Pathophysiologic Mechanisms in REM Sleep Behavior Disorder Mark W. Mahowald, MD, Carlos H. Schenck, MD, and Michel A. Cramer Bornemann, MD

Corresponding author Mark W. Mahowald, MD

Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN 55415, USA. E-mail: [email protected] Current Neurology and Neuroscience Reports 2007, 7:167–172 Current Medicine Group LLC ISSN 1528-4042 Copyright © 2007 by Current Medicine Group LLC

REM sleep behavior disorder (RBD) is a fascinating experiment in nature predicted by animal studies in 1964. A defining feature of REM sleep is active paralysis of all somatic musculature (sparing the diaphragm to permit respiration). RBD is characterized by the absence of REM atonia, permitting the appearance of dream-enacting behaviors. These oneiric behaviors may be violent or injurious. RBD typically affects men over the age of 50 years. Longitudinal follow-up has shown that the majority of individuals with RBD will eventually develop additional signs and symptoms of a number of neurodegenerative disorders, most notably one of the synucleinopathies (Parkinson’s disease, dementia with Lewy body disease, multiple system atrophy, or pure autonomic failure), often after a prolonged interval lasting more than 10 years. RBD is also a common manifestation of narcolepsy. RBD may be induced by medications, especially the tricyclic antidepressants and serotonin-specific reuptake inhibitors. In most cases, clonazepam is a highly effective treatment.

Introduction In experiments reported in 1965, bilateral lesions of pontine regions adjacent to the locus coeruleus in cats caused absence of the expected atonia associated with REM sleep [1]. This allowed the cats to demonstrate prominent motor behaviors (oneiric behaviors) during REM sleep [1]. The cat animal model has recently been extended to the rat [2]. Recognition of REM sleep behavior disorder (RBD) as a distinct clinical entity followed the report in 1986 of a series of adult humans with RBD [3]. RBD typically affects men over 50 years of age. The disorder most frequently presents with the complaint of dra-

matic, violent, potentially injurious motor activity during sleep. These behaviors include talking, yelling, swearing, grabbing, punching, kicking, jumping, or running out of the bed. Injuries are not uncommon and include ecchymoses, lacerations, or fractures involving the individual or bed partner [3]. Interestingly, this increased aggressive dream content experienced by patients with RBD is not associated with increased daytime aggressiveness [4]. The reported motor activity usually correlates with remembered dream mentation, leading to the patient’s complaint of “acting out my dreams.” Sleep disruption is an infrequent complaint. In some cases, bruxism, somniloquy, or periodic limb movements of sleep may be the heralding or primary manifestation of this disorder. The duration of behaviors is brief, and upon awakening from an episode there is usually rapid return of alertness and orientation. Some patients adopt extraordinary measures to prevent injury during sleep, such as tethering themselves to the bed with a rope or belt, sleeping in sleeping bags, or sleeping on a mattress on the floor in a room devoid of furniture. Due to its association with REM sleep, the timing of the behaviors during the sleep period ranges from 90 minutes after sleep onset to the final awakening in the morning. Often there may be a prodromal period lasting for several years of progressively more prominent vocalization and/or motor activity during sleep. The frequency of the episodes ranges from once every few weeks to multiple nightly episodes.

Acute RBD Acute onset of RBD is almost always induced by medications, usually tricyclic antidepressants, monoamine oxidase inhibitors, serotonin-specific reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors [5]. Iatrogenic RBD is becoming much more common, reflecting widespread prescribing practices involving these antidepressant medications.

Chronic RBD The chronic form of RBD was initially thought to be idiopathic in most cases. However, long-term follow-up has

