Management of REM sleep behavior disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment

Free AccessReview ArticlesManagement of REM sleep behavior disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment Michael Howell, MD, Alon Y. Avidan, MD, MPH, Nancy Foldvary-Schaefer, DO, MS, Roneil G. Malkani, MD, Emmanuel H. During, MD, Joshua P. Roland, MD, Stuart J. McCarter, MD, Rochelle S. Zak, MD, Gerard Carandang, MS, Uzma Kazmi, MPH, Kannan Ramar, MD, MBBS Michael Howell, MD Address correspondence to: Michael Howell, MD, Department of Neurology, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455; Email: E-mail Address: [email protected] Department of Neurology, University of Minnesota, Minneapolis, Minnesota Search for more papers by this author , Alon Y. Avidan, MD, MPH David Geffen School of Medicine at UCLA, Los Angeles, California Search for more papers by this author , Nancy Foldvary-Schaefer, DO, MS Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio Search for more papers by this author , Roneil G. Malkani, MD Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois Search for more papers by this author , Emmanuel H. During, MD Department of Neurology, Division of Movement Disorders, Icahn School of Medicine at Mount Sinai, New York, New York Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, New York Search for more papers by this author , Joshua P. Roland, MD Thirty Madison, New York, New York Department of Pulmonology, Critical Care, and Sleep Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California Search for more papers by this author , Stuart J. McCarter, MD Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota Search for more papers by this author , Rochelle S. Zak, MD Sleep Disorders Center, University of California, San Francisco, San Francisco, California Search for more papers by this author , Gerard Carandang, MS American Academy of Sleep Medicine, Darien, Illinois Search for more papers by this author , Uzma Kazmi, MPH American Academy of Sleep Medicine, Darien, Illinois Search for more papers by this author , Kannan Ramar, MD, MBBS Division of Pulmonary and Critical Care Medicine, Center for Sleep Medicine, Mayo Clinic, Rochester, Minnesota Search for more papers by this author Published Online:April 1, 2023https://doi.org/10.5664/jcsm.10426Cited by:1SectionsAbstractEpubPDFSupplemental Material ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutABSTRACTThis systematic review provides supporting evidence for a clinical practice guideline for the management of rapid eye movement (REM) sleep behavior disorder in adults and children. The American Academy of Sleep Medicine commissioned a task force of 7 experts in sleep medicine. A systematic review was conducted to identify randomized controlled trials and observational studies that addressed interventions for the management of REM sleep behavior disorder in adults and children. Statistical analyses were performed to determine the clinical significance of critical and important outcomes. Finally, the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence for making recommendations. The literature search identified 4,690 studies; 148 studies provided data suitable for statistical analyses; evidence for 45 interventions is presented. The task force provided a detailed summary of the evidence assessing the certainty of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations.Citation:Howell M, Avidan AY, Foldvary-Schaefer N, et al. Management of REM sleep behavior disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2023;19(4):769–810.INTRODUCTIONThis systematic review is intended to provide supporting evidence for the accompanying clinical practice guideline1 on the management of rapid eye movement (REM) sleep behavior disorder and update the evidence review conducted for the previously published American Academy of Sleep Medicine (AASM) Best Practice Guide.2BACKGROUNDREM sleep is characterized by vivid dream mentation in the setting of near-complete skeletal muscle paralysis, sparing the diaphragm and extraocular muscles through brainstem-induced skeletal muscle atonia. REM sleep facilitates the maturation of brain circuits, especially during early development, and REM sleep motor paralysis confers motor quiescence despite the activation of emotional salient, complex, and often violent, memory traces.3,4REM paralysis is the end result of an intricate and vulnerable pathway, primarily localized in the dorsal pons and medulla, with descending inhibitory tone on the spinal motoneurons. When pathology disrupts these brainstem pathways, descending motor signals are no longer blocked and patients enact dreams, resulting in REM sleep behavior disorder (RBD). RBD behaviors, consistent with the spectrum of dream mentation, range from simple hand gestures to aggressive and violent dream enactment semiology with episodes that may