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Alpha-synucleinopathies can be identified in their prodromal phase, raising several ethical issues. In this review, we first provide definitions of prodromal α-synucleinopathies and discuss the importance of distinguishing between prodromes and risk factors. Next, we discuss the implications of a diagnosis of prodromal α-synucleinopathy and considerations regarding prognostic counseling in both clinical and research settings. We review available data on patient preferences regarding disclosure as well as providers' perspectives. We examine the pros and cons of disclosing a diagnosis of prodromal α-synucleinopathy, taking into consideration the differences between clinical and research settings. Asking about willingness to know in clinical and research settings and the shared decision-making process applied to prognostic counseling is discussed. Concerning research settings, ethical aspects regarding clinical trials are addressed. Availability of direct-to-consumer technologies will likely lead to novel contexts requiring prognostic counseling, and future neuroprotective or neuromodulating treatments may require further considerations on the timing, role, and importance of prognostic counseling. Recommendations on how to address ethical gaps should be a priority for patients, medical professional societies, and research workgroups. Ethical issues must be considered as an integral part of the overall clinical and research approach to prodromal synucleinopathies.

Sleep disorders, daytime sleepiness, and autonomic dysfunction are commonly reported among patients with multiple system atrophy and Parkinson disease (PD). We aimed to assess sleep and autonomic function in these patients to evaluate the relationships between sleep disorders, excessive daytime sleepiness, and autonomic function.Twenty patients with multiple system atrophy (n = 7) and PD (n = 13) underwent clinical assessment including questionnaires for autonomic function and sleep. Cardiovascular autonomic function tests and 2-night video-polysomnography were followed by administration of the Multiple Sleep Latency Test. Rapid eye movement sleep without atonia was quantified in the chin, flexor digitorum superficialis, tibial anterior, and sternocleidomastoid muscles.Rapid eye movement sleep behavior disorder was associated with orthostatic hypotension (The relationship of autonomic dysfunction with rapid eye movement sleep without atonia in PD and multiple system atrophy is accounted for by shared brainstem neuropathology and likely identifies patients in a more advanced stage of disease. Excessive daytime sleepiness is found exclusively in PD and may be secondary to levodopa treatment and not related to α-synuclein disease.Eckhardt C, Fanciulli A, Högl B, et al. Analysis of sleep, daytime sleepiness, and autonomic function and multiple system atrophy and Parkinson disease: a prospective study.

Study Objectives To investigate the frequency and characteristics of large muscle group movements (LMMs) during sleep in healthy adults. Methods LMMs were scored following the International Restless Legs Syndrome Study Group criteria in 100 healthy participants aged 19–77 years. A LMM was defined as a temporally overlapping increase in EMG activity and/or the occurrence of movement artifacts in at least two channels. LMM indices and durations in total sleep time (TST), NREM and REM sleep, and association with arousals, awakenings, and/or respiratory events were calculated. Correlations of LMMs indices and durations with sleep architecture, respiratory and motor events, and subjective sleep quality were investigated. Results Median LMMs index in TST was 6.8/h (interquartile range (IQR), 4.5–10.8/h), median mean duration 12.4 s (IQR 10.7–14.4 s). Mean LMMs duration was longer in NREM (median 12.7 s, IQR 11.1–15.2 s) versus REM sleep (median 10.3 s, IQR 8.0–13.5s), p Conclusions This is the first study providing normative data on LMMs frequency in healthy adults. LMMs are a ubiquitous phenomenon often associated with other events. Correlation with arousals and respiratory events suggests a potential clinical significance of LMMs in adults that awaits further investigation.

Background and ObjectivesRecent studies fueled doubts as to whether all currently defined central disorders of hypersomnolence are stable entities, especially narcolepsy type 2 and idiopathic hypersomnia. New reliable biomarkers are needed, and the question arises of whether current diagnostic criteria of hypersomnolence disorders should be reassessed. The main aim of this data-driven observational study was to see whether data-driven algorithms would segregate narcolepsy type 1 and identify more reliable subgrouping of individuals without cataplexy with new clinical biomarkers.MethodsWe used agglomerative hierarchical clustering, an unsupervised machine learning algorithm, to identify distinct hypersomnolence clusters in the large-scale European Narcolepsy Network database. We included 97 variables, covering all aspects of central hypersomnolence disorders such as symptoms, demographics, objective and subjective sleep measures, and laboratory biomarkers. We specifically focused on subgrouping of patients without cataplexy. The number of clusters was chosen to be the minimal number for which patients without cataplexy were put in distinct groups.ResultsWe included 1,078 unmedicated adolescents and adults. Seven clusters were identified, of which 4 clusters included predominantly individuals with cataplexy. The 2 most distinct clusters consisted of 158 and 157 patients, were dominated by those without cataplexy, and among other variables, significantly differed in presence of sleep drunkenness, subjective difficulty awakening, and weekend-week sleep length difference. Patients formally diagnosed as having narcolepsy type 2 and idiopathic hypersomnia were evenly mixed in these 2 clusters.DiscussionUsing a data-driven approach in the largest study on central disorders of hypersomnolence to date, our study identified distinct patient subgroups within the central disorders of hypersomnolence population. Our results contest inclusion of sleep-onset REM periods in diagnostic criteria for people without cataplexy and provide promising new variables for reliable diagnostic categories that better resemble different patient phenotypes. Cluster-guided classification will result in a more solid hypersomnolence classification system that is less vulnerable to instability of single features.

