Disorders of arousal from non-rapid eye movement sleep in adults

INTRODUCTION — Disorders of arousal from non-rapid eye movement (NREM) sleep are parasomnias that include confusional arousals, sleepwalking, sleep terrors, and their variants. They are classified as distinct entities, but in reality, they represent a spectrum of sleep-related behaviors that occur as a result of incomplete transition out of deep NREM sleep.

While disorders of arousal typically present in childhood, they may continue into adulthood, remit and recur in adulthood, or present de novo in adults. NREM disorders of arousal must be distinguished from other sleep-related conditions that occur in adults, including rapid eye movement (REM) sleep behavior disorder (RBD), movement disorders of sleep, and sleep-related seizures.

Disorders of arousal are an important cause of sleep-related injury in adults. Management consists primarily of education, environmental and behavioral modifications to promote safety, and identification of predisposing and triggering factors to minimize the number of episodes.

The clinical features, diagnosis, and management of disorders of arousal in adults will be reviewed here. A more general approach to abnormal movements and behaviors during sleep is presented elsewhere. Other parasomnias in adults and disorders of arousal and other parasomnias in children are also reviewed separately. (See "Approach to abnormal movements and behaviors during sleep" and "Rapid eye movement sleep behavior disorder" and "Parasomnias of childhood, including sleepwalking".)

EPIDEMIOLOGY — Disorders of arousal are more prevalent in children than adults, and estimates in adults are largely drawn from survey studies.

Confusional arousals occur in 15 to 17 percent of children and tend to remit spontaneously in most cases; the prevalence in adults is approximately 2 to 4 percent [1,2]. A cross-sectional study of over 19,000 noninstitutionalized adults found that while over 15 percent of the sample reported confusional arousals in the prior year, all but 0.9 percent were in association with other sleep disorders (circadian rhythm disorders or long sleepers), psychiatric disorders (bipolar or panic disorder), or use of psychotropic drugs (mainly antidepressant medications) [3].

Sleepwalking affects approximately 15 percent of children and 4 percent of adults, with peak prevalence between ages 8 and 12 years [1,4]. Onset in adulthood is observed in approximately 15 percent of cases, and childhood-onset sleepwalking continues into adulthood in 20 percent of cases [5].

Sleep terrors affect up to 3 percent of adults, often in association with other disorders of arousal [1]. In a series of 100 adult sleepwalkers, sleep terrors were reported by 64 percent and sleep talking by 92 percent [5].

PATHOPHYSIOLOGY AND GENETICS — Sleep and wakefulness are not mutually exclusive states. Therefore, dysfunction in the orchestration of neural pathways regulating wake, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep can produce state dissociation, resulting in the ability to perform complex motor behaviors outside of consciousness.

Disorders of arousal manifest when there is an incomplete dissociation of NREM sleep into wakefulness, leading to clinical states of sleep with central nervous system activation of skeletal muscle and autonomic networks. Sleep inertia and sleep fragmentation each promote the occurrence of abnormal behaviors. Accordingly, NREM arousal instability, represented by changes in cyclic alternating patterns, is often observed in affected individuals [6].

Activation of central pattern generators has also been implicated. Pattern generators are genetically determined or learned neural circuits located in the mesencephalon, pons, and spinal cord that code for self-sustained patterns of behavior that are essential for survival. Activation of central pattern generators results in primitive behaviors that would normally be suppressed during wakefulness, including eating, locomotion, aggression, and sex [7].

Genetic factors play a role, particularly in the case of sleepwalking. Compared with the general population, first-degree relatives of sleepwalkers have a 10-fold or higher increased likelihood of sleepwalking [4]. In a series of 100 adult sleepwalkers, 57 percent had a positive familial history, which in the majority of cases was a first-degree relative [5]. Family studies have identified several potential candidate genes, including the adenosine deaminase gene on chromosome 20q12 [8].