consist of shouting, thrashing, punching, and kicking. These more-pronounced behaviors can result in injury to the patient or bed partner.3,4RBD is a parasomnia characterized by increased muscle tone in REM sleep accompanied by abnormal limb movements, vocalizations, and dreams. Loss of skeletal atonia normally present in REM sleep permits an individual with RBD to talk and move when dreaming. Vocalizations, jerks, and complex motor behaviors occur during REM sleep, often associated with REM sleep dream content. The clinical presentation ranges from unnoticed sleep disruption to severe injuries to patients/bed partners.RBD is common, with a 1% prevalence affecting approximately 80 million people worldwide, and is most common (5%) among older adults.5,6 Injuries result when patients with vigorous limb movements hit a wall, window, object, or bed partner when reacting toward an imaginary threat. Falls out of bed are common, as dreamers will suddenly arise and leap out from bed.Complex motor behaviors during sleep are not unique to RBD and must be differentiated from non-REM (NREM) parasomnias, such as sleepwalking and sleep terrors.3,4 In addition, arousals out of REM sleep from sleep-disordered breathing can result in dream enactment (pseudo-RBD) and periodic limb movements can also mimic RBD. Finally, sleep-related epilepsy can manifest with recurrent, abnormal complex nocturnal motor activity and behaviors. As REM sleep occurs predominantly during the second half of the night, RBD events usually arise in the final hours of the sleep period, often immediately prior to patients awakening for the day. REM sleep is characterized by a low threshold for arousal, accounting for the observation that patients with RBD typically orient quickly after an episode and are usually able to provide a detailed and elaborate narrative of the dream content that correlates with the witnessed behaviors. For example, a patient may be described by a bed partner as shouting and kicking vigorously. When awoken the patient may say they were trying to stomp on a poisonous snake that was trying to bite them. This is in contrast to disorders of arousal that emanate out of deep NREM sleep, where patients are often confused, difficult to arouse, and amnestic to the event. Paradoxically, the disruption of REM motor tone does not appear to culminate in clear daytime dysfunction, except for traumatic injuries, as patients with RBD typically do not describe excessive daytime sleepiness or insomnia. Rather, insomnia or daytime sleepiness is reported by bed partners, whose sleep is often fragmented and unrefreshing as they may lay awake anxious about their safety and for their partner’s well-being.RBD is most often caused by alpha-synuclein neurodegeneration, characterized by abnormal accumulation of aggregates of alpha-synuclein protein in neurons. Early in the course of these disorders, the pathology may originate in the enteric plexus of the gut (leading to constipation) where, over several years, it slowly ascends rostrally through the vagus nerve and later through the brainstem to the dopamine-producing basal ganglia and, ultimately, the cerebral cortex. Lurching neuron to neuron, alpha-synuclein pathology relentlessly spreads through REM sleep generators in the pons, disabling the protective mechanism promoting REM skeletal muscle atonia.3,7Thus, RBD most often represents a prodromal syndrome, manifesting as dream enactment prior to the phenoconversion into dementia with Lewy bodies (DLB), Parkinson’s disease (PD), or other neurodegenerative disorder. Most people with RBD phenoconvert slowly over years and sometimes decades as patients slowly evolve from subtle symptoms of anosmia (loss of sense of smell), constipation, orthostasis, and dream enactment to motor symptoms and cognitive dysfunction, once the alpha-synuclein pathology reaches the rostral brainstem and cerebral cortex. Ultimately, most people with RBD develop a neurodegenerative disorder. A recent investigation of over 1,200 individuals with RBD indicated a 74% phenoconversion rate to a neurodegenerative disorder within 12 years.8While neurodegeneration is the most common etiology, RBD may be encountered in the setting of other neurological disturbances. These include orexin deficiency in the setting of narcolepsy type 1; discrete pontine lesions impacting the REM generators such as stroke, demyelinating disease in multiple sclerosis, and brainstem tumors; neurogenetic disorders such as spinocerebellar ataxia type 3; as well as paraneoplastic neurological disorders and autoimmune diseases.3,4 Among patients < 50 years of age, antidepressants are the most common etiology of RBD, particularly the serotonergic antidepressant medications resulting in serotonergic RBD (5-hydroxytryptamine or 5-HT RBD).9,10 Serotonin inhibits REM sleep and it has been assumed that, by augmenting serotonergic