Assessing REM Sleep Behaviour Disorder: From Machine Learning Classification to the Definition of a Continuous Dissociation Index

Objectives: Rapid Eye Movement Sleep Behaviour Disorder (RBD) is regarded as a prodrome of neurodegeneration, with a high conversion rate to α–synucleinopathies such as Parkinson’s Disease (PD). The clinical diagnosis of RBD co–exists with evidence of REM Sleep Without Atonia (RSWA), a parasomnia that features loss of physiological muscular atonia during REM sleep. The objectives of this study are to implement an automatic detection of RSWA from polysomnographic traces, and to propose a continuous index (the Dissociation Index) to assess the level of dissociation between REM sleep stage and atonia. This is performed using Euclidean distance in proper vector spaces. Each subject is assigned a dissociation degree based on their distance from a reference, encompassing healthy subjects and clinically diagnosed RBD patients at the two extremes. Methods: Machine Learning models were employed to perform automatic identification of patients with RSWA through clinical polysomnographic scores, together with variables derived from electromyography. Proper distance metrics are proposed and tested to achieve a dissociation measure. Results: The method proved efficient in classifying RSWA vs. not-RSWA subjects, achieving an overall accuracy, sensitivity and precision of 87%, 93% and 87.5%, respectively. On its part, the Dissociation Index proved to be promising in measuring the impairment level of patients. Conclusions: The proposed method moves a step forward in the direction of automatically identifying REM sleep disorders and evaluating the impairment degree. We believe that this index may be correlated with the patients’ neurodegeneration process; this assumption will undergo a robust clinical validation process involving healthy, RSWA, RBD and PD subjects.

Possible predictors of phenoconversion in isolated REM sleep behaviour disorder: a systematic review and meta-analysis

BackgroundA number of promising biomarkers for predicting imminent α-synucleinopathies have been suggested in isolated rapid eye movement sleep behaviour disorder (iRBD). However, existing evidence is conflicting without quantitative evaluation.MethodsPubMed, Web of Science and ClinicalTrials.gov were searched through June 2021 to identify possible predictors of phenoconversion from iRBD to Parkinson’s disease (PD). The pooled HRs and standardised mean differences (SMDs) with 95% CIs were calculated using fixed-effects or random-effects model.ResultsA total of 123 studies were included in the meta-analysis. Significant motor dysfunction (HR 1.83, 95% CI 1.33 to 2.51, I2=86.8%, p<0.001), constipation (HR 1.52, 95% CI 1.26 to 1.84, I2=8.3%, p=0.365), orthostatic hypotension (HR 1.93, 95% CI 1.05 to 3.53, I2=54.9%, p=0.084), hyposmia (HR 2.78, 95% CI 1.83 to 4.23, I2=23.9%, p=0.255), mild cognitive impairment (HR 2.27, 95% CI 1.58 to 3.27, I2=0%, p=0.681) and abnormal colour vision (SMD −0.34, 95% CI −0.63 to −0.05, I2=45.6%, p=0.087) correlated with susceptibility to PD. The process can also be traced by putaminal dopamine transporter imaging (HR 2.60, 95% CI 1.94 to 3.48, I2=0%, p=0.781) and tonic electromyographic activity (HR 1.50, 95% CI 1.04 to 2.15, I2=70%, p=0.018).ConclusionsThe predictive value of each biomarker was initially highlighted with comprehensive evaluation. Combining specific predictors with high sensitivity is promising for detecting phenoconversion in the prodromal stage. Large-scale and multicentre studies are pivotal to extend our findings.

Proton pump inhibitors associated with rapid eye movement sleep behaviour disorder

We present the case of a 65-year-old woman diagnosed with rapid eye movement sleep behaviour disorder (REMBD) based on typical symptoms and confirmed with an inpatient polysomnogram. She was prescribed clonazepam and later temazepam but continued to have intrusive symptoms. She subsequently recalled that the onset of dream enactment coincided with starting high-dose omeprazole for acid reflux. With this insight, she stopped the omeprazole. Within days, the dream enactment and nocturnal movements subsided. She stopped taking the temazepam and was symptom free for a few months. However, she was started on lansoprazole for recurrent dyspepsia. Once again she experienced violent movements in sleep. This is the first time an association between proton pump inhibitors (PPIs) and REMBD has been reported. PPIs have many effects on the central nervous system and should be considered as a possible provoking factor in people presenting with REMBD.

Efficacy and safety of treatments for REM sleep behaviour disorder in Parkinson’s disease: a systematic review and Bayesian network meta-analysis protocol

IntroductionSleep disorders are the main non-motor characteristics of Parkinson’s disease (PD). The quality of life is significantly impacted by rapid eye movement sleep behaviour disorder (RBD). It is not clearly evidenced in the literature that some medications can reduce the dream activities of patients with PD and RBD and improve sleep quality. And, they have side effects that may increase the severity of this disease. To further understand which medication has better efficacy and fewer adverse effects for patients with PD and RBD, it is necessary to perform a network meta-analysis.Methods and analysisThis protocol is performed accordingly to the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols and the Cochrane Collaboration Handbook.A thorough literature selection will be conducted up to September 2021 using PubMed, Cochrane Library (The Cochrane Database of Systematic Reviews) and Embase. We will not only include randomised controlled trials, but prospective, retrospective cohort, case–control, nested case–control, case–cohort, cross-sectional and case series. We will use the Cochrane Collaboration tool to assess the risk of bias. Pairwise and network meta-analyses will be conducted using the R netmeta package and Stata V.14.0. The relative ranking probability of the best intervention will be estimated using the surface under the cumulative ranking curve. Additionally, sensitivity analysis, subgroup analysis, quality assessment and publication bias analysis will be performed.Ethics and disseminationNo research ethics approval is required for this systematic review, as no confidential patient data will be used. We will disseminate our findings through publication in a peer-reviewed journal and conference presentations, and our review will support development of a BMJ Rapid Recommendations providing contextualised clinical guidance based on this body of evidence.PROSPERO registration numberCRD42020206958.