Association with sleep-related hypermotor epilepsy — Disorders of arousal have a strong association with sleep-related hypermotor epilepsy, previously known as nocturnal frontal lobe epilepsy [9]. A common pathophysiologic mechanism involving cholinergic pathways in the ascending arousal system has been hypothesized [10]. In families with autosomal dominant nocturnal frontal lobe epilepsy, causative mutations have been identified in various subunits of the nicotine acetylcholine receptor gene (eg, CHRNA4, CHRNB2, CHRNA2) and in the corticotrophin-releasing hormone gene [11,12]. Receptor mutations confer a gain of function, with increased sensitivity to acetylcholine that may lead to changes in the excitability of cortical and subcortical networks and, at the same time, altering arousal mechanisms and destabilizing sleep. The lifetime prevalence of disorders of arousal is nearly fivefold greater in relatives of probands with sleep-related hypermotor epilepsy than controls [13], and approximately one-third of probands report a personal or family history of parasomnia [14]. (See "Sleep-related epilepsy syndromes", section on 'Sleep-related focal epilepsies'.)

CLINICAL FEATURES — Disorders of arousal constitute a spectrum of complex sleep-related behaviors that arise as a result of incomplete arousal from deep non-rapid eye movement (NREM) sleep. The behaviors most commonly arise from slow wave sleep (stage N3), usually in the first third of the major sleep period (figure 1). They may also arise from other NREM stages anytime during sleep, including daytime naps. (See "Stages and architecture of normal sleep", section on 'NREM sleep'.)

Clinical manifestations — Affected individuals exhibit a spectrum of behaviors outside of consciousness, generally without dream imagery and followed by partial or complete amnesia for the event (table 1). In contrast to sleep-related seizures, disorders of arousal are not typically stereotyped and vary over time. Several minutes of confusion after an event is typically followed by a return to sleep.

Confusional arousals — Confusional arousals (also referred to as Elpenor syndrome, sleep drunkenness, or sleep inertia) are episodes of mental confusion or confusional behavior during an arousal or awakening from nocturnal sleep or a daytime nap. They represent an interval of "excessive sleep inertia," defined as confusion and disorientation during and following arousals from slow wave sleep. Responsiveness to environmental stimuli is reduced, although patients appear to be awake and may exhibit goal-directed behaviors.

Speech is generally slow and devoid of content. Affected individuals typically appear bewildered and have little to no memory of the event. Unlike in sleepwalking and sleep terrors, motor features in confusional arousals are less complex and do not include any form of ambulation (as in sleepwalking) or sympathetic activation (as in sleep terrors) [15].

The duration of a confusional arousal is usually a few minutes to less than 15 minutes, although episodes as long as several hours have been described. Episodes typically arise from slow wave sleep during the first part of the sleep period, but they can also arise during the transition from sleep to wakefulness in the morning or from light NREM sleep.

In adults, confusional arousals are often observed in patients with other sleep and/or psychiatric disorders [3]. As with other disorders of arousal, precipitants include sleep deprivation, use of sedative hypnotics or sleep aids before bedtime, and sudden awakening from sleep. (See 'Common precipitating factors' below.)

Sleep-related abnormal sexual behavior — Sleep-related abnormal sexual behavior (also referred to as atypical sexual activity during sleep, sexsomnia, or sleep sex) is a confusional arousal variant that is characterized by abnormal sexual behaviors without awareness or intention and followed by partial or complete morning amnesia [16]. Behaviors may include prolonged or violent masturbation and sexual vocalizations, initiation of sexual intercourse with bed partners, or sexual assault of minors or adults who may be in close proximity to the patient.

The prevalence of this variant in the general population is not well known. Symptoms suggestive of sexsomnia were reported by 8 percent of a cohort of 832 patients presenting to a sleep disorders clinic [17].

As in other types of confusional arousals, episodes typically occur during NREM sleep, one to two hours after sleep onset [18]. Many patients have comorbid obstructive sleep apnea (OSA), the treatment of which can reduce or eliminate sexual behaviors. Episodes may occur in isolation or in association with sleepwalking, REM sleep behavior disorder (RBD), or parasomnia overlap disorder. (See 'Common precipitating factors' below and 'Differential diagnosis' below.)

Sleep-related sexual behavior disorder is the mostly commonly suspected or implicated sleep disorder in criminal allegations involving sleep-related violence [19]. In a systematic review of medical-legal cases involving sleep-related abnormal sexual behavior, defendants were largely male, while assault victims were usually female and, in most cases, minors in close physical proximity (eg, sleeping in the same bed, room, or home) [20].

Sleep terrors — Sleep terrors (also referred to as night terrors or pavor nocturnus) are characterized by a sudden arousal from sleep associated with sitting up in bed, intense fear, a piercing scream, and intense autonomic activation including tachycardia, tachypnea, diaphoresis, facial flushing, and mydriasis (table 2).

