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: 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 , 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), 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 centers,6,13,40-42 but in patients younger than recall and selection biases may be responsible for the age 50 years in whom nondegenerative etiologies such reporting of more violent dream content, with patients as narcolepsy and autoimmunity appear to be more fre- being both more likely to remember and report violent quent, women and men have an approximately equal dream mentation and enactment behaviors and to seek

646 Movement Disorders, Vol. 32, No. 5, 2017 REM SLEEP BEHAVIOR DISORDER IN SYNUCLEINOPATHIES medical attention and receive referral to sleep medicine disease.63 All RBD questionnaires suffer from the specialists when their behaviors are violent or poten- inability to accurately distinguish RBD from mimics tially injurious.2,50-53 The nightmare content often such as non-rapid eye movement (NREM) sleep para- includes animal characters or people, with vivid dream somnias, arousals from other sleep disorders such as recall having been linked to a greater risk of injury in sleep apnea, or nocturnal confusion in dementia one study.54 A recent study concentrating on dream patients, so diagnostic confirmation by polysomnogra- mentation during laboratory polysomnography found phy is strongly preferred whenever possible. that Parkinson’s disease patients with RBD had more negative dream content than those without RBD and REM Sleep Without Atonia tended to have more intense actions, but there were no differences between groups for action-filledness or vivid- Polysomnographic REM sleep without atonia ness, emotional valence, or threats.50 Vocalization with (RSWA) is the neurophysiologic substrate of RBD, screaming or shouting, laughing, or crying, with speech and is required for RBD diagnosis, except when REM frequently being intelligible and paralleling dream con- sleep is not obtained during a polysomnography tent, may accompany violent limb movements including recording or is not readily available or is overly expen- arm flailing, punching, choking, scratching, squeezing, sive (ie, in resource-poor practice settings or in large- kicking, or running. A spectrum of injuries have been scale epidemiologic studies); see Figure 1.1 RSWA is reported as a consequence of RBD, including bruising, identified qualitatively in most clinical practice set- lacerations, fractures, and subdural hematomas.6,54,55 tings, but in research settings it is quantitatively Patients should be asked about prior injury and falls defined by visual or automated methods.64-70 Visually from bed, which may indicate a greater risk of further identified RSWA is of 3 types: phasic/transient (short injuriousattacksandsuggestthatprompttreatmentisa bursts of muscle activity), tonic (sustained graded priority.54 increased-voltage background muscle activity), or Although polysomnographic loss of REM sleep ato- “any” (either phasic or tonic). Several quantitative nia is a requisite for a confident diagnosis whenever methods are available as references for RBD diagnos- possible and available, probable RBD may be diag- tic cutoffs for use in research and clinical nosed on clinical grounds when a clear history of settings.60,64,65,70 dream enactment-type behaviors is present. There are RSWA may be present as an isolated or incidental find- several well-validated screening measures for making ing during polysomnography and has also been called the diagnosis of clinically probable RBD for resource- “subclinical RBD,” although this terminology implies poor areas, when polysomnography is inaccessible, or that the natural history of isolated RSWA is known, when REM sleep is not recording during polysomnog- which is currently not the case. One recent study found raphy.48,56-61 These include the REM Sleep Behavior that isolated RSWA without RBD was present in up to Disorder Screening Questionnaire (RBDSQ),59 the 25% of a general community population sample.71 In Innsbruck REM Sleep Behavior Disorder Question- those without dream enactment symptoms, isolated/inci- niare,60 and the RBD-HK.58 The Mayo Sleep Ques- dental polysomnographic RSWA appears to be most fre- tionnaire (MSQ) is another well-validated diagnostic quent in older men and in those receiving antidepressant tool for RBD screening in older patients with cognitive medication.10,72 Evidence that polysomnographic RSWA impairment and/or , which may be is a biomarker for underlying neurodegeneration has administered either to the bed partner (informant ver- included the presence of positive neurodegenerative bio- sion; an especially helpful tool for elderly patient pop- markers in patients with isolated RSWA,73 associations ulations when cognitive impairment is common, with measures of