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 (PD) 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. An approach to abnormal movements and behaviors during sleep and other specific parasomnias in adults are discussed separately. (See "Approach to abnormal movements and behaviors during sleep" and "Disorders of arousal from non-rapid eye movement sleep in adults" and "Nightmares and nightmare disorder in adults".)
EPIDEMIOLOGY — The prevalence of rapid eye movement (REM) sleep behavior disorder (RBD) is approximately 0.5 to 1.25 percent in the general population and approximately 2 percent in older adults [1-4]. Although this translates to 40 to 100 million expected patients worldwide, the vast majority of cases go unrecognized [2].
Among younger adults (<40 years old), RBD most frequently occurs in the setting of antidepressant medication exposure or narcolepsy [5,6]. RBD is rare among children, with most cases being associated with narcolepsy type 1, antidepressant medication use, and rarely with brainstem tumors and various neuropsychiatric disorders [6-8]. Occasionally, there can be isolated dream enactment behavior or dream enactment with a non-REM parasomnia such as sleepwalking [9,10]. (See "Parasomnias of childhood, including sleepwalking".)
Since isolated RBD is a prodromal syndrome of alpha-synuclein neuropathology, it is widespread among patients with Parkinson disease (PD) (33 to 50 percent), multiple system atrophy (80 to 95 percent), and dementia with Lewy bodies (80 percent) [5,11-15]. Environmental and behavioral risk factors for RBD largely overlap with those for PD. Patients with confirmed or possible RBD are more likely to smoke; have fewer years of education; report heavy alcohol use; have a concurrent mood disorder; use antidepressants; and report a history of traumatic brain injury, welding work, and pesticide exposure [16-18].
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 [3]. Much of the discrepancy may be due to referral bias, since males often have more aggressive and violent RBD episodes compared with females [3,19]. Female patients with RBD are also younger and more commonly present in the setting of associated autoimmune disorders or serotonergic RBD [20]. Among older adult females, RBD may be less likely to be witnessed, as females more often outlive their male bed partners [21].
PATHOGENESIS — Physiologically, rapid eye movement (REM) sleep is associated with skeletal muscle atonia, producing paralysis. This confers a protective measure, preventing people from acting what they dream in the setting of dream mentation. Quiescence of motor activity during REM sleep may also facilitate sleep-related memory consolidation.
The 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. While the exact lesion that causes RBD is unknown, evidence suggests that in both isolated and medication-induced REM sleep behavior disorder (RBD), the loss of REM sleep atonia is related to dysfunction of the subcoeruleus complex in the rostral pons [5,22].
In narcolepsy, orexin-mediated 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 [23]. Orexin, secreted from the lateral hypothalamus, promotes state (ie, wake, non-REM, REM) stability and prevents frequent transitioning between states. Orexin deficiency associated with narcolepsy leads to REM-wake instability, which promotes wake-like motor activity in parallel with REM dream mentation [24-26].
ETIOLOGY — Rapid eye movement (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 or possibly unmasking 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 provoking medication or comorbid neurodegenerative disorder, it is the presumed cause of all cases of isolated RBD (previously referred to as idiopathic RBD) [27].
The pontine and medullary nuclei that control REM sleep are early targets in the natural history of synucleinopathies [5]. This pathology, which ultimately manifests in either PD, MSA, or DLB, thus initially presents to medical attention with vigorous dream-enactment behavior.
RBD confirmed by video polysomnography is among the strongest early predictors of PD [28,29]. 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 [30-33]. However, symptoms are typically either dismissed as clinically insignificant or misattributed to some other etiology.
The interval between the onset of RBD and the parkinsonian triad of resting tremor, bradykinesia, and cogwheel rigidity may vary from months to decades. This process, when an individual at risk for disease begins to express the defining clinical characteristics of the disease, is referred to as phenoconversion. In the largest multicenter study of over 1000 patients with isolated RBD, the annual phenoconversion rate was 6 percent, with 74 percent phenoconverting within 12 years of RBD diagnosis [34]. Even among the rare cases of apparently persistent isolated RBD, neuroimaging biomarkers have demonstrated impending neurodegeneration [35], and postmortem examinations have revealed diffuse Lewy body pathology typical of alpha-synuclein degeneration [36]. (See 'Prognosis and counseling' below.)