Affected individuals appear frightened and confused and are inconsolable and difficult to arouse. They typically have no recollection of events the following morning. In contrast to children, adults typically present with explosive episodes during which they may bolt out of bed in a violent or agitated manner and have partial dream recollection after the event. Episodes typically last several minutes and are followed by the individual calmly and quietly returning to sleep.

Sleepwalking — Sleepwalking (somnambulism) is characterized by a sequence of complex behaviors in sleep, including ambulation that is more elaborate and seemingly goal-directed than what is seen with confusional arousals. Episodes begin with a confusional arousal that is followed by the individual leaving the bed. Ambulation is typically slow and quiet, with the eyes open. More agitated behaviors, such as running, jumping, vocalization, and other automatic or purposeless behaviors, occasionally occur. Preparing foods, eating, cleaning, rearranging furniture, driving, and inappropriate behaviors such as urinating in a closet may be observed.

Episodes usually terminate spontaneously with the patient waking up in a different location or returning to bed without incident. Patients appear confused and can be agitated or aggressive when aroused. Self-injury is not uncommon. Violent acts, including homicide and sexual molestation, have been reported. Complete amnesia is typical, although some patients have partial recollection of their behavior.

Episode frequency varies, ranging from isolated, rare occurrences to multiple events per night for several nights followed by prolonged remission. Higher episode frequency has been associated with earlier onset of sleepwalking [21].

Sleep-related eating disorder — Sleep-related eating disorder (SRED) (sleep eating) is a variant of sleepwalking characterized by recurrent episodes of involuntary eating associated with diminished levels of consciousness during an arousal from sleep and not linked to daytime eating disturbances such as bulimia nervosa, binge eating disorder, or anorexia nervosa.

Formal criteria for SRED also specify that the recurrent episodes of eating and drinking during the main sleep period must be accompanied by consumption of inedible or toxic substances (eg, high caloric processed foods, frozen foods, cat food, cigarettes, or cleaning solutions), insomnia, sleep-related injury, occurrence of dangerous behaviors in the search for or while cooking food, morning anorexia, or adverse health consequences from recurrent binge eating of high caloric food, including weight gain, metabolic disorders (eg, diabetes mellitus, hyperlipidemia), hypertension, and OSA [16].

Like sleepwalking, episodes typically occur in the first one-third of the sleep period. This disorder generally presents in young adulthood and preferentially affects females. In a study that compared the clinical and polysomnographic features of SRED with sleepwalking and controls, patients with SRED were more likely to be female, to have a disease onset in adulthood, and to have nightly episodes [22]. Common comorbid symptoms included insomnia, anxiety, daytime sleepiness, past or current sleepwalking (two-thirds), and former or current eating behavior problems.

The absent or diminished level of awareness during the nocturnal food intake is the primary feature distinguishing SRED from eating disorders and night eating syndrome, a disorder characterized by excessive eating between dinner and bedtime or following complete awakening from sleep [23]. (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis".)

Psychotropic medications, including sedative-hypnotics, have been implicated in some cases of SRED [24]. In addition to sleepwalking, sleep disorders associated with SRED include OSA, periodic limb movement disorder (PLMD), circadian rhythm disorders, narcolepsy, and restless legs syndrome (RLS). (See 'Common precipitating factors' below.)

Common precipitating factors — Disorders of arousal are often provoked or exacerbated by sleep deprivation, recovery from sleep deprivation (due to slow wave sleep rebound), or physical and emotional stress. Other precipitants include fever, menses, environmental stimuli, and internal stimuli such as bladder distention. Comorbid sleep disorders, particularly OSA and periodic limb movements, can provoke or exacerbate episodes by way of increasing number of arousals from sleep.

A variety of medications and substances can precipitate events, including psychotropic medications (eg, anticholinergics, lithium, antipsychotics) and sedative-hypnotic agents, most notably the nonbenzodiazepine benzodiazepine receptor agonists (eg, zolpidem, zaleplon, eszopiclone). In 2007, the US Food and Drug Administration (FDA) strengthened warnings on the risk of complex sleep behaviors for sedative-hypnotic agents as a class [25], and in 2019, FDA added a boxed warning for nonbenzodiazepines on the risk of rare but serious injury related to these adverse effects [26]. In the setting of nonbenzodiazepines such as zolpidem, behaviors are often prolonged and can include eating, sexual activity, and driving while not fully awake [27]. Rare serious injuries including death have been reported via mechanisms such as accidental overdose, motor vehicle crash, and drowning [26]. Higher dose or drug-drug interactions have been implicated in some, but not all, reports [28]. (See "Pharmacotherapy for insomnia in adults", section on 'Benzodiazepine receptor agonists'.)