phenotypic severity of parkinsonism making dream recall problematic) or instead directly such as gait freezing and cognitive impairment,74,75 serial to the patient when a bed partner is not avail- progression of the amount of RSWA over time in those able.48,56,61 The RBD Single Question (RBD1Q) is with idiopathic RBD,76 and association with greater phe- administered to the patient and poses essentially the noconversion risk.77 Isolated RSWA may also indicate same core question regarding dream enactment as the heightened risk for phenoconversion to idiopathic RBD MSQ.57 Both the RBD1Q and MSQ have shown ade- during longitudinal follow-up, as 1 recent pilot study of quate sensitivity and specificity compared with poly- those with isolated RSWA in Innsbruck showed that somnography and may be preferable for use in 7%-14% developed clinical RBD over longitudinal fol- patients with parkinsonism, because these tools were low-up.73 When RSWA is found during polysomnogra- shown to be more specific than the RBDSQ for the phy as an apparently incidental or isolated finding, this confirmatory presence of polysomnographic REM should prompt further thorough history taking with the sleep atonia loss,62 and both screening questionnaires patient and bed partner, because 44% of patients with used together were superior to either used alone in idiopathic RBD in the largest reported series to date were another large independent cohort with Parkinson’s unaware of their dream-enacting behaviors and 70% of

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FIG. 1. REM sleep atonia loss, also known as REM sleep without atonia (RSWA), in a 56 year-old man with REM sleep behavior disorder. Note in the top 30 second polysomnogram epoch that there is relatively normal muscle atonia level preserved in the submentalis (chin) EMG lead (6th channel, blue arrow), and that the predominant muscle activity abnormality is excessive phasic/transient muscle activity seen throughout the limb EMG channels (7th through 10th channels; channels 7-8 are right and left anterior tibilalis, and channels 9-10 are left and right flexor digitorum superficialis muscles, respectively). By contrast, the bottom 30 second epoch shows normal levels of REM sleep atonia in the submentalis and limb EMG channels (6th through 10th channels). [Color figure can be viewed at wileyonlinelibrary.com] patients reported good sleep quality without substantial paralleling dream content, and RSWA, in the absence of sleep disturbance.42 diagnostic features of PD, DLB, MSA, PAF, or another symptomatic underlying neurological disorder.1 Given its Idiopathic RBD as a Prodromal very strong association with incipient PD and synuclein- opathy, some have instead suggested that the term Feature of PD and Other “cryptogenic” RBD be used, referring to the assumed Synucleinopathies underlying presence of a synucleinopathy. Converging evidence supporting an underlying synu- Idiopathic RBD is diagnosed based on the presence of cleinopathy as the cause of idiopathic RBD in most sleep-related complex motor behavior, most often cases, at least when presenting typically in older-age

648 Movement Disorders, Vol. 32, No. 5, 2017 REM SLEEP BEHAVIOR DISORDER IN SYNUCLEINOPATHIES patients, stems from: (1) longitudinal cohort studies; (2) dopaminergic uptake in patients with idiopathic RBD multimodality demonstrations of neurodegenerative bio- compared with controls, a consistent finding across marker presence in iRBD patients; and (3) especially single-photon emission computed tomography, PET, pathologic evidence from both living patients with idio- and novel susceptibility-weighted MRI techniques.79,100- pathic RBD, as well as RBD decedents. 104 Variability of DaT uptake abnormalitiesisreflected Longitudinal cohort studies of idiopathic RBD among different studies, with a newer study also finding patients both from sleep centers and the general popu- that the presence of RBD may confer a greater tendency lation have demonstrated a convincing, consistent, and towardDaTscanabnormalitiesinPD-RBDthaninPD very strong association with the future development of patients without RBD.105 A recent study also found evi- a defined neurodegenerative disease, predominantly dence for loss of dorsolateral nigral signal hyperintensity the synucleinopathies of PD, nonamnestic MCI, DLB, on brain MRI in the majority of 15 patients with idio- and MSA.7,13,14,41,78-81 The risk of phenoconversion pathic RBD compared with controls.104 Transcranial over a short-term follow-up of 2-5 years is between ultrasonography has also shown substantial nigra hyper- approximately 15% and 35%, whereas long term, echogenicity in idiopathic RBD patients compared with more than 6-15 years, this risk is in the range of 41%- controls.79,101 Functional imaging studies have found 91.9%, growing larger with longer follow-up after defective central