Even prior to the onset of a neurodegenerative syndrome, patients with RBD have evidence of diffuse and progressive neuropathology.
●Neuroimaging studies such as dopamine transporter (DAT) imaging demonstrate coincident and progressive dopaminergic abnormalities in patients with RBD before motor symptoms arise [33,35,37-39].
●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 [40,41].
●Cortical abnormalities similar to those in PD and DLB have been demonstrated using magnetic resonance imaging (MRI), functional MRI, and electroencephalography (EEG) [38,42-44].
●Phosphorylated alpha-synuclein deposits can be detected in the autonomic nerve fibers of the submandibular, salivary, and parotid glands in patients with RBD as well as those with PD [45,46].
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 (AD), spinal cerebellar ataxia type 3, Huntington disease, and myotonic dystrophy type 2 [5,47-50].
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 [51].
Among patients with mild cognitive impairment (MCI) when a clinician is concerned about the possibility of impending AD, inquiring about dream enactment is useful. A straightforward question such as, "Have you ever been told that you act out your dreams (such as thrash, punch, or kick)?" helps distinguish patients who will ultimately go on to develop DLB (when answered in the affirmative) versus AD (when answered in the negative) [52]. Further, in distinguishing DLB from AD, the presence of RBD symptoms is even more specific than tremor, a parkinsonian sign [53].
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 [54].
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, as well as Wilson disease and cerebellar degeneration [55-58]. (See "Paraneoplastic and autoimmune encephalitis".)
Post-traumatic stress disorder increases the odds of developing RBD in war veterans. This association has been noted even in the absence of comorbid traumatic brain injury [59]. (See "Sleep-wake disorders in patients with traumatic brain injury", section on 'Abnormal movements or behaviors during sleep'.)
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 [24,26]. Alpha-synuclein biomarkers are absent in patients with narcolepsy-related RBD, suggesting that they do not have an increased risk of neurodegeneration [60].
Pontine lesions — Structural lesions in the brainstem due to vascular, demyelinating, neoplastic, and traumatic etiologies can trigger dream-enactment behavior [36,61-63]. Brain imaging in such cases typically demonstrates pontine tegmentum pathology.
Medications — Approximately half of all RBD patients develop dream enactment after initiating a serotonergic antidepressant medication, typically a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), or serotonin modulating agent [64,65]. Serotonergic RBD appears to be the most prevalent form of RBD among the young (<40 years old) [20,64].
The magnitude of risk associated with SSRIs and SNRIs is not well characterized. In a retrospective study of over 10,000 polysomnography (PSG) exams, REM sleep without atonia (RSWA), a PSG marker of RBD, was identified in 12 percent of participants who were taking an SSRI or SNRI versus 2 percent of the entire study population, representing a 10-fold increase in relative risk [66]. Only 7 of the patients with antidepressant-associated RSWA carried a clinical diagnosis of RBD (0.5 percent). There was no difference in risk between SSRIs and SNRIs, and the study was not powered to distinguish differential risk among specific agents. In clinical practice, bupropion has traditionally been singled out as the least likely antidepressant to cause or exacerbate RBD based on its unique mechanism of action, although in at least one study, patients on bupropion were just as likely to have RSWA as patients on other antidepressants [67].
Serotonergic raphe nuclei in the pons have an activating effect on the REM-off nuclei, suggesting a plausible pathological mechanism by which exogenous serotonergic agents could trigger dream enactment [5]. Additionally, serotonergic 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 serotonergic RBD have other prodromal markers of alpha-synuclein neurodegeneration, such as anosmia, constipation, abnormalities in color vision, and subtle motor impairments [68]. These deficits are not well explained by serotonergic mechanisms and suggest that serotonergic antidepressants may unmask RBD in individuals at risk of underlying neurodegeneration.
Other, less commonly reported medications that induce RBD include classes of agents also known to affect REM sleep. Emergent RBD has been reported in a patient with PD treated with suvorexant, a dual orexin receptor antagonist used for treatment of insomnia [69]. Other rare causes include beta blockers and cholinesterase inhibitors [2,70,71]. Withdrawal from alcohol, benzodiazepines, and barbiturates can precipitate RBD episodes as well.