Video-polysomnography (VPSG) and prolonged video-EEG-monitoring (pVEEG-M) are neurophysiological investigation modalities. Depending on indication either is performed, but occasionally patients undergo both (during the same or separate stays). We sought to assess the reasons and potential benefits of dual diagnostic assessments with both modalities.A retrospective chart-review was performed to identify patients who underwent both VPSG and pVEEG-M during the 10 year period between 2007 and 2017. One-hundred-nine patients were identified who had undergone both studies. Patients were grouped according to indication and outcome.One-hundred-nine patients had both, a VPSG and pVEEG-M, in 62 (56.9%) the studies were performed because of separate diagnoses independent from each other. In 47 patients (43.1%) investigation with both modalities was needed to clarify the suspected diagnosis or to refute differential diagnoses. Out of these 47, 11 (10.1% of the whole group) arrived a new final diagnosis whereas in 36 (33%) the primary diagnosis was corroborated with the second modality.In the majority of cases VPSG plus pVEEG-M were indicated to diagnose or monitor different comorbid diseases (e.g. sleep-related breathing disorder and epilepsy). In the other cases, performing both modalities was useful to achieve a higher diagnostic accuracy or to refute differential diagnoses.VPSG and pVEEG-M are neurophysiological investigations which complement each other, especially in case of two different comorbid diseases in a single patient, to rule out differential diagnosis or when a higher diagnostic certainty is seeked.

Differentiation of central disorders of hypersomnolence (DOH) is challenging but important for patient care. This study aimed to investigate whether biomarkers derived from sleep structure evaluated both by manual scoring as well as with artificial intelligence (AI) algorithms allow distinction of patients with different DOH. We included video-polysomnography data of 40 narcolepsy type 1 (NT1), 26 narcolepsy type 2 (NT2), 23 patients with idiopathic hypersomnia (IH) and 54 participants with subjective excessive daytime sleepiness (sEDS). Sleep experts manually scored sleep stages. A previously validated AI algorithm was employed to obtain automatic hypnograms and hypnodensity graphs (where each epoch is represented as a mixture of sleep stage probabilities). One-thousand-three features describing sleep architecture and instability were extracted from manual/automatic hypnogram and hypnodensity graphs. After feature selection, random forest classifiers were trained and tested in a 5-fold-cross-validation scheme to distinguish groups pairwise (NT1-vs-NT2, NT1-vs-IH, …) and single groups from the pooled remaining ones (NT1-vs-rest, NT2-vs-rest,…). The accuracy/F1-score values obtained in the test sets were: 0.74 ± 0.04/0.79 ± 0.05 (NT1-vs-NT2), 0.89 ± 0.09/0.91 ± 0.08 (NT1-vs-IH), 0.93 ± 0.06/0.91 ± 0.07 (NT1-vs-sEDS), 0.88 ± 0.04/0.80 ± 0.07 (NT1-vs-rest), 0.65 ± 0.10/0.70 ± 0.09 (NT2-vs-IH), 0.72 ± 0.12/0.60 ± 0.10 (NT2-vs-sEDS), 0.54 ± 0.19/0.38 ± 0.13 (NT2-vs-rest), 0.57 ± 0.11/0.35 ± 0.18 (IH-vs-sEDS), 0.71 ± 0.08/0.35 ± 0.10 (IH-vs-rest) and 0.76 ± 0.08/0.71 ± 0.13 (sEDS-vs-rest). The results confirm previous findings on sleep instability in patients with NT1 and show that combining manual and automatic AI-based sleep analysis could be useful for better distinction of NT2 from IH, but no precise sleep biomarker of NT2 or IH could be identified. Validation in a larger and multi-centric cohort is needed to confirm these findings.

STUDY OBJECTIVES: The objective of this study was to evaluate interrater reliability between manual sleep stage scoring performed in 2 European sleep centers and automatic sleep stage scoring performed by the previously validated artificial intelligence–based Stanford-STAGES algorithm. METHODS: Full night polysomnographies of 1,066 participants were included. Sleep stages were manually scored in Berlin and Innsbruck sleep centers and automatically scored with the Stanford-STAGES algorithm. For each participant, we compared (1) Innsbruck to Berlin scorings (INN vs BER); (2) Innsbruck to automatic scorings (INN vs AUTO); (3) Berlin to automatic scorings (BER vs AUTO); (4) epochs where scorers from Innsbruck and Berlin had consensus to automatic scoring (CONS vs AUTO); and (5) both Innsbruck and Berlin manual scorings (MAN) to the automatic ones (MAN vs AUTO). Interrater reliability was evaluated with several measures, including overall and sleep stage-specific Cohen’s κ. RESULTS: Overall agreement across participants was substantial for INN vs BER (κ = 0.66 ± 0.13), INN vs AUTO (κ = 0.68 ± 0.14), CONS vs AUTO (κ = 0.73 ± 0.14), and MAN vs AUTO (κ = 0.61 ± 0.14), and moderate for BER vs AUTO (κ = 0.55 ± 0.15). Human scorers had the highest disagreement for N1 sleep (κ(N1) = 0.40 ± 0.16 for INN vs BER). Automatic scoring had lowest agreement with manual scorings for N1 and N3 sleep (κ(N1) = 0.25 ± 0.14 and κ(N3) = 0.42 ± 0.32 for MAN vs AUTO). CONCLUSIONS: Interrater reliability for sleep stage scoring between human scorers was in line with previous findings, and the algorithm achieved an overall substantial agreement with manual scoring. In this cohort, the Stanford-STAGES algorithm showed similar performances to the ones achieved in the original study, suggesting that it is generalizable to new cohorts. Before its integration in clinical practice, future independent studies should further evaluate it in other cohorts. CITATION: Cesari M, Stefani A, Penzel T, et al. Interrater sleep stage scoring reliability between manual scoring from two European sleep centers and automatic scoring performed by the artificial intelligence–based Stanford-STAGES algorithm. J Clin Sleep Med. 2021;17(6):1237–1247.

International audience; Objective: This multilanguage study used simple speech recording and high-end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α-synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early-stage Parkinson disease (PD).Methods: We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5-3.4 years), 149 with PD (mean duration of disease across language groups 1.7-2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12-month follow-up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria.Results: No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12-month follow-up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups.Interpretation: Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021;90:62-75.

