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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.

Periodic limb movements during sleep (PLMS) are identified as a common finding in patients with restless legs syndrome (RLS). Although PLMS are observed in more than 80% of RLS patients in Western countries, little is known about Asian RLS patients and no data are available about Japanese patients. This cross-sectional study aimed to investigate ethnic differences in clinical information and polysomnographic variables including PLMS between Austrian and Japanese RLS patient undergoing nocturnal polysomnography (n-PSG). One hundred Austrian and 139 Japanese consecutive patients diagnosed with RLS who underwent n-PSG were included [Austrian 54.5 ± 13.6 years, 40 females (40%); Japanese 50.2 ± 18.9 years, 88 females (63.3%)]. Medical records and n-PSG data were reviewed retrospectively. Epidemiological, clinical and n-PSG variables were compared between the two groups. Rate of patients with PLMS ≥ 5/h and those with PLMS ≥ 15/h were higher in Austrian than in Japanese RLS patients (80.0 vs. 56.1%, P

Analysis of sleep for the diagnosis of sleep disorders such as Type-1 Narcolepsy (T1N) currently requires visual inspection of polysomnography records by trained scoring technicians. Here, we used neural networks in approximately 3,000 normal and abnormal sleep recordings to automate sleep stage scoring, producing a hypnodensity graph—a probability distribution conveying more information than classical hypnograms. Accuracy of sleep stage scoring was validated in 70 subjects assessed by six scorers. The best model performed better than any individual scorer (87% versus consensus). It also reliably scores sleep down to 5 s instead of 30 s scoring epochs. A T1N marker based on unusual sleep stage overlaps achieved a specificity of 96% and a sensitivity of 91%, validated in independent datasets. Addition of HLA-DQB1*06:02 typing increased specificity to 99%. Our method can reduce time spent in sleep clinics and automates T1N diagnosis. It also opens the possibility of diagnosing T1N using home sleep studies., The diagnosis of sleep disorders such as narcolepsy and insomnia currently requires experts to interpret sleep recordings (polysomnography). Here, the authors introduce a neural network analysis method for polysomnography that could reduce time spent in sleep clinics and automate narcolepsy diagnosis.

Die REM-Schlaf-Verhaltensstorung (REM Sleep Behavior Disorder, RBD) ist eine Parasomnie, die durch Ausagieren von Traumen gekennzeichnet ist und durch eine Storung der physiologischen Muskelatonie des REM-Schlafs ermoglicht wird. In den letzten Jahren wurden die diagnostischen Kriterien und die Methoden zur Diagnosestellung aktualisiert. In diesem Ubersichtsartikel werden die derzeitigen Erkenntnisse zur Diagnose und Therapie vorgestellt. Es wurde eine selektive Literaturrecherche durchgefuhrt. Obwohl mehrere Fragebogen zum Screening fur RBD entwickelt wurden, kann eine sichere Diagnose nur anhand einer Polysomnographie gestellt werden. Neue Methoden zur Auswertung der EMG-Aktivitat im REM-Schlaf wurden in den letzten Jahren vorgeschlagen und Cut-off-Werte wurden etabliert. In die International Classification of Sleep Disorders sind die neuesten Cut-off-Werte fur Scoring von EMG-Aktivitat im REM-Schlaf eingegangen. Der von der SINBAR (Sleep INnsbruck BARcelona)-Gruppe vorgeschlagene Cut-off von 27 % Muskelaktivitat im REM-Schlaf ist auch in die ICSD-3 ubernommen worden. Die am besten untersuchten Therapien bei RBD sind Clonazepam und Melatonin.

Die Schlafmedizin umfasst die in der internationalen Klassifikation fur Schlafmedizin zusammengefassten diagnostischen Untergruppen der Insomnien, der schlafbezogenen Atmungsstorungen, Hypersomnien, Parasomnien, zirkadianen Rhythmusstorungen und schlafbezogenen Bewegungsstorungen. Sie hat sich in den letzten Jahren zu einem gut umschriebenen Fachgebiet entwickelt, welches in vielen Landern auch bereits als eigenstandige, oder additionale Zusatzbezeichnung erworben und gefuhrt werden kann. Die Schlafmedizin ist bereits per definitionem fur Neurologen und Psychiater besonders relevant, da Schlaf und Wachheit nicht nur im Gehirn generiert werden, sondern der Schlaf auch dem Gehirn vorwiegend dient. Spezifische Funktionsstorungen des Gehirns konnen spezifische schlafmedizinische Erkrankungsbilder hervorrufen. In diesem Artikel werden fur Neurologen und Psychiater relevante schlafmedizinische Erkrankungen und ausgewahlte neue Publikationen vorgestellt, hauptsachlich zum Thema Restless-Legs-Syndrom (RLS), Narkolepsie und REM-Schlaf-Verhaltensstorung (RBD).

