As the literature on RBD grows, a researcher who with his colleagues originally identified and named the parasomnia discusses clinical findings, therapy options, and comorbidities, and also shares a patient case study.

REM sleep behavior disorder (RBD) was formally identified and named at the Minnesota Regional Sleep Disorders Center in 1986-1987.1,2 Among the 10 patients in the original series, nine were males, their mean age was 62 years, and most of them responded to bedtime clonazepam therapy. They had presented primarily on account of violent dream-enacting behaviors that had caused injuries to themselves and to their spouses. Video-polysomnography (vPSG) documented both the loss of REM sleep atonia on the submental electromyogram (EMG) and a range of abnormal motor-behavioral events during REM sleep. These findings epitomize the classic clinical profile of RBD, as confirmed by two large series.3 (However, it is possible that just as many middle-aged and older females have RBD, but without sufficient aggression to cause injury and warrant medical attention.) Also, five of these patients had diverse neurologic disorders that had triggered the onset of RBD, and the other five patients had “idiopathic RBD” without any associated disorder. The literature on RBD continues to grow exponentially,4 and so it is timely to provide an update on RBD.

Clinical and Polysomnographic (PSG) Findings in RBD

The International Classification of Sleep Disorders, 3rd Edition (ICSD-3),5 published in 2014, contains the following diagnostic criteria for RBD:

A. Repeated episodes of sleep related vocalization and/or complex motor behaviors.
B. These 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.
C. Polysomnographic recording demonstrates REM sleep without atonia (RWA).
D. The disturbance is not better explained by another sleep disorder, mental disorder, medication, or substance use.

Notes
1. Criterion B can be fulfilled by observation of repetitive episodes during a single night of video polysomnography.
2. The observed vocalizations or behaviors often correlate with simultaneously occurring dream mentation, leading to the frequent report of “acting out one’s dreams.”
3. Criterion C: The most current evidence-based data that are in accordance with AASM 30-sec epoch scoring guidelines should be utilized.
4. Upon awakening, the individual is typically awake, alert, coherent, and oriented.
5. On occasion, there may be patients with a typical clinical history of RBD with dream-enacting behaviors, who also exhibit typical RBD behaviors during video-polysomnography, but do not demonstrate sufficient RWA, based on the current evidence-based data, to satisfy the PSG criteria for diagnosing RBD. Such patients may be provisionally diagnosed with RBD, based on clinical judgment. The same rule applies when video polysomnography is not readily available.
6. Medications may possibly unmask latent RBD with preexisting RWA, according to current expert opinion. Therefore, medication-induced RBD can be diagnosed as RBD, using clinical judgment, pending future longitudinal studies.

It is important to note that the diagnosis of RBD does not require dream-enactment,5 since about 30% of reported RBD cases in the world literature do not have dream-enactment (usually in patients with neurodegenerative disorders, including dementia), as reviewed.6

Autonomic nervous system activation (viz, tachycardia) is uncommon during REM sleep motor-behavioral activation in RBD, in contrast to the disorders of arousal. Periodic limb movements (PLMs) during NREM and REM sleep are very common with RBD and may disturb the sleep of the bed partner. These PLMs are rarely associated with EEG signs of arousal, and the frequent presence of PLMs in RBD is not associated with any increased association of restless legs syndrome. Sleep architecture—and the customary cycling among REM and NREM sleep stages—are usually preserved in RBD, although some patients show a shift toward stage N1 sleep (particularly in neurodegenerative disorders).3,5

There has been an advance over time from the qualitative determination of RWA to a more rigorous, quantitative determination of RWA, to assist with the diagnosis of RBD. The most current evidence-based objective data provide the following guidelines accepted by the AASM for detecting RWA and guidelines for their interpretation supporting the diagnosis of RBD:

Any (tonic/phasic) chin EMG activity combined with bilateral phasic activity of the flexor digitorum superficialis muscles in >27% of REM sleep, scored in 30-sec epochs.7