Additional data suggests that SRED is more common in patients with RLS, potentially related to use of hypnotics to help address sleep-onset insomnia [29].

Polysomnographic features — Specific motor patterns roughly corresponding to the traditional phenotypes of disorders of arousal have been described based on video polysomnography analysis [30]. In order of increasing complexity and decreasing frequency, these include:

●Simple arousal movements (SAMs) consisting of head flexion/extension

●Limb movement with head flexion/extension or partial trunk and head flexion/extension

●Rising arousal movements comprising a complete trunk flexion followed by sitting with feet in or out of bed

●Complex arousal movements (CAMs) characterized by getting out of bed and walking

Electrographic features of disorders of arousal are more variable and less definitive than those associated with seizures [31]. Whereas seizure patterns typically evolve in frequency, field, and/or amplitude, disordered arousals are characterized by generalized hypersynchronous delta waves with superimposed faster frequencies without considerable evolution.

The arousal itself can consist of any frequency, including rhythmic delta activity suggestive of a persistent sleep pattern or a predominance of alpha activity that is more widespread and less reactive than the waking background, suggestive of partial wakefulness. Electroencephalogram (EEG) state dissociation, with a posteriorly dominant alpha rhythm and anterior delta activity combined with vertex waves or sleep spindles (consistent with light sleep), has been reported [32]. An increase in delta power immediately preceding the arousal and/or an increase in slow wave sleep percentage across the sleep period may also be observed [33]. In one study, a slow wave sleep arousal index >6.8/hour had a sensitivity and specificity of 79 and 82 percent for predicting disorders of arousal; when combined with at least one recorded event on video, the correct classification was predicted in over 91 percent [34]. (See "Polysomnography in the evaluation of parasomnias and epilepsy", section on 'NREM parasomnias'.)

DIAGNOSIS — A comprehensive clinical history that includes the timing, frequency, semiology, and evolution of typical events is often sufficient to diagnose disorders of arousal (table 1), particularly in children. The history should be obtained from the patient as well as from relevant observers, as patients often have little or no memory of the events. Review of home videos can be extremely useful. (See 'Clinical manifestations' above.)

In addition to the event description, the history should include questions about personal and family history of similar events in childhood, sleep deprivation, symptoms of other sleep disorders such as obstructive sleep apnea (OSA), medications, and other factors that may be contributing to the emergence of events. (See 'Common precipitating factors' above.)

When the clinical history is atypical or there is suspicion for a comorbid sleep disorder such as OSA or periodic limb movement disorder (PLMD), polysomnography (PSG) with expanded electromyographic (EMG) montage should be performed. For patients with suspected sleep-related seizures, a PSG with expanded electroencephalography (EEG) is recommended. Additional indications for PSG in patients with suspected disorders of arousal are listed in the table and include the following (table 3):

●Potentially injurious night behaviors or behaviors otherwise disruptive to the bed partner or household members

●Daytime symptoms such as excessive sleepiness, since sleepiness is not usually the result of a parasomnia, per se

●Sleep disruption out of proportion to what would be expected based on the frequency of sleep-related events

●Failure to respond to appropriate therapy

The diagnostic yield of PSG with EEG in adults with suspected disorders of arousal is illustrated by the following studies:

●In a study of 124 consecutive patients referred for PSG for the evaluation of a suspected disorder of arousal, the utility of PSG varied significantly based on the history [35]. When the clinical history was typical for a disorder of arousal, PSG rarely identified a different sleep disorder or unsuspected precipitant (5 percent, respectively). When the diagnosis was not clinically obvious or the history had unusual features, however, the yield of PSG was higher: other sleep diagnoses were identified in 18 percent of patients and potential precipitants were identified in 24 percent.