Introduction Individuals with idiopathic rapid eye movement sleep behavior disorder (iRBD) are at high risk for a clinical diagnosis of an α‐synucleinopathy (aSN). They could serve as a key population for disease‐modifying trials. Abnormal dopamine transporter (DAT) imaging is a strong candidate biomarker for risk of aSN diagnosis in iRBD. Our primary objective was to identify a quantitative measure of DAT imaging that predicts diagnosis of clinically‐defined aSN in iRBD. Methods The sample included individuals with iRBD, early Parkinson’s Disease (PD), and healthy controls (HC) enrolled in the Parkinson Progression Marker Initiative, a longitudinal, observational, international, multicenter study. The iRBD cohort was enriched with individuals with abnormal DAT binding at baseline. Motor and nonmotor measures were compared across groups. DAT specific binding ratios (SBR) were used to calculate the percent of expected DAT binding for age and sex using normative data from HCs. Receiver operative characteristic analyses identified a baseline DAT binding cutoff that distinguishes iRBD participants diagnosed with an aSN in follow‐up versus those not diagnosed. Results The sample included 38 with iRBD, 205 with PD, and 92 HC who underwent DAT‐SPECT at baseline. Over 4.7 years of mean follow‐up, 14 (36.84%) with iRBD were clinically diagnosed with aSN. Risk of aSN diagnosis was significantly elevated among those with baseline putamen SBR ≤ 48% of that expected for age and sex, relative to those above this cutoff (hazard ratio = 17.8 [95%CI: 3.79–83.3], P = 0.0003). Conclusion We demonstrate the utility of DAT SBR to identify individuals with iRBD with increased short‐term risk of an aSN diagnosis.

STUDY OBJECTIVES: Reduced gray matter volume in the posterior cingulate cortex (PCC) has recently been found in patients with non–rapid eye movement (NREM) parasomnia, providing a neuroanatomical substrate for the arousal state dissociation. It remains unclear whether PCC changes in NREM parasomnias might also play a role in cognitive or affective dysfunction in these patients. The aim of this exploratory study was to investigate neurobehavioral correlates of PCC abnormalities in patients with NREM parasomnia. METHODS: The Reinforcement Sensitivity Theory of Personality Questionnaire and the Stress Coping Questionnaire were used to assess personality and stress coping in 15 patients with NREM parasomnia and 15 age- and sex-matched healthy controls. Patients’ left PCC gray matter volume was quantified with voxel-based morphometry on 3 Tesla T1-weighted magnetic resonance imaging data. RESULTS: In the Reinforcement Sensitivity Theory of Personality Questionnaire, increased trait reactivity of the behavioral inhibition system and goal-drive persistence contributed most to the discrimination of patients and controls. In the Stress Coping Questionnaire, patients showed an increased negative coping trait (ie, anxious rumination) related to an increase in adjusted left PCC volume. CONCLUSIONS: The results suggest subclinical behavioral abnormalities in patients with NREM parasomnias. Such traits might trigger maladaptive emotion regulation processes related to a relative PCC volume increase. The findings encourage further longitudinal studies on this topic, which can provide insights into the causal relations underlying the PCC volume–behavior correlation. Such future studies will have a more direct implication for the clinical management of patients with NREM parasomnias. CITATION: Ramm M, Urbanek A, Failing A, et al. Increased behavioral inhibition trait and negative stress coping in non–rapid eye movement parasomnias. J Clin Sleep Med. 2020;16(10):1737–1744.

Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan–Meier survival analysis. Results: A 5′-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5′ risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3′ of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3′ variant rs356182) had an opposite direction of effect in iRBD compared to PD. Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3′ of SNCA. Several 5′ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584–598.

Background: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy. Objective: To examine the role of PSAP mutations in iRBD. Methods: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p = 0.018). Results: Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more. Conclusion: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.

This scientific commentary refers to ‘Sleep deprivation impairs molecular clearance from the human brain’ by Eide et al. (doi:10.1093/brain/awaa443).

Video-polysomnography (v-PSG) is essential for diagnosing rapid eye movement (REM) sleep behavior disorder (RBD). Although there are current American Academy of Sleep Medicine standards to diagnose RBD, several aspects need to be addressed to achieve harmonization across sleep centers. Prodromal RBD is a stage in which symptoms and signs of evolving RBD are present, but do not yet meet established diagnostic criteria for RBD. However, the boundary between prodromal and definite RBD is still unclear. As a common effort of the Neurophysiology Working Group of the International RBD Study Group, this manuscript addresses the need for comprehensive and unambiguous v-PSG recommendations to diagnose RBD and identify prodromal RBD. These include: (1) standardized v-PSG technical settings; (2) specific considerations for REM sleep scoring; (3) harmonized methods for scoring REM sleep without atonia; (4) consistent methods to analyze video and audio recorded during v-PSGs and to classify movements and vocalizations; (5) clear v-PSG guidelines to diagnose RBD and identify prodromal RBD. Each section follows a common template: The current recommendations and methods are presented, their limitations are outlined, and new recommendations are described. Finally, future directions are presented. These v-PSG recommendations are intended for both practicing clinicians and researchers. Classification and quantification of motor events, RBD episodes, and vocalizations are however intended for research purposes only. These v-PSG guidelines will allow collection of homogeneous data, providing objective v-PSG measures and making future harmonized multicentric studies and clinical trials possible.

Background and ObjectivesAnti-IgLON5 disease is a recently described neurologic disease that shares features of autoimmunity and neurodegeneration. Abnormal movements appear to be frequent and important but have not been characterized and are underreported. We describe the frequency and types of movement disorders in a series of consecutive patients with this disease.MethodsIn this retrospective, observational study, the presence and phenomenology of movement disorders were assessed with a standardized clinical questionnaire. Available videos were centrally reviewed by 3 experts in movement disorders.ResultsSeventy-two patients were included. In 41 (57%), the main reason for initial consultation was difficulty walking along with one or several concurrent movement disorders. At the time of anti-IgLON5 diagnosis, 63 (87%) patients had at least 1 movement disorder with a median of 3 per patient. The most frequent abnormal movements were gait and balance disturbances (52 patients [72%]), chorea (24 [33%]), bradykinesia (20 [28%]), dystonia (19 [26%]), abnormal body postures or rigidity (18 [25%]), and tremor (15 [21%]). Other hyperkinetic movements (myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias) occurred in 26 (36%) patients. The craniofacial region was one of the most frequently affected by multiple concurrent movement disorders (23 patients [32%]) including dystonia (13), myorhythmia (6), chorea (4), or myokymia (4). Considering any body region, the most frequent combination of multiple movement disorders consisted of gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea observed in 31 (43%) patients. In addition to abnormal movements, 87% of patients had sleep alterations, 74% bulbar dysfunction, and 53% cognitive impairment. Fifty-five (76%) patients were treated with immunotherapy, resulting in important and sustained improvement of the movement disorders in only 7 (13%) cases.DiscussionMovement disorders are a frequent and leading cause of initial neurologic consultation in patients with anti-IgLON5 disease. Although multiple types of abnormal movements can occur, the most prevalent are disorders of gait, generalized chorea, and dystonia and other dyskinesias that frequently affect craniofacial muscles. Overall, anti-IgLON5 disease should be considered in patients with multiple movement disorders, particularly if they occur in association with sleep alterations, bulbar dysfunction, or cognitive impairment.