RBD sleep and dream-related behaviors reported by history and documented during vPSG include both violent3 and nonviolent5,8 and even pleasant behaviors: talking, smiling, laughing, singing, whistling, shouting, swearing profanities, crying, chewing, gesturing, reaching, grabbing, arm flailing, clapping, slapping, punching, kicking, sitting up, looking around, leaping from bed, crawling, running, dancing, searching for a treasure or other objects. Walking, however, is quite uncommon with RBD, and leaving the room is especially rare, and probably accidental. The person with RBD is attending to the dream action with eyes closed, and so is unaware of the actual environment and thereby at risk for injury, especially when engaged in aggressive and violent behaviors.

Sleeptalking with RBD runs the spectrum from short and garbled to long-winded and clearly articulated speech. Angry speech with shouting and profanity, and also humorous speech with laughter, can emerge.

Because RBD occurs during REM sleep, it usually appears at least 90 minutes after sleep onset, unless there is coexisting narcolepsy, in which case RBD can emerge shortly after sleep onset during a SOREMP (sleep-onset REM period). Although irregular jerking of the limbs may occur nightly (comprising the “minimal RBD syndrome”), the major behavioral episodes appear intermittently with a frequency minimum of usually once every 1-2 weeks up to a maximum of four times nightly on 10 consecutive nights.

There is typically no history of irritable, aggressive, or violent behavior during the day. A controlled study using validated scales found that despite having more aggressive dreams, RBD patients were not more aggressive while awake.9 Furthermore, a study of consecutive referrals to a sleep center found that the majority of patients diagnosed with RBD reported symptoms on specific questioning only, underlining the importance of eliciting a comprehensive history for the diagnosis of RBD.10

Documented injuries to the patient and bed partner resulting from RBD include: bruises; subdural hematomas; lacerations (including arteries, nerves, tendons); fractures (including high cervical fractures); dislocations, sprains, abrasions, rug burns; tooth chipping; scalp injury from hair pulling. Published cases of RBD (as of 200911) associated with potentially lethal behaviors include: choking/headlock (n=22-24); diving from bed (n=10); defenestration (n=7); and punching a pregnant bed partner (n=2). The potential for injury to self or bed partner raises important and challenging clinical issues, such as in ICU settings.12

RBD is uncommon in childhood and adolescence, and idiopathic RBD in children is especially rare, and when present, it can at times be an initial manifestation of narcolepsy-cataplexy. RBD in this age group is most commonly found in association with narcolepsy-cataplexy, or it can be psychotropic medication-induced (as therapy of cataplexy or depression/anxiety), related to brainstem tumor, or to a variety of rare conditions.3

Younger Adult vs Older Adult Onset RBD

Classic RBD is a male-predominant disorder that usually emerges after the age of 50 and that usually signals the future emergence of parkinsonism/dementia, to be discussed below. However, any age group, from early childhood to age 88 years, can be affected with RBD. The profile of RBD emerging in adults before age 50 years is now recognized to comprise a separate subgroup of RBD patients with different demographics and associated features, including greater gender parity, and increased rates of idiopathic cases, parasomnia overlap disorder (POD) cases, narcolepsy-cataplexy cases, antidepressant medication use, and possibly autoimmune diseases.13 Also, the clinical presentation of RBD in younger adults differs from that in older adults in being less aggressive and violent on the basis of greater female representation and narcolepsy representation that manifest with more mild RBD behaviors.