International audience; Rapid eye movement (REM) sleep behavior disorder (RBD) is a prodromal condition for Parkinson's disease (PD) and other synucleinopathies, which often occurs many years before the onset of PD. We analyzed 261 RBD patients and 379 controls for nine PD-associated SNPs and examined their effects, first upon on RBD risk and second, on eventual progression to synucleinopathies in a prospective follow-up in a subset of patients. The SCARB2 rs6812193 (OR = 0.67, 95 % CI = 0.51-0.88, p = 0.004) and the MAPT rs12185268 (OR-0.43, 95 % CI-0.26-0.72, p = 0.001) were associated with RBD in different models. Kaplan-Meier survival analysis in a subset of RBD patients (n = 56), demonstrated that homozygous carriers of the USP25 rs2823357 SNP had progressed to synucleinopathies faster than others (log-rank p = 0.003, Breslow p = 0.005, Tarone-Ware p = 0.004). As a proof-of-concept study, these results suggest that RBD may be associated with at least a subset of PD-associated genes, and demonstrate that combining genetic and prodromal clinical data may help identifying individuals that are either more or less susceptible to develop synucleinopathies. More studies are necessary to replicate these results, and identify more genetic factors affecting progression from RBD to synucleinopathies.

The prevalence of REM sleep behavior disorder (RBD) has been estimated to be around 0.5 % in the general population, while in patients with Parkinson’s disease the frequency ranges between 40 and 46 %. Current criteria for the diagnosis of RBD do not specify a clear quantitative cut-off for muscle activity, that is, how much EMG activity during REM sleep is normal, and at what point does it become abnormal? It is important that RBD be correctly diagnosed as (1) RBD can be the first manifestation of a neurodegenerative disease, (2) it can involve serious injury to the patient and/or bed partner, and (3) because it is a treatable disorder. In this review we seek to improve this situation and to move toward a more objective diagnosis of RBD. The time has come to move from a qualitative diagnosis of RBD to a quantitative diagnosis. Increased tonic and phasic muscle activity can and should be quantified. Cut-offs have now been established: the combination of “any” EMG activity in the mentalis muscle with both phasic flexor digitorum superficialis muscles yielded a cut-off of 32 % (AUC 0.998) for patients with idiopathic RBD and with Parkinson RBD. Such cut-offs help make the diagnosis of RBD more objective and avoid false positive diagnosis.

While rapid eye movement (REM) sleep behaviour disorder (RBD) in animals has been associated with stuctural brain stem lesions since the very beginning of RBD research, human brain imaging of RBD did not reveal specific results at first. It was later that single cases of symptomatic RBD due to inflammatory, neoplastic or ischemic lesions were described. Only recently, systematic voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) studies for RBD have been performed. The SINBAR Sleep Innsbruck Barcelona Group investigated 26 idiopathic RBD (iRBD) patients and 14 age-matched controls with both statistical parametric mapping (SPM) and DTI. Substantial decreases of fractional anisotropy in midbrain tegmentum and rostral pons were found, and mean diffusivity was increased in midbrain and pontine reticular formation. In addition VBM revealed an increase of gray matter densities in both hippocampi of iRBD patients. The Marburg group performed DTI in 12 iRBD and 12 controls and reported microstructural changes in the brainstem, substantia nigra, olfactory region, left temporal lobe, coronal radiata and the right visual stream. A recent study performed VBM in 20 iRBD and compared the findings to 18 age-matched controls. This study found significant gray matter volume reduction in the anterior lobes of the cerebellum, the pontine tegmentum and the left parahippocampal gyrus. In summary, the areas highlighted from these studies are in line with areas regulating features of REM sleep, and in part with evolving synucleinopathies.

