REVIEW REM Sleep Behavior Disorder in Parkinson’s Disease and Other Synucleinopathies 1,2 Erik K. St Louis, MD, MS, * Angelica R. Boeve, BA,1,2 and Bradley F. Boeve, MD1,2 1Center for Sleep Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA 2Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA ABSTRACT: Rapid eye movement sleep behavior dis- eye movement sleep behavior disorder are frequently order is characterized by dream enactment and complex prone to sleep-related injuries and should be treated to motor behaviors during rapid eye movement sleep and prevent injury with either melatonin 3-12 mg or clonazepam rapid eye movement sleep atonia loss (rapid eye move- 0.5-2.0 mg to limit injury potential. Further evidence-based ment sleep without atonia) during polysomnography. Rapid studies about rapid eye movement sleep behavior disorder eye movement sleep behavior disorder may be idiopathic are greatly needed, both to enable accurate prognostic or symptomatic and in both settings is highly associated prediction of end synucleinopathy phenotypes for individ- with synucleinopathy neurodegeneration, especially Parkin- ual patients and to support the application of symptomatic son’s disease, dementia with Lewy bodies, multiple system and neuroprotective therapies. Rapid eye movement sleep atrophy, and pure autonomic failure. Rapid eye movement behavior disorder as a prodromal synucleinopathy repre- sleep behavior disorder frequently manifests years to dec- sents a defined time point at which neuroprotective thera- ades prior to overt motor, cognitive, or autonomic impair- pies could potentially be applied for the prevention of ments as the presenting manifestation of synucleinopathy, Parkinson’s disease, dementia with Lewy bodies, multiple along with other subtler prodromal “soft” signs of hypo- system atrophy, and pure autonomic failure. VC 2017 Inter- smia, constipation, and orthostatic hypotension. Between national Parkinson and Movement Disorder Society 35% and 91.9% of patients initially diagnosed with idio- pathic rapid eye movement sleep behavior disorder at a Key Words: REM sleep behavior disorder; REM sleep center later develop a defined neurodegenerative sleep without atonia; Parkinson’s disease; synucleinop- disease. Less is known about the long-term prognosis of athy; Dementia with Lewy bodies; multiple system atro- community-dwelling younger patients, especially women, phy; pure autonomic failure; polysomnography; and rapid eye movement sleep behavior disorder associ- treatment ated with antidepressant medications. Patients with rapid Rapid eye movement sleep behavior disorder (RBD) sleep and loss of normal REM sleep muscle atonia is characterized by dream enactment and complex (also known as REM sleep without atonia) during pol- motor behaviors during rapid eye movement (REM) ysomnography.1 When RBD is unassociated with other overt neurological impairments, it is known as ------------------------------------------------------------ *Correspondence to: Erik K. St Louis, MD, Center for Sleep Medicine, idiopathic RBD. RBD may also be symptomatic and Mayo Clinic, 200 First Street SW, Rochester, MN 55905; StLouis.Erik@ related to several underlying definable etiologies mayo.edu including synucleinopathies and other neurodegenera- Funding agencies: This publication was supported by CTSA grant UL1 tive diseases, autoimmune/inflammatory disorders, TR000135 from the National Center for Advancing Translational Science 2-16 (NCATS) and grants P50 AG016574, UO1 AG006786, and RO1 brain lesions, or medication-induced cases. RBD is AG015866, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy highly associated with synucleinopathy neurodegenera- Body Dementia Program, and the Little Family Foundation. Its contents are solely the responsibility of the authors and do not necessarily repre- tion, especially Parkinson’s disease (PD), dementia sent the official views of the NIH. with Lewy bodies (DLB), multiple system atrophy 1-7,13,14,17-23 Received: 24 October 2016; Revised: 15 March 2017; Accepted: 16 (MSA), and pure autonomic failure (PAF). March 2017 RBD may manifest initially as the presenting manifes- Published online in Wiley Online Library tation of a synucleinopathy that occurs years to deca- (wileyonlinelibrary.com). DOI: 10.1002/mds.27018 des prior to the evolution of overt motor, cognitive, or Movement Disorders, Vol. 32, No. 5, 2017 645 ST. LOUIS ET AL autonomic impairments. RBD frequently emerges with frequency.15,43-45 The likelihood of RBD increases 5- temporal proximity to other subtle, heterogenous pro- fold in patients receiving antidepressants, and a psychi- dromal “soft” signs, including cognitive or motor defi- atric diagnosis increases the likelihood of RBD 9- to cits, mood