Sleep Medicine 14 (2013) 699–702

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Sleep Medicine

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Preface

Rapid eye movement sleep behavior disorder: current knowledge and futuredirections

In 1986–1987, rapid eye movement sleep behavior disorder(RBD) was formally identified and named, and effective therapywith clonazepam was utilized [1,2]. Among the 10 patients in theoriginal series, five had diverse neurologic disorders etiologicallylinked with RBD, and five were idiopathic [2]. As a larger groupof idiopathic RBD (iRBD) patients was gathered and followedlongitudinally, a surprisingly strong and specific association witheventual parkinsonism and dementia (and also mild cognitiveimpairment) became apparent [3–8], which has spurred a major,growing, multinational research effort [9–11], including the forma-tion of the IRBD-SG (International RBD Study Group) [10], to beelaborated below.

The polysomnographic (PSG) hallmark of RBD consists of elec-tromyographic (EMG) abnormalities during REM sleep, referredto as loss of REM atonia or REM without atonia (RWA), featuringincreased muscle tone or increased phasic muscle twitching. RBDrepresents how one of the defining features of mammalian REMsleep, viz. generalized skeletal muscle atonia, (i.e., REM atonia)can become severely impaired, resulting in behavioral releaseduring REM sleep and a major clinical disorder [1,12]. Asdemonstrated by RBD, REM atonia serves an important protectivefunction, as it allows the dreaming human or other mammal toengage in a full spectrum of physically active dreams while beingsimultaneously paralyzed, and thus unable to actually move. Aperson with RBD moves with eyes closed and with completeunawareness of the actual surroundings—a highly vulnerable statefor the dreamer [12,13]. The clinical manifestation of RBD usuallyis (but not necessarily) dream-enacting behavior [14], with theenacted dreams often involving confrontation and aggression withunfamiliar people and animals, and the dreamer rarely is theprimary aggressor. Otherwise, in the minority of cases there areabnormal behaviors during REM sleep without any associateddreaming. Injury to oneself or bed partner is common in iRBD[12,13].

Various PSG and clinical components of RBD had been recog-nized since 1966 by investigators in the United States, Europeand Japan, as reviewed [1,12,15]. (For example, clomipramine ther-apy of cataplexy in a group of patients with narcolepsy commonlyproduced RWA in one early study from 1976 [16]). A more contem-porary example involved fluoxetine-induced clinical RBD (and notjust RWA) that persisted for at least 19 months after discontinua-tion of the fluoxetine [17], and this report stimulated subsequentreports of antidepressant-induced RBD but never buproprion, adopaminergic–noradrenergic agent, as reviewed [18]. Bupropionshould be considered the antidepressant of choice for clinicaldepression associated with RBD, unless otherwise contraindicated.Although the association of RBD with pharmacologic treatments,

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especially antidepressants, is well known among sleep physicians,it is virtually unknown among psychiatrists or neurologists.

An experimental animal model of RBD was reported in 1965 byJouvet and Delorme in Lyon, France [12,19], produced by brainstemlesions in the peri locus ceruleus area of the pons that released aspectrum of oneiric behaviors during REM sleep (called paradoxicalsleep and active sleep by basic scientists). These oneiric behaviors incats closely match the repertoire of RBD behaviors in humans. Re-search has expanded greatly with the experimental animal modelsof RBD (that now include cats, rats, and mice, with the latter beinga transgenic mouse model with deficient glycine and GABA neuro-transmission [10,12,20,21]), and on the neuroanatomy and neuro-chemistry subserving REM atonia and the phasic motor system inREM sleep. Also, research on clinical RBD has grown exponentially[22], as reflected by more than 100 peer-reviewed journal articlesinvolving RBD being published yearly. RBD is clearly situated at abusy and strategic crossroads of sleep medicine, neurology andthe neurosciences. This Special Issue of Sleep Medicine is dedicatedto RBD, with a focus on current knowledge and future directions.Many of the key basic science and clinical components of RBDare addressed. This issue reaffirms how knowledge on RBD has ex-ploded in breadth and depth across the basic and clinical sciencesin the 27 years since it was formally identified. The ‘‘RBD odyssey’’[23] exemplifies the vital cross-fertilization between clinical andbasic science promoted by the discovery of RBD and the ongoingdevelopment and refinement of experimental animal models ofRBD. The bridge between sleep researchers and both clinical andbasic scientists exploring neurodegenerative disorders has createda whole new area of research – and the International RBD StudyGroup.