Parasomnia Overlap Disorder

POD is a variant of RBD that consists of RBD combined with a disorder of arousal (confusional arousals, sleepwalking, and sleep terrors),5,14 although it is now known to also consist of RBD combined with sleep-related eating disorder, sexsomnia, or sleep-related rhythmic movement disorder.15 Diagnostic criteria for both RBD and a disorder(s) of arousal, or for both RBD and one of the other disorders just mentioned, must be met.5 POD is male-predominant but less so than RBD. Most cases begin during childhood or adolescence. Virtually all age groups can be affected. It can be idiopathic or symptomatic of a broad set of neurological and other disorders. A recent update of POD documents a broad range of clinical disorders now recognized to be associated with POD.15

Differential Diagnosis

RBD is one of several disorders that can manifest as injurious dream-related behaviors in adults.3,5 In general, RBD involves attempted enactment of altered dreams, with rapid awakening from an episode that usually occurs 2 or more hours after sleep onset. In contrast, sleepwalking and sleep terror episodes often emerge within 2 hours after sleep onset and are not usually associated with rapid alertness; in adults, there can be associated dreaming, but dreams are usually more fragmentary and lack plot development, in comparison to RBD dreams. “OSA pseudo-RBD” presents with severe obstructive sleep apnea/hypopnea induced arousals with aggressive dream-enactment in older males, together with loud snoring and daytime sleepiness, and responds to CPAP therapy.16 Sleep-related seizures at times can involve dream-enacting behaviors.3

Management of RBD

Maximizing the safety of the sleeping environment is imperative to protect the patient and the bed partner. Bed partners should sleep separately until RBD is brought under control. The bed should be placed far from a window, and potentially injurious bedside objects, including night tables, lamps, and firearms, should be removed.

Pharmacotherapy is effective in the majority of cases for controlling both the problematic behaviors of RBD and the frequently associated dream disturbance. Clonazepam is the established primary pharmacotherapy of RBD in most cases, with a typical dose of 0.25 mg – 1.0+ mg at bedtime, and is usually well tolerated.3,17 Clonazepam is not usually associated with dosage tolerance (habituation effect), despite years of nightly therapy.17 To date, there have been no double-blind, controlled, randomized trials of clonazepam (or other) therapy of RBD. A recognized co-first-line therapy of RBD is bedtime melatonin at robust pharmacologic doses ranging from 3 to 15 mg. The American Academy of Sleep Medicine has published its best practice guidelines for the treatment of RBD, which identify clonazepam and melatonin as being the primary pharmacotherapies, and include a list of various secondary pharmacotherapies.18 Clonazepam may carry an increased risk of side effects compared to melatonin,19 and its prolonged duration of action may result in morning sedation and gait impairment, especially in patients with parkinsonism. Also, clonazepam therapy of RBD should not be initiated until any comorbid OSA is controlled with appropriate therapy, such as nasal CPAP therapy. Interestingly, a new animal model of RBD, viz a transgenic mouse model with impaired glycine and GABA neurotransmission, is responsive to both clonazepam and melatonin, thus mirroring the therapeutic response in human RBD.20

Any comorbid OSA should be treated and aggravating medications (viz, antidepressants, beta-blockers, etc), if possible, eliminated. The majority of medication-induced RBD cases are self-limited following discontinuation of the offending agent. It should be noted that the only antidepressant that has not been reported to trigger or aggravate RBD is bupropion, a dopaminergic-noradrenergic agent, which should therefore be considered to be the antidepressant of choice in a depressed RBD patient, unless otherwise contraindicated.

Occasionally, RBD will be refractory to pharmacotherapy. Jumping or otherwise falling out of the bed during dream-enactment is a particularly high-risk behavior. However, as REM sleep is characterized by a low arousal threshold, patients are readily responsive to complex auditory processing. This phenomenon is often noted by bed partners who describe an ability to calm patients down with a simple phrase such as, “Frank, you are having a dream, lie back down.” A customized bed alarm system has been developed that delivers a calming message at the onset of dream-enactment, which can prevent the patient from leaving the bed and avert sleep-related injury.21

Idiopathic REM Sleep Behavior Disorder (iRBD) as a Harbinger of Future Parkinsonism

