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Rapid eye movement sleep behavior disorder
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Rapid eye movement sleep behavior disorder
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Literature review current through: Nov 2017. | This topic last updated: Jul 24, 2017.

INTRODUCTION — Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by dream-enactment behaviors that emerge during a loss of REM sleep atonia. RBD dream enactment ranges in severity from benign hand gestures to violent thrashing, punching, and kicking. Patients typically present to medical attention with a concern related to injurious or potentially injurious actions to themselves and/or their bed partner.

In spontaneously occurring cases, RBD is a prodromal syndrome of alpha-synuclein neurodegeneration. Thus, the vast majority of RBD patients will eventually demonstrate signs and symptoms of Parkinson disease or a related disorder (eg, multiple system atrophy or dementia with Lewy bodies), often after a prolonged interval. Prior to the emergence of a parkinsonian syndrome, patients may have subtle sensory, motor, and cognitive deficits, including anosmia and constipation, consistent with an impending neurologic disorder.

A careful history should distinguish RBD from related parasomnias such as sleepwalking. In-laboratory video polysomnography can exclude other sleep disorders, quantify REM atonia and capture dream-enactment behaviors, confirming the diagnosis. The main focus of treatment is to reduce behavioral events and prevent sleep-related injury; this can be achieved through changes in the sleeping environment and, if necessary, oral bedtime melatonin and/or clonazepam.

This topic will review the clinical features, evaluation, and management of RBD in adults. Other parasomnias, many of which occur or begin in childhood, are discussed separately. (See "Sleepwalking and other parasomnias in children".)

EPIDEMIOLOGY — REM sleep behavior disorder (RBD) affects approximately 0.5 percent in the general population and 2 percent of the older adult population [1,2]. Although this translates to 35 million expected patients worldwide, the vast majority of cases go unrecognized [2]. In contrast with RBD, rare and intermittent dream-enactment behavior is a more common and mostly benign occurrence. Particularly high-risk groups for isolated dream-enactment behaviors include college students and postpartum women [3].

Among younger adults (<40 years old), RBD most frequently occurs with antidepressant medications or in the setting of narcolepsy [4,5]. RBD is rare among children, with most episodes of reported dream enactment behavior either isolated or due to a non-REM parasomnia such as sleepwalking [6]. (See "Sleepwalking and other parasomnias in children".)

Since spontaneous RBD is a prodromal syndrome of alpha-synuclein neuropathology, it is widespread among patients with Parkinson disease (33 to 50 percent), multiple system atrophy (80 to 95 percent), and dementia with Lewy bodies (80 percent) [4,7-11]. Environmental and behavioral risk factors for RBD overlap with Parkinson disease. In particular, RBD patients are more likely to smoke; have fewer years of education; and report a history of traumatic brain injury, welding work, and pesticide exposure [12].

RBD has a strong male predominance in published series (as high as 9:1 male to female ratio), but female cases are likely underreported and underdiagnosed. Women often have less injurious dream enactment and are therefore less likely to receive medical attention [13]. Older women are also less likely than men to have witnessed parasomnia behaviors because they often outlive their male spouses [14].

PATHOGENESIS — Under normal conditions, the active dream mentation that characterizes REM sleep is not behaviorally enacted due to paralysis of skeletal musculature. This REM sleep atonia leads to a quiescence of motor activity, allowing for sleep-related memory consolidation during REM sleep.

The normal physiologic suppression of motor activity during REM sleep is the cumulative result of multiple neuronal circuits that predominantly originate in the pons and ultimately terminate on spinal cord motor neurons. In both spontaneous and medication-induced REM sleep behavior disorder (RBD), the loss of REM sleep atonia appears to be related to dysfunction of pontine REM-on nuclei in the preceruleus and sublateral dorsal pons and REM-off nuclei in the ventral lateral portion of the periaqueductal grey matter and lateral pontine tegmentum [4].

In narcolepsy, hypothalamic pathology is implicated in the failure to suppress REM sleep-related motor activity. In these cases, dysfunction in the neurotransmitter orexin can precipitate RBD [15]. Orexin, secreted from the lateral hypothalamus, promotes state stability and prevents frequent transitioning between states (ie, wake, non-REM, REM). Orexin deficiency associated with narcolepsy leads to REM-wake instability, which promotes wake-like motor activity in parallel with REM dream mentation [16-18].