Study objectives To identify a fast and reliable method for rapid eye movement (REM) sleep without atonia (RWA) quantification. Methods We analyzed 36 video-polysomnographies (v-PSGs) of isolated REM sleep behavior disorder (iRBD) patients and 35 controls’ v-PSGs. Patients diagnosed with RBD had: i) RWA, quantified with a reference method, i.e. automatic and artifact-corrected 3-s Sleep Innsbruck Barcelona (SINBAR) index in REM sleep periods (RSPs, i.e. manually selected portions of REM sleep); and ii) v-PSG-documented RBD behaviors. We quantified RWA with other (semi)-automated methods requiring less human intervention than the reference one: the indices proposed by the SINBAR group (the 3-s and 30-s phasic flexor digitorum superficialis (FDS), phasic/”any”/tonic mentalis), and the REM atonia, short and long muscle activity indices (in mentalis/submentalis/FDS muscles). They were calculated in whole REM sleep (i.e. REM sleep scored following international guidelines), in RSPs, with and without manual artifact correction. Area under curves (AUC) discriminating iRBD from controls were computed. Using published cut-offs, the indices’ sensitivity and specificity for iRBD identification were calculated. Apnea-hypopnea index in REM sleep (AHIREM) was considered in the analyses. Results RWA indices from FDS muscles alone had the highest AUCs and all of them had 100% sensitivity. Without manual RSP selection and artifact correction, the “30-s phasic FDS” and the “FDS long muscle activity” had the highest specificity (85%) with AHIREM < 15/h. RWA indices were less reliable when AHIREM≥15/h. Conclusions If AHIREM

Sleep disorders in Parkinson disease have attracted the attention of clinicians and researchers for decades. Recently, major advances in their clinical characterization, polysomnographic description, pathophysiologic understanding, and treatment took place. Parkinson disease encompasses the whole spectrum of sleep medicine: every category of sleep disorder can be observed in these patients. Video polysomnography frequently is indicated, sometimes followed by multiple sleep latency/maintenance of wakefulness tests. Additional studies may include actigraphy, cardiorespiratory polygraphy, and dim light melatonin assessment. Treatment needs to be specific to the underlying sleep disorder and can include medications and nondrug treatments, for example, behavioral therapy and light therapy.

International audience; Background: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD).Objective: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD.Methods: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests.Results: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls.Conclusion: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.

Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving alpha-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal alpha-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest alpha-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of alpha-synucleinopathy patients with isolated RBD might develop.

BACKGROUND AND PURPOSE: Some epilepsy syndromes (sleep-related epilepsies, SREs) have a strong link with sleep. Comorbid sleep disorders are common in patients with SRE and can exert a negative impact on seizure control and quality of life. Our purpose was to define the standard procedures for the diagnostic pathway of patients with possible SRE (scenario 1) and the general management of patients with SRE and comorbidity with sleep disorders (scenario 2).METHODS: The project was conducted under the auspices of the European Academy of Neurology, the European Sleep Research Society and the International League Against Epilepsy Europe. The framework entailed the following phases: conception of the clinical scenarios; literature review; statements regarding the standard procedures. For the literature search a stepwise approach starting from systematic reviews to primary studies was applied. Published studies were identified from the National Library of Medicine's MEDLINE database and Cochrane Library.RESULTS: Scenario 1: Despite a low quality of evidence, recommendations on anamnestic evaluation and tools for capturing the event at home or in the laboratory are provided for specific SREs. Scenario 2: Early diagnosis and treatment of sleep disorders (especially respiratory disorders) in patients with SRE are likely to be beneficial for seizure control.CONCLUSIONS: Definitive procedures for evaluating patients with SRE are lacking. Advice is provided that could be of help for standardizing and improving the diagnostic approach of specific SREs. The importance of identifying and treating specific sleep disorders for the management and outcome of patients with SRE is underlined.

Isolated REM sleep behaviour disorder (RBD) is an early-stage α-synucleinopathy in most, if not all, affected subjects. Detection of pathological α-synuclein in peripheral tissues of patients with isolated RBD may identify those progressing to Parkinson’s disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-time quaking-induced conversion (RT-QuIC) provided evidence of α-synuclein seeding activity in CSF and olfactory mucosa of patients with α-synucleinopathies. The aim of this study was to explore RT-QuIC detection of α-synuclein aggregates in olfactory mucosa of a large cohort of subjects with isolated RBD compared to patients with Parkinson’s disease and control subjects. This cross-sectional case-control study was performed at the Medical University of Innsbruck, Austria, the Hospital Clinic de Barcelona, Spain, and the University of Verona, Italy. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated RBD, 41 matched Parkinson’s disease patients and 59 matched control subjects were analysed by α-synuclein RT-QuIC in a blinded fashion at the University of Verona, Italy. Median age of patients with isolated RBD was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was α-synuclein RT-QuIC positive in 44.4% isolated RBD patients, 46.3% Parkinson’s disease patients and 10.2% control subjects. While the sensitivity for isolated RBD plus Parkinson’s disease versus controls was 45.2%, specificity was high (89.8%). Among isolated RBD patients with positive α-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative α-synuclein RT-QuIC (P