We will now provide an overview of this issue, with highlights,which consists of 15 original and review articles on RBD. Threearticles are written by basic scientists, and 12 by clinical scientists.

Two basic science papers are review articles, and one is an ori-ginal article. Seven clinical papers are review articles and five areoriginal articles. Ramaligam et al [24] summarize research fromthe past five decades on the neural circuitry regulating REM atoniaand identify REM-active glutamatergic neurons in the pontine SLD(sublaterodorsal nucleus) as being a critical area, as descendingprojections from the SLD activate neurons in the VMM (ventrome-dial medulla), from where inhibitory descending projections to thespinal cord ultimately produce the REM atonia. A clinical correlateof these experimental rat findings to human RBD associated withneurodegenerative disorders is that damage to the SLD appearscritical for triggering RBD in humans, based on neuropathologicfindings in humans. Luppi et al. [25] focus on the potential rolesof brainstem glutamate, GABA, and glycine dysfunction in the

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pathophysiology of RBD, and propose alternative explanations forRBD apart from SLD damage. In the article presenting original databy Hsieh et al. [26], experiments in rats found that yet anotherbrainstem region may be implicated in human RBD, involvingGABA-B receptor mechanisms in the external cortex of the inferiorcolliculus. (The limbic region has also been implicated with RBD ina published series of RBD patients with autoimmune limbicencephalitis whose RBD was controlled with immunosuppressivetherapy [27]).

Among the 12 clinical RBD papers in this issue, many topics arecovered, including assessments, RBD in various clinical popula-tions, and generating therapy protocols in RBD. We will now touchon the highlights of the clinical papers grouped within these topics.

Frauscher et al. [28] address important practical and also re-search aspects of EMG scoring of RBD, to maximize the sensitivityand specificity of this process for RBD diagnosis. The authors callattention to the recent literature that has helped move the fieldforward from a qualitative approach to a quantitative approachto scoring the EMG in REM sleep, using both visual and com-puter-assisted methods. The Lam-Wing group review the variousrating scales in the assessment of RBD, both for screening purposesand for tracking changes with therapy [29]. The paper by Miyam-oto and Miyamoto [30] review the RBD literature on abnormalneuroimaging findings in RBD, with their paper focusing on trans-cranial ultrasound and positron-emission tomography and single-photon emission computed tomography imaging. Magnetic reso-nance imaging findings in RBD have been published, but are not in-cluded in this review. Neuroimaging is a vital component of thefuture of RBD research, including longitudinal research utilizingneuroprotective agents, a topic addressed in the final paper of thisspecial issue.

Topics not addressed in this special issue include RBD in chil-dren and adolescents, altered dreaming in RBD, acute RBD, symp-tomatic (secondary) RBD, the strong RBD link with periodic limbmovements in NREM and REM sleep (but rarely associated withRLS symptoms), lack of a treatment trial in RBD, despite guidelinesbeing given, parasomnia overlap disorder and status dissociatus,differential diagnosis, dopaminergic pathways in RBD and RBD–PD, and their interaction with the brainstem GABA system, forensic(medical-legal) aspects of RBD, and a variety of other topics per-taining to RBD, especially a consensus on diagnostic criteria forRWA and RBD, which hopefully will be forthcoming within thenext few years. An updated section on RBD will be published inthe International Classification of Sleep Disorders, 3rd Edition,published by the American Academy of Sleep Medicine, which iscurrently in the final steps of preparation.

De Cock [33] reviews the fascinating findings previously pub-lished by her with the Arnulf group in Paris on the striking normal-ization of movements, behaviors, and speech during REM sleep inParkinson disease (PD) and MSA patients compared to their wake-ful movements, behaviors, and speech. These findings raise impor-tant questions about the neurophysiology of dissociated states andalso about the apparent existence of motor pathways in REM sleepthat bypass the common, but in PD patients disturbed indirectpathway of the basal ganglia and how those beneficial pathwaysmight be utilized therapeutically during wakefulness in thesepatients.

