiosomnia persisted at 18 months, independent of the severity of TBI and other clinical characteristics. Compared with healthy controls, patients with TBI required significantly more sleep per 24 hours at both six months (8.3 versus 7.1 hours) [31] and 18 months after injury (8.1 versus 7.1 hours) [40].
●Two-thirds of patients with TBI had objective evidence of excessive daytime sleepiness on MSLT at 18 months, and symptoms were largely unrecognized by patients.
●As in the earlier phases of injury, patients underestimated their degree of sleepiness and sleep need on sleep logs and questionnaires.
EVALUATION — Sleep-wake disorders are common after TBI and should be suspected in patients presenting with a broad range of sleep complaints. The goals of the evaluation are to define the sleep complaint, diagnose specific treatable sleep disorders, and identify any additional medical and psychiatric comorbidities that may be contributing to the sleep disturbances.
Most sleep-wake disorders are diagnosed using a combination of both subjective and objective screening tools in the clinic [88]. Subjective tools include a sleep history and questionnaires completed by patients, while objective tools include actigraphy, polysomnography (PSG), multiple sleep latency test (MSLT), and the maintenance of wakefulness test (MWT).
Patients with TBI may overestimate insomnia complaints, whereas they underestimate excessive daytime sleepiness and sleep need [16,31,34,40,89,90]. These observations stress the importance of objective sleep testing in patients with TBI.
History — The goals of the history are to refine the sleep complaint and identify potential causes.
●Assess multiple domains – Questions should target multiple sleep domains, including perceived sleep quality, sleep latency, sleep duration, sleep disturbances (including abnormal movements or behaviors during sleep), sleep medication use, daytime dysfunction, and daytime sleepiness. The Pittsburgh Sleep Quality Index (PSQI) (table 2 and table 3) is a clinical questionnaire encompassing multiple sleep domains that can be useful to guide a structured interview [91] and has been partially validated in the TBI population [34,92,93]. In TBI populations, a more stringent cutoff score (eg, ≥8 instead of >5) may improve PSQI validity [92,94].
●Quantify sleepiness – For patients who complain predominantly of excessive daytime sleepiness, the history should attempt to differentiate sleepiness from other common complaints such as fatigue, lack of energy, or weakness. The Epworth Sleepiness Scale (ESS) (calculator 1) is a widely used instrument for quantifying subjective sleepiness that has also been partially validated in patients with TBI [34,92,93]. Scores of 10 or more points are generally considered abnormal and support the complaint of excessive daytime sleepiness. As with other measures, ESS scores should be used in combination with other tools, as patients with TBI may underestimate their degree of daytime impairment [34]. (See "Quantifying sleepiness", section on 'Epworth Sleepiness Scale (ESS)'.)
●Review sleep diaries – In patients whose predominant complaint is insomnia, the history should elicit a detailed description of sleep habits over a 24-hour period and trends over time. This includes questions about sleep quantity and quality, sleep timing and regularity, quality of the sleep environment, and daytime symptoms. A sleep diary or log, to be completed by the patient in advance or following the initial evaluation, can be particularly helpful to supplement the history (table 4 and table 5).
Sleep diaries have the advantage of assessing sleep quality, sleep quantity, and circadian patterns over many days or weeks. Review of a sleep diary can provide clues to circadian sleep-wake rhythm disturbances, which are often mistaken for insomnia (see 'Circadian sleep-wake rhythm disturbances' above). To more objectively assess circadian sleep-wake rhythm disorders, actigraphy recordings for two to three weeks are very useful. (See 'Actigraphy' below.)
●Obtain collateral history – Collateral information from family members and bed partners should be obtained if possible. In particular, bed partners are a more reliable source than the patient for information about snoring, periodic limb movements, acting out of dreams, sleep walking, and other parasomnias. Loud or habitual snoring and witnessed apneas can suggest a diagnosis of obstructive apnea and should prompt PSG, especially if the presenting complaint is daytime sleepiness. (See 'Polysomnography' below.)