activity, these exogenous agents induce RBD. However, recent studies have found other subtle neurodegenerative findings such as constipation and hyposmia among patients with medication-associated RBD.11 This important finding suggests that increased serotonergic activity does not induce RBD per se but more likely unmasks it early in a patient who would otherwise develop a synucleinopathy later in life.RBD classification is based on presumed etiology. When occurring in the absence of an identifiable neurological syndrome such as DLB, PD, or narcolepsy, dream enactment with polysomnography (PSG) confirmation of REM sleep without atonia (RWA) has been termed idiopathic RBD. Idiopathic RBD has historically been used until recently, despite the high likelihood that patients have alpha-synuclein degeneration of REM brainstem circuits and will later develop more clinically fulminant pathology. As idiopathic implies an uncertain etiology, a more accurate term currently used among RBD investigators is isolated RBD, when RBD occurs in the absence of a clear neurological syndrome.12,13 To be consistent with the evolving nomenclature, we will use the term isolated RBD but recognize that, for many of the studies reviewed, isolated RBD referred to idiopathic RBD.Patients whose RBD dream enactment occurs in the setting of a neurodegenerative disorder, narcolepsy, or less commonly, with focal brainstem lesions, such as strokes, have been classified as having secondary (and occasionally symptomatic) RBD due to a medical condition.4 Onset of RBD with temporal association or exacerbation with the initiation of a medication is classified as drug-induced RBD, despite the previously mentioned concerns that these patients, in particular those with 5-HT RBD, appear to have an increased risk of later neurodegeneration.RBD presents a unique window of opportunity by which one may alter the natural history and prevent the course to phenoconversion. Ongoing investigations are establishing protocols for the development of clinical trials to test neuroprotective therapies.14,15 As no therapy has yet been clearly demonstrated to alter disease course, this guideline is specifically focused on symptomatic management of disruptive dream enactment behavior (DEB), aimed at minimizing the frequency and severity of injurious nocturnal behaviors, and impact on quality of life. It is hoped that, prior to the next Clinical Practice Guideline, innovative disease-modifying therapies will emerge with the prospect of delaying, preventing, or reversing parkinsonian and other neurodegenerative disorders.DEBs can be dramatic, life threatening, and often terrifying to patients and bed partners, highlighting the critical need to establish a diagnosis of RBD and provide definitive management. Since its original description in 1986, investigators have attempted to identify effective RBD treatments.16 Early therapies included benzodiazepines, antidepressants, and antiseizure agents. The majority of early treatment data were case series or small, uncontrolled clinical trials. In 2010, the AASM published a Best Practice Guide for the treatment of RBD and concluded that optimizing safety intervention was supported by the highest recommended evidence (“level A”). This was followed by suggested evidence for clonazepam and melatonin (level B), with lower quality data.2 However, in the last 10 years a number of studies, including placebo-controlled investigations, have contributed substantially to the existing RBD literature, catalyzing the AASM to assemble a task force (TF) to augment the RBD management armamentarium for clinicians and their patients.In addition to reducing the frequency and severity of disruptive dream enactment, sleep clinicians are encouraged to disclose to patients with RBD the risk of impending neurodegenerative syndromes. Patient autonomy includes respect for a patient’s right to know, or if they so choose, the right not to know, their risk of future disease. Because of this, the TF elected to also explore best practices regarding the disclosure of high-risk syndromes among patients with RBD.METHODSExpert task forceThe AASM commissioned a TF of sleep medicine clinicians with expertise in RBD. The TF was required to disclose all potential conflicts of interest (COIs), per the AASM’s COI policy, prior to being appointed to the TF and throughout the research and writing of these documents. In accordance with the AASM’s COI policy, TF members with a level 1 conflict were not allowed to participate. TF members with a level 2 conflict were required to recuse themselves from any related discussion or writing responsibilities. All relevant COIs are listed in the Disclosures section.Patient, Intervention, Comparison, and Outcomes (PICO) questionsPatient, Intervention, Comparison, and Outcomes (PICO) questions were developed based on a review of the existing AASM Best