The multicenter paper from North America and Europe pub-lished by Boeve et al. [34] presents data on the pathologic sub-strates of RBD in 172 patients who underwent post mortembrain autopsy. The preponderance of cases (83%) was male, andthe vast majority of cases were found to have a synucleinopathy(DLB, n = 97; PD, n = 32, MSA, n = 19). A wider spectrum of disor-ders that can underlie RBD came to be appreciated from this au-topsy study. This large study clearly confirms the value ofneuropathologic examination of post mortem brains in RBD

and encourages future multi center research collaboration in thisarea.

Postuma et al. [31] discuss the major implications of how themanifestation of often violent iRBD predicts future neurodegener-ative disease, thus signaling the need for developing neuroprotec-tive therapy. There is the unprecedented opportunity, as stated bythe authors, to directly examine the evolution of prodromal diseaseinto defined neurodegenerative disorders. The authors also reviewthe growing number of prodromal/predictive markers of futureneurodegeneration found in iRBD, along with the evolution of mo-tor and non motor markers in the prodromal stages. This timelyand enormously important topic calls attention to the pressingneed for neuroscience research to develop a host of promising neu-roprotective agents that can be clinically tested for efficacy in fur-ther prolonging, or ideally halting the progression from iRBD toovert neurodegenerative disorders. Despite a wealth of compellingdata supporting the need for neuroprotective therapy of iRBD, todate there seems to be no especially promising neuroprotectiveagent to be tested. That is the major challenge to the neurosciencefield presented by the cumulative neurologic and sleep medicinedata in RBD—to develop promising neuroprotective agents to betested clinically. A major problem for this research effort is the lackof a suitable animal model of idiopathic PD; recently, a marmosetmonkey MPTP model of acute-onset RBD with early PD has beendeveloped that may hold some future research promise [35]]. Fur-thermore, the relevance of isolated RWA (also known as sub-clin-ical RBD), i.e., the PSG marker of RBD but without any clinicalhistory of RBD, to the development of future neurodegenerativedisease also needs to be addressed [20,36], as patients with theearliest identified markers for future neurodegenerative diseasewould be the optimal patients for neuroprotective studies. If a sub-group of patients with RWA (identified incidentally in sleep labo-ratories during evaluations) could be identified to have increasedrisk for future neurodegeneration (e.g. males >50 years withRWA, with established criteria being used for RWA), then those pa-tients could be enrolled in such studies, along with clinical iRBDpatients.

Ju [37] addresses one of the new frontiers in the RBD literaturein her review article on RBD affecting adults under the age of50 years. The clinical profile of these patients differs considerablyfrom the ‘‘classic’’ profile of RBD patients recognized since 1986,insofar as the younger RBD adult patients (‘‘early onset RBD’’) havea different clinical presentation, have much more gender parity (incontrast to the male predominance in classic RBD), and have an in-creased proportion of idiopathic cases. They also have an increasedproportion of parasomnia overlap disorder cases, cases associatedwith narcolepsy–cataplexy (NC), and cases with use of antidepres-sant medications (and presumably also mood disorders), alongwith a possibly increased proportion with autoimmune diseases.Concerning the latter possibility, the increasingly recognizedstrong link of RBD with NC suggests possible shared autoimmunemechanisms, as both conditions share abnormal HLA typing[12,38], and perhaps autoimmune mechanisms also play a role inearly onset RBD (as presumably occurs with NC), in contrast tothe stronger link of RBD with neurodegenerative disorders in themore classic older-age onset of RBD. These considerations dovetailwith the paper by Dauvilliers et al. [39] in which they propose thatthe RBD-narcolepsy association represents a distinct phenotype,compared to the ‘‘classic’’ RBD phenotype in regard to absence ofmajor gender discrepancy, a shift to more elementary movementsand less complex behaviors in REM sleep, earlier age of onset ofRBD, less vigorous and violent behaviors, and a strong link withhypocretin deficiency, as found in most cases of NC but not inRBD unassociated with narcolepsy [40]. The strong RBD–NC linkis a fascinating anomaly of nature, demonstrating striking inverserepresentations of motor-behavioral dyscontrol across wakeful-

Preface / Sleep Medicine 14 (2013) 699–702 701

ness and REM sleep in the same patient: cataplexy, with sudden,emotionally-triggered intrusions of atonia in wakefulness, and in-creased muscle tone and muscle twitching with behavioral releaseduring emotionally charged dreams in REM sleep.