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shown that most patients will eventually exhibit signs and symptoms of a variety of degenerative neurologic disorders, most notably the synucleinopathies, which include Parkinson’s disease (including juvenile Parkinson’s disease), dementia with Lewy body disease, multiple system atrophy (Shy-Drager syndrome, striatonigral degeneration, olivopontocerebellar degeneration), and pure autonomic failure [6,7••,8]. In one series, more than two thirds of male patients initially diagnosed with idiopathic RBD eventually developed symptoms of one of the synucleinopathies [9], with the average interval between the onset of RBD and the first other symptom of the underlying neurodegenerative disease being over 10 years. Parkinson’s disease and RBD are likely physiologically and anatomically linked [10]. This is supported by the fact that impaired olfactory and color discrimination is common in both [11,12••]. RBD is also seen in non–synucleinopathyrelated Parkinson’s disease and in progressive supranuclear palsy (a tauopathy) [13,14•]. The clinical features of RBD are identical in the idiopathic cases and in those with Parkinson’s disease or multiple system atrophy [15]. One interesting question is why there is such a striking male predominance in “cryptogenic” RBD, when there is not such a male predominance in the underlying neurodegenerative conditions. One highly speculative suggestion is that violence across all species is predominant in males [16–18]. There is evidence that the presentation of RBD is different in males (violent dream-enacting behaviors) than in females (less violent dream-enacting behaviors), skewing the reported male predominance [19]. Interestingly, there is a striking (77%) male predominance in patients with Parkinson’s disease who display RBD [20]. RBD is also frequently seen in patients with narcolepsy. One questionnaire survey found that 36% of patients with narcolepsy had symptoms suggestive of RBD [21•]. In addition, RBD in narcolepsy may be worsened or triggered by the administration of tricyclic antidepressants or serotonin-specific reuptake inhibitors prescribed for the symptom of cataplexy [22]. RBD-like symptoms are also present in the recently described “agrypnia excitata,” which includes fatal familial insomnia, Morvan fibrillary chorea, and delirium tremens [23,24]. RBD has been associated with myriad neurologic conditions [25]. The fact that most patients with RBD will eventually be found to have an underlying neurodegenerative or medication-induced etiology questions the existence of true “idiopathic” RBD [26]. Consequently, the term “cryptogenic” RBD has been proposed, with the implication being that if patients with RBD are followed long enough and carefully enough, the underlying condition will eventually declare itself [27].

Case Example A 76-year-old woman was seen in the sleep disorders clinic for evaluation of a 5-month history of progressively severe

dream-enacting behaviors. She reported very vivid dreams during which she is trying to save someone or prevent herself from being harmed. Most recently, she sustained a severe facial injury when she flew out of bed dreaming she was jumping from a rowboat to escape pursuit. She was on no medications known to affect sleep. Her father had Parkinson’s disease. On initial examination there was no evidence of extrapyramidal disease. Polysomnographic study revealed prominent increased tonic and phasic electromyogram activity during REM sleep (Fig. 1). These oneiric behaviors ceased with nightly benzodiazepine administration. A few months later, she produced serial handwriting samples demonstrating progressive micrographia and tremor. She is being closely followed for the probable development of Parkinson’s disease.

Pathophysiology The three states of being (wakefulness, REM sleep, and non–REM sleep) are each associated with a number of physiologic variables that usually occur in concert to produce a fully declared state. REM sleep contains two types of variables: tonic (occurring throughout the REM period), and phasic (occurring intermittently during a REM period). Tonic elements include a desynchronized electroencephalogram (EEG) and somatic muscle atonia (sparing the diaphragm). Phasic REM elements include rapid eye movements, middle ear muscle activity, and extremity twitches. The tonic electromyogram suppression of REM sleep is the result of active inhibition of motor activity originating in the perilocus coeruleus region and terminating on the anterior horn cells via the medullary reticularis magnocellularis nucleus. The three states of being are not mutually exclusive, as sleep-wake states may oscillate rapidly or their component physiologic variables may become dissociated. In RBD, the REM sleep state is incomplete; all elements are present except the atonia, permitting motor activity to occur that parallels dream mentation generated by the activated REM sleep state. The observed motor activity may result from either impairment of tonic REM muscle atonia or from increased phasic locomotor drive during REM sleep. Although the original animal model was produced with lesions of the locus coeruleus region, it is clear from later animal studies that the atonia of REM sleep is determined or influenced by a number of brainstem regions [28–30]. Recent studies have suggested that dysfunction of the retrorubral nucleus and ventral pontine junction may release motor activity into both waking and sleeping states [31]. This activity may be mediated by N-methyl-D-aspartate receptors [32]. Enkephalin-containing neurons have also been implicated in hyperpolarization of brainstem and spinal somatic motoneurons during REM sleep [33]. In animal studies, the degree of aggression associated with REM sleep without atonia may be influenced by additional lesions of the nervous system [34].

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LOC-A2 256 uV ROC-A1 256 uV C3-A2 128 uV O2-A1 128 uV CHIN1-CHIN2 204.8 uV ARM/R-ARM/L 1.64 mV

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ECG1-ECG2 2.05 mV

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LEG/L-LEG/R 3.28 mV

Figure 1. This 2-minute epoch of REM sleep demonstrates prominent submental, extensor digitorum, and anterior tibialis tonic and phasic EMG activity associated with technologist-noted “quivering” and “body jerking.” A1—left mastoid; A2—right mastoid; ARM— extensor digitorum EMG; C3—left central EEG; CHIN—submental EMG; ECG—electrocardiogram; EMG—electromyogram; LEG—anterior tibialis EMG; LOC—left outer canthus; O2—right occipital EEG; ROC—right outer canthus.