ETIOLOGY — REM sleep behavior disorder (RBD) is the clinical manifestation of a variety of central nervous system pathologies, all of which result in a failure to inhibit spinal motoneurons. These include: alpha-synuclein and other forms of neurodegeneration, orexin deficiency (narcolepsy), structural pontine lesions, and toxic effects from medications.

Alpha-synuclein neurodegeneration — Alpha-synuclein pathology, as seen in Parkinson disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), is the most common cause of RBD. In the absence of an offending medication or comorbid neurologic disorder, it is the presumed cause of all cases of what is variably referred to as spontaneous, cryptogenic, or idiopathic RBD.

The pontine nuclei that control REM sleep are early targets in the natural history of synucleinopathies [4]. This pathology, which ultimately manifests in either PD, MSA, or DLB, thus initially presents to medical attention with vigorous dream-enactment behavior.

Polysomnographically-confirmed RBD is among the strongest early predictors of PD [19,20]. Other nonmotor findings of PD, such as anosmia and constipation, often coincide with RBD and are manifestations of alpha-synuclein pathology in the olfactory bulb and enteric plexus [21-24]. However, symptoms are typically either dismissed as clinically insignificant or misattributed to some other clinical diagnosis.

The interval between the onset of RBD and the parkinsonian triad of resting tremor, bradykinesia, and cogwheel rigidity may vary from months to decades. In case series, approximately half of patients convert to a neurologic disorder within 10 years [25-27]. In a longitudinal study of 93 patients diagnosed with idiopathic RBD, the estimated risk of developing a neurodegenerative disorder (primarily PD or DLB) was 18 percent at 5 years, 41 percent at 10 years, and 52 percent at 12 years [26]. In studies with long-term follow-up, nearly all patients (80 to 90 percent) eventually convert to a neurologic disorder [28,29]. Even among the rare cases of apparently persistent idiopathic RBD, neuroimaging biomarkers demonstrate impending neurodegeneration [30], and postmortem examinations reveal diffuse Lewy body pathology typical of alpha-synuclein degeneration [31].

Even prior to the onset of a neurodegenerative syndrome, RBD patients have evidence of diffuse and progressive neuropathology.

Neuroimaging studies demonstrate coincident and progressive dopaminergic abnormalities in patients with RBD before motor symptoms arise [24,32,33].

Cholinergic denervation has also been reported in the brains of patients with RBD; similar to cholinergic impairment in PD, these findings are correlated with cognitive decline [34].

Cortical abnormalities similar to those in PD and DLB have been demonstrated using magnetic resonance imaging (MRI), functional MRI, and electroencephalography (EEG) [33,35-37].

Phosphorylated alpha-synuclein deposits can be detected in the autonomic nerve fibers of the submandibular gland in patients with RBD as well as those with PD [38].

Non-synuclein neurologic disorders — Less commonly, RBD occurs in non-synuclein neurodegenerative disorders such as progressive supranuclear palsy, frontotemporal dementia, amyotrophic lateral sclerosis, Alzheimer disease, spinal cerebellar ataxia type 3, Huntington disease, and myotonic dystrophy type 2 [4,39-42].

In these patients, it is uncertain whether the various neuropathologies that characterize these disorders also cause RBD. Some of the disorders affect pontine regions that control REM sleep, suggesting a unifying pathogenesis. However, some investigations suggest that the presence of RBD indicates comorbid alpha-synuclein pathology. This has been demonstrated in patients with cognitive impairment that was presumed to be due to Alzheimer pathology, in whom careful postmortem evaluations have demonstrated diffuse brain stem alpha-synuclein pathology [43].

With the exception of spinocerebellar ataxia type 3, these disorders are associated with a much lower prevalence of RBD compared with the alpha-synuclein disorders. In addition, symptoms of RBD in these cases typically arise after other neurologic deficits have manifested, rather than before [44].

RBD has also been described in association with paraneoplastic and autoimmune encephalitides such as IgLON5 encephalopathy, anti-leucine rich glioma inactivated 1 (LGI1) encephalitis, anti-contactin associated protein-like 2 (Caspr2) encephalitis, and cerebellar degeneration [45-47]. (See "Paraneoplastic and autoimmune encephalitis".)

Narcolepsy and state boundary control — Approximately 50 percent of patients with narcolepsy have RBD. The association is greatest among patients with narcolepsy type 1 (narcolepsy with cataplexy), and the pathogenesis (orexin deficiency) is distinct from other forms of RBD. (See 'Pathogenesis' above.)