In 1996, our group reported that 38% of a series of males >50 years originally diagnosed with iRBD had developed a parkinsonian disorder,22 and then in 2013 we published extended longitudinal data on this series with findings that 81% (21/26) had developed a parkinsonian disorder—and no other condition.23 The interval between the onset of iRBD to the emergence of parkinsonism was 14+-6 years (range, 5-29 years). Thirteen patients had Parkinson’s disease (PD), four had dementia with Lewy bodies (DLB), two had multiple system atrophy (MSA—PD with autonomic dysfunction), and two had the Lewy body variant of Alzheimer’s disease (AD) (autopsy-confirmed). The two latter cases were notable because the clinical diagnoses in these two patients were AD and RBD, without any findings suggestive of parkinsonism. And yet the autopsy findings found both AD and PD neuropathology. Identical longitudinal findings of iRBD patients were reported by the Barcelona group: 82% (36/44) converted to a neurodegenerative disorder at a mean interval of 11.5 years (range, 5-23 years) from RBD onset.24 The emergent neurological disorders closely matched our Minnesota findings: 16 patients had PD, 4 had DLB, 1 had MSA, and 5 had Mild Cognitive Impairment. The authors concluded that “in most patients diagnosed with iRBD, this parasomnia represents the prodromal phase of a Lewy body disorder….iRBD is a candidate for the study of early events and progression of this prodromal phase and to test disease-modifying strategies to slow or stop the neurodegenerative process.” These bold findings have spurred a major growing multinational research effort, including the formation of the International RBD Study Group in 2009, which has published nine papers to date, including guidelines for assessing any future promising disease-modifying therapy.25

Clearly, given the data just described, patients diagnosed with iRBD must be informed of the increased risk of future neurodegeneration and they should be urged to undergo longitudinal neurological examinations and cognitive screens for early detection of PD and/or dementia. This should also apply to younger adults diagnosed with RBD, as a retrospective study from the Mayo Clinic found extraordinarily long intervals (up to 50 years) between presumed RBD onset and parkinsonism onset.26

RBD and Neurodegenerative Disorders

A full range of neurologic disorders, including neurodegenerative disorders, can be etiologically linked with the onset of RBD, and most likely reflects the neuroanatomical location of the lesion that disrupts the brainstem nuclei and/or pathways subserving REM-atonia and the customary inhibition of motor-behavioral activity during REM sleep.27 However, a selective and very strong association of RBD with the alpha-synuclein neurodegenerative disorders (PD, MSA, DLB) is now recognized. RBD can precede, emerge concurrently with, or develop after the emergence of an alpha-synuclein disorder.28 The synucleinopathies comprise a set of neurodegenerative disorders that share a common pathologic lesion composed of aggregates of insoluble alpha-synuclein protein in selectively vulnerable populations of neurons and glial cells. These pathologic aggregates appear to be closely linked to the onset and progression of clinical symptoms and the degeneration of affected brain regions in neurodegenerative disorders.28,29 The strong presence of RBD in the alpha-synuclein disorders is indicated by these published findings: 30-50% in PD, 50-80% in DLB, and 80-95% in MSA.29,30 The presence of RBD in PD is associated with widespread increased PD morbidity, including increased level of PD motor impairment, increased level of cognitive impairment, increased visual hallucinations, increased autonomic dysfunction, and greater impairment in quality of life status. A recent study found that of 80 PD patients who were newly diagnosed with RBD and who were dementia-free at baseline, 34% (27/80) developed dementia (PDD) at 4.4-year follow-up.31 RBD with PD at baseline in this study dramatically increased the dementia risk, with an odds ratio of 49.7 (p = 0.001).

The strong link between RBD and parkinsonism is scientifically understandable. The REM-atonia nuclei and circuits and the REM sleep phasic motor nuclei and circuits are located in the brainstem extra-pyramidal region, and they have strong reciprocal connections with the motor nuclei degenerating from parkinsonism. This topic has been recently reviewed in depth.28