Restless legs syndrome (RLS) is a common multifactorial disease. Some genetic risk factors have been identified. RLS susceptibility also has been related to iron. We therefore asked whether known iron-related genes are candidates for association with RLS and, vice versa, whether known RLS-associated loci influence iron parameters in serum. RLS/control samples (n=954/1814 in the discovery step, 735/736 in replication 1, and 736/735 in replication 2) were tested for association with SNPs located within 4 Mb intervals surrounding each gene from a list of 111 iron-related genes using a discovery threshold of P=5 × 10(-4). Two population cohorts (KORA F3 and F4 with together n=3447) were tested for association of six known RLS loci with iron, ferritin, transferrin, transferrin-saturation, and soluble transferrin receptor. Results were negative. None of the candidate SNPs at the iron-related gene loci was confirmed significantly. An intronic SNP, rs2576036, of KATNAL2 at 18q21.1 was significant in the first (P=0.00085) but not in the second replication step (joint nominal P-value=0.044). Especially, rs1800652 (C282Y) in the HFE gene did not associate with RLS. Moreover, SNPs at the known RLS loci did not significantly affect serum iron parameters in the KORA cohorts. In conclusion, the correlation between RLS and iron parameters in serum may be weaker than assumed. Moreover, in a general power analysis, we show that genetic effects are diluted if they are transmitted via an intermediate trait to an end-phenotype. Sample size formulas are provided for small effect sizes.European Journal of Human Genetics advance online publication, 29 August 2012; doi:10.1038/ejhg.2012.193.

Schlafstorungen und Schlafmangel sind in unserer modernen Gesellschaft weit verbreitet. Zwar hat das mediale Interesse an der Funktion und Bedeutung des Schlafs betrachtlich zugenommen, doch stellt sich die Frage, wie sehr der Stellenwert gesunden und ausreichenden Schlafs im Allgemeinen und das Schlafverhalten im Einzelnen dadurch beeinflusst bzw. verandert wird. In einer fur die osterreichische Bevolkerung reprasentativen Umfrage (n=1000, 478 Manner, 522 Frauen) wurden neben allgemeinen Schlafmerkmalen auch die subjektive Schlafqualitat, Schlafgewohnheiten und Hinweise auf Schlafstorungen in Zusammenhang mit demographischen und gesundheitlichen Aspekten untersucht. Rund 76% der Stichprobe gaben eine durchschnittliche Schlafdauer zwischen 6 und 8 h und eine normale Einschlaflatenz an. 90% waren mit ihrem Schlaf subjektiv zufrieden. 54% schlafen am Wochenende langer; Mittagsschlaf halten 23%, wobei hier der Anteil an Pensionisten relativ hoch ist. 87% schlafen immer im selben Bett, 31% schlafen standig allein, 46% immer mit Partner. Haufige Schlafstorungen gaben 18% an, wobei mehr als 70% keinerlei Masnahmen dagegen setzten. Von der Subpopulation, die aktiv ihre Schlafstorung behandelt, greifen immerhin 45% zu Schlafmitteln. Niedrigere Bildung und geringere berufliche Qualifikation sind mit einer verminderten Schlafqualitat assoziiert, ebenso Ubergewicht und Mangel an sportlicher/korperlicher Aktivitat. Trotz reichhaltigen Medienangebots nutzen die Osterreicher an erster Stelle Arzte und Apotheken als Informationsquelle uber Schlaf und Schlafstorungen. Diese deskriptive Darstellung der Schlafgewohnheiten und -storungen der Osterreicher bietet einen ersten Einblick in die Komplexitat von Schlaf und den Einfluss von potenziellen Storfaktoren.

Hintergrund Die Pravalenz von erhohter Tagesschlafrigkeit wurde in vielen Landern untersucht, wobei sich die Ergebnisse je nach gewahlter Definition und Methodik stark unterschieden. Die vorliegende Untersuchung wurde durchgefuhrt, um die Haufigkeit von erhohter Tagesschlafrigkeit in der osterreichischen Bevolkerung und den Zusammenhang mit verschiedenen schlaf- und gesundheitsbezogenen Faktoren zu erheben.

The European Restless Legs Syndrome (RLS) Study Group performed the first multi-center, long-term study systematically evaluating RLS augmentation under levodopa treatment. This prospective, open-label 6-month study was conducted in six European countries and included 65 patients (85% treatment naive) with idiopathic RLS. Levodopa was flexibly up-titrated to a maximum dose of 600 mg/day. Presence of augmentation was diagnosed independently by two international experts using established criteria. In addition to the augmentation severity rating scale (ASRS), changes in RLS severity (International RLS severity rating scale (IRLS), clinical global impression (CGI)) were analyzed. Sixty patients provided evaluable data, 35 completed the trial and 25 dropped out. Augmentation occurred in 60% (36/60) of patients, causing 11.7% (7/60) to drop out. Median time to occurrence of augmentation was 71 days. The mean maximum dose of levodopa was 311 mg/day (SD: 105). Patients with augmentation compared to those without were significantly more likely to be on higher doses of levodopa (≥300 mg, 83 vs. 54%, P = 0.03) and to show less improvement of symptom severity (IRLS, P = 0.039). Augmentation was common with levodopa, but could be tolerated by most patients during this 6-month trial. Patients should be followed over longer periods to determine if dropout rates increase with time. peerReviewed