In narcolepsy type 1, orexin deficiency results in an admixture of sleep and wake phenomena throughout a 24-hour period. This failure to separate wake from sleep results in classical clinical features of excessive daytime sleepiness, nocturnal sleep fragmentation, sleep paralysis, cataplexy, and hypnagogic and hypnopompic hallucinations. (See "Clinical features and diagnosis of narcolepsy in adults".)

The dream-enactment behavior of narcolepsy-related RBD is caused by a failure of orexin to stabilize REM sleep, with a resulting intrusion of wakeful muscle tone [16,18].

Pontine lesions — Structural lesions in the brainstem due to vascular, demyelinating, neoplastic, and traumatic etiologies can trigger dream-enactment behavior [31,48-50]. Brain imaging in such cases typically demonstrates pontine tegmentum pathology.

Medications — Antidepressant medications acutely precipitate or exacerbate dream-enactment behavior in up to 6 percent of patients, and medication-induced RBD may be the most prevalent form of RBD among the young (<40 years old) [51,52].

Implicated medication classes include tricyclic and tetracyclic antidepressants, monoamine oxidase inhibitors, serotonin-specific reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors [52-54]. Emergent RBD has also been reported in a patient with PD treated with suvorexant, an orexin receptor antagonist used for treatment of insomnia [55].

The exact mechanism of toxic RBD associated with antidepressants is unknown, but likely relates to serotonergic effects. The serotonergic raphe nuclei in the pons have an activating effect on the REM-off nuclei, suggesting a plausible pathological mechanism [4]. Alternatively, toxic RBD may not represent a de novo induction of RBD, but instead may be revealing individuals predisposed to parkinsonian syndromes. This is supported by observations that patients with toxic RBD have other prodromal markers of alpha-synuclein neurodegeneration, such as anosmia, constipation, abnormalities in color vision, and subtle motor impairments [56]. These findings suggest that antidepressants may in some cases unmask RBD in individuals at risk of neurodegeneration.

CLINICAL FEATURES — Patients with REM sleep behavior disorder (RBD) exhibit motor behaviors during REM sleep. Polysomnography may or may not capture a motor event but commonly demonstrates abnormal sustained or phasic muscle activity during REM sleep, as measured by chin or limb electromyography (EMG). In most cases, symptom onset is gradual and progressive, with a delay of several years between the onset of symptoms and diagnosis.

Dream-enactment behaviors — The defining symptom of RBD is repeated episodes of sleep-related vocalization and/or complex motor behaviors during REM sleep, correlating with dream mentation.

The movements of RBD are short in duration (less than 60 seconds) and appear purposeful, such as throwing a ball or flailing to protect oneself. They range in severity from benign hand gestures to violent thrashing, punching, and kicking. Sleep-related vocalizations may be loud and laden with expletives. Sleep-related injuries can arise from jumping out of bed or striking a bed partner. Events that involve leaving the bed or waking up on the floor pose the highest risk for self-injury.

In a cohort study of 203 consecutive patients with RBD followed at a tertiary care sleep clinic over a median of five years, just over half of patients were aware of their sleep behaviors [57]. The majority of patients had experienced at least one episode of punching (87 percent), kicking (82 percent), falling out of bed (77 percent; in most cases less than five times), gesturing (73 percent), or knocking over the nightstand (67 percent). Nearly all patients also reported vocalizations, most commonly talking (96 percent), screaming (90 percent), and moaning (64 percent). In both men and women, about 60 percent of patients and 20 percent of bed partners had sustained injury.

Symptoms predominantly occur in the second half of the sleep period, when REM sleep is most prevalent. The frequency of events ranges from nightly to annually [2,58].

Patients often sleep through mild events. With more vigorous dream enactment, they typically wake up for a brief period of time and then fall back asleep. Dream content is often recalled at the time of awakening and is typically unpleasant (eg, dreaming of being attacked or chased, arguing with someone, or falling off a cliff) [57]. Patients may appear briefly confused when they first awaken but quickly orient to their surroundings.

Dream content in patients with RBD is not more violent than in normal individuals, despite the violent behaviors. Patients are no more likely than controls to exhibit daytime violence or personality disturbances [59,60].

Among narcolepsy patients with RBD, dream enactment tends to occur earlier in the sleep period and is composed of more simple movements that are less violent.