Study Objectives To evaluate interrater reliability for artifact correction in the context of semiautomated quantification of rapid eye movement (REM) sleep without atonia (RWA) in the mentalis and flexor digitorum superficialis (FDS) muscles. Methods We included video-polysomnographies of 14 subjects with apnea–hypopnea index in REM sleep (AHIREM) < 15/h and 11 subjects with AHIREM ≥ 15/h. Eight subjects had isolated REM sleep behavior disorder. A validated algorithm (www.osg.be) automatically scored phasic and “any” EMG activity in the mentalis muscle, and phasic EMG activity in the FDS muscles. Four independent expert scorers performed artifact correction according to the SINBAR (Sleep Innsbruck Barcelona) recommendations. Interrater reliability for artifact correction was computed with B-statistics. The variability across scorers of four RWA indices (phasic mentalis, “any” mentalis, phasic FDS and SINBAR—i.e. “any” mentalis and/or phasic FDS–EMG activity indices) was computed. With Friedman tests, we compared B-statistics obtained for mentalis and FDS muscles, and the variability of the RWA indices. Influence of AHIREM and REM sleep behavior disorder (RBD) diagnosis on the RWA indices variability was evaluated with linear regressions. Results Interrater reliability for artifact correction was higher in the FDS than in the mentalis muscle (p < 0.001). Phasic FDS activity was minimally affected by artifacts. Accordingly, the phasic FDS EMG activity index had the lowest variability across scorers (p < 0.001). Variability across scorers of the RWA indices including the mentalis muscle increased with AHIREM and was independent from RBD diagnosis. Conclusions Due to the consistently found low number of artifacts, phasic FDS activity is a reliable measure of RWA.

Nightmare disorder and recurrent isolated sleep paralysis are rapid eye movement (REM) parasomnias that cause significant distress to those who suffer from them. Nightmare disorder can cause insomnia due to fear of falling asleep through dread of nightmare occurrence. Hyperarousal and impaired fear extinction are involved in nightmare generation, as well as brain areas involved in emotion regulation. Nightmare disorder is particularly frequent in psychiatric disorders and posttraumatic stress disorder. Nonmedication treatment, in particular imagery rehearsal therapy, is especially effective. Isolated sleep paralysis is experienced at least once by up to 40% of the general population, whereas recurrence is less frequent. Isolated sleep paralysis can be accompanied by very intense and vivid hallucinations. Sleep paralysis represents a dissociated state, with persistence of REM atonia into wakefulness. Variations in circadian rhythm genes might be involved in their pathogenesis. Predisposing factors include sleep deprivation, irregular sleep–wake schedules, and jetlag. The most effective therapy consists of avoiding those factors.

This systematic review and meta-analysis evaluated the diagnostic accuracy of screening instruments for restless legs syndrome (RLS) and reports sensitivity, specificity, positive (PPV) and negative predictive values (NPV). Searches for primary studies were conducted in electronic databases. Of the 1541 citations identified, 52 were included in the meta-analysis. The methodological quality of each study was evaluated using QUADAS-2. Only 14 studies assessed the reference standard in all participants or in all screen-positives and a selection of screen-negatives. Bivariate meta-analysis of these 14 studies estimated median sensitivity to be 0.88 (0.72-0.96) and specificity 0.90 (0.84-0.93); based on a population prevalence of 5%, the calculated PPV was 0.31 (0.27-0.34). For all 52 studies, with either full or partial verification of RLS status, we constructed best-case scenario sensitivities and specificities at pre-defined levels of prevalence: across all samples, when prevalence is 5%, the median best-case scenario PPV is 0.48 with significant between-study heterogeneity. No RLS screening instruments can currently be recommended for use without an expert clinical interview in epidemiological studies. For conditions with statistically low prevalence such as RLS, the specificity, not the sensitivity, of a screening instrument determines true prevalence. Therefore, future instruments should maximize specificity. We provide guidelines on RLS ascertainment in epidemiological studies that requires a two-step process with clinical interview following a screening test, and given the poor reporting quality of many RLS epidemiological studies, we include an RLS reporting checklist.

Background and purpose Functional connectivity studies revealed alterations within thalamic, salience, and default mode networks in restless legs syndrome patients. Methods Eighty‐two patients with restless legs syndrome (untreated, n = 30; on dopaminergic medication, n = 42; on alpha‐2‐delta ligands as mono‐ or polytherapy combined with dopaminergic medication, n = 10), and 82 individually age‐ and gender‐matched healthy controls were studied with resting‐state functional magnetic resonance imaging. Connectivity of 12 resting‐state networks was investigated with independent component analysis, and network topology was studied with graph methods among 410 brain regions. Results Patients with restless legs syndrome showed significantly higher connectivity within salience (p = 0.029), executive (p = 0.001), and cerebellar (p = 0.041) networks, as well as significantly lower (p, This resting‐state functional magnetic resonance imaging study applied graph methods, which revealed dopaminergic‐related alterations in a broad array of brain networks in restless legs syndrome (RLS) patients. In particular, lower cerebello‐parietal connectivity was present in untreated RLS, but not in medicated patients. RLS patients treated solely with dopaminergic medication presented with higher thalamo‐frontal connectivity compared to untreated patients.