Practice Guide on the treatment of RBD and an examination of systematic reviews, meta-analyses, and guidelines published for adult and pediatric populations. The AASM Board of Directors approved the final list of PICO questions presented in Table 1 before the literature searches were performed.Table 1 PICO questions.1Population: Adult* and pediatric patients diagnosed with isolated RBDIntervention: Clonazepam, melatonin, paroxetine, pramipexole, ramelteon, rivastigmine, sodium oxybate, yi-gan san, adrenocorticotropic hormone, agomelatine, bed alarm, carbamazepine, clomipramine, desipramine, donepezil, escitalopram, haloperidol, lamotrigine, phenobarbital, quetiapine, sertraline, triazolam, vortioxetine, zopicloneComparison: Placebo; other intervention; no treatmentOutcome: Frequency of significant bed partner sleep disruption; frequency of dream enactment episodes; frequency and/or intensity of unpleasant dreams and nightmares; change in REM motor tone (tonic and/or phasic); quality of life; sleep quality; daytime motor function; treatment-related worsening in sedation or cognitive impairment**; treatment-related worsening in gait stability**; treatment-related worsening in symptoms of depression or anxiety**2Population: Adult and pediatric patients diagnosed with secondary RBD due to medical condition (including neurological diseases, dementia, stroke, sleep disorders, DLB, MSA, Parkinson’s disease, narcolepsy)Intervention: Cannabidiol, carbidopa-levodopa, clonazepam, deep brain stimulation, donepezil, IV immunoglobulin, light therapy, melatonin, memantine, pramipexole, ramelteon, rivastigmine, rotigotine, sodium oxybate, yi-gan san, bed alarm, buspirone, carbamazepine, clozapine, desipramine, haloperidol, hypnotherapy, levetiracetam, levodopa, methotrexate, nelotanserin, olanzapine, plasma exchange, PAP therapy, quetiapine, temazepam, tiapride, triazolam, zonisamide, zopicloneComparison: Placebo; other intervention; no treatmentOutcome: Frequency of significant bed partner sleep disruption; frequency of dream enactment episodes; frequency and/or intensity of unpleasant dreams and nightmares; change in REM motor tone (tonic and/or phasic); quality of life; sleep quality; daytime motor function; treatment-related worsening in sedation or cognitive impairment**; treatment-related worsening in gait stability**; treatment-related worsening in symptoms of depression or anxiety**3Population: Adult and pediatric patients diagnosed with drug-induced RBD (antidepressants such as paroxetine, fluoxetine, imipramine, venlafaxine, mirtazapine; beta-blockers)Intervention: Clonazepam, drug discontinuationComparison: Placebo, other intervention, or no treatmentOutcome: Frequency of significant bed partner sleep disruption; frequency of dream enactment episodes; frequency and/or intensity of unpleasant dreams and nightmares; change in REM motor tone (tonic and/or phasic); quality of life; sleep quality; daytime motor function; treatment-related worsening in sedation or cognitive impairment**; treatment-related worsening in gait stability**; treatment-related worsening in symptoms of depression or anxiety***This PICO population includes the following special categories: adults with OSA on CPAP, adults with untreated OSA & risk of falls, adults with depression and RBD, pregnancy, adults with PTSD + RBD, patients with RBD in risky occupations (law enforcement shift workers), parasomnia overlap, status dissociates. **These outcomes are considered side-effects of the interventions. CPAP = continuous positive airway pressure, DLB = dementia with Lewy bodies, IV = intravenous, MSA = multiple systems atrophy, OSA = obstructive sleep apnea, PAP = positive airway pressure, PICO = Population, Intervention, Comparison, Outcome, PTSD = post-traumatic stress disorder, RBD = rapid eye movement sleep behavior disorder, REM = rapid eye movement.In addition, the TF identified a list of patient-oriented, clinically relevant outcomes to determine whether the various interventions, compared with no treatment, should be recommended for clinical practice. Input from stakeholders (patients, caregivers, and health care providers) was also taken into consideration. The TF rated the relative importance of each outcome to determine which outcomes were critical for decision making. A summary of the outcomes by PICO is presented in Table 2.Table 2 Outcomes by PICO question.OutcomesAdult and Pediatric Patient PopulationsIsolated RBDSecondary RBD due to Medical ConditionDrug-induced RBDFrequency of significant bed partner sleep disruption√*√*√*Frequency and/or intensity of dream enactment episodes√*√*√*Treatment-related worsening in sedation or cognitive impairment√*√*√*Treatment-related worsening in gait stability√*√*√*Treatment-related worsening in symptoms of depression or anxiety√*√*√*Frequency and/or intensity of unpleasant dreams and nightmares√√√Change in REM