cholinergic and peripheral noradrener- diagnosis and especially after symptom onset, gic neurotransmission in idiopathic RBD patients.106,107 although progression may be highly variable among Both structural and functional imaging studies of corti- individuals. One study of RBD patients with long cal thickness and diffuse resting-state metabolic network symptom duration suggested that phenoconversion dysfunction have shown patterns similar to those seen may take more than 50 years in some individuals; in Parkinson’s disease, with cortical thinning in the fron- however, these patients did not have early-life poly- tal cortex as well as the lingual and fusiform gyri, and somnography confirmation of RSWA, so it is unclear metabolic abnormalities in the posterior cortical and whether dream enactment per se occurred earlier in brain stem areas in idiopathic RBD patients have been life or whether childhood/early-life NREM disorder of shown to predict phenoconversion to defined neurode- arousal (ie, sleep terrors, confusions generative parkinsonian disorders.108-110 arousals, sleep walking) may have instead explained Two recent studies have confirmed the presence of the earlier-life behavior of these a-synuclein immunoreactivity in peripheral tissues of patients.7,13,14,24,41,78,79,81 Among older adults in the patients with idiopathic RBD relative to con- general community, probable RBD positivity on the trols.111,112 One targeted submandibular gland tissue MSQ screening questionnaire confers a hazard ratio of via ultrasound-guided biopsy, finding that the majority 2.2 (95% CI, 1.3-3.9).36 of patients with polysomnographically confirmed idio- There is also abundant evidence from multiple clinical pathic RBD had direct evidence for a-synuclein pro- investigations showing that idiopathic RBD patients fre- tein pathology by immunohistochemistry analyses quently demonstrate the presence of neurodegenerative using 129-phosphorylated antiserine monoclonal anti- biomarkers consistent with an underlying synucleinop- body.111 Another found that a minority of idiopathic athy, including: (1) clinical symptoms and signs of RBD patients showed immunostaining for the same hyposmia and constipation, orthostatic hypotension, antibody in submucosal nerve fibers or ganglia on sleepiness, and gait initiation abnormalities, factors that colonic tissue biopsy in 4 of 17 patients with idio- may portend a higher phenoconversion risk to an overt pathic RBD and none of 14 controls.112 Postmortem synucleinopathy11,12,14,25,28,74,82-84; (2) neuropsychologi- pathologic studies have also proven underlying synu- cal dysexecutive, attention, visuoperceptual, and visual cleinopathy presence in RBD decedents, both in those short-term memory and decision-making impairments still having idiopathic RBD at the time of death, as that may progress over time22,27,80,85-90; (3) neurophysi- well as those who had already developed overt symp- ological abnormalities of electroencephalographic slow- tomatic cognitive, motor, and autonomic involve- ing and in event-related potentials91-94;and(4)imaging ment.3,81,113,114 Typical pathology of Lewy bodies and abnormalities signifying local brain stem involvement neurites with neuronal loss is most frequently seen. likely to impact REM sleep atonia control in the dorsal One exceptional autopsied case of idiopathic RBD pons, as well as more diffuse involvement in brain net- that evolved nonmotor symptoms of hyposmia, works signifying diffuse subcortical and cortical pathol- depression, mild cognitive impairment, and constipa- ogy. Structural and functional neuroimaging studies tion over a 10-year time course and who lacked par- have demonstrated localized dorsal pontine lesions with kinsonism or dementia at the time of death altered neuromelanin signal intensity in this region demonstrated widespread central and peripheral ner- neighboring the locus ceruleus/subceruleus.8,95-99 Presyn- vous system synucleinopathy.115 Other pathologies are aptic dopamine transporter (DaT) uptake studies have also commonly found in patients with RBD, often shown abnormally decreased nigrostriatal putamenal intermingling with synucleinopathy, including