Increased incidence rates of narcolepsy type-1 (NT1) have been reported worldwide after the 2009–2010 H1N1 influenza pandemic (pH1N1). While some European countries found an association between the NT1 incidence increase and the H1N1 vaccination Pandemrix, reports from Asian countries suggested the H1N1 virus itself to be linked to the increased NT1 incidence. Using robust data-driven modeling approaches, that is, locally estimated scatterplot smoothing methods, we analyzed the number of de novo NT1 cases (n = 508) in the last two decades using the European Narcolepsy Network database. We confirmed the peak of NT1 incidence in 2010, that is, 2.54-fold (95% confidence interval [CI]: [2.11, 3.19]) increase in NT1 onset following 2009–2010 pH1N1. This peak in 2010 was found in both childhood NT1 (2.75-fold increase, 95% CI: [1.95, 4.69]) and adulthood NT1 (2.43-fold increase, 95% CI: [2.05, 2.97]). In addition, we identified a new peak in 2013 that is age-specific for children/adolescents (i.e. 2.09-fold increase, 95% CI: [1.52, 3.32]). Most of these children/adolescents were HLA DQB1*06:02 positive and showed a subacute disease onset consistent with an immune-mediated type of narcolepsy. The new 2013 incidence peak is likely not related to Pandemrix as it was not used after 2010. Our results suggest that the increased NT1 incidence after 2009–2010 pH1N1 is not unique and our study provides an opportunity to develop new hypotheses, for example, considering other (influenza) viruses or epidemiological events to further investigate the pathophysiology of immune-mediated narcolepsy.

Study Objectives The differentiation of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) or its prodromal phase (prodromal RBD) from other disorders with motor activity during sleep is critical for identifying α-synucleinopathy in an early stage. Currently, definite RBD diagnosis requires video polysomnography (vPSG). The aim of this study was to evaluate automated 3D video analysis of leg movements during REM sleep as objective diagnostic tool for iRBD. Methods A total of 122 participants (40 iRBD, 18 prodromal RBD, 64 participants with other disorders with motor activity during sleep) were recruited among patients undergoing vPSG at the Sleep Disorders Unit, Department of Neurology, Medical University of Innsbruck. 3D videos synchronous to vPSG were recorded. Lower limb movements rate, duration, extent, and intensity were computed using a newly developed software. Results The analyzed 3D movement features were significantly increased in subjects with iRBD compared to prodromal RBD and other disorders with motor activity during sleep. Minor leg jerks with a duration < 2 seconds discriminated with the highest accuracy (90.4%) iRBD from other motor activity during sleep. Automatic 3D analysis did not differentiate between prodromal RBD and other disorders with motor activity during sleep. Conclusions Automated 3D video analysis of leg movements during REM sleep is a promising diagnostic tool for identifying subjects with iRBD in a sleep laboratory population and is able to distinguish iRBD from subjects with other motor activities during sleep. For future application as a screening, further studies should investigate usefulness of this tool when no information about sleep stages from vPSG is available and in the home environment.

Background: Individuals with rapid eye movement (REM)-sleep behavior disorder (RBD) are likely to progress to synucleinopathies, mainly Parkinson's disease (PD), dementia with Lewy-bodies (DLB) and multiple system atrophy (MSA). The genetics of RBD only partially overlaps with PD and DLB, and the role of LRRK2 variants in risk for RBD is still not clear.Methods: The full coding sequence, exon-intron boundaries and 5′ and 3′ untranslated regions of LRRK2 were sequenced using targeted next-generation sequencing. A total of 350 RBD patients and 869 controls were sequenced, and regression and burden models were used to examine the association between LRRK2 variants and RBD.Results: No pathogenic mutations that are known to cause PD were identified in RBD patients. The p.N551K-p.R1398H-p.K1423K haplotype was associated with a reduced risk for RBD (OR = 0.66, 95% CI 0.44–0.98, p = 0.0055 for the tagging p.N551K substitution). A common variant, p.S1647T, was nominally associated with risk for RBD (OR = 1.28, 95% CI 1.05–1.56, p = 0.029). Burden analysis identified associations with domains and exons that were derived by the variants of the protective haplotype, and no burden of other rare variants was identified.Conclusions: Carriers of the LRRK2 p.N551K-p.R1398H-p.K1423K haplotype have a reduced risk for developing RBD, yet PD-causing mutations probably have minor or no role in RBD. Additional work is needed to confirm these results and to identify the mechanism associated with reduced risk for RBD.

The objective of the current review was to update the previous evidence-based medicine review of treatments for restless legs syndrome published in 2008. All randomized, controlled trials (level I) with a high quality score published between January 2007 and January 2017 were reviewed. Forty new studies qualified for efficacy review. Pregabalin, gabapentin enacarbil, and oxycodone/naloxone, which did not appear in the previous review, have accrued data to be considered efficacious. Likewise, new data enable the modification of the level of efficacy for rotigotine from likely efficacious to efficacious. Intravenous ferric carboxymaltose and pneumatic compression devices are considered likely efficacious in idiopathic restless legs syndrome. Bupropion and clonidine were reviewed, but the lack of data determined a rating of insufficient evidence for efficacy. The following interventions continue to be considered efficacious as in 2008: levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin. Bromocriptine, oxycodone, carbamazepine, and valproic acid are considered likely efficacious. Oral iron is nonefficacious in iron-sufficient subjects, but its benefit for patients with low peripheral iron status has not been adequately evaluated. Restless legs syndrome augmentation has been identified as a significant long-term treatment complication for pramipexole more than pregabalin and possibly for all dopaminergic agents more than α2δ ligands. Therefore, special monitoring for augmentation is required for all dopaminergic medications as well as tramadol. Other drugs also require special safety monitoring: cabergoline, pergolide, oxycodone, methadone, tramadol, carbamazepine, and valproic acid. Finally, we also highlighted gaps and needs for future clinical research and studies of restless legs syndrome. © 2018 International Parkinson and Movement Disorder Society.

BACKGROUND: MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. OBJECTIVE: To study the role of MAPT variants in rapid eye movement sleep behavior disorder. METHODS: Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT-associated variants and the entire coding sequence of MAPT were analyzed. Age-, sex-, and ethnicity-adjusted analyses were performed to examine the association between MAPT, PD, and rapid eye movement sleep behavior disorder. RESULTS: MAPT-H2 variants were associated with PD (odds ratios: 0.62-0.65; P = 0.010-0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12-2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48-0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder. CONCLUSIONS: Our results confirm the protective effect of the MAPT-H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus. © 2018 International Parkinson and Movement Disorder Society.