Clinical course — Symptoms of RBD typically begin in late adulthood. The median age of diagnosis is 60 to 70 years [61-64]. In most cases, symptom onset is gradual and progressive, with a delay of several years between the onset of symptoms and diagnosis. Patients typically present to medical attention with a concern related to injurious or potentially injurious actions to themselves and/or a bed partner.

Neurologic findings — Patients with spontaneous RBD often have subtle, progressive motor and cognitive features consistent with early neurodegeneration. Typical findings include mild postural instability and gait abnormalities, including freezing of gait, consistent with subtle parkinsonism. Quantitative motor testing reveals bradykinesia imperceptible on a clinical exam.

Cognitive impairments are similar to those seen in patients with Parkinson disease (PD) and dementia with Lewy bodies, with progressive deficits in visuoconstructional skills, facial expression recognition, and color identification [4,65-67]. Many patients will describe pareidolia (the tendency to interpret a vague visual feature as familiar, such as a face in the sand), a finding that correlates with underlying occipital dysfunction consistent with impending Lewy body disease [68].

Comorbid olfactory dysfunction, constipation, and orthostatic hypotension are frequently noted in cases of spontaneous RBD [22,69,70]. Like the motor and cognitive deficits, these impairments are similar to those seen in patients with PD [24]. (See "Clinical manifestations of Parkinson disease".)

Among patients with PD, those with RBD are more likely to have freezing of gait, a higher frequency of falls, and a greater clinical and pathologic disease burden than patients without RBD [71-73]. Interestingly, many of the same brainstem regions implicated in the pathophysiology of RBD mediate the pathogenesis of freezing of gait [74].

Polysomnography — Polysomnography is necessary for definitive diagnosis of RBD and to exclude other sleep disorders that can mimic RBD.

The characteristic polysomnographic finding of RBD is REM sleep without atonia (RSWA), which is an elevation of motor tone during REM sleep as measured by EMG in the chin and/or limb leads (figure 1) [75,76]. Formal polysomnographic criteria for RSWA developed by the American Academy of Sleep Medicine require either of the following [76]:

Sustained elevation of chin EMG activity during REM sleep (greater than 50 percent of the 30-second epoch duration compared with minimum amplitude in non-REM sleep)

Excessive bursts of transient muscle activity in the chin or limb EMG during REM sleep (at least half of all 3-second mini epochs on a 30-second page)

Optimally, both upper and lower extremity EMG should be used when evaluating for RBD. Alternate EMG derivations that make use of upper extremity EMG to improve sensitivity for detecting RSWA are reviewed separately. (See "Polysomnography in the evaluation of parasomnias and epilepsy", section on 'REM sleep behavior disorder'.)

When present, RSWA tends to occur during every REM cycle but is most prominent in the final REM period of the night. There is little correlation between the severity of polysomnographic findings and clinical symptoms. While dramatic behaviors are rarely captured during polysomnography, more subtle, seemingly purposeful hand movements suggestive of dream enactment are often observed.

RSWA is occasionally detected in individuals without a reported history of dream-enactment behaviors, particularly in patients taking antidepressants [77,78] and in older adults. The reported prevalence of so-called isolated RSWA ranges from 10 to 15 percent and varies according to how RSWA is defined [78-81]. The proportion of patients with isolated RSWA who later develop RBD has not been established; in one small study, 1 of 14 individuals with RSWA progressed to RBD over a mean of 8.6 years [82].

In patients with comorbid narcolepsy, polysomnography may also demonstrate frequent shifts between REM and non-REM sleep and consistent sleep state boundary dysfunction [16]. (See "Clinical features and diagnosis of narcolepsy in adults".)

DIAGNOSIS — A diagnosis of REM sleep behavior disorder (RBD) should be suspected in patients with a clinical history of recurrent dream-enactment behavior and confirmed with polysomnography [2,76].

Evaluation — The clinical evaluation should include a detailed review of the sleep-wake complaints, a neuropsychiatric history, and complete physical and neurologic examination. A report from a bed partner is particularly helpful, as many patients are unable to properly recall the sleep-related events.

RBD can often be detected with one question asked of the bed partner: "Have you ever seen the patient appear to 'act out his or her dreams' (punched or flailed arms in the air, shouted, or screamed) while sleeping?" [44].

The history should also pay specific attention to the timing of abnormal vocalizations or behaviors during the night. This feature helps distinguish RBD from other parasomnias such as confusional arousals, sleepwalking, and sleep terrors. (See 'Differential diagnosis' below.)