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Alzheimer’s disease pathology of beta-amyloidosis and falling, fluctuations, psychiatric comorbidity, and peri- tau, progressive supranuclear palsy, neuronal brain odic leg movements of sleep.120 The motor phenotype iron accumulation type 1, other neurodegenerative of PD-RBD patients appears to be more severe than pathologies, or brain lesions. However, synucleinop- those without RBD, with a greater tendency toward an athy was the underlying pathology in 94% of autop- akinetic-rigid state with lesser tremor predominance, sied patients in the largest multicenter autopsy series less levodopa responsiveness, greater levodopa dose- of RBD.3 equivalent requirements, earlier and more severe gait freezing, longer duration of disease, and longer dura- Secondary/Symptomatic RBD in tion of levodopa treatment.121,122 Motor progression Parkinson’s Disease also appears to be faster in PD patients with RBD and RSWA than those with preserved REM atonia.123 The 75 RBD has been strongly associated with PD and other degree of RSWA is associated with gait freezing. synucleinopathies.5,7,14,41 In one study of 457 PD PD-RBD patients also have greater cognitive impair- patients, 46% had RBD.118 RBD symptoms may precede ment and EEG slowing than PD patients without PD diagnosis or develop in parallel or follow the RBD, even before the presence of dementia, and PD- development of any stage of PD.6 When secondary or RBD is strongly associated with mild cognitive impair- symptomatic to overt underlying parkinsonism, RBD ment (MCI) and visuoconstructional and visuospatial 27,124 characteristics appear similar to idiopathic RBD. An inter- neuropsychological test domain impairments. esting paradox of waking parkinsonian motor impair- Patients with PD-RBD-MCI are at greater risk of ment is that motor control and speech appear to improve evolving dementia, hallucinations, and cognitive fluc- during RBD dream enactment movements compared with tuation than PD patients without RBD, with the 125 waking dysfunctional bradykinesia and rigidity, becom- amount of tonic RSWA also predicting dementia. ing much more rapid and fluid, possibly because of the However, in one recent study of newly diagnosed bypass of motor processing by the basal ganglia during PD patients with and without RBD, there were no dif- sleep.116 The amount of REM muscle atonia loss appears ferences in neurocognitive, motor, or polysomno- to predict the development of PD, with one study finding graphically determined sleep measures, demonstrating that iRBD patients who developed PD had 73% abnormal the heterogeneity of the PD-RBD phenotype at presen- 126 tonic chin muscle activity, compared with only 41% in tation. Another study identified both probable RBD those who remained disease free; similarly, patients who symptoms and polysomnographically confirmed RBD developed dementia also had increased chin tonic chin as being comparable or even more potent biomarkers tone of 54%.77 Interestingly, it has been noted that PD of progression in recently diagnosed Parkinson’s dis- patients with RBD (PD-RBD) are more likely to have psy- ease as motor severity ratings on the UPDRS, auto- chiatric comorbidity compared with PD patients without nomic symptoms, or measured neuroimaging cortical 127 RBD, suggesting that PD-RBD may be a distinct pheno- and hippocampal volumes. type of disease or at least that the presence of RBD may This converging evidence suggests that compared reflect a greater burden of disease severity.117 with PD patients without RBD, PD-RBD may represent a distinct synucleinopathy phenotype with more rapid PD-RBD: Is It a Distinct Phenotype? evolution toward greater cognitive and autonomic impairments, with an end phenotype of PD dementia There is substantial evidence that PD associated with (generally diagnosed when motor symptoms are present RBD (PD-RBD) may signify a distinct phenotype com- for more than 1 year before cognitive decline). Alterna- pared with PD without RBD, reflecting more severe tively, dementia with Lewy bodies is generally diag- and diffuse disease and association with nosed when motor symptoms are present for less than clinically distinctive features including greater quality- 1 year prior to cognitive decline. Although currently of-life impairments, cognitive impairment, psychiatric proposed Movement Disorder Society criteria for PD comorbidity, and slowing of waking EEG background, diagnosis suggest that PD may be diagnosed even in the autonomic insufficiency, motor disability, longer disease presence of DLB, this currently remains controversial, duration, and greater severity.117-119 In one study, a as many if not most believe that PD and DLB are dis- clinical RBD diagnosis, but not isolated polysomno- tinct diagnoses rather than under the rubric of idio- graphic RSWA without dream enactment, had a strong pathic PD117,128-130 (Fig. 2). association with earlier dementia and greater motor dis- ability in PD patients.118 Another polysomnographic RBD in Other Synucleinopathies study of a large PD cohort found that RBD was seen in 46% of patients, with equal frequency in men and Dementia With Lewy Bodies and RBD women, and that PD-RBD was associated with older Dementia with Lewy bodies (DLB) is characterized age, higher Hoehn and Yahr stage, and more frequent by dementia combined variously with features of

650 Movement Disorders, Vol. 32, No. 5, 2017 REM SLEEP BEHAVIOR DISORDER IN SYNUCLEINOPATHIES

well as in limbic and neocortical structures that under- lie the cognitive deficits.