CLINICAL FEATURES — Patients with rapid eye movement (REM) sleep behavior disorder (RBD) exhibit abnormal dream mentation and well as a wide spectrum of motor behaviors during REM sleep. Video polysomnography 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 [72]. 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 [2,73].
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) [72]. 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 [74,75].
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 [76-79]. 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 isolated 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 dysarthria and limb bradykinesia imperceptible on a clinical exam [80,81].
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, color identification, and executive function [5,81-85]. 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 [86].
Comorbid olfactory dysfunction, constipation, and orthostatic hypotension are frequently noted in cases of isolated RBD [31,81,87,88]. Like the motor and cognitive deficits, these impairments are similar to those seen in patients with PD [33]. (See "Clinical manifestations of Parkinson disease".)
Among patients with PD, those with RBD suffer a greater clinical burden with more rapid cognitive impairment, more psychiatric comorbidities, poorer treatment response, and more widespread brain atrophy compared with PD patients without RBD [89-93]. RBD appears to specifically predict more freezing of gait, and many of the same brainstem regions implicated in the pathophysiology of RBD mediate the pathogenesis of freezing of gait [94].
DIAGNOSIS — A diagnosis of rapid eye movement (REM) sleep behavior disorder (RBD) should be suspected in patients with a clinical history of recurrent dream-enactment behavior and confirmed with video polysomnography [2,95].
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?" [54].
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, as RBD is more likely to occur in the second half of the sleep period (figure 1). (See 'Differential diagnosis' below.)
Patients should be asked about potentially offending medications (eg, antidepressants (table 1)) 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 (PD) [5]. In young patients, symptoms of RBD should prompt consideration of comorbid narcolepsy.
In-laboratory video polysomnography is necessary for a definitive diagnosis of RBD. Even when abnormal behavior does not occur during the study, REM sleep without atonia (RSWA) 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) [2,96]. Home sleep apnea testing is not a useful test for RBD. (See 'Video polysomnography' below.)
Additional testing such as neuroimaging, electroencephalography, and neuropsychological batteries are warranted only if there is further evidence suggesting a neurodegenerative disorder [97]. Tests that identify central nervous system dopamine dysfunction, such as dopamine transporter (DAT) imaging, or other markers of synuclein pathology, such as metaiodobenzylguanidine (MIBG, iobenguane I-123) cardiac scintigraphy, are not necessary for the diagnosis of RBD, but can be clinically useful in predicting and monitoring the course of the disease [5,98,99]. (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".)
Video polysomnography — Video 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 RSWA, which is an elevation of motor tone during REM sleep as measured by electromyography (EMG) in the chin and/or limb leads (figure 2) [95,96,100]. Formal polysomnographic criteria for RWA developed by the American Academy of Sleep Medicine and others are reviewed separately. (See "Polysomnography in the evaluation of parasomnias and epilepsy", section on 'REM sleep behavior disorder'.)
When present, RWA tends to occur during every REM cycle but is most prominent in the final REM period of the night. While there is little correlation between the severity of polysomnographic findings and clinical symptoms, significant progression of RWA over time may correlate with progression to RBD in subjects with isolated RWA [101,102]. Dramatic behaviors are rarely captured during polysomnography; by contrast, more subtle, seemingly purposeful hand movements suggestive of dream enactment, referred to as REM sleep behavior events (RBEs), are often observed.
RWA is occasionally detected in individuals without a reported history of dream-enactment behaviors, particularly in patients taking serotonergic antidepressants [66,67,103] and in older adults [104]. The reported prevalence of isolated RWA in adults without a history of RBD ranges from 10 to 15 percent and varies according to how RWA is defined [66,104-107]. The proportion of patients with isolated RWA who later develop RBD has not been established; in one small study, 1 of 14 individuals with RWA progressed to RBD over a mean of 8.6 years [101]. Video PSG criteria for prodromal RBD have been proposed [100]. (See "Polysomnography in the evaluation of parasomnias and epilepsy", section on 'REM sleep behavior disorder'.)