Patients should be asked about potentially offending medications (eg, antidepressants) as well as ancillary symptoms of alpha-synuclein neurodegenerative disorders, such as difficulty with smell, syncope, bowel motility, visual hallucinations, and tremor. When chronic, unexplained anosmia, orthostasis, and constipation coexist with RBD, they are highly suggestive of an imminent alpha-synuclein disorder such as Parkinson disease [4]. In young patients, symptoms of RBD should prompt consideration of comorbid narcolepsy.

Polysomnography is necessary for a definitive diagnosis of RBD. Even when abnormal behavior does not occur during the study, REM sleep without atonia is characteristically present and required for the diagnosis. Polysomnography is also helpful in excluding other sleep-disrupting conditions (eg, obstructive sleep apnea, nocturnal seizures, periodic limb movements) [2,75]. (See 'Polysomnography' above.)

Additional testing such as neuroimaging, electroencephalography, and neuropsychological batteries are warranted only if there is further evidence suggesting a neurodegenerative disorder [83]. Tests that identify central nervous system dopamine dysfunction, such as a DaTscan, or other markers of synuclein pathology, such as metaiodobenzylguanidine (MIBG) cardiac scintography, are not necessary for the diagnosis, but can be clinically useful in predicting and monitoring the course of the disease [4,84,85]. (See "Diagnosis and differential diagnosis of Parkinson disease" and "Clinical features and diagnosis of dementia with Lewy bodies" and "Multiple system atrophy: Clinical features and diagnosis".)

Diagnostic criteria — According the third edition of the International Classification of Sleep Disorders (ICSD-3), a diagnosis of RBD requires all of the following [2]:

Repeated episodes of sleep-related vocalization and/or complex motor behaviors

Behaviors are documented by polysomnography to occur during REM sleep or, based on clinical history of dream enactment, are presumed to occur during REM sleep

Presence of REM sleep without atonia on polysomnography (see 'Polysomnography' above)

Absence of epileptiform activity during REM sleep, unless RBD can be clearly distinguished from any concurrent REM sleep-related seizure disorder

The sleep disturbance is not better explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of REM sleep behavior disorder (RBD) includes disorders of arousal, other REM-associated parasomnias such as nightmares, sleep-disrupting conditions such as periodic limb movement disorder and obstructive sleep apnea, nocturnal seizures, and dissociative psychiatric disorders. Although these disorders may sometimes be distinguished from each other by history, overnight polysomnography is required for definitive diagnosis.

Non-REM parasomnias – The most common disorders to be distinguished from RBD are the non-REM (NREM) parasomnias: confusional arousals, sleepwalking, and sleep terrors. Unlike RBD, non-REM parasomnias usually present in childhood. Additional aspects of the history that are helpful in distinguishing NREM parasomnias from RBD include:

Duration and timing of the events – RBD consists of brief dream enactment (<60 seconds) occurring in the latter half of the sleep period, followed by alertness and orientation upon awakening. This presentation contrasts with sleepwalking, in which there is often a lifelong history of prolonged, amnestic, complex, nonviolent activities emanating from the first half of the sleep period. Similarly, confusional arousals are more prolonged (>60 seconds) and more often occur in the first half of the night. (See "Disorders of arousal from non-rapid eye movement sleep in adults", section on 'Confusional arousals'.)

Response upon awakening – Sleepwalking subjects are difficult to awaken and only rarely report dream mentation. In contrast, patients with RBD often recall dream content if awakened and are alert and oriented afterwards.

Nature of vocalizations – In RBD, sleep-related vocalizations may be loud and laden with expletives. This contrasts with normal sleep talking, which is more typical of daytime conversation and occurs during both NREM and REM sleep [84]. Sleep terrors may be accompanied by a loud vocalization but have other features distinct from RBD. They are mostly limited to preadolescence and characterized by amnestic episodes of intense fear initiated by a sudden scream. They may last several minutes, during which time the patient is inconsolable. While the parents are often frightened by the episodes, they are amnestic and nearly universally benign to the child [84]. (See "Sleepwalking and other parasomnias in children", section on 'Clinical features'.)