Current Treatment Options for REM Sleep Behaviour Disorder

The symptomatic treatment of REM sleep behaviour disorder (RBD) is very important to prevent sleep-related falls and/or injuries. Though clonazepam and melatonin are usually considered the first-line symptomatic therapy for RBD, their efficiency has not been proven by randomized clinical trials. The role of dopamine agonists in improving RBD symptoms is controversial, and rivastigmine, memantine, 5-hydroxytryptophan, and the herbal medicine yokukansan have shown some degree of efficacy in short- and medium-term randomized clinical trials involving a low number of patients. The development of potential preventive therapies against the phenoconversion of isolated RBD to synucleinopathies should be another important aim of RBD therapy. The design of long-term, multicentre, randomized, placebo-controlled clinical trials involving a large number of patients diagnosed with isolated RBD with polysomnographic confirmation, directed towards both symptomatic and preventive therapy for RBD, is warranted.

Prevalence and correlates of REM sleep behaviour disorder in patients with major depressive disorder: a two-phase study

ObjectiveTo investigate the prevalence and clinical correlates of video polysomnography (vPSG)-confirmed rapid eye movement sleep behaviour disorder (RBD) in patients with major depressive disorder (MDD).MethodsThis is a clinic-based two-phase epidemiological study. In phase 1, patients with MDD were screened by a validated questionnaire, RBD Questionnaire-Hong Kong (RBDQ-HK). In phase 2, a subsample of both the screen-positive (RBDQ-HK >20) and screen–negative patients with MDD underwent further clinical and sleep assessment (vPSG) to confirm the diagnosis of RBD (MDD+RBD). Poststratification weighting method was used to estimate the prevalence of MDD+RBD. The total likelihood ratio and the probability of prodromal Parkinson’s disease (PD) were calculated from prodromal markers and risk factors, as per the Movement Disorder Society research criteria.ResultsA total of 455 patients with MDD were screened (median age (IQR)=52.66 (15.35) years, 77.58% woman, 43.74% positive). Eighty-one patients underwent vPSG and 12 of them were confirmed MDD+RBD. The prevalence of MDD+RBD was estimated to be 8.77% (95% CI: 4.33% to 16.93%), with possibly male predominance. MDD+RBD were associated with colour vision and olfaction deficit and a higher probability for prodromal PD.ConclusionsAlmost 9% of patients with MDD in the psychiatric outpatient clinic has vPSG-confirmed RBD. Comorbid MDD+RBD may represent a subtype of MDD with underlying α-synucleinopathy neurodegeneration. Systematic screening of RBD symptoms and necessity of vPSG confirmation should be highlighted for capturing this MDD subtype with a view to enhance personalised treatment and future neuroprotection to prevent neurodegeneration.

VMAT2 availability in Parkinson’s disease with probable REM sleep behaviour disorder

REM sleep behaviour disorder (RBD) can be an early non-motor symptom of Parkinson’s disease (PD) with pathology involving mainly the pontine nuclei. Beyond the brainstem, it is unclear if RBD patients comorbid with PD have more affected striatal dopamine denervation compared to PD patients unaffected by RBD (PD-RBD−). To elucidate this, we evaluated the availability of vesicular monoamine transporter 2 (VMAT2), an index of nigrostriatal dopamine innervation, in 15 PD patients with probable RBD (PD-RBD+), 15 PD-RBD−, and 15 age-matched healthy controls (HC) using [11C]DTBZ PET imaging. This technique measured VMAT2 availability within striatal regions of interest (ROI). A mixed effect model was used to compare the radioligand binding of VMAT2 between the three groups for each striatal ROI, while co-varying for sex, cognitive function and depression scores. Multiple regressions were also computed to predict clinical measures from group condition and VMAT2 binding within all ROIs explored. We observed a significant main effect of group condition on VMAT2 availability within the caudate, putamen, ventral striatum, globus pallidus, substantia nigra, and subthalamus. Specifically, our results revealed that PD-RBD+ had lower VMAT2 availability compared to HC in all these regions except for the subthalamus and substantia nigra, while PD-RBD− was significantly lower than HC in all these regions. PD-RBD− showed a negative relationship between motor severity and VMAT2 availability within the left caudate. Our findings reflect that both PD patient subgroups had similar denervation within the nigrostriatal pathway. There were no significant interactions detected between radioligand binding and clinical scores in PD-RBD+. Taken together, VMAT2 and striatal dopamine denervation in general may not be a significant contributor to the pathophysiology of RBD in PD patients. Future studies are encouraged to explore other underlying neural chemistry mechanisms contributing to RBD in PD patients.