In patients with comorbid narcolepsy, polysomnography may also demonstrate frequent shifts between REM and non-REM sleep and consistent sleep state boundary dysfunction [24]. (See "Clinical features and diagnosis of narcolepsy in adults".)
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 RSWA on polysomnography (see 'Video 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, or substance use disorder
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of rapid eye movement (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, although sleepwalking in adulthood may, like RBD, be associated with higher odds of developing Parkinson disease [108]. 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 (figure 1). (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 [98]. 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 [98]. (See "Parasomnias of childhood, including sleepwalking", 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 [98]. 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 [5,97]. This phenomenon has been referred to as pseudo-RBD.
●Periodic limb movements – Periodic limb movements (PLMs) 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, PLMs occur primarily during NREM sleep, are periodic (approximately every 45 seconds), and are unrelated to dream mentation [2,95]. Rare cases of frequent and vigorous periodic limb movements during both NREM and REM sleep, mimicking RBD, have been described [53]. These pseudo-RBD patients often respond to therapies, such as dopaminergic agents, which are frequently used in the treatment of PLMs. (See 'Management' below and "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'.)
●Sleep-related hypermotor epilepsy – RBD is occasionally confused with sleep-related hypermotor epilepsy (previously called nocturnal frontal lobe epilepsy). This syndrome, which can be familial or sporadic, is characterized by stereotyped, recurrent (up to 20 episodes a night), abnormal behaviors. Electroencephalography may (but not universally) reveal epileptic activity. Compared with RBD, patients with sleep-related hypermotor epilepsy are younger (typically presenting in adolescence) and fully unaware of nighttime behaviors [97]. (See "Sleep-related epilepsy syndromes", section on 'Nocturnal (sleep-related) focal epilepsies'.)
MANAGEMENT — 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 (algorithm 1).
In the absence of large clinical trials, recommendations are based primarily on observational studies and accumulated clinical experience in concerned patients at risk for life-threatening injury [98,109,110]. Although small controlled trials have failed to show consistent improvement with pharmacotherapy, the authors' experience is that both melatonin and clonazepam are effective in suppressing rapid eye movement (REM) sleep behavior disorder (RBD) behaviors in the majority of patients, and that melatonin may be better tolerated, particularly among older adults with neurodegenerative disorders (table 2). A clinical practice guideline from the American Academy of Sleep Medicine is in development.
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.
The punching, kicking, and jumping behaviors can result in hematomas, fractures, lacerations, and joint dislocations [111]. Bed partners are frequently the target of violent dream enactment, and RBD has rarely been implicated in charges of domestic assault [112,113].
Firearms should not be accessible, and sharp or easily breakable furniture and objects (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 [98].
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 [112]. 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 [114].
Reversible factors — Medications known to exacerbate RBD, including the serotoninergic antidepressants, should be discontinued or avoided if possible in patients with RBD (table 1) [115]. Many cases of medication-associated dream enactment are self-limited following discontinuation of the offending medication.
Of note, bupropion, a dopaminergic/noradrenergic reuptake inhibitor, has not been reported to induce RBD. Bupropion is therefore a preferred antidepressant, unless otherwise contraindicated, in patients with RBD and depression who require pharmacotherapy. (See 'Medications' above.)
In patients with a sleep-fragmenting condition such as obstructive sleep apnea, dream-enactment behavior often resolves when the underlying disorder is treated [5,98]. The duration and circadian timing of sleep should be optimized as well.
Pharmacotherapy — All patients with frequent, disruptive, or injurious behaviors should be treated with pharmacotherapy to reduce behaviors and lower risk of injury.
Melatonin (preferred) — Melatonin is our preferred first-line therapy in patients with frequent, disruptive or injurious behaviors (algorithm 1). It tends to be better tolerated than the alternative first-line therapy, clonazepam, especially in older adults with neurodegenerative disorders [116].
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 [116-118]. Lower doses are generally not effective [119].
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 [116-118,120-122]. In a retrospective study that included 45 patients with RBD, melatonin and clonazepam were similarly effective, and melatonin was better tolerated [122]. 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 2). Use of time-release melatonin has a theoretical but unproven advantage over immediate release formulations. For time-release melatonin, a suggested starting dose is 5 mg, titrating by 5 mg every one to two weeks to a maximum of 15 mg nightly.