●In 100 adults with a history of sleep-related injury, PSG combined with EEG provided conclusive diagnostic information in 65 percent of cases and was helpful in another 26 percent [36]. The most common diagnoses were night terrors/sleepwalking (54 percent), REM sleep behavior disorder (36 percent), and dissociative disorders (7 percent).

●In a PSG-EEG analysis of 120 events in 44 patients with sleep-related frontal epilepsy or a disorder of arousal, 94 percent of events were correctly classified using a diagnostic decision tree based on a cluster analysis [32]. Semiologic features strongly favoring a disorder of arousal included interactive behavior, failure to wake after the event, indistinct offset, crying or sobbing, coherent speech in sentences, and normal arousal behaviors (eg, scratching and rubbing the face). In contrast, hypermotor features, grunting, grimacing, and dystonic posturing favored frontal lobe seizures.

In the same study, sleep stage at event onset was also discriminatory (82 percent of seizures occurred during NREM stage 1 or 2, and 100 percent of disorders of arousal arose from slow wave sleep), whereas ictal EEG features were much less useful. Only 38 percent of seizures were associated with definitive ictal patterns.

While abnormal behaviors are rarely recorded in the sleep laboratory, sleep deprivation for 24 hours and forced arousal from auditory stimuli can provoke sleepwalking and other disorders of arousal, thereby increasing the yield of testing [37]. The widespread availability of smartphones renders recording of events at home easier than ever. Home videos can be very useful, particularly in cases of low event frequency. (See "Polysomnography in the evaluation of parasomnias and epilepsy", section on 'NREM parasomnias'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of non-rapid eye movement (NREM) disorders of arousal includes sleep-related seizures, other parasomnias such as rapid eye movement (REM) sleep behavior disorder (RBD), psychiatric disorders, sleep-related breathing disorders, and sleep-related movement disorders. In adults, sleep-related seizures and RBD are the most common and important entities to distinguish from disorders of arousal (table 4).

Sleep-related seizures — Like parasomnias, sleep-related seizures may occur during entry into sleep, within sleep, or during arousals from sleep [38]. While the majority of sleep-related seizures involve networks engaging the frontal lobes, up to 30 percent have an extra-frontal origin [39]. There is often a genetic component. (See "Sleep-related epilepsy syndromes", section on 'Sleep-related focal epilepsies'.)

Sleep-related seizures can manifest in many ways, but those most often confused with disorders of arousal feature repetitive, high-amplitude, and high-velocity movements of the trunk and proximal extremities or asymmetric tonic activity [14,40,41]. The ictal sequence of behaviors is rapid and includes extrapyramidal signs, such as tonic or dystonic posturing of the limbs, choreoathetoid or ballistic movements, and vocalization. Seizures are highly stereotyped and frequent, with abrupt onset and offset, often with preserved consciousness. They tend to occur in clusters from NREM stages N1 and N2.

Compared with disorders of arousal, sleep-related seizures are typically shorter in duration (10 to 30 seconds) (table 4); longer seizures may evolve to bilateral convulsive seizures. Prolonged seizures lasting 30 to 180 seconds characterized by arousal and agitated walking, running, jumping, and pacing with variable degrees of responsiveness have been described [14,42].

The Frontal Lobe Epilepsy and Parasomnias (FLEP) scale may be used as an adjunct to the clinical history when there is uncertainty regarding the etiology of complex sleep-related behaviors [43]. The scale consists of 11 semiologic features that differentiate frontal lobe seizures and disorders of arousal and other parasomnias. A score of zero or less favors the diagnosis of NREM arousal disorder, whereas a score >3 supports sleep-related seizures; scores of 1 to 3 are indeterminate, and these patients may require further evaluation. The scale has high positive and negative predictive values (91 and 100 percent), but misdiagnosis can occur, especially in RBD [44]. Recording episodes on video-electroencephalography (video-EEG) and polysomnography (PSG) remains necessary when the diagnosis is unclear. Review of home videos can also be helpful.

REM sleep behavior disorder — RBD involves dream-enacting behaviors during REM sleep, which predominates in the last one-third of the sleep cycle, most commonly affecting older adult males in association with alpha-synuclein neurodegenerative diseases including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. Behaviors include hallucinations, vocalizations, and complex dream enactment motor activity corresponding to altered dream mentation [45]. In contrast to disorders of arousal, patients with RBD typically wake up abruptly at the end of an episode (table 4). Some are able to recount coherent dream content of being confronted, chased, or attacked. Unlike sleepwalking, individuals with RBD rarely walk out of the room, and episodes occur with the eyes closed. PSG in patients with RBD shows characteristic excessive augmentation of electromyography (EMG) tone in the chin or limb leads, most characteristically recorded from the flexor digitorum superficialis muscles during REM sleep [16]. (See "Rapid eye movement sleep behavior disorder".)