Gutachterliche Fragestellungen bei Patienten mit einem Restless-Legs-Syndrom (RLS) nehmen stetig zu. Darum hat die “AG Motorik und Schlaf” der DGSM erstmals Empfehlungen zur Begutachtung und sozialmedizinischen Einschatzung des RLS erarbeitet. Im Folgenden werden die spezifischen Empfehlungen zur Beurteilung des RLS im Rahmen gutachterlicher Verfahren zusammengefasst (aus [5]). Diese Konsensusleitlinie soll eine Grundlage zur Vereinheitlichung und Qualitatssicherung in der Begutachtung des RLS darstellen und nicht in individuelle Begutachtungen eingreifen.

To investigate the effect of the dopamine D2 and D1 receptor agonist cabergoline on sleep, periodic leg movements (PLMs) in sleep, and early morning motor performance in patients with Parkinson's disease (PD). It was hypothesized that cabergoline had long-lasting beneficial effects on sleep and PLMs in sleep in patients with PD, after a single evening intake. A total of 15 patients with idiopathic PD underwent two nights of polysomnography and motor tests (UPDRS, tapping test) before and after 6-8 weeks of treatment with cabergoline (dosage: 3-6 mg/day). Additionally, patients completed a subjective sleep visual analog scale (VAS) before and during cabergoline treatment. Compared to baseline values, treatment with cabergoline did not change sleep efficiency or the amount of stage 1 and stage 2 sleep. The number of awakenings (22.4+/-10.1 vs 32.5+/-13.3, p

Im Rahmen des Morbus Parkinson treten Schlafstorungen auf, welche in erster Linie auf den Dopaminmangel selbst, die nachtliche Akinese, Pharmakotherapie sowie Begleitfaktoren wie Alter und Depression zuruckgefuhrt werden. Diese Storungen betreffen sowohl die Mikro- und Makrostruktur des NonREM- und REM-Schlafes als auch Motorik, respiratorische und autonome Funktionen. Seit kurzem finden auch Tagesschlafrigkeit sowie die Frage der Wechselwirkungen zwischen Schlaf- und Wachmotorik beim M. Parkinson vermehrt Beachtung. Die Erkennung und Behandlung von Schlafstorungen ist nicht nur wegen des assoziierten Selbst- und Fremdgefahrdungspotenzials (z. B. bei REM sleep behavior disorder, Tagesschlafrigkeit) von herausragender Bedeutung, sondern auch fur die Lebensqualitat des Patienten und seiner Angehorigen. Aufgrund der ausergewohnlichen Haufigkeit (ca. 70%) von Schlafstorungen beim M. Parkinson und diesen u. U. weitreichenden Konsequenzen sollte eine systematische Schlafanamnese und ggf. die spezifische Therapie bei jedem Parkinson-Patienten integraler Bestandteil der Behandlung sein.

We identified association of restless legs syndrome (RLS) with PTPRD at 9p23-24 in 2,458 affected individuals and 4,749 controls from Germany, Austria, Czechia and Canada. Two independent SNPs in the 5' UTR of splice variants expressed predominantly in the central nervous system showed highly significant P values (rs4626664, P(nominal/lambda corrected) = 5.91 x 10(-10), odds ratio (OR) = 1.44; rs1975197, P(nominal/lambda corrected) = 5.81 x 10(-9), OR = 1.31). This work identifies PTPRD as the fourth genome-wide significant locus for RLS.

Luigi Ferini-Strambi • Wolfgang Oertel • Yves Dauvilliers • Ronald B. Postuma • Sara Marelli • Alex Iranzo • Isabelle Arnulf • Birgit Hogl • Raffaele Manni • Tomoyuki Miyamoto • Maria-Livia Fantini • Monica Puligheddu • Poul Jennum • Karel Sonka • Joan Santamaria • Marco Zucconi • Paola M. V. Rancoita • Smeranda Leu-Semenescu • Birgit Frauscher • Michele Terzaghi • Masayuki Miyamoto • Marcus Unger • Karin Stiasny-Kolster • Alex Desautels • Christina Wolfson • Amelie Pelletier • Jacques Montplaisir