MSA and RBD Multiple system atrophy (MSA) is characterized by varying degrees of parkinsonism, cerebellar ataxia, and autonomic failure. MSA is an adult-onset neuro- degenerative disease that is sporadic and relatively rare.139 Detailed cognitive assessment of patients with MSA has been very limited because of the focus on autonomic and parkinsonian motor symptoms and limited survival in these patients. In one study, RBD did not appear to be an early predictor of cognitive impairments in patients with MSA.139 More than 88% of patients with MSA appear to also have 140 FIG. 2. Theoretical model of RBD and its relationship to different clini- RBD. There is a greater need for prospective studies cal manifestations of synucleinopathies. Idiopathic RBD may remain involving iRBD patients to assess autonomic and as an isolated syndrome with or without additional cognitive, auto- nomic, or motor “soft signs” that may or may not evolve toward more motor functioning to determine whether MSA may be definitive, clinically overt, “full-blown” synucleinopathy subtypes of developing. DLB, MSA, PD or PD with dementia (PDD). Patients with parkinsonism and dementia are considered to have PDD if cognitive decline occurs longer than one year after the emergence of parkinsonism, and DLB if PAF and RBD patients present with cognitive decline less than one year after emer- Like MSA, pure autonomic failure (PAF) presents gence of parkinsonism. (Reproduced with permission from Elsevier, Inc., McCarter et al, 2013.117) with changes in autonomic functioning. Distinct from MSA, the life expectancy in patients with PAF is rela- tively normal, and there is no parkinsonism, cerebellar parkinsonism, recurrent fully formed visual hallucina- ataxia, or stridor. Although the majority of patients 129 tions, and fluctuations in cognition and/or arousal. with MSA (88%-90%) also have RBD, those with Clinically probable DLB refers to the presence of 2 of PAF are less likely to have sleep-related abnormali- these core features, and clinically possible DLB refers ties,141 although RBD may occur in some patients 129 to one of these features. DLB is the second most with an apparent PAF phenotype.142 When RBD does common form of dementia after Alzheimer’s disease occur in those with features of PAF, this suggests and therefore a major clinical and societal issue. either PAF associated with underlying Lewy body dis- 131 Approximately 80% of DLB patients have RBD, ease or MSA presenting initially with isolated auto- and in almost all instances, RBD has preceded the nomic dysfunction. A recent study of a PAF patient 132 other core features by years or decades. Because of cohort suggested that probable RBD combined with the high frequency of RBD in DLB and the relative 2,3,18,19 hyposmia predicted eventual Lewy body disease, specificity of RBD in the synucleinopathies, whereas probable RBD without hyposmia instead RBD has been recently elevated in the diagnostic con- evolved to MSA.143 sideration for DLB, so that the presence of RBD plus one other core feature qualifies for the diagnosis of clinically probable DLB.129,133 Differential Diagnosis/Other Causes Patients with DLB have impairment in key cognitive of RBD domains, particularly in visuoperceptive functions and Other Neurodegenerative Disorders and RBD attention/executive functions.133,134 Bradykinesia and rigidity are also present in DLB and are more often RBD has been reported to occur in association with 144 symmetrical and accompanied by less rest tremor than clinically diagnosed Alzheimer’s disease, yet when in PD.133,135,136 RBD is present, concurrent Lewy body pathology Patients who develop DLB often experience symp- should be strongly suspected, as in the largest series of toms of RBD prior to cognitive deficits, therefore autopsied RBD patients to date, in which synucleinop- making the diagnosis of RBD pivotal in tracking the athy was present in 94% of patients.3 RBD has also potential progression of dementia.18,19 Cognitive defi- been reported in association with progressive supranu- cits in RBD closely resemble the deficits found in clear palsy (PSP), although RBD symptoms appear DLB.27,137 more likely to parallel motor dysfunction in PSP than Autopsies of patients with RBD/DLB demonstrate in synucleinopathies.145 RBD appears very rare degenerative changes in some of the key brain stem in other primary ,146 although it has structures involved in REM sleep control,2,3,138 as been reported in association with Guadeloupean