Parasomnia overlap disorder — Parasomnia overlap disorder is a subtype of RBD characterized by RBD and either a disorder of arousal, sleep-related eating disorder (SRED), sexsomnia, or rhythmic movement disorder (RMD) [16]. In the original series, parasomnia overlap disorder was present in 21 percent of RBD cases and 28 percent of sleepwalking/sleep terrors cases [46]. The disorder is male-predominant but less so than RBD, with an earlier age of onset (often in childhood or adolescence). It can be associated with a variety of neurologic and psychiatric disorders including narcolepsy, multiple sclerosis, brain tumors, Creutzfeldt-Jakob disease [47], autoimmune encephalitis, and substance abuse. In contrast to RBD, parasomnia overlap disorder does not appear to be a risk factor for alpha-synuclein neurodegenerative disorders [48,49].

Others

●Status dissociatus – Status dissociatus (agrypnia excitata and oneiric stupor) is a rare condition characterized by a state dissociation without clear sleep stages but with REM-related behaviors resembling RBD [50]. It has been described in association with fatal familial insomnia, delirium tremens, alcohol or benzodiazepine withdrawal syndromes, and autoimmune encephalitis. Affected individuals have severe and persistent insomnia, loss of slow wave sleep, marked motor and autonomic sympathetic activation, and episodes of dream enactment. (See "Diseases of the central nervous system caused by prions", section on 'Fatal familial insomnia' and "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Paraneoplastic neuromyotonia'.)

●Sleep-related dissociative disorders – Dissociative disorders typically present between the second and fourth decades of life usually in females, but children and older adults may also be affected [51]. Most patients have psychiatric comorbidities, including mood disorders, post-traumatic stress disorder, chronic pain disorders, somatization, histrionic personality, or a history of sexual abuse.

Episodes are not stereotyped and feature screaming, running, self-mutilating, violent behaviors, tossing of the body, asynchronous movements, side-to-side head movements, pelvic thrusting, opisthotonic posturing, and prolonged body flaccidity. Vocalizations, moaning and crying, emotive speech, stuttering, and heart rate elevations may be observed. Patients may have complete amnesia for episodes, which can last from minutes to an hour or longer, usually with waxing and waning motor manifestations. Episodes emerge at the transition from wake to sleep or shortly following awakening; EEG confirms evidence of wakefulness during behavioral unresponsiveness. Some patients have comorbid psychogenic nonepileptic seizures [52]. (See "Psychogenic nonepileptic seizures: Etiology, clinical features, and diagnosis" and "Functional neurological symptom disorder (conversion disorder) in adults: Clinical features, assessment, and comorbidity".)

●Nocturnal panic attacks – Nocturnal panic refers to a sudden waking from sleep in a state of intense fear or discomfort accompanied by physical symptoms (eg, heart palpitations, shortness of breath, heavy sweating) and cognitive symptoms (eg, fear of dying, going crazy, losing control), similar to those associated with daytime panic. Episodes occur during late stage N2 or early stage N3 sleep. Between 44 and 71 percent of patients with panic disorder experience at least one nocturnal attack, 18 to 45 percent report regular and frequent nocturnal panic attacks, and 2 percent have mainly nocturnal attacks [53]. (See "Panic disorder in adults: Epidemiology, clinical manifestations, and diagnosis".)

●Nocturnal wandering associated with cognitive impairment – Behavioral disorders including nocturnal wandering are a common feature of advanced stages of dementia. Due to cognitive impairment, affected individuals usually have no memory for episodes, even when self-injury has occurred.

●Alcohol and drug-related behaviors – Patients under the influence of alcohol or drugs may exhibit abnormal sleep-related behaviors similar to sleepwalking and nocturnal confusion without recollection thereafter. In contrast to disorders of arousal, intoxicated individuals typically exhibit euphoria, flushed skin, and decreased social inhibition. More severe intoxication produces progressively severe impairments of balance and decision-making ability that can potentially lead to violent or erratic behavior as well as nausea or vomiting.