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 [116]. 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.
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 (starting at 0.25 to 0.5 mg orally at bedtime) has long been recognized as a treatment for RBD. The usual effective dose range for RBD is 0.5 to 1 mg nightly. 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 [123].
In four 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 [72,76,77,124]. It was reassuring that clonazepam therapy had sustained efficacy, and without significant dose escalation, over years of nightly use [124]. However, 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 [120,123,125-127]. In two prospective studies, clonazepam was not associated with an improvement in symptoms among treatment-naïve patients [128,129].
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 [72].
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 [114,130]. 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 2). Clonazepam undergoes hepatic metabolism and should be used with caution in patients with hepatic impairment.
Others
●Cholinergic agents – In patients who fail melatonin and clonazepam therapy, cholinergic agents may be useful. In one small, placebo-controlled, crossover trial, the acetylcholinesterase inhibitor rivastigmine reduced the number of dream-enactment behavior episodes (as noted by bed partners) in patients with Parkinson disease (PD) and RBD [131]. Rivastigmine is administered by transdermal patch, and dosing typically starts at 4.6 mg applied every 24 hours. The dose can be titrated up to a maximum of 13.3 mg daily. Donepezil, another cholinesterase inhibitor, has also been reported to improve RBD symptoms in three patients [132].
These agents are both commonly used in the treatment of dementia with Lewy bodies and PD dementia and thus may be a good choice for patients with RBD who also have cognitive impairment. However, rivastigmine should be used with caution among patients with autonomic symptoms.
●Dopamine agonists – While dopaminergic medications (eg, levodopa, pramipexole, ropinirole) are the standard therapy for daytime motor symptoms of PD, they are rarely effective for RBD alone.
Pramipexole has been reported to effectively treat RBD when there are frequent PLMs during non-REM sleep. In these cases, it is possible that pramipexole appears effective because it is helping to pacify nocturnal motor activity and by addressing an underlying sleep fragmenting condition, PLM disorder (PLMD) [133-135]. Thus, we recommend avoiding pramipexole for the treatment of RBD unless frequently ancillary, dopaminergic responsive motor activity is present on PSG.
●Others – Other agents with some reported success include imipramine, carbamazepine, sodium oxybate, triazolam, zopiclone (available outside the United States), quetiapine, and clozapine [109,120,126,136].
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 [137-140].
PROGNOSIS AND COUNSELING
Risk of neurodegenerative disease — Most patients with isolated RBD eventually develop an alpha-synuclein neurodegenerative disorder with a phenotype of Parkinson disease (PD), dementia with Lewy bodies, or multiple system atrophy [111,141-143]. While the interval between the onset of dream enactment and diagnosis of PD or a related disorder can vary from months to decades, the conversion rate is approximately 6 percent every year and approximately 75 percent at 12 years from RBD diagnosis [34,144].
Risk factors for conversion to an alpha-synucleinopathy are well studied [144], although an individualized risk assessment remains difficult. No single biomarker for phenoconversion in people with RBD fulfills the ideals of precision, accuracy, availability, and cost effectiveness [27]. Some biomarkers may appear early and change very slowly over time (eg, olfaction, color discrimination), while others may appear closer to phenoconversion (eg, motor signs, cognitive impairment). In a multicenter prospective cohort study of 1280 patients with isolated RBD and a mean follow up of 4.6 years, the strongest risk factors for conversion to a neurodegenerative disorder were abnormal quantitative motor testing (hazard ratio [HR] 3.2), objective motor exam findings (HR 3.0), olfactory dysfunction (HR 2.6), erectile dysfunction in males (HR 2.1), abnormal color vision (HR 1.7), and constipation (HR 1.7) [34]. The presence of attentional or visuospatial dysfunction has been associated with earlier development of a dementia phenotype, as opposed to a motor phenotype [145].
Ancillary tests such as dopamine transporter (DAT) imaging and tissue alpha-synuclein also predict increased risk for earlier conversion [39,99,146-149], although their sensitivity and specificity are not sufficiently high to support routine use in individual patients with isolated RBD outside of the context of a clinical trial. These investigations are best used in combination with ancillary findings of neurodegeneration, in particular deficits in olfaction [150]. (See 'Alpha-synuclein neurodegeneration' above and 'Neurologic findings' above.)