Case Vignette: Idiopathic RBD Developing Into Parkinson’s Disease

A 54-year-old married man presented with his wife on account of a 3-year history of thrashing around in bed, jerking his limbs, kicking and punching his wife, and sometimes jumping out of bed during sleep while having confrontational and violent dreams. These episodes occurred 3 or more nights weekly, and appeared after he had been asleep for at least 2 hours. He had always been a good sleeper, and never had any episodes of sleepwalking, sleep terrors, leg jerking, or nightmares during childhood, adolescence, or early adulthood. However, his wife noticed that 10 years previously he began to moan and talk in his sleep and also move around in their bed and jerk his arms and legs while remaining asleep. Then 3 years ago, he became aware that his dreams had become more vivid and intense, and also he was being confronted by unfamiliar people who were threatening him and sometimes attacking him, forcing him to defend himself or flee from danger (when he would jump out of bed). He would swear out loud at his assailants, which surprised his wife because he never swore while awake. His wife noticed a marked increase in his level of physical activity during sleep. He was not just twitching and jerking his body and limbs, as he had done for years, but now he was also extensively moving his arms, legs, and body while apparently having disturbing dreams. He would be talking and shouting while he was fighting back at the people who were threatening him or attacking him in his dreams. He could become very agitated while lying next to his wife in bed, and during his dream-enactments he pounded the mattress or punched his wife, or leapt out of bed and ran around the room while yelling and swearing out loud.

He usually awakened quickly from these dream-enacting episodes, and immediately he would be oriented to his room, his bed, and his wife. He would be aware that he was having another “crazy dream” and wondered how they kept happening and what was causing them. His wife was quite considerate and consoled him by saying that she knew he was not acting out violent dreams on purpose. Also, since she regularly observed that his eyes were closed during these episodes, that reinforced her notion that he was asleep and dreaming, and not willfully in control of his actions.

vPSG confirmed the diagnosis of RBD, with substantial loss of REM-atonia. There was frequent limb twitching and jerking during REM sleep and one dream-enacting episode during his third REM sleep period when he sat up in bed while flailing his arms and shouting out loud, “Get out of here!” He woke up quickly and told the sleep technologist that he had been dreaming that “some hoodlums had broken into the house.” Treatment with bedtime clonazepam, 0.75 mg, prevented any future major RBD episode, and his wife reported that his twitching and jerking during sleep had been reduced considerably, he was quieter in bed, and she felt safe again. The patient and wife were informed about his increased risk for parkinsonism, and he was advised to be evaluated and followed regularly by a neurologist experienced in managing PD patients.

Two years later, the patient began having problems buttoning his shirt, and his balance and gait were becoming unsteady. His wife noticed that he would “shuffle along” when he walked, and also he had lost most of his arm swing. He had become more rigid and had lost his usual fluid movements. He smiled less, hardly blinked his eyes anymore, and seemed to have a much less expressive face. He also had become frequently constipated and had lost most of his sense of smell. In the mornings, he would comment on an excess of saliva pooling in his mouth. He seemed to be becoming depressed, less interested in doing things, and with a more negative outlook. He was also becoming a more nervous person, but did not have a tremor. Referral to a neurologist confirmed the diagnosis of Parkinson’s disease.

Carlos Schenck

Carlos H. Schenck, MD

Conclusion

RBD is the only parasomnia in the ICSD-3 that requires vPSG confirmation, and it usually can be well controlled with securing the safety of the sleeping environment in tandem with appropriate pharmacotherapy. RBD can be associated with a broad range of neurologic disorders, particularly neurodegenerative disorders and narcolepsy-cataplexy, and it can be triggered by antidepressant and other medications. An index of suspicion for RBD must be maintained by the sleep clinician, since patients with RBD may not report their symptoms for various reasons. Validated screening questionnaires for RBD are available.32 RBD commonly heralds future neurodegeneration, which adds a layer of complexity and need for increased vigilance in the long-term management of RBD patients. Sleep clinicians are encouraged to keep abreast of the rapidly growing clinical and research literature on RBD.

Carlos H. Schenck, MD, is a member of the Minnesota Regional Sleep Disorders Center, a senior staff psychiatrist at Hennepin County Medical Center, professor of psychiatry at the University of Minnesota Medical School in Minneapolis, and a member of Sleep Review’s editorial advisory board.

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