Background Rotigotine is a unique dopamine agonist with activity across D1 through D5 receptors as well as select adrenergic and serotonergic sites. This study reports the 2-year follow-up safety and efficacy data of an ongoing open-label multicenter extension study (NCT00498186) of transdermal rotigotine in patients with moderate to severe restless legs syndrome (RLS). Methods Patients received a once-daily patch application of an individually optimized dose of rotigotine between 0.5 mg/24 h to 4 mg/24 h. Safety assessments included adverse events (AEs) and efficacy was measured by the International RLS Study Group Severity Rating Scale (IRLS), RLS-6 scales and Clinical Global Impression (CGI). Quality of life (QoL) was measured by QoL-RLS. Results Of 310 patients who completed a 6-week placebo-controlled trial (SP709), 295 (mean age 58 ± 10 years, 66% females) were included in the open-label trial SP710. 64.7% (190/295 patients) completed the 2-year follow-up; 29 patients discontinued during the second year. Mean daily rotigotine dose after 2 years was 2.93 ± 1.14 mg/24 h with a 2.9% dose increase from year 1. Rotigotine was generally well tolerated. The rate of typical dopaminergic side effects, nausea and fatigue, was low (0.9% and 2.3%, respectively) during the second year; application site reactions were frequent but lower than in year 1 (16.4% vs. 34.5%). The IRLS total score improved from baseline of SP709 (27.8 ± 5.9) by 17.2 ± 9.2 in year 2 completers. Similar improvements were observed in RLS-6 scales, CGI scores and QoL-RLS. The responder rate in the CGI change item 2 ("much" and "very much" improved) was 95% after year 2. Conclusions Transdermal rotigotine is an efficacious and well-tolerated long-term treatment option for patients with moderate to severe RLS with a high retention rate during 2 years of therapy. Trial registration NCT00498186

Dear Editor, We read with interest the study by Tatjana Cronlein and co-workers [1] and congratulate the authors on the work. Their study adds nicely to the existing evidence that comorbidity is important in insomnia and should be taken into account while evaluating these patients [2–4]. In a recent study, which the authors unfortunately fail to acknowledge in their list of references, our group has investigated with polysomnography 20 patients with otherwise unexplained insomnia [5] who were compared to healthy controls and patients with idiopathic restless legs syndrome (RLS). These 20 CNS-active drug-free insomniac patients in our study had been attentively selected from 153 consecutive insomnia patients who fulfilled general criteria for insomnia according to ICSD 2 (similar to DSM 4 criteria for insomnia), after exclusion of RLS and other sleep, neurological, or psychiatric comorbidity, by both thorough history taking and polysomnographic evaluation. Interestingly, in that study, 60% of patients had periodic leg movements during sleep (PLMS) ≥10/h and fulfilled periodicity and time distribution through the night criteria similar or identical to patients with RLS [6]. It must be recognized that the exact contribution of PLMS in patients without RLS to insomnia is incompletely understood or controversially discussed [7, 8], and that the contribution of PLMS to cardiovascular risk is still hypothetical [9]. In addition, the diagnostic concept of periodic limb movement disorder, which has been developed to describe patients with insomnia and PLMS (among other criteria), is still strongly debated, as well as the question if PLMS should be treated in the absence of RLS (e.g., [10]). However, since PLMS can be found with a certain frequency also in normal controls aged above 40 years [11], the lack of a control group precludes Cronlein et al. [1] from proving a causative role of PLMS in their insomniac patients. Moreover, several of the patients with PLMS alone in their group were under antidepressant therapy with substances known to be able to induce PLMS [12]. Correctly, the authors reduced the dosage of these drugs in these patients. However, it is well known that insomnia and depression constitute a tight association. This casts additional doubts on the real role of PLMS in insomnia in these patients in whom they might have appeared only as a consequence of their therapy. Nevertheless, we agree with the authors that polysomnography is useful in patients with otherwise unexplained insomnia. Thus the authors are in line not only with our own study [5], but also with many others [2–4].

Nat. Genet. 43, 66–71 (2011); published online 19 December 2010; corrected after print 22 September 2011 In the version of this article initially published, the percentage reduction of P2RY11 expression in CD8+ T lymphocytes was incorrectly given as 339%, when it should have been 72%. The percentagewas not given for NK cells and should have been 70%.

Nat. Genet. 41, 708–711 (2009); published online 3 May 2009; corrected after print 26 June 2009 In the version of this article initially published, Seung-Chul Hong was incorrectly listed as Sheng Seung-Chul Hong. The error has been corrected in the HTML and PDF versions of the article.