●Screen for psychiatric comorbidities – Given the frequent comorbidity of psychiatric disorders in patients with TBI and their implications for treatment, the history should also probe for symptoms of depression, anxiety, and posttraumatic stress disorder (PTSD). Patients can be screened for depression by asking about depressed mood, loss of interest or pleasure in activities, change in appetite or weight, psychomotor retardation or agitation, low energy, poor concentration, thoughts of worthlessness or guilt, and recurrent thoughts of death or suicide. A two- or nine-item screening tool such as the Patient Health Questionnaire (PHQ)-9 or its abbreviated form is easy to use, reliable, and valid in primary care settings (table 6). (See "Screening for depression in adults".)
●Review medications and substances – The medication list should be reviewed in all patients to identify potentially contributing agents. A wide variety of medications used in the management of acute complications of TBI may contribute to daytime sleepiness, including antiepileptic drugs, opioid analgesics, benzodiazepines, antipsychotics, and certain antidepressants (table 7). The list is similarly long for drugs that may cause or aggravate insomnia (eg, glucocorticoids, bronchodilators, and central nervous system stimulants) (table 8). Opioids, alcohol use, and substance abuse are also relevant for sleep disturbances including sleep-related breathing disorders. (See "Sleep-disordered breathing in patients chronically using opioids".)
Laboratories — Basic laboratories are likely to be of low yield in the evaluation of sleep-wake disorders. Serum thyroid stimulating hormone (TSH) and ferritin may be useful in ruling out sleep-wake disturbances secondary to thyroid disorders and iron insufficiency. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults", section on 'Low iron stores'.)
Cerebrospinal (CSF) markers and saliva melatonin measurements are not currently used clinically but may hold promise in the future.
Actigraphy — Actigraphy records rest-activity patterns using an accelerometer to detect motion, often combined with a light detector, usually worn on the nondominant wrist. Actigraphy results are an objective counterpart to data obtained from a sleep diary. (See "Actigraphy in the evaluation of sleep disorders".)
Although not widely available for clinical purposes in the United States and moderately expensive, actigraphy can be useful as an objective measure of sleep-wake patterns in patients with a complaint of excessive daytime sleepiness. It also has the advantage over PSG of recording activity patterns over long periods of time (ie, weeks to months). An actigraphy pattern showing much longer sleep times on weekends than weekdays supports a diagnosis of insufficient sleep syndrome in patients with a complaint of daytime sleepiness.
Consumer wearable devices with sleep-tracking technologies, on the other hand, might appeal as an attractive alternative to actigraphy and in-laboratory sleep testing. However, implementation of most devices into clinical practice is limited by insufficient or absent validation and accuracy studies. (See "Actigraphy in the evaluation of sleep disorders", section on 'Consumer wearable devices'.)
Actigraphy has been used in many studies of adult patients with TBI [13,17,42,51,95,96], though caution should be exercised regarding using activity as a surrogate for sleep in patients with locomotor limitations including spasticity, paresis, depression, and/or agitation. Even in the absence of these limitations, actigraphy may underestimate the level of sleep disruption compared with polysomnography [97].
Actigraphy may be particularly useful in confirming rest-activity patterns in patients with suspected Kleine-Levin syndrome associated with TBI. (See 'Excessive daytime sleepiness' above.)
Polysomnography — PSG is not necessary in all patients with sleep-wake complaints but should be obtained in selected patients, based on the history. Given the higher prevalence of sleep-wake disorders in patients with TBI, there should be a low threshold to obtain PSG for any sleep history or complaint that is suspicious for sleep apnea (eg, excessive daytime sleepiness, snoring, comorbid obesity) or hypersomnia. (See "Overview of polysomnography in adults".)
If obstructive sleep apnea (OSA) is the overriding suspicion based on the history, home sleep apnea testing is an alternative to in-laboratory PSG. (See "Home sleep apnea testing for obstructive sleep apnea in adults".)
Multiple sleep latency test — Like PSG, an MSLT is not necessary in all patients with sleep-wake complaints but is suggested in selected patients, particularly those with a chief complaint of excessive daytime sleepiness who have had sleep apnea ruled out by PSG. (See "Quantifying sleepiness", section on 'Multiple sleep latency test (MSLT)'.)