Neuroimaging studies suggest dopaminergic abnormalities in RBD. Single photon emission computed tomography (SPECT) studies have found reduced striatal dopamine transporters [35,36], and decreased striatal dopaminergic innervation has been reported [37]. Decreased blood flow in the upper portion of the frontal lobe and pons has been reported [38], as has functional impairment of brainstem neurons [39]. Positron emission tomography and SPECT studies have revealed decreased nigrostriatal dopaminergic projections in patients with multiple system atrophy and RBD [40]. Decreased blood flow in the upper portion of the frontal lobe and pons has been found in one MRI and SPECT study [41]. Impaired cortical activation as determined by electroencephalographic spectral analysis in patients with idiopathic RBD supports the relationship between RBD and neurodegenerative disorders [42].

Prevalence RBD is more common than previously thought. A recent phone survey of over 4900 individuals between the ages of 15 and 100 years indicated an overall prevalence of violent behaviors in general during sleep of 2%, one quarter of which were likely due to RBD, giving an overall prevalence of RBD at 0.5% [43]. Another survey estimated the prevalence of RBD to be 0.38% in elderly individuals [44].

Differential Diagnosis The differential diagnosis includes any condition that may result in complex behaviors arising from the sleep period. These include sleepwalking, sleep terrors, nocturnal seizures, psychogenic dissociative states, post-traumatic stress disorder, nocturnal panic disorder, delirium, and malingering [5]. The timing of the episodes during the sleep period, reports of dream mentation appropriate to the observed behavior, brief duration, and complete alertness and orientation upon awakening may help to distinguish RBD from other causes of violent nocturnal movements. However, parasomnias associated with prominent motor activity may have similar clinical features, and accurate diagnosis by history alone is often not possible. Recently, an “overlap parasomnia” with clinical and polygraphic features of both sleep terrors and RBD has been identified [45].

Evaluation and Diagnosis A detailed review of the sleep-wake complaints should be followed by a medical, neurologic, and psychiatric history and examination. Information from a bed partner is most valuable. As it is often impossible to differentiate RBD from other parasomnias by history alone, formal polysomnographic study is mandatory. Such polysomnographic studies

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must be more extensive than those performed for many other sleep disorders, with an expanded EEG montage, monitors for movements of all four extremities, continuous technologist observation, and audiovisual recording. Diagnostic criteria are 1) history of problematic sleep behavior (or videotaped documentation of such behaviors) and 2) polygraphic evidence of excessive augmentation of chin electromyogram tone or of excessive chin or limb electromyogram twitching. Other common findings include a high percentage of slow wave sleep and frequent periodic and aperiodic extremity movements during non– REM sleep [5]. A single night of recording is generally sufficient to establish the diagnosis, because REM sleep polysomnographic abnormalities are usually present even when a behavioral episode does not occur. Such additional neurologic or psychiatric evaluations as CT or MRI brain scan, waking EEG, evoked potential studies, and neuropsychological tests are warranted if there is evidence by history or examination suggesting a psychiatric disorder or a structural abnormality of the central nervous system.

Treatment The acute form appears to be self-limited following discontinuation of the offending medication or completion of withdrawal. About 90% of patients with chronic RBD respond well to clonazepam administered 30 minutes prior to bedtime. The dose ranges from 0.5 mg to 2.0 mg, and there has been little, if any, tendency to develop tolerance, dependence, abuse, or adverse side effects despite years of continuous administration and efficacy [46]. Interestingly, polygraphically there is little change in the muscle tone during REM sleep following effective treatment [47]. Clonazepam appears to decrease REM sleep phasic activity, but has no effect upon REM sleep atonia [48]. Melatonin at doses up to 12 mg at bedtime or pramipexole may also be effective [49,50,51•]. Isolated anecdotal response to a number of other medications has been reported with imipramine, gabapentin, clonidine, and monoamine oxidase inhibitors [5]. Underlying obstructive sleep apnea should be ruled out before prescribing clonazepam [52]. The treatment of Parkinson’s disease–associated RBD is the same as for idiopathic RBD [53]. Pallidotomy has been effective in one case of RBD associated with Parkinson’s disease, whereas chronic bilateral subthalamic stimulation was not [54–57]. In the acute and idiopathic chronic form, the prognosis with treatment is excellent, but there are few if any prolonged remissions. In the symptomatic chronic form, the prognosis parallels that of the underlying neurologic disorder. Complications include fractures, lacerations, ecchymoses, and nocturnal falls. RBD-related sleep injury has resulted in subdural hematomas [58]. Sleep-related violence may have forensic science implications [59••].

Interestingly, there may be spontaneous improvement in RBD symptoms with progression of the underlying neurodegenerative condition [60].

Conclusions RBD is often an early harbinger of neurodegnerative disorders and usually responds to pharmacologic treatment. RBD is a fascinating experiment in nature, underscoring the importance and benefit of close collaboration between sleep medicine clinicians and basic science sleep researchers.

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