Parasomnia overlap disorder – Parasomnia overlap disorder is characterized by RBD and either a disorder of arousal, sleep-related eating disorder, sexsomnia, or rhythmic movement disorder [2]. Compared with RBD, parasomnia overlap disorder has an earlier age of onset (often in childhood or adolescence) and may be comorbid with a variety of neurologic and psychiatric disorders such as narcolepsy and multiple sclerosis. (See "Disorders of arousal from non-rapid eye movement sleep in adults", section on 'Parasomnia overlap disorder'.)

Nightmares – Nightmares are REM-related phenomena consisting of disturbing mentation and recalled in vivid detail. Unlike RBD, nightmares are not associated with motor activity or sleep-related injury [84]. In fact, nightmares are often characterized by sleep paralysis, an inability to move, defend oneself, or scream. (See "Nightmares and nightmare disorder in adults".)

Obstructive sleep apnea – Behaviors that may mimic RBD can occur when REM sleep is fragmented by obstructive sleep apnea. However, these parasomnia-like behaviors resolve once the sleep-disordered breathing is effectively treated [4,83]. This phenomenon has been referred to as pseudo-RBD.

Periodic limb movements – Periodic limb movements are lower extremity "triple flexion responses" (dorsiflexion of the ankle, flexion of the knee and hip) along with dorsiflexion of the toe, akin to the Babinski response. Unlike RBD, periodic limb movements occur primarily during NREM sleep, are periodic (approximately every 45 seconds), and are unrelated to dream mentation [2,76]. Rare cases of frequent and vigorous periodic limb movements during both NREM and REM sleep, mimicking RBD, have been described [86]. (See "Polysomnography in the evaluation of abnormal movements during sleep", section on 'Periodic limb movements of sleep'.)

Sleep-related dissociative disorder – The behavior in sleep-related dissociative disorder is often prolonged, and electroencephalography demonstrates wakefulness throughout the episode. Patients typically have comorbid daytime dissociative disorders. (See "Approach to abnormal movements and behaviors during sleep", section on 'Panic or dissociative events'.)

Nocturnal frontal lobe epilepsy – RBD is occasionally confused with nocturnal frontal lobe epilepsy (NFLE). NFLE is characterized by stereotyped, recurrent (up to 20 times episodes a night), abnormal behaviors. Electroencephalography may (but not universally) reveal epileptic activity. Compared with RBD, patients with NFLE are younger (typically presenting in adolescence) and fully unaware of nighttime behaviors [83]. (See "Disorders of arousal from non-rapid eye movement sleep in adults", section on 'Nocturnal seizures'.)

TREATMENT — Establishing a safe sleeping environment is the primary goal of treatment. This can be achieved through modification of the sleep environment and, if necessary, pharmacotherapy.

In the absence of clinical trials comparing different treatment strategies, recommendations are based on observational studies and clinical experience [84,87,88]. While both melatonin and clonazepam are effective in suppressing REM sleep behavior disorder (RBD) behaviors in the majority of patients, melatonin is preferred as initial therapy based on its favorable side effect profile (table 1).

Medications known to exacerbate RBD, including serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants, should be discontinued or avoided if possible in patients with RBD [89]. Most cases of toxic RBD are self-limited following discontinuation of the offending medication. In patients with a sleep-fragmenting condition such as obstructive sleep apnea, dream-enactment behavior often resolves when the underlying disorder is treated [4,84].

Safe sleeping environment — The frequency of dream enactment behaviors is not predictive of injury, so all patients with RBD and their bed partners should be counseled on modifying the sleeping environment to prevent injury. For patients with mild symptoms, this may be all that is needed.

Firearms should not be accessible, and sharp or easily breakable items (such as lamps) should be removed from the immediate sleeping area. In the event of continued vigorous behaviors, sleeping alone is advised. Many patients resort to using padded bed rails or sleeping in a sleeping bag [84].

Other novel strategies are in development. Exiting the bed while acting out a dream is a high-risk behavior that may result in traumatic injury [90]. A bed alarm that delivers a customized calming message at the onset of dream enactment can prevent a patient from exiting the bed and avert sleep-related injury [91].

Melatonin — Melatonin is our preferred first-line therapy in patients with frequent, disruptive or injurious behaviors. Melatonin is an endogenous hormone normally secreted by the pineal gland in response to evening darkness, entraining circadian rhythms. By an uncertain mechanism, melatonin in high doses at bedtime (6 to 18 mg) augments REM sleep atonia and improves RBD symptoms [92-94]. It tends to be better tolerated than the alternative first-line therapy, clonazepam [94].