A mean sleep latency less than eight minutes is generally considered to be objective evidence of excessive daytime sleepiness. Several specific sleep disorders can also be diagnosed in the appropriate clinical setting. Examples include the following:
●If excessive daytime sleepiness persists for three months after TBI with a mean sleep-onset latency of less than eight minutes and with fewer than two sleep-onset rapid eye movement (REM) periods, then the diagnosis is "hypersomnia caused by medical condition," or "posttraumatic hypersomnia" [98].
●In the case of a short mean sleep-onset latency and the occurrence of multiple sleep-onset REM periods (SOREMPs), "posttraumatic narcolepsy" or "narcolepsy caused by medical condition" should be distinguished from insufficient sleep syndrome (ie, chronic sleep deprivation), which can also present with enhanced REM sleep pressure [99].
TREATMENT — Treatment of sleep-wake disturbances after TBI depends on the dominant symptom or specific sleep-wake disorder and relevant comorbidities (figure 1). The goals of treatment are symptom mitigation, functional recovery, and improvement in quality of life [13,100,101].
Symptom-directed therapy
Excessive daytime sleepiness — Excessive daytime sleepiness is often multifactorial. Any underlying conditions identified during the evaluation that may contribute to daytime sleepiness should be addressed and treated, including:
●Depression and anxiety
●Obstructive sleep apnea (OSA)
●Circadian sleep-wake rhythm disturbances, such as delayed sleep-wake phase disorder
●Restless legs syndrome
●Insufficient sleep
●Adverse effects from medications; if feasible, discontinue the medication or change the timing of administration
For patients with persistent symptoms or no other identifiable causes, pharmacologic treatment options include wakefulness-promoting agents (modafinil, armodafinil) and stimulants such as methylphenidate. Of these, we suggest modafinil or armodafinil as first-line therapy, based on supporting data in case reports and two small placebo-controlled randomized trials in patients with TBI, as well as indirect data from larger randomized trials in patients with narcolepsy [102-105]. Methylphenidate is an alternative to modafinil and armodafinil that is less well studied in patients with TBI [106,107].
Modafinil is typically started at a dose of 100 mg twice daily (first dose upon awakening, second dose at midday) and can be titrated up to 200 mg twice daily as needed by symptomatic benefit. Armodafinil has a longer half-life and is typically dosed at 50, 150, or 250 mg once daily in the morning.
In a randomized, placebo-controlled, multicenter trial of 117 adults with a history of TBI, baseline Epworth Sleepiness Scale (ESS) score ≥10, and sleep latency less than eight minutes on a multiple sleep latency test (MSLT), patients treated with armodafinil 250 mg daily for 12 weeks showed significant improvement in sleep latency compared with placebo (+7.2 versus +2.4 minutes) [102]. Subjective sleepiness was improved on some measures but not others at various doses of armodafinil (50, 150, or 250 mg/day). Similar results were reported in a smaller randomized trial of modafinil [103]. Modafinil and armodafinil were well tolerated in both trials; headache is the most common side effect of both drugs.
Morning bright light therapy has been studied as a nonpharmacologic treatment option in posttraumatic fatigue and may also have some benefit for daytime sleepiness. The premise of light therapy is to help subclinical circadian sleep-wake rhythm disturbances that may be contributing to sleepiness. Four small trials in patients with TBI and persistent fatigue found significant reductions in fatigue and daytime sleepiness after four or six weeks of morning blue or white light therapy compared with placebo or no treatment [108-112].
Other novel treatments being studied include dietary supplementation with branched chain amino acids (BCAAs), which improved wakefulness and cognition in an animal model of mild to moderate TBI [22,113]. The mechanism of action of BCAAs was the restoration of excitatory glutamate within presynaptic terminals on wake-promoting orexin neurons in the hypothalamus [24]. A small double-blind, placebo-controlled randomized trial of BCAA supplementation in 32 veterans in the chronic phase of recovery from TBI found improvements in both subjective insomnia severity and actigraphically-determined sleep measures, providing rationale for larger studies [114].
Insomnia — Pharmacologic and behavioral approaches for insomnia in patients with a history of TBI are generally similar to those in the general population. (See "Overview of the treatment of insomnia in adults".)
In patients with TBI, special consideration should be paid to cognitive impairment, which may increase the risk of side effects from sedative/hypnotic medications, and comorbid affective disorders, which are common in patients with TBI and may require additional therapy.