Movement Disorders, Vol. 32, No. 5, 2017 651 ST. LOUIS ET AL parkinsonism, a taopathy,147 and was also recently Pathophysiology of RBD reported to be strongly associated with the IgLON5 autoimmunity syndrome, which has demonstrated Mechanisms for RSWA and RBD remain poorly pontine and hypothalamic tau deposition in autopsied understood, with most previous knowledge concerning patients.148 Rare examples of autopsy-proven Alz- REM sleep atonia control stemming from animal heimer’s disease and PSP with RBD have been docu- lesion and functional models. RBD and RSWA patho- mented.3,56 Although RBD may occur in a variety of physiology is reviewed extensively elsewhere in this defined neurodegenerative disorders, the strongest issue.158 Regulation of REM sleep involves several key association of RBD is with the synucleinopathies.2,3 pontine nuclei, especially the glutamatergic subcoeru- leus/sublateral dorsal nucleus,, and REM atonia con- Narcolepsy, Autoimmune Disorders, Brain trol is also influenced significantly by the medullary Lesions, and RBD magnocellular reticular formation.159-165 The hypo- When patients present with RBD at a younger age, thalamus, thalamus, substantia nigra, basal forebrain, arbitrarily before age 50, other nondegenerative etiolo- and frontal cortex also modulate REM sleep regula- gies should be considered, including narcolepsy, auto- tion.159,160,166 Decreased hypocretin levels also corre- immunity, and antidepressant-associated RBD. Of late with RSWA, suggesting that hypocretin may these, narcolepsy type 1 (narcolepsy with cataplexy) stabilize the REM-on and REM-off pontine centers has been clearly associated with RBD and altered and network functioning, at least in those with narco- REM sleep atonia control leading to RSWA.149 In nar- lepsy,167 although in iRBD, hypocretin levels were colepsy, RSWA has been reported to occur with or found to be normal.168 Physiologic REM twitching without RBD, and REM sleep atonia loss with follows a predictable temporal pattern, increasing increased amounts of REM sleep muscle tone is found throughout REM sleep periods, mediated by GABAer- in patients with narcolepsy compared with con- gic and glycinergic inhibitory drive onto motoneurons trols.150,151 In one polysomnography study of narco- that steadily declines as REM progresses, enabling lepsy patients, 50% were found to have RBD,151 and more frequent twitching, and suggesting that failure of 36% of surveyed narcoleptic patients endorsed possi- these GABAergic and glycinergic networks may facili- ble RBD symptoms.152 RBD onset in association with tate pathophysiologic twitching in RBD.169 narcolepsy tends to have a much earlier onset, often Braak staging may parallel RSWA and RBD devel- between the first and fourth decades of life, compared opment in idiopathic RBD patients who later develop with an age older than 50 years in most iRBD or PD and DLB.138,170 Braak staging holds that Lewy symptomatic RBD associated with neurodegenerative body deposition and Lewy neurite accumulation disease, possibly given REM sleep-state instability in begin in the dorsal motor nucleus of the medulla hypocretin-deficient narcolepsy (type 1). Antidepres- (stage 1), subsequently progressing rostrally onto and sants have also been reported to induce clinical RBD through the magnocellularis reticular nucleus, dorsal symptoms in those with narcolepsy.149 pontine subceruleus region (the human homologue of In younger and some older patients, RBD may pre- the sublateral dorsal nucleus), and olfactory bulb and sent as a syndromic manifestation of a paraneoplastic anterior olfactory nucleus (stage 2). Stages 1-3 com- and autoimmune neurologic disorder, such as in Mor- prise a presymptomatic phase of parkinsonism, pre- van syndrome (anti-voltage-gated potassium channel ceding the onset of motor or cognitive symptoms. antibody syndrome), IgLON5 autoimmunity, and Patients with RBD would be conceptualized as being brain stem lesions caused by inflammatory, neoplastic, in Braak stage 2 given concurrent symptoms of hypo- or cerebrovascular disorders.8,98,153-157 smia and findings of cardiac denerva- tion.12,14,25,28,82,107 In Braak stage 3, Lewy body Association With Antidepressants/Psychiatric pathology progresses farther to involve the substantia Disorders nigra, pedunculopontine nucleus, and the amygdala. In addition, selective serotonin reuptake inhibitors, Braak stage 4 represents sufficient nigral degeneration selective norepinephrine reuptake inhibitors, and tricy- to cause clinical parkinsonism, and