In several observational studies and one small randomized trial, the majority of patients treated with melatonin experienced at least partial improvement in the frequency and severity of RBD symptoms and a reduced likelihood of injury [92-97]. In a retrospective study that included 45 patients with RBD, melatonin and clonazepam were similarly effective, and melatonin was better tolerated [97]. Approximately two-thirds of patients treated with melatonin reported at least mild improvement in symptoms, and 12 percent had complete resolution of RBD behaviors. Patients on melatonin reported fewer falls and injuries post-treatment compared with clonazepam.

The dose of melatonin required to suppress behaviors in patients with RBD varies. In our experience, most patients achieve significant improvement with doses ranging from 6 to 18 mg nightly. We typically start with 3 mg at night and then increase in 3 mg increments until the disruptive and injurious behaviors have ceased (table 1).

Melatonin tends to be well tolerated at these doses, with occasional patients developing gastrointestinal distress or headache that is dose limiting. Other reported side effects are usually mild and include sleepiness, fatigue, dizziness, unsteadiness, and cognitive alteration [94]. Melatonin is not regulated by the US Food and Drug Administration and is available in a variety of formulations over-the-counter. Unlicensed, nonprescription products can vary widely due to differences in the type of preparation and additives used. In our experience, most formulations appear to be clinically equivalent. Melatonin undergoes hepatic metabolism and should be used with caution in patients with hepatic impairment. (See "Physiology and available preparations of melatonin", section on 'Melatonin preparations'.)

Behaviors typically return when melatonin is reduced or discontinued, and most patients require lifelong therapy. If behaviors are inadequately suppressed with melatonin, low-dose clonazepam is an effective add-on or alternative therapy.

Clonazepam — Low-dose clonazepam (0.5 to 1 mg at bedtime) has long been recognized as a treatment for RBD. Like melatonin, the therapeutic mechanisms of clonazepam in RBD are not fully understood, although it is thought that clonazepam may reduce the frequency of unpleasant dreams, thus decreasing violent dream enactment behavior [98].

In three large case series, clonazepam was associated with complete resolution of RBD symptoms in 55 to 79 percent of patients and partial reduction in an additional 11 to 32 percent [57,61,62]. Long-term follow-up studies describe more mixed results, ranging from sustained benefit without dose escalation to a high incidence of increasing dose requirements and ultimately treatment failure [95,98-101]. In one prospective study, clonazepam was not associated with an improvement in symptoms among treatment-naïve patients [102].

Although low doses of clonazepam (0.5 to 1 mg at bedtime) are typically sufficient to suppress RBD behaviors, side effects can limit its utility. In a cohort study that included 167 patients treated with clonazepam (mean effective dose 1 mg), 39 percent of patients reported side effects, most commonly morning sedation and dizziness, leading to drug discontinuation in 9 percent [57].

Side effects can be particularly problematic among older adults and in the setting of advanced neurodegenerative disease, where its prolonged duration of action may result in morning sedation as well as gait and cognitive impairment [91,103]. In such patients, we suggest a lower initial dose (eg, 0.125 or 0.25 mg) and close monitoring for the emergence of toxicity (table 1). Clonazepam undergoes hepatic metabolism and should be used with caution in patients with hepatic impairment.

Other therapies — In patients who fail melatonin and clonazepam therapy, cholinergic agents may be useful. In one small, placebo-controlled, crossover trial, the cholinesterase inhibitor rivastigmine reduced the number of dream-enactment behavior episodes (as noted by bed partners) in patients with Parkinson disease (PD) and RBD [104]. Donepezil, another cholinesterase inhibitor, has also been reported to improve RBD symptoms in three patients [105].

While dopaminergic medications are the standard therapy for motor symptoms of PD, they are rarely effective for nonmotor symptoms such as RBD and only in certain cases. In mild RBD with frequent comorbid periodic limb movements, pramipexole decreases nocturnal behaviors [106]. In another study, pramipexole was associated with a decrease in distressing nocturnal behaviors and periodic limb movements, but had no effect on REM sleep atonia [107]. Levodopa has been reported to improve RBD symptoms in three patients with PD and one patient with dementia with Lewy bodies [108,109].

Other agents with some reported success include imipramine, carbamazepine, sodium oxybate, triazolam, zopiclone (available outside the United States), quetiapine, and clozapine [87,95,100,110].