●Behavioral approaches – Cognitive-behavioral therapy for insomnia (CBT-I) and acupuncture are the best studied approaches in patients with TBI [115-118]. A systematic review of 10 studies on behavioral interventions to improve sleep after TBI found evidence to support CBT-I, sleep-hygiene-related interventions, alone or in combination with other treatments, and morning blue light therapy [119].
Acupuncture may have some benefit as well [116,117]. In a sham-controlled trial in 60 veterans with refractory sleep disturbance after mild TBI, twice weekly sessions of acupuncture for five weeks led to modest short-term improvements in subjective and actigraphic sleep parameters, although benefits were not sustained at a four-week follow-up visit [117]. Treatment was well tolerated in patients with and without concurrent posttraumatic stress disorder (PTSD).
●Pharmacotherapy – With all pharmacologic therapies for insomnia, patients should be treated with the lowest effective dose and for the shortest time period possible [120,121]. Limited data in patients with TBI suggest that benzodiazepine and nonbenzodiazepine receptor agonists are similarly effective [122].
Melatonin has appeal based on its circadian effects and relative safety. However, supportive evidence for a clinical benefit of melatonin in patients with insomnia associated with TBI is limited [123-125]. In a crossover randomized trial of 33 adults recovering from TBI, melatonin improved subjective sleep quality and some objective measures of sleep quality, increased sleep efficiency, and reduced anxiety without causing daytime sleepiness [124]. A trial in children aged 8 to 18 years with persistent postconcussion symptoms found that 3 or 10 mg of melatonin increased sleep duration, and the higher dose improved sleep efficiency [126].
Pleiosomnia — There are no specific therapies for increased sleep need after TBI. Nonetheless, the symptom can be quite disturbing to patients, particularly those with a sleep need of 12 hours per day or more. Reassurance that the symptom is common after TBI may be helpful.
One possibility is that increased sleep need represents a necessary physiologic response to the injured brain; if this is the case, curtailing sleep could counteract a necessary healing response. On the other hand, pleiosomnia might be solely due to damage to wake-maintaining systems. In this case, tailored treatment strategies may emerge in the future.
Specific disorders
Circadian sleep-wake rhythm disorders — Therapeutic approaches to circadian sleep-wake rhythm disorders in the general population include behavioral modifications, light therapy, and melatonin. (See "Delayed sleep-wake phase disorder", section on 'Management'.)
These approaches have been used with some success in patients with TBI in case reports and small studies [123,127]. Melatonin (5 mg) and amitriptyline (25 mg) were examined in a pilot randomized, placebo-controlled crossover study of seven patients with post-TBI chronic sleep disturbances [123]. While there were no significant differences in sleep latency, duration, quality, or daytime alertness for either drug compared with baseline, melatonin was associated with a trend towards improved daytime alertness, and patients on amitriptyline reported increased sleep duration.
Parasomnias — Parasomnias seen in the post-TBI population include non-rapid eye movement (NREM) parasomnias such as nightmares and rapid eye movement (REM) sleep behavior disorder (RBD).
All parasomnias are exacerbated by sleep deprivation or sleep fragmentation, and therefore the first-line approach to treatment is to identify and treat causes of poor sleep quality (ie, improve sleep hygiene, avoid alcohol, treat sleep apnea and restless legs syndrome).
●Nightmares – PTSD-related nightmares can be effectively treated with prazosin and/or image-rehearsal therapy with or without CBT-I [128]. If parasomnias persist despite treatment of secondary causes, and are bothersome to the patient, low-dose clonazepam is often helpful (ie, 0.5 to 2 mg nightly). Management of nightmares with and without comorbid PTSD is reviewed in more detail separately. (See "Posttraumatic stress disorder in adults: Treatment overview" and "Nightmares and nightmare disorder in adults".)
●RBD – In patients with RBD, which can result in violent dream enactment, establishing a safe sleeping environment is the primary goal of treatment. This can be achieved through modification of the sleep environment and pharmacotherapy, if necessary. Medications known to cause or exacerbate RBD, such as serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants, should be discontinued or avoided if possible. Low-dose clonazepam and high-dose melatonin are effective therapies in patients with RBD characterized by frequent, disruptive or injurious behaviors. (See "Rapid eye movement sleep behavior disorder", section on 'Management'.)