motor tone—tonic and/or phasic√√√Quality of life√√√Sleep quality√√√Daytime motor function√√√*Critical outcomes. PICO = Population, Intervention, Comparison, Outcome, RBD = rapid eye movement sleep behavior disorder, REM = rapid eye movement.The TF set a clinical significance threshold (CST) for tools of interest for each outcome to determine whether the mean changes in the outcomes assessed were clinically significant based on their clinical expertise, other AASM guidelines, and available literature. The CST was defined as the minimum level of improvement in the outcome of interest that would be considered clinically important to clinicians and patients. A summary of the CSTs for the clinical outcome measures is presented in Table 3. Where no clearly established threshold values could be determined, CSTs were determined based on consensus in conjunction with TF literature review of commonly used thresholds for the various tools, gathering input from other sleep specialists, clinical judgment, and experience.Table 3 Summary of clinical significance thresholds for critical and important outcome measures.Outcome ToolClinical Significance Threshold*Expected ChangeFrequency of significant bed partner sleep disruption CGI-I1.5 points OR65% of patients reporting changeDecreaseImprovementFrequency and/or intensity of dream enactment episodes Simple motor behaviors (PSG—during REM sleep)33% (10% for placebo studies) OR50% of patients reporting changeDecreaseImprovement Complex motor behaviors (PSG—during REM sleep)33% (10% for placebo studies) OR50% of patients reporting changeDecreaseImprovement CGI-I1.5 points OR65% of patients reporting changeDecreaseImprovement RBDQ (Factor 2 score)10% OR50% of patients reporting changeDecreaseImprovementTreatment-related worsening in sedation or cognitive impairment ESS2 points OR10% of patients reporting changeIncreaseDecline KESS2 points OR10% of patients reporting changeIncreaseDecline MMSE3 points OR10% of patients reporting changeDecreaseDecline Letter Fluency10% OR33% of patients reporting changeDecreaseDecline MFQ1 point OR10% of patients reporting changeIncreaseDeclineTreatment-related worsening in gait stability10% of patients reporting changeDeclineTreatment-related worsening in symptoms of depression or anxiety NPI4 points OR20% of patients reporting changeIncreaseDeclineFrequency and/or intensity of unpleasant dreams and nightmares RBD frequency33% (10% for placebo studies) OR50% of patients reporting changeDecreaseImprovement RBD intensity33% (10% for placebo studies) OR50% of patients reporting changeDecreaseImprovement RBD episodes per week or month33% (10% for placebo studies) OR50% of patients reporting changeDecreaseImprovement RBDQ (Factor 1 score)10% OR50% of patients reporting changeDecreaseImprovementChange in REM motor tone—tonic and/or phasic Phasic EMG%10% OR50% of patients with change in REM motor toneDecreaseImprovement Tonic EMG%10% OR50% of patients with change in REM motor toneDecreaseImprovement REM Atonia Index10% OR50% of patients with change in REM motor toneIncreaseImprovementQuality of life SF-36 (physical score)10% OR50% of patients reporting changeIncreaseImprovement SF-36 (mental score)10% OR40% of patients reporting changeIncreaseImprovement UPDRS (total score)4.1 points OR50% of patients reporting changeDecreaseImprovement Schwab and England20% OR60% of patients reporting changeIncreaseImprovement CGI-I1.5 points OR50% of patients reporting changeDecreaseImprovementSleep quality RBDQ (total score)10% OR50% of patients reporting changeDecreaseImprovement PSQI3 points OR50% of patients reporting changeDecreaseImprovementDaytime motor function UPDRS (Part III score)2.3 points OR50% of patients reporting changeDecreaseImprovement*The clinical significance thresholds apply to the comparison of post-treatment effects between intervention and placebo as well as a pre-post treatment difference. CGI-I = Clinical Global Impressions–Improvement Scale, EMG = electromyography, ESS = Epworth Sleepiness Scale, KESS = Korean Epworth Sleepiness Scale, MFQ = Mayo Fluctuation Questionnaire, MMSE = Mini-Mental State Examination, NPI = Neuro-psychiatric Inventory, PSQI = Pittsburgh Sleep Quality Index, RBD = rapid eye movement sleep behavior disorder, RBDQ = RBD Questionnaire (includes Korean, Japanese, and Hong Kong versions), REM = rapid eye movement, RWA = REM sleep without atonia, SF-36 = Short-Form Questionnaire (36-item), UPDRS = Unified Parkinson’s Disease Rating Scale.Literature searches, evidence review, and data extractionThe TF performed an extensive review of the scientific literature to retrieve articles that addressed the PICO questions. Separate literature searches were performed by the AASM research staff for each PICO question using the and Embase databases. Articles that met inclusion criteria but did not report outcomes of interest were rejected from the