Patients with sleep-related motor and behavioral disorders present to a variety of subspecialty clinics (neurology, sleep medicine, respiratory medicine, psychiatry). Diagnosing these disorders can be difficult, and sometimes they have a significant impact on quality of life. Alongside a number of common and well-recognized conditions, several new disease entities have been described in recent years that present with abnormal nocturnal motor phenomena (such as ADCY5-associated disease and anti-IgLON5 disease). Our understanding of the neural basis and prognostic significance of other sleep-related disorders has also grown, particularly rapid eye movement sleep behavior disorder. This review (along with a collection of previously unpublished videos) is intended to aid in the recognition and treatment of these patients. The recent change in terminology from nocturnal frontal lobe epilepsy to sleep-related hypermotor epilepsy is also discussed. © 2018 International Parkinson and Movement Disorder Society.

Das Restless-legs-Syndrom (RLS) ist ein haufiges neurologisches Krankheitsbild. Studien zeigten, dass es mit internistischen und neurologischen Erkrankungen assoziiert auftritt. Anhand dreier assoziierter neurologischer Erkrankungen soll die Bedeutung des RLS fur die neurologische Versorgung beurteilt werden. Mittels systematischer Recherche in PubMed hinsichtlich samtlicher Studien zum RLS in Kombination mit Polyneuropathien (PNP), der Parkinson-Erkrankung (PD) und Multipler Sklerose (MS) erfolgte eine Einordnung nach Methodik und Aufbau in hohe, mittlere oder geringe Studienqualitat. Von 16 Studien zum RLS und MS wurden 10 als „hoch“ eingestuft. Die hohe Assoziationsbreite zwischen 13,3 bis zu 65,1 % aufgrund unterschiedlicher Methodik verhindert trotz der eindeutig erhohten Pravalenz eine zusammenfassende Aussage. Bei 30 Studien zum idiopathischen Parkinson-Syndrom wurden 17 mit hoher Qualitat gefunden. Das RLS tritt mit dem idiopathischen Parkinson-Syndrom nur unter Therapie gehauft auf und hier proportional zur Dauer der dopaminergen Behandlung. Von 24 Studien zu PNP wurden nur 5 als „hoch“ eingestuft, eine erhohte RLS-Pravalenz wurde fur die erworbene PNP nachgewiesen mit heterogener Datenlage fur hereditare Formen. Fur die diskutierten Erkrankungen besteht eine erhohte Pravalenz fur eine Assoziation mit RLS, die moglicherweise pathophysiologisch durch die Erkrankungen bestimmt wird. Aber auch hier liegen moglicherweise genetische Pradispositionen vor, die in Zukunft hoffentlich genauer klassifiziert werden konnen.

Studies on brain iron content in restless legs syndrome (RLS) using magnetic resonance imaging (MRI) are heterogeneous. In this study, we sought to leverage the availability of a large dataset including a range of iron-sensitive MRI techniques to reassess the association between brain iron content and RLS with added statistical power and to compare these results to previous studies.The relaxation rates RIn our cohort, RLS patients had increased RNormal and increased iron content of subcortical brain areas detected in this study is not in line with the hypothesis of reduced brain iron storage, but favors CSF investigations and post mortem studies indicating alteration of brain iron mobilization and homeostasis in RLS.

Objectives The objective of this study was to investigate perceptual decision‐making and reflection impulsivity in drug naïve patients with restless legs syndrome (RLS) and patients with dopaminergic therapy. Methods A total of 35 RLS patients (20 who were drug naïve regarding dopaminergic medication and 15 patients treated with dopaminergic therapy without augmentation or impulse control disorders) were included in this study. We used the Beads task and the Pixel task which assess reflection impulsivity and perceptual decision‐making, respectively. Results were compared to 20 healthy controls. Results Both RLS patient groups gathered less evidence than healthy controls in the Beads task before making a decision (P < 0.001), but patients with dopaminergic treatment gathered less information than drug naïve patients (P = 0.026). Moreover, both patient groups made more choices against the evidence than healthy controls (both P < 0.01), but there was no difference between the two patient groups. In the Pixel task, we found an effect of task difficulty on reaction times with patients and controls responding faster with reduced task difficulty. There was neither an effect of group on reaction times nor an effect of group on error rates. Conclusions Reflection impulsivity is common in RLS patients, regardless whether they are drug naïve or treated with dopaminergic therapy. Thus, RLS patients tend to gather less information compared to healthy controls which could have a negative effect on decision‐making in daily life and should be investigated further.

Few studies have addressed dreaming in patients with sleep apnea. We hypothesized that respiratory events and subsequent oxygen desaturation act as an important physiological trigger and may thus influence dream content in patients with a sleep-related breathing disorder.Seventy-six patients (28 women, mean age 54 years, range 20-82) who underwent polysomnography because of suspected sleep apnea participated in this study. Dream reports and dream questionnaires were collected immediately after first morning awakening, at 5:30 AM, at the sleep laboratory. Dream content analysis with respect to possible respiratory-related content was performed. Patients were stratified into primary snoring, mild, moderate, and severe sleep apnea groups.In 63 patients sleep apnea was diagnosed (mild n = 31, 49.2%, moderate n = 13, 20.6%, severe n = 19, 30.2%), and 13 subjects in whom a sleep-related breathing disorder was not confirmed were included as a control group with primary snoring. There was no significant difference in respiratory-related dream topics between patients and controls. Also, no influence of respiratory parameters measured during polysomnography on dream content was detectable.We failed to detect a difference in dream content between patients with sleep apnea and controls. Further studies are required to determine whether these results indicate that the incorporation of respiratory events into dreams is absent in patients with sleep apnea or represents a bias due to the collection of dream content in the early morning hours.