alteration, hyposmia, constipation, and 10-fold.15 RBD most frequently begins in the fifth or orthostatic hypotension, which may vary in initial sixth decade of life, although some idiopathic RBD temporal onset and sequence of evolution and which cases onset may commence at any age with a long clini- are associated with a higher risk of eventual pheno- cal course of RBD symptoms prior to eventual overt conversion to a defined neurodegenerative disorder defined neurodegenerative disease, and RBD is also when present in idiopathic RBD.2,12,14,21,24-32 seen in younger patients with antidepressant use and This article will comprehensively review RBD, probable underlying narcolepsy, autoimmunity, or including recent evidence concerning RBD epidemiol- developmental disorders.9,10,15,24,46 ogy, suggesting that it is has likely been previously Some risk factors for RBD appear similar to those underrecognized; its strong association with the synu- found in Parkinson’s disease, such as lower educa- cleinopathies, especially idiopathic RBD, PD, nonam- tional level, previous head injury, occupational pesti- nestic mild cognitive impairment (MCI), DLB, MSA, cide exposure, and farming, but there also appear to and PAF; evidence concerning RBD as a marker of be some distinct risk factors such as smoking, ischemic disease extent and severity in association with PD; and heart disease, and inhaled corticosteroids.11,29 Unlike relevant clinical considerations concerning the diagno- Parkinson’s disease, caffeine use and smoking do not sis, differential diagnosis, pathophysiology, and treat- appear to be protective in patients with RBD. One ment of RBD. recent study of risk factors in PD patients found that smoking was associated with PD patients with RBD, Epidemiology when compared with PD patients without RBD.29,47 It is also unclear whether previous psychiatric history The prevalence of idiopathic RBD (iRBD) was previ- and antidepressant use are risk factors or another ously estimated to be between 0.38% and 0.5% within expression of prodromal neurodegeneration.11,12 Risk the general population, based on a large phone survey factors for phenoconversion to a neurodegenerative study of violent sleep behaviors.33 However, RBD disorder include a family history of dementia, auto- patients account for up to 4.8% of patients presenting nomic and motor symptoms, lower likelihood of pesti- to sleep clinics.34 The best current prevalence estimate cide exposure, and possibly clonazepam use.29 was provided by a recent Korean population-based study with polysomnographic confirmation, which Diagnosis of RBD showed that age- and sex-adjusted RBD prevalence was 2.01% overall (idiopathic RBD, 1.15%), with another RBD diagnosis requires a history of complex motor 4.95% having isolated polysomnographic REM sleep behaviors during sleep or complex motor behaviors without atonia (RSWA) but no dream enactment, occurring during REM during polysomnography, as although some of these patients may have also actually well as RSWA during polysomnography and the sleep had RBD if a complete history had been available.35 disturbance not being better explained by another disor- Further population-based studies using well-validated der.1 ThecorediagnosticclinicalfeatureofRBDisa RBD survey assessments have also consistently shown history of dream enactment, and because the patients that probable RBD (without polysomnographic confir- themselves may or may not be aware of the behaviors, mation) is likely even more frequent, affecting 5%- obtaining collateral history from patients’ bed partners 6.8% of the older general population after age 60-70 is crucial, especially if the patients have underlying cog- years.36,37 In fact, 2 studies that were not actually nitive impairment.2,48 A contrary hypothesis is that focused on RBD prevalence showed striking frequencies patients may be “dreaming out their acts” rather than of probable RBD symptoms in 10.9% from a post- acting out dreams, given that REM twitches may physi- stroke hospital sample and 13% in an elderly commu- ologically promote motor learning and development, nity sample.38,39 Although prevalence studies lacking and thus limb movements may provide sensory feedback polysomnography may overestimate RBD frequency, via brain stem structures to the cortex, generating dream they do suggest that the burden of disease related to content, rather than vice versa.49 Characteristically RBD has previously been vastly underestimated in the although inconstantly, described dream mentation general population. RBD has been reported to be more includes aggressive themes of being chased or defending common in men than in women in large case series oneself against attacking persons or animals, although from sleep