final evidence base. The key terms, search limits, and inclusion/exclusion criteria specified by the TF are detailed in the supplemental material. Randomized controlled trials (RCTs) and observational studies that were cited in the prior AASM practice parameters were included for data analysis only if they met the current inclusion criteria.The initial search of using the systematic review methods filter was performed in December 2018. A second literature search of Embase was performed in June 2019. A third literature search of and Embase was performed in February 2020 to identify studies that were published since the second literature search to update the body of evidence for the review. The TF reviewed previously published guidelines, systematic reviews, and meta-analyses to pearl, or “spot check,” for references that may have been missed during the prior searches. The TF identified a total of 4,690 articles (including 107 studies identified through pearling/spot checking) that were screened for inclusion/exclusion in the guideline.The TF set inclusion and exclusion criteria, which are presented in the supplemental material and summarized in Figure 1. All abstracts were reviewed for inclusion/exclusion criteria by 2 TF members. Any discrepancies between the reviewers were discussed and resolved by the Chair. A total of 148 studies were determined to be suitable for meta-analysis and/or grading.Figure 1: Evidence-base flow diagram.RBD = rapid eye movement sleep behavior disorder.Download FigureStatistical and meta-analysis and interpretation of clinical significanceMeta-analyses were performed on outcomes of interest, when possible, for each PICO question. Comparisons of various interventions to no treatment were performed using data obtained from RCTs. The pooled results for each continuous outcome measure are expressed as the mean difference between the intervention and comparator. Data from baseline and last-treatment time points from nonrandomized trials were also compared. These are presented in a table format in the supplemental material (Tables S1–S186). Data from crossover trials were treated as parallel groups. Some studies had data presented in the form of median and interquartile range. These were converted into data expressed as means and standard deviation.17,18 If outcome data were not presented in the format necessary for statistical analysis (ie, mean, standard deviation, and sample size), then the data were reported as a percentage of patients reporting an improvement (or worsening) in a particular outcome, and presented qualitatively in a table format in the supplemental material. Some studies combined patient groups, such as individuals with isolated RBD along with those who had RBD due to a medical disorder, most commonly PD. Care was taken to identify and separate individuals and individual treatment responses across these groups.Meta-analyses and pre-post analyses were performed using Review Manager 5.3 software (The Cochrane Collaboration, London, United Kingdom) by pooling data across studies for each outcome measure. All analyses were performed using a random-effects model. Interpretation of clinical significance for the outcomes of interest was conducted by comparing the mean difference in effect of each treatment approach with the CST (see Table 3). There was insufficient evidence to perform meta-analyses for some outcome measures. For some interventions, none of the accepted publications provided data that could be used for statistical analysis.For adverse events, all data presented in the accepted papers were used for statistical and meta-analysis. Whenever possible, meta-analyses were performed by pooling data across studies for each outcome and adverse event.Patient representativesTwo patient stakeholders who provided input on the PICO outcomes were invited by the TF to provide their feedback on patient values and preferences for the interventions. These patient representatives were well-informed patient advocates who were previously involved in RBD clinical studies and research workgroups. Prior to their involvement, the 2 patient representatives were educated on the AASM’s guideline development process and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) concepts.GRADE assessment for developing recommendationsThe evidence was assessed according to the GRADE process for the purposes of making clinical practice recommendations. The TF decided to only apply the GRADE process for those interventions that were Food and Drug Administration (FDA)–approved and/or available for use in the United States and had supporting evidence from a total of at least 3 patients for a particular PICO (isolated RBD, secondary RBD due to medical condition, or drug-induced RBD). If an intervention did not have the minimum of 3 patients or was not FDA-approved and/or available for use in the United States, the