Surgeries for PD do not improve RBD symptoms or the polysomnographic findings of RBD. In four case series of patients with PD, deep brain stimulation of the subthalamic nuclei was associated with improvement in subjective sleep quality and sleep architecture on polysomnography; however, there was little to no improvement in dream-enactment behavior or REM atonia [111-114].

PROGNOSIS AND COUNSELING — Patients with REM sleep behavior disorder (RBD) and their bed partners are prone to sleep-related injuries. The punching, kicking, and jumping behaviors can result in hematomas, fractures, lacerations, and joint dislocations [28]. As bed partners are frequently the target of violent dream enactment, RBD has forensic implications, with patients occasionally arrested for domestic assault [90].

Most patients with spontaneous RBD (80 to 90 percent) eventually develop a neurodegenerative disorder [28,29]. While the interval between the onset of dream enactment and Parkinson disease or related disorders can vary from months to decades, the conversion rate is approximately 50 percent every 10 years [25-27]. In a 10-year prospective cohort study of 89 patients with idiopathic RBD, the strongest risk factors for conversion to a neurodegenerative disorder were subtle motor dysfunction (hazard ratio [HR] 3.9), abnormal color vision (HR 3.1), olfactory dysfunction (HR 3.8), and nonuse of antidepressants (HR 3.5) [115].

The ethical principles of autonomy, informed consent, and respect for persons support disclosing the risk of future neurodegenerative disease to patients with RBD [116,117]. A diagnosis of RBD is not absolutely predictive of the development of neurodegenerative disease, but rather suggests an increased susceptibility. Risk estimates are derived from selected populations and do not equate to definitive information on a patient's individual risk. Discussing the association between RBD and neurodegenerative disease openly with patients and their families during clinical encounters gives them the opportunity to ask questions and avoids the potential for misinformation obtained on the internet.

Patients should also be counseled that Parkinson disease and other disorders are treatable conditions. In addition, if effective neuroprotective therapies for alpha-synuclein neurodegeneration are identified, patients with RBD could benefit from early treatment. As a biophysiological marker of alpha-synuclein neurodegeneration, RBD provides a unique opportunity to potentially identify neuroprotective therapies to impede or halt Parkinson disease. A consortium of multinational investigators, the International Rapid Eye Movement Sleep Behavior Disorder Study Group, meets annually to promote the development of collaborative clinical trials [118].


Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by dream enactment that emerges after a loss of REM sleep atonia. Behaviors are brief, correlate with dream mentation, mainly occur in the second half of the night, and, when violent, can result in injury to the patient or bed partner. (See 'Dream-enactment behaviors' above.)

The prevalence of RBD is estimated at 0.5 percent in the general population, with higher frequencies among older adults and those with Parkinson disease (PD), multiple system atrophy, and dementia with Lewy bodies. (See 'Epidemiology' above.)

Most cases of RBD are caused by alpha-synuclein neurodegeneration. RBD is also caused by antidepressant medications, narcolepsy, and pontine lesions such as those from stroke or multiple sclerosis. (See 'Etiology' above.)

The diagnosis of RBD is based upon a history of dream-enactment behavior and REM sleep without atonia, as documented by polysomnography. (See 'Diagnosis' above.)

The differential diagnosis of RBD includes non-REM parasomnias (confusional arousals, sleepwalking, sleep terrors); nightmares; benign sleeptalking; nocturnal frontal lobe epilepsy; as well as sleep-fragmenting conditions such as obstructive sleep apnea and periodic limb movements. (See 'Differential diagnosis' above.)

All patients with RBD and their bed partners should be counseled on ways to alter the sleeping environment to prevent injury. (See 'Safe sleeping environment' above.)

For patients with frequent, disruptive or injurious behaviors, we recommend pharmacotherapy (Grade 1B). We suggest melatonin as initial therapy rather than clonazepam (Grade 2C). A typical starting dose of melatonin for RBD is 3 mg at bedtime, increased in 3 mg increments until behaviors subside (table 1). Most patients find relief with doses between 6 and 18 mg. Low-dose clonazepam is an effective alternative or add-on therapy but may be less well tolerated, particularly in patients with comorbid neurodegenerative disease. (See 'Melatonin' above and 'Clonazepam' above.)

Most patients with spontaneous RBD eventually develop either PD or another disorder of alpha-synuclein neurodegeneration. The RBD to PD conversion rate is approximately 50 percent every decade. The presence of anosmia, constipation, and orthostasis increases the likelihood of earlier conversion. (See 'Prognosis and counseling' above.)

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