further Lewy pro- clic antidepressants have been associated with the gression into other rostral structures. In Braak stages development of RBD symptoms, as well as RSWA 5 and 6, Lewy pathology progresses to involve limbic without dream enactment symptoms. It remains structures and the neocortex, with the development unclear whether the association between RBD, RSWA, of cognitive impairment.170 However, some RBD, and antidepressants is mediated by reversible pharma- PD, and DLB patients do not follow a Braak model cologic effects of antidepressants or whether antide- of progression, as there may be RBD onset well after pressants may be simply unveiling RSWA and RBD in the development of cognitive, motor, or autonomic predisposed individuals with a covert underlying symptoms in some patients, or RBD is not universally synucleinopathy.10,12,15,44 seen in all patients with synucleinopathy,

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TABLE 1. Medications associated with worsening or and locking away firearms outside the bedroom. aggravation of RBD Advising separate bedrooms for injury prevention may also be necessary in some cases. A novel bed alarm Caused by acute administration Caused by withdrawal system that may alert the patient out of RBD behav- Selective serotonin-reuptake inhibitors Ethanol iors has been proposed to treat some patients and may Selective serotonin/norepinephrnie-reuptake Benzodiazepines be most useful in patients who also have sleep walking inhibitors or leave the bed with dream enactment behavior.175 Tricyclic antidepressants Barbiturates Monoamine oxidase inhibitors Meprobamate Comorbid obstructive sleep apnea should also be Mirtazapine Pentazocine treated because this may improve the frequency and Cholinesterase inhibitors severity of RBD behaviors. Part of the care of patients Beta blockers with idiopathic RBD also involves consideration for Tramadol Caffeine prognostic counseling concerning the risk of pheno- conversion to a defined neurodegenerative disorder. Reproduced with permission from McGrane I.R, Leung JG, St Louis EK, Given the difficulties in individualizing risk at the cur- Boeve BF. Melatonin therapy for REM sleep behavior disorder: a critical rent time, this remains a controversial subject without review of evidence. Sleep Med 2015;16(1):19-26.184 clear evidence available regarding patients’ preferences for counseling or for the benefits or harms of counsel- representing the variability of topographic onset and ing. The decision to provide counseling should be progression across patients. approached on a highly individual basis and should Given the difficulties in applying Braak’s model to involve the patient in determining how much he or many Lewy body disease presentations, alternative clas- 176 she wishes to know about phenoconversion risk. sifications schemes such as the Unified Staging System The mainstays of pharmacotherapy remain melato- have been proposed to enable classification of the full 177-184 171 nin and clonazepam. Both are modestly effective spectrum of heterogenous Lewy body diseases. The and prevent injury, although melatonin may be more Unified Staging System classifies the Lewy body diseases impactful for injury prevention178 and have fewer side by distribution of pathology, as follows: I. olfactory effects.178 Adverse effects are dose related and include bulb only; IIa, brain stem predominant; IIb, limbic pre- morning sedation, headache, or daytime sleepiness. dominant; III, brain stem and limbic; and IV, neocorti- Melatonin may be particularly desirable for treating cal. Progression through these stages has been patients with symptomatic RBD with comorbid sleep correlated with increasing Lewy-type a-synucleinop- apnea or memory problems, with a recommended athy density scores pathologically and with worsening dose of 3 to 12 mg at bedtime and an average effective 171 clinical signs of cognitive and motor functioning. dose of 6 mg. Melatonin may actually alter the pathol- This staging strategy also might better explain frequent ogy of RBD by increasing REM sleep atonia (and prodromal and progressive nonmotor symptoms and thereby diminishing RSWA).163,180,183,184 Clonazepam 172 signs that precede and accompany PD. 0.25 to 1.0 mg may be given just prior to bedtime. Thus far there has been a relative paucity of studies Clonazepam does not appear to impact the amount of evaluating genetic factors in RBD. One recent study RSWA and likely has its effect through modulating showed a strong association