Objective: To determine the usefulness of dopamine transporter (DAT) imaging to identify idiopathic REM sleep behavior disorder (IRBD) patients at risk for short-term development of clinically-defined synucleinopathy. Methods: Eighty-seven patients with polysomnography-confirmed IRBD underwent 123I-FP-CIT DAT-SPECT. Results were compared with 20 matched controls without RBD who underwent DAT-SPECT. In patients, FP-CIT uptake was considered abnormal when values were two standard deviations below controls' mean uptake. After DAT-SPECT, patients were followed-up during 5.7 ± 2.2 (range, 2.6-9.9) years. Results: Baseline DAT deficit was found in 51 (58.6%) patients. During follow-up 25 (28.7%) subjects developed clinically-defined synucleinopathy (Parkinson disease in 11, dementia with Lewy bodies in 13, multiple system atrophy in one) with mean latency of 3.2 ± 1.9 years from imaging. Kaplan-Meier survival analysis showed increased risk of incident synucleinopathy in patients with abnormal DAT-SPECT than with normal DAT-SPECT (20% vs. 6% at three years, 33% vs. 18% at five years; log rank test, p=0.006). Receiver operating characteristics curve revealed that reduction of FP-CIT uptake in putamen greater than 25% discriminated patients with DAT deficit who developed synucleinopathy from patients with DAT deficit that remained disease-free after three years of follow-up. At 5-year follow-up, DAT-SPECT had 75% sensitivity, 51% specificity, 44% positive predictive value, 80% negative predictive value, and like-hood ratio 1.54 to predict synucleinopathy. Interpretation: DAT-SPECT identifies IRBD patients at short-term risk for synucleinopathy. Decreased FP-CIT putamen uptake greater than 25% predicts synucleinopathy after three years follow-up. These observations may be useful to select candidates for disease-modification trials in IRBD. This article is protected by copyright. All rights reserved.

BACKGROUND: Excessive daytime sleepiness (EDS) is common and disabling in Parkinson’s disease (PD). Predictors of EDS are unclear, and data on biological correlates of EDS in PD are limited. We investigated clinical, imaging and biological variables associated with longitudinal changes in sleepiness in early PD. METHODS: The Parkinson’s Progression Markers Initiative is a prospective cohort study evaluating progression markers in participants with PD who are unmedicated at baseline (n=423) and healthy controls (HC; n=196). EDS was measured with the Epworth Sleepiness Scale (ESS). Clinical, biological and imaging variables were assessed for associations with EDS for up to 3 years. A machine learning approach (random survival forests) was used to investigate baseline predictors of incident EDS. RESULTS: ESS increased in PD from baseline to year 3 (mean±SD 5.8±3.5 to 7.55±4.6, p

Objective:To report the presentation, main syndromes, human leukocyte antigen (HLA) association, and immunoglobulin G (IgG) subclass in the anti-IgLON5 disease: a disorder with parasomnias, sleep apnea, and IgLON5 antibodies.Methods:This was a retrospective clinical analysis of 22 patients. The IgG subclass was determined using reported techniques.Results:Patients' median age was 64 years (range 46–83). Symptoms that led to initial consultation included sleep problems (8 patients; 36%), gait abnormalities (8; 36%), bulbar dysfunction (3; 14%), chorea (2; 9%), and cognitive decline (1; 5%). By the time of diagnosis of the disorder, 4 syndromes were identified: (1) a sleep disorder with parasomnia and sleep breathing difficulty in 8 (36%) patients; (2) a bulbar syndrome including dysphagia, sialorrhea, stridor, or acute respiratory insufficiency in 6 (27%); (3) a syndrome resembling progressive supranuclear palsy (PSP-like) in 5 (23%); and (4) cognitive decline with or without chorea in 3 (14%). All patients eventually developed parasomnia, sleep apnea, insomnia, or excessive daytime sleepiness. HLA-DRB1*10:01 and HLA-DQB1*05:01 were positive in 13/15 (87%) patients; the DRB1*10:01 allele was 36 times more prevalent than in the general population. Among 16 patients with paired serum and CSF samples, 14 had IgLON5 antibodies in both, and 2 only in serum (both had a PSP-like syndrome). Twenty of 21 patients had IgG1 and IgG4 antibodies; the latter predominated in 16.Conclusions:Patients with IgLON5 antibodies develop a characteristic sleep disorder preceded or accompanied by bulbar symptoms, gait abnormalities, oculomotor problems, and, less frequently, cognitive decline. IgG4 subclass antibodies predominate over IgG1; we confirm a strong association with the HLA-DRB1*10:01 allele.

Restless legs syndrome is a frequent neurological disorder with potentially serious and highly distressing treatment complications. The role and potential implications of periodic leg movements during sleep range from being a genetic risk marker for restless legs syndrome to being a cardiovascular risk factor. The diagnosis of restless legs syndrome in patients with daytime movement disorders is challenging and restless legs syndrome needs to be differentiated from other sleep-related movement disorders. This article provides an update on the diagnosis of restless legs syndrome as an independent disorder and the role of periodic leg movements and reviews the association of restless legs syndrome with Parkinson's disease and other movement disorders. © 2017 International Parkinson and Movement Disorder Society.

Background and purpose: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by abnormal behaviours during REM sleep. Several studies showed that iRBD is a prodromal stage of synucleinopathies. Therefore, identifying iRBD in the general population is of utmost importance. In this study, we explore whether the assessment of rest–activity rhythm features can distinguish patients with iRBD from patients with disorders characterized by other pathological motor activity during sleep and healthy controls. Methods: Nineteen patients with video-polysomnographic diagnosis of iRBD, 39 patients with other disorders with motor activity during sleep [19 with restless leg syndrome (RLS) and 20 with untreated sleep apnea syndrome (SAS)] and 16 healthy controls underwent 2-week actigraphy and video-polysomnography, and completed REM sleep behavior disorder screening questionnaires. Non-parametric analyses were applied to assess the rest–activity rhythm features. Results: Patients with iRBD showed lower sleep efficiency, increased estimated wake after sleep onset and increased frequency of prolonged activity bouts compared to those with RLS and controls, while no difference emerged compared with SAS patients. Moreover, patients with iRBD presented increased occurrence of estimated nap in comparison to those with RLS, those with SAS and controls. The I&nbsp

Contains fulltext : 218278.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes. METHODS: We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low-frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth. RESULTS: Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni-corrected significance by the other to show a differential burden of low-frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine-mapping potentially causative domains within these genes. INTERPRETATION: Differential burden with intragenic low-frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2020;87:184-193.