In den westlichen industrialisierten Ländern (Europa, USA) ist das Restless-Legs-Syndrom (RLS) mit einer Prävalenz von 7–10 % eine der häufigsten neurologischen und schlafmedizinischen Erkrankungen. Diagnosekriterien wurden erstmalig 1995 von der International RLS Study Group festgelegt. Diese wurden im Jahr 2002 in einer Konsensuskonferenz revidiert und im Jahr 2003 publiziert. Die Diagnose wird anamnestisch anhand der klinischen Symptome gestellt. In den letzten Jahren wurden mehrere standardisierte RLS-Fragebögen für klinische Studien und für die tägliche Praxis entwickelt. Mit den speziell für dieses Krankheitsbild entwickelten Fragebögen können die diagnostische Sicherheit, der Schweregrad der Erkrankung, Nebenwirkungen der Behandlung, eine eventuelle Zunahme der Beschwerden unter Behandlung sowie Auswirkungen der RLS-Symptomatik erfasst werden, beispielsweise auf die Lebensqualität.

ZusammenfassungViele Psychopharmaka haben sedierende Nebenwirkungen. Da zahlreiche psychische Erkrankungen mit Ein- und Durchschlafstörungen einhergehen, lassen sich diese Nebenwirkungen teilweise gezielt therapeutisch nutzen. Die sedierende Wirkung von Psychopharmaka kann jedoch auch ein schwerwiegendes Problem in der Behandlung darstellen. Tagesmüdigkeit, vermehrtes Schlafbedürfnis und daraus folgende körperliche Inaktivität können unter anderem zu verstärktem sozialen Rückzug, verstärkter depressiver Symptomatik, Gewichtszunahme, Herz-Kreislauf-Erkrankungen oder Obstruktiver Schlafapnoe führen. In diesem Kapitel wird eine Übersicht über Psychopharmaka gegeben, die häufig zur Sedierung führen.

Die Schlafbezogene Essstörung gehört zu den Parasomnien. Wesentliches Charakteristikum ist das unwillkürliche Auftreten von Essepisoden aus dem NREM-Schlaf heraus. Für die Episoden besteht allenfalls partielle Erinnerung. Während der Episoden sind die meisten Betroffenen schwer erweckbar, andere wiederum sind bei Bewusstsein. Eine Gefährdung der Betroffenen kann in dem unbeabsichtigten Konsum von gesundheitsschädlichen Stoffen wie zum Beispiel Spülmittel bestehen.

L-Tryptophan ist eine essenzielle Aminosäure und biologische Vorstufe des im Gehirn gebildeten Serotonins, dem eine den Schlaf steuernde Wirkung zugeschrieben wird. Da Schlafstörungen mit einem Serotoninmangel in Verbindung gebracht worden sind, soll das Serotonin im Gehirn durch die L-Tryptophangabe substituiert werden.

Zu den am häufigsten benutzten Stimulanzien gehören Koffein, Amphetamine und Amphetaminderivate, wie Metamphetamin, sowie Methylphenidat, Pemolin, das in Deutschland nicht mehr erhältlich ist, und Modafinil. Psychostimulanzien finden in der Behandlung der Narkolepsie oder der Aufmerksamkeitsdefizit-Hyperaktivitätsstörung medizinische Anwendung. Die Entwicklung einer Abhängigkeit kommt am häufigsten bei den Amphetaminderivaten sowie bei Methylphenidat vor. Modafinil scheint ein geringeres Suchtpotenzial als Amphetamine zu besitzen. Stimulanzien führen zur Erhöhung der Vigilanz, Verlängerung der Schlaflatenz und Verkürzung der Schlafdauer. Beim Absetzen der Stimulanzien kommt es meistens zu Rebound-Phänomenen, im akuten Entzug wurde eine Zunahme der Schlafdauer und des REM-Schlafs beschrieben.

Bei gelegentlichem Konsum bewirkt Alkohol eine Verkürzung der Einschlaflatenz, führt aber nach dem Einschlafen zu unruhigem und fragmentiertem Schlaf. Bei regelmäßigem Gebrauch kommt es bezüglich des Einschlafens zu einem Verlust des positiven Effekts infolge einer Toleranzentwicklung. Nach übermäßigem Konsum kann das Absetzen von Alkohol zu ausgeprägten Ein- und Durchschlafstörungen führen. Diese Rebound-Insomnie kann den weiteren Konsum und schließlich die Entwicklung einer körperlichen und psychischen Abhängigkeit fördern.

Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find new entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 individuals with RLS (cases) and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including three on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (rg = 0.96). Locus annotation prioritized druggable genes such as glutamate receptors 1 and 4, and Mendelian randomization indicated RLS as a causal risk factor for diabetes. Machine learning approaches combining genetic and nongenetic information performed best in risk prediction (area under the curve (AUC) = 0.82-0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up and provided evidence that nonlinear interactions are likely relevant to RLS risk prediction.

Restless legs syndrome (RLS) is a common sleep-related movement disorder in populations of European descent and disease risk is strongly influenced by genetic factors. Common variants have been assessed extensively in several genome-wide association studies, but the contribution of rarer genetic variation has not been investigated at this scale. We therefore genotyped a case–control set of 9246 individuals for mainly rare and low frequency exonic variants using the Illumina ExomeChip. However, standard single variant and gene-level association tests were negative. This does not preclude a role of rare variants in RLS, but is likely due to the small sample size and the limited selection of rare genetic variation captured on the array. Therefore, exome or whole genome sequencing should be performed rather than increasing the sample size of ExomeChip studies in order to identify rare risk variants for RLS.