between RBD and gluco- either dreaming or complex motor behaviors at a cerebrosidase (GBA) mutations, both in idiopathic supratentorial level. It has the potential disadvantages RBD and in PD patients. GBA mutation carriers had of exacerbating comorbid obstructive sleep apnea and an OR of 6.24 for RBD, whereas Parkinson’s disease cognitive impairment.181,182 Adverse effects of clonaz- patients had an OR for probable RBD of 3.13, com- epam may include sedation, sexual dysfunction, and 173 pared with controls. In another study, 2 PD-related imbalance. Various second- or third-line alternatives genetic loci, SCARB2 rs6812193 and MAPT that have been advanced for RBD treatment include rs12185268, were associated with RBD, whereas zopiclone (available only in Europe), donepezil, ramel- homozygous carriers of the USP25 rs2823357 single- teon, Yi-Gan San, and, recently, even cannabinoids.177 nucleotide polymorphism showed more rapid progres- Medications that may aggravate or worsen RBD 174 sion to a synucleinopathy. should also be considered. Table 1 lists medications that have been associated with precipitating or wors- Treatment of RBD ening RBD frequency and severity, so these agents should be either discontinued if possible or reduced or Bedroom safety principles important to consider in switched to alternative medications less likely to all parasomnia patients include considering moving worsen RBD whenever feasible. An example of such a the mattress to the floor or placing additional mat- favorable switch may be from a selective serotonin tresses or foam on the neighboring floor to prevent reuptake inhibitor such as fluoxetine or sertraline to injuries from falls, padding sharp bedside furniture, bupropion.

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12. Postuma RB, Gagnon JF, Tuineaig M, et al. Antidepressants and Conclusions REM sleep behavior disorder: isolated side effect or neurodegen- erative signal? Sleep 2013;36(11):1579-1585. RBD is characterized by dream enactment and com- 13. Postuma RB, Gagnon JF, Vendette M, Fantini MI, Massicotte- plex motor behaviors during rapid eye movement Marquez J, Montplaisir J. Quantifying the risk of neurodegenera- tive disease in idiopathic REM sleep behavior disorder. Neurol- (REM) sleep and REM sleep atonia loss (REM sleep ogy 2009;72(15):1296-1300. without atonia) during polysomnography. Whether 14. Postuma RB, Gagnon JF, Vendette M, Montplaisir JY. Markers idiopathic or symptomatic, RBD is highly associated of neurodegeneration in idiopathic rapid eye movement sleep behaviour disorder and Parkinson’s disease. Brain 2009;132(Pt with synucleinopathy neurodegeneration, especially 12):3298-3307. PD, DLB, MSA, and PAF. Prodromal RBD may herald 15. Teman PT, Tippmann-Peikert M, Silber MH, Slocumb NL, Auger synucleinopathies by years to decades prior to the RR. Idiopathic rapid-eye-movement : associations with antidepressants, psychiatric diagnoses, and other factors, in eventual overt motor, cognitive, or autonomic impair- relation to age of onset. Sleep Med 2009;10(1):60-65. ments. Melatonin 3-12 mg and clonazepam 0.5-1.0 mg 16. Wing YK, Li SX, Mok V, et al. Prospective outcome of rapid eye are the treatments of choice for RBD to limit injury movement sleep behaviour disorder: psychiatric disorders as a potential early marker of Parkinson’s disease. J Neurol Neurosurg potential. Further evidence about RBD, its clinical Psychiatry 2012;83(4):470-472. course, and its treatment are greatly needed. RBD as a 17. Boeve BF, Silber MH, Ferman TJ. REM sleep behavior disorder prodromal synucleinopathy represents a defined time in Parkinson’s disease and dementia with Lewy bodies. J Geriatr Psychiatry Neurol 2004;17(3):146-157. when neuroprotective therapies could potentially be 18. Ferman TJ, Boeve BF, Smith GE, et al. Inclusion of RBD applied for the prevention of Parkinson’s disease, improves the diagnostic classification of dementia with Lewy bod- dementia with Lewy bodies, and multiple system atro- ies. Neurology 2011;77(9):875-882. phy. 19. Ferman TJ, Boeve BF, Smith GE, et al. Dementia with Lewy bod- ies may present as dementia and REM sleep behavior disorder without parkinsonism or hallucinations. J Int Neuropsychol Soc Acknowledgments: The project described was supported by the 2002;8(7):907-914. National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through 20. McCarter SJ, St Louis EK, Boeve BF. Mild cognitive impairment Grant Number 1 UL1 RR024150-01. 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