●Sleep-related breathing disorders – Obstructive sleep apnea (OSA) and other forms of sleep-disordered breathing can trigger acute confusional states and postoperative delirium in older adult patients [54]. Given the increasing prevalence of OSA with age, these disorders should be considered in the presentation of abnormal sleep-related behaviors in adults. A substantial proportion of both adults [55] and children [56] who meet criteria for chronic NREM parasomnias have OSA as an underlying precipitant. In such cases, successful treatment of the underlying OSA often resolves the parasomnia, as well. PSG or home sleep apnea testing is necessary to diagnose OSA, as clinical signs and symptoms are insensitive and nonspecific. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

●Sleep-related movement disorders – Sleep-related movement disorders are characterized by more simplistic movements than those of disorders of arousal, usually occurring immediately prior to sleep onset and sustained into light sleep. Examples include restless legs syndrome (RLS), periodic limb movement disorder (PLMD), rhythmic movement disorder (RMD), bruxism, and nocturnal cramps [16]. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults" and "Approach to abnormal movements and behaviors during sleep", section on 'Periodic or rhythmic movements'.)

●Kleine-Levin syndrome – Kleine-Levin syndrome (KLS) is a central disorder of hypersomnolence associated with prolonged sleep inertia that may occasionally be difficult to differentiate from confusional arousals. During periods of prolonged sleep, patients with KLS experience mental confusion and incoherent speech. However, KLS has additional distinctive features that are not typically seen in patients with confusional arousals, including prolonged periods of sleep, abnormal behaviors and irritability, hypersexuality, and hyperphagia during wakefulness [57,58]. (See "Kleine-Levin syndrome (recurrent hypersomnia)", section on 'Clinical features'.)

MANAGEMENT — Management of disorders of arousal from non-rapid eye movement (NREM) sleep includes behavioral and preventive strategies, recommended in all patients, and pharmacotherapy, typically reserved for more severe and injury-prone cases (table 5) [59]. There have been few prospective studies and no clinical trials in adults with disorders of arousal, and recommendations are based primarily on clinical experience, case reports, and case series.

Patients who have underlying obstructive sleep apnea (OSA) or restless legs syndrome (RLS), which could serve as triggers for a NREM parasomnia, should receive treatment for the underlying sleep disorder.

Behavioral and preventive strategies aim to reduce or eliminate priming and precipitating factors and establish environmental safety for patients and bystanders. Reassurance and education regarding factors that increase episode frequency is critical. This includes:

●Avoidance of sleep deprivation, alcohol, and medications associated with disorders of arousal, most notably, nonbenzodiazepine benzodiazepine receptor agonists such as zolpidem (see 'Common precipitating factors' above)

●Maintenance of consistent and regular sleep-wake cycles (in some cases avoiding shift work)

Changes in the sleep environment should be minimized and the bedroom should be safeguarded to avoid injury. Depending upon the frequency and severity of the events, a variety of environmental modifications may be necessary, such as:

●Use of padding on nearby furniture and on the floor beside the bed.

●Lowering the mattress to the floor, or using a bedroom on the ground floor in a multilevel home.

●Securing doors and windows with locks, a bedroom door alarm, and/or barriers at the top of the stairs.

●Removing sharp and dangerous objects from the bedroom. If firearms are stored in the house, it is critical to store and lock them elsewhere.

●In the case of sleep-related eating disorder (SRED), highly sought after foods should be secured outside of the kitchen. Locks may be needed on the refrigerator or kitchen cabinetry.

Parents and caregivers, bed partners, and bystanders should be educated on how to safely interact with the patient during episodes so as not exacerbate agitation, worsen confusion, or provoke violent, self-protective behavior. This generally involves allowing the patient to move freely without being physically restrained while ensuring safety. Observers should not yell or scream in an effort to arouse the patient, but rather, gently coax the patient back to bed.

Cognitive behavioral therapy for insomnia, in particular guided imagery, relaxation training, hypnosis, and mindfulness-based stress reduction (MBSR) has been effective in isolated cases and observational series [60,61]. Anticipatory awakening, whereby the patient is awoken from sleep shortly before episodes are expected to occur, has been used effectively in children for confusional arousals, sleep terrors, and sleepwalking. (See "Parasomnias of childhood, including sleepwalking", section on 'Behavioral measures'.)