ZUSAMMENFASSUNGDas Restless-legs-Syndrom (RLS) ist eine der häufigsten neurologischen Erkrankungen. Gutachterliche Fragestellungen bei RLS-Patienten nehmen seit den vergangenen Jahren stetig zu. Daher hat die AG Motorik und Schlaf der Deutschen Gesellschaft für Schlafforschung und Schlafmedizin (DGSM) 2006 erstmals Empfehlungen zur Begutachtung und sozialmedizinischen Einschätzung des RLS erarbeitet. Im Folgenden werden die spezifischen Empfehlungen zur Beurteilung des RLS im Rahmen gutachterlicher Verfahren in einer Neubearbeitung vorgestellt. Diese Empfehlungen stellen eine Grundlage zur Vereinheitlichung und Qualitätssicherung in der Begutachtung des RLS dar, sie sollen jedoch nicht in die individuelle Freiheit und Verantwortung des jeweils beauftragten Gutachters eingreifen. Da bisher keine evidenzbasierten Studien über das RLS vorliegen, die die Besonderheiten der gutachterlichen Situation berücksichtigen, sind diese Empfehlungen als Konsensusdokument konzipiert.

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

Background Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. Methods In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p <= 5 x 10(-8)) were tested for replication in an independent GWAS of 30770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. Findings We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1.92, 95% CI 1 85-1.99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). Interpretation Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations.

Introduction: Potential alterations of intrinsic functional connectivity in idiopathic restless legs syndrome (RLS) are to be assumed since RLS is considered a network disorder. Whole-brain-based investigation of intrinsic functional connectivity networks including the sensorimotor systems in patients with RLS was compared with matched healthy controls.Methods: 'Resting-state' functional MRI (1.5T) from 26 patients with RLS and 26 matched controls were analyzed using standardized seed-based analysis procedures. The motor/sensorimotor, sensory thalamic, ventral and dorsal attention, basal ganglia-thalamic, cingulate, and brainstem networks were used for voxel-based group comparisons between RLS patients and controls.Results: Significantly increased connectivities were observed in the sensory thalamic, ventral and dorsal attention, basal ganglia-thalamic, and cingulate networks in RLS patients, whereas no differences could be demonstrated for the motor/sensorimotor and the brainstem system. The pattern of functional connectivity alterations was positively correlated with increasing symptom severity.Conclusions: Abnormally increased regional BOLD synchronization appears to be a key feature of intrinsic brain architecture in RLS. Alterations in cortical and sub-cortical functional networks support the notion that the underlying pathophysiology of RLS is beyond the sensorimotor and the brainstem system and may be also associated with altered attentional control of sensory inputs. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

STUDY OBJECTIVES:Diffusion tensor imaging (DTI) allows the study of white matter microstructure in the central nervous system. The aim of this study was to examine the DTI metrics of the cervical spinal cord and the brainstem up to the midbrain in patients with idiopathic restless legs (RLS) compared to matched healthy controls.METHODS:DTI analysis of the cervical spinal cord and the brainstem up into the midbrain was performed in 25 patients with idiopathic RLS and 25 matched healthy controls. Data analysis in the brain was performed by voxelwise comparison of fractional anisotropy (FA) maps at group level. Cervical spinal cord data analysis was performed by slicewise analysis of averaged FA values in axial slices along the spinal cord.RESULTS:Voxelwise comparison of FA maps in the brainstem showed significant microstructural alterations in two clusters in the midbrain bilaterally. Slicewise comparison of the FA maps in the cervical spinal cord showed a trend for lower FA values at the level of the second and third vertebra area in the patient sample.CONCLUSIONS:The imaging data suggest that significant alterations in the midbrain in RLS can be visualized by DTI and might correlate to a macroscopically subtle process with changes of the tissue microstructure in the corresponding tracts. An additional area of interest is regionally clustered in the upper cervical spinal cord with a tendency toward altered diffusion metrics. These results might be addressed by further studies, e.g., at higher magnetic field strengths.

Objectives Restless legs syndrome (RLS) is one of the most common neurological disorders in Caucasian populations with prevalence rates between 5% and 15%. A recent study conducted in rural northern Tanzania documented a prevalence of only 0.013%. This result requires further investigation of the epidemiology of RLS in Africa, as prevalence rates seem to vary among different ethnicities. Patients/methods We conducted a community-based door-to-door study in an urban environment in eastern Africa (Kinondoni district, Dar es Salaam, Tanzania), where 35.008 people aged 14 years and above were screened for RLS according to the essential diagnostic criteria. Sampling was performed by the method of cluster sampling with probability-proportional-to-size. Results One hundred and sixty-four people screened positively for RLS (0.47%). Ninety-two of those were subject to detailed history taking and physical examination. Four people could finally be diagnosed with RLS, yielding a RLS prevalence rate of 0.037% (95% CI 0.015%; 0.059%) among the people in Kinondoni. Conclusion These results support previous findings that RLS has a very low prevalence in Tanzania despite the fact that only part of the questionnaire-positive RLS people could be interviewed face-to-face, and show that this is independent of whether assessed in a rural or an urban population. According to our results it seems that indigenous Tanzanian people (which are considered representative for the population of Eastern Africa) are less prone to RLS compared to Caucasian populations. Whether the reasons for this discrepancy in prevalence are primarily genetic, environmental or have a cultural/social component remains to be determined. In addition, the study points to a limited application of the essential diagnostic criteria in settings of non-Caucasian populations. Irrespective of ethnic origin, we support the necessity of detailed history and physical examination as performed in the second part of our study to exclude RLS mimics and verify the diagnosis of RLS.