Jennum et al. [41] review the various comorbidities associatedwith RBD, including how the presence of RBD in PD confers in-creased morbidity across many dimensions of PD (cognition, motorinvolvement, hallucinations, etc.) compared to PD without RBD.They discuss how greater pathologic involvement of brain regions,with strategic damage, can explain this increased morbidity ofRBD–PD compared to RBD without PD. This important topic alsohas been recently reviewed in an editorial [20] that commentedon a milestone paper reporting that nearly half of a very largegroup of PD patients had comorbid RBD [42].

The Lam-Wing group addresses a new branch of RBD researchinvolving psychiatric populations, in which the authors suggestthat mood disorders per se and not just antidepressant use (sparingbupropion) may be risk factors for RBD that is characterized by in-tense dream-related abnormal mood states that may facilitatedream enactment [43].

Finally, the multi authored paper by Schenck et al. [10] (involv-ing 39 authors from 13 countries) exemplifies the successful col-laborations of the International RBD Study Group that became aformal entity in 2009 and that has convened for six internationalsymposia to formulate research projects, with three publicationsto date [9–11]. This paper establishes the methods to be used inan active treatment study of RBD, involving clonazepam vs melato-nin, tracking both the rate of efficacy and the rate and type of sideeffects. It also addresses the methodology to be optimally used inneuroprotective treatment trials.

Topics not addressed in this special issue include RBD in chil-dren and adolescents, altered dreaming in RBD, acute RBD, symp-tomatic (secondary) RBD, the strong RBD link with periodic limbmovements in NREM and REM sleep (but rarely associated withRLS symptoms), lack of a treatment trial in RBD, despite guidelinesbeing given, parasomnia overlap disorder and status dissociatus,differential diagnosis, dopaminergic pathways in RBD and RBD–PD, and their interaction with the brainstem GABA system, forensic(medical-legal) aspects of RBD, and a variety of other topics per-taining to RBD, especially a consensus on diagnostic criteria forRWA and RBD, which hopefully will be forthcoming within thenext few years. An updated section on RBD will be published inthe International Classification of Sleep Disorders, 3rd Edition,published by the American Academy of Sleep Medicine, which iscurrently in the final steps of preparation.

In conclusion, this Special Issue of Sleep Medicine dedicated toRBD confirms how RBD is situated at a strategic and busy cross-roads of sleep medicine and the neurosciences. RBD offers greatbreadth and depth of research opportunities, including extensiveinter disciplinary and multinational research opportunities. Finally,we advocate the need to assume the role of ‘‘guardians of REM ato-nia’’ in various contexts, including the study of new psychotropicdrugs and other neuropsychoactive drugs prior to general clinicalrelease. Another context for proactively assessing disturbance ofREM atonia and emergence of RBD involves patients who have re-cently become abstinent from alcohol and drug abuse (especiallycocaine, amphetamine). We believe that a formal video-PSGassessment looking for any disturbance of REM atonia and releaseof abnormal behaviors during REM sleep should be mandatorywith newly developed drugs, together with proactively eliciting ahistory of drug-induced RBD in these subjects. Sleep specialistsshould inform psychiatrists and other physicians who prescribepsychotropic drugs about the need to monitor for RBD and to be-come aware of clinical scenarios related to the disruption of REMatonia. The state of scientific advances should make it imminentto predict which newly developed drugs pose greater or lesser risks

on the integrity of REM atonia and predisposition for RBD, and onreleasing sleep-disruptive PLMs.

Conflict of interest

The ICMJE Uniform Disclosure Form for Potential Conflicts ofInterest associated with this article can be viewed by clicking onthe following link: http://dx.doi.org/10.1016/j.sleep.2013.04.011.

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Carlos H. Schenck⇑Minnesota Regional Sleep Disorders Center,

Department of Psychiatry, University of Minnesota Medical School,Hennepin County Medical Center, 701 Park Avenue South,

Minneapolis, MN 55415, United States

Claudia Trenkwalder, MD Paracelsus-Elena Klinik,Center of Parkinsonism and Movement Disorders,

Kassel, University of Goettingen,Goettingen⇑ Tel.: +1 612 873 6201; fax: +1 612 904 4207

E-mail address: schen010@umn.edu

Available online 12 June 2013