Pharmacotherapy is rarely necessary [62]. Benzodiazepines, particularly clonazepam, are the best studied option in patients with frequent or injurious episodes who fail to respond to nonpharmacologic measures (table 5) [59,62-65]. In case series, treatment with low-dose clonazepam (0.5 to 1 mg at bedtime) is effective in eliminating sleepwalking and sleep terrors in the majority of patients [61,63,64]. Melatonin may also provide improvement in patients with sleepwalking who do not initially respond to interventions focused on improving sleep hygiene [61].

Other therapies with some report of benefit include selective serotonin reuptake inhibitors for sleep-related abnormal sexual behavior [66] or SRED [24,67], and dopamine agonists for SRED related to RLS [65,68]. For patients with SRED unrelated to RLS, emerging data, including results of a small trial, suggest that topiramate reduces eating symptoms and weight [24,69-72]. Side effects (eg, cognitive dysfunction, paresthesias) are relatively common, however [72].

PROGNOSIS — There are few long-term studies of natural history or treatment outcomes in adults with disorders of arousal. Anecdotally, most patients benefit from education, reassurance, and nonpharmacologic therapies.

Among patients referred to a sleep specialist, the vast majority are able to achieve an acceptable level of symptom control or complete resolution with an approach that includes sleep hygiene, treatment of concurrent sleep disorders, management of exacerbating factors, and pharmacotherapy if necessary. In a retrospective series of 512 adults with NREM parasomnias or parasomnia overlap disorder seen at a single sleep disorders center, approximately one-third of patients did not require pharmacotherapy, and 13 percent of patients improved with sleep hygiene alone (primarily those with confusional arousals, sleepwalking, and sleep terrors) [61]. Benzodiazepines were the most commonly used medications and were associated with a good response in 80 percent of patients.

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: Parasomnias, hypersomnias, and circadian rhythm disorders".)

SUMMARY AND RECOMMENDATIONS

●Pathophysiology – Disorders of arousal from non-rapid eye movement (NREM) sleep include confusional arousals, sleepwalking, sleep terrors, and their variants. Although they are classified as distinct entities, these disorders represent a spectrum of sleep-related behaviors that result from incomplete arousal from deep NREM sleep. (See 'Pathophysiology and genetics' above.)

While disorders of arousal most commonly present in childhood, they may persist into adulthood, remit and recur in adulthood, or present de novo in adults. (See 'Epidemiology' above.)

●Clinical features – Disorders of arousal are manifested by a spectrum of behaviors outside of consciousness, generally without dream imagery and followed by partial or complete amnesia for the event (table 1). All are most likely to occur in the first third of the sleep period, when deep NREM sleep (stage N3) predominates. They share common priming factors, including sleep deprivation, biopsychosocial stressors, certain medications (eg, short-acting hypnotics), and sleep disorders associated with arousals, particularly obstructive sleep apnea (OSA). (See 'Clinical manifestations' above and 'Common precipitating factors' above.)

●Diagnosis – A comprehensive clinical history that includes the timing, frequency, semiology, and evolution of typical events is often sufficient to diagnose disorders of arousal and distinguish them from other types of sleep-related events. Polysomnography is necessary when there is clinical suspicion for a comorbid sleep disorder such as OSA or when the history raises concern for seizures or other alternative diagnoses. (See 'Diagnosis' above.)

●Differential diagnosis – Disorders of arousal from NREM sleep must be differentiated from other causes of abnormal motor activity or behaviors during sleep, including rapid eye movement (REM) sleep behavior disorder (RBD), sleep-related seizures, and dissociative disorders. (See 'Differential diagnosis' above.)

●Management – Treatment is supportive, with a focus on education, reassurance, and behavioral modifications to minimize episode frequency and ensure safety of the patient and bystanders (table 5).

•All patients – Sleep deprivation should be avoided, any potentially offending medications or substances should be withdrawn if possible, and comorbid sleep disorders such as OSA should be treated. (See 'Management' above.)

•Frequent or injurious episodes – For most patients with frequent or injurious disorders of arousal despite elimination of potential triggers, we suggest treatment with clonazepam at bedtime (Grade 2C). A dopamine agonist is a reasonable alternative in patients with sleep-related eating disorder associated with restless legs syndrome/Willis-Ekbom disease. (See 'Management' above.)