Prognostic disclosure — A discussion about the neurodegenerative risks associated with a diagnosis of RBD is usually appropriate but must be balanced by uncertainties, especially with regard to patient-specific risk, and by patient preferences with regard to disclosure [151-153]. Clinicians should bear in mind that a diagnosis of RBD is not a guarantee of future 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.
Clinicians may reasonably worry about causing excess anxiety by disclosing a possible neurodegenerative condition to middle-aged and older patients with RBD. Some experts suggest only disclosing information to patients who desire the information. However, withholding risk information may harm the provider-patient relationship, as patients and caregivers are likely to discover the association through an internet search. More research in this area is needed. In a study of over 100 patients with established PD who were surveyed, patients were asked to consider whether they would have wanted to know about their risk of PD years before the diagnosis [154]. Responses varied significantly based on certain qualifiers: only 46 percent said they would have wanted to know if there were no medical therapies available, while 85 percent said they would have wanted to know if they were given instructions on how lifestyle changes may alter the course of disease.
It can be useful to share general information first and gauge receptivity and level of distress before disclosing more specific detail. Communication should be tailored to the individual patient and take into account age, comorbidities, examination findings, caregiver support, medical literacy, and sociocultural background. Another approach is to provide information about neurodegenerative risk in RBD to the primary care clinician, who may have a longstanding relationship with the patient and have more knowledge of their values and preferences.
Disclosure can take place gradually, over several visits. During this time, the clinician is monitoring for early signs of neurodegeneration that may further inform risk. When risk is discussed, it is important to provide balanced information that includes actionable steps that may be taken for those who wish to make lifestyle changes.
Discussing the association openly with patients, families, and caregivers has several potential benefits. It provides patients with the opportunity to ask questions and avoids the potential for misinformation obtained on the internet. Patients can be counseled that PD and other disorders are treatable conditions. In the event that effective neuroprotective therapies for alpha-synuclein neurodegeneration are identified, patients with RBD could benefit from early treatment. As an example, growing evidence suggests that intermittent intense aerobic exercise may decrease PD risk [155]. Considering the cardiovascular benefits of aerobic exercise, all RBD patients should be encouraged to maintain an active lifestyle with at least 30 minutes of intense aerobic exercise three to four times per week.
As a biophysiological marker of alpha-synuclein neurodegeneration, RBD provides a unique opportunity to potentially identify neuroprotective therapies to impede or halt PD. 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 [156]. For interested patients, the North American Prodromal Synucleinopathy (NAPS) Consortium is recruiting patients with RBD for trials of potential disease-modifying therapies.
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".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Rapid eye movement (REM) sleep behavior disorder (The Basics)")
Patients and caregivers can also be referred to the NAPS Consortium website for educational material and information on research opportunities.
SUMMARY AND RECOMMENDATIONS
●Definition – 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.)
●Prevalence – The prevalence of RBD is estimated at 0.5 to 1.25 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.)
●Etiology – Most cases of RBD are caused by alpha-synuclein neurodegeneration. RBD is also caused by antidepressant medications (table 1), narcolepsy, and pontine lesions such as those from stroke or multiple sclerosis. (See 'Etiology' above.)
●Diagnosis – The diagnosis of RBD is based upon a history of dream-enactment behavior and REM sleep without atonia (RSWA), as documented by polysomnography. (See 'Diagnosis' above.)
●Differential diagnosis – 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.)
●Management (algorithm 1)
•Establish safe sleeping environment – 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.)
•Reversible factors – Medications known to exacerbate RBD, including the serotoninergic antidepressants, should be discontinued or avoided if possible. Sleep disorders such as obstructive sleep apnea should be diagnosed and treated. (See 'Reversible factors' above.)
•Pharmacotherapy – 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 2). Most patients find relief with doses between 6 and 18 mg. (See 'Melatonin (preferred)' above.)
Low-dose clonazepam (0.25 to 1 mg) is an effective alternative or add-on therapy but may be less well tolerated, particularly in patients with comorbid neurodegenerative disease. (See 'Clonazepam' above.)
●Prognosis and counseling – Most patients with isolated 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.)