In patients with purported "trauma-associated sleep disorder," which may or may not be nosologically distinct from idiopathic RBD, dream enactment behavior is instead characterized by a triggering traumatic event and autonomic hyperarousal [58,59,129]. The treatment of choice has been reported anecdotally to be prazosin, rather than clonazepam and melatonin [60]. However, it should be noted that prazosin failed to show benefit in alleviating distressing dreams or sleep quality in a large multisite randomized clinical trial of 304 veterans with chronic PTSD [130]. (See "Nightmares and nightmare disorder in adults", section on 'Prazosin'.)
Obstructive sleep apnea — Behavioral modifications, including weight loss, and positive airway pressure (PAP) therapy are the cornerstones of therapy for OSA. Both have been shown to improve outcomes in the general population in randomized trials [131-133], and their effects may be additive [134]. (See "Obstructive sleep apnea: Overview of management in adults", section on 'Goals of PAP therapy'.)
Individuals with OSA in the post-TBI setting should be treated similarly, although literature in this patient population is sparse. In the one study that examined continuous PAP (CPAP) therapy in patients with TBI, CPAP therapy was associated with a decreased apnea hypopnea index (AHI) and improved sleep quality three months after administration, but it did not improve excessive daytime sleepiness as measured by the MSLT [135]. CPAP adherence and medication side effects were not taken into account, however, which could explain the lack of improvement in daytime sleepiness.
The potential consequences of untreated OSA in patients with TBI were illustrated by a small case control study that included 19 TBI patients with OSA and 16 TBI patients without OSA on nocturnal polysomnography [136]. Patients with OSA performed significantly worse than those without OSA on tasks of sustained attention and memory. Such deleterious effect of OSA on cognition has been confirmed in 60 patients with moderate to severe TBI [137].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Increased intracranial pressure and moderate-to-severe traumatic brain injury".)
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Sleep-wake disturbances arise in approximately one-third of patients in the acute phase after mild traumatic brain injury (TBI) and approximately half of patients in the chronic phase. (See 'Epidemiology' above.)
●Mechanisms – The pathophysiology of posttraumatic sleep-wake disturbances may be explained in part by reductions in wake-promoting neurotransmitters such as orexin and histamine. (See 'Pathophysiology' above.)
●Clinical features – The most common manifestations are excessive daytime sleepiness, increased sleep need (pleiosomnia), and insomnia (figure 1). (See 'Excessive daytime sleepiness' above and 'Increased sleep need (pleiosomnia)' above and 'Insomnia' above.)
Less commonly, patients experience circadian sleep-wake rhythm disturbances; abnormal movements or behaviors during sleep, such as sleep talking, bruxism, and dream enactment; and sleep-disordered breathing. (See 'Circadian sleep-wake rhythm disturbances' above and 'Abnormal movements or behaviors during sleep' above and 'Sleep-disordered breathing' above.)
●Evaluation – Sleep-wake disorders are diagnosed by history, supplemented by objective sleep testing in selected patients. The goals of the evaluation are threefold (see 'History' above):
•Refine the sleep complaint through a comprehensive sleep history
•Diagnose specific treatable sleep disorders
•Identify medical and psychiatric comorbidities that may be contributing to the sleep disturbances
●Management – Treatment varies according to the dominant symptom or specific sleep disorder as well as relevant comorbidities. Treatment strategies in patients with a history of TBI are generally similar to those in the general population (figure 1). (See 'Symptom-directed therapy' above and 'Specific disorders' above.)
•Excessive sleepiness – In patients with TBI who have persistent and bothersome excessive daytime sleepiness that cannot be explained by other causes or comorbidities, we suggest treatment with a wake-promoting agent such as modafinil (Grade 2C). A stimulant such as methylphenidate is an alternative therapy that has not been well studied in patients with TBI. (See 'Excessive daytime sleepiness' above.)
•Insomnia – Pharmacologic and behavioral approaches for insomnia in patients with a history of TBI are generally similar to those in the general population. Special consideration should be paid to cognitive impairment, which may increase the risk of side effects from sedative/hypnotic medications, and comorbid affective disorders, which are common in patients with TBI and may require additional therapy. (See 'Insomnia' above.)
Do you want to add Medilib to your home screen?