Karin Stiasny-Kolster

Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions

Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.

The REM sleep behavior disorder screening questionnaire--a new diagnostic instrument.

Many patients with assumed idiopathic REM sleep behavior disorder (RBD) may actually represent an early clinical manifestation of an evolving neurodegenerative disorder, such as the α‐synucleinopathies, Parkinsons disease or multiple system atrophy. Early detection of these patients is clinically relevant for long‐term prospective as well as future neuroprotective studies. For this purpose, we validated a 10‐item patient self‐rating questionnaire (maximum total score 13 points) covering the clinical features of RBD. The RBD screening questionnaire (RBDSQ) was applied to 54 patients with polysomnographically confirmed RBD (29 men; mean age 53.7 ± 15.8 years), 160 control subjects (81 men; mean age 50.8 ± 15.5 years) in whom RBD was excluded by history and polysomnography (PSG, control group 1) and 133 unselected healthy subjects (58 men; mean age 46.9 ± 12.3 years; no PSG, control group 2). In most subjects (n = 153) of control group 1, other sleep‐wake disturbances were present. The mean RBDSQ score in the RBD group was 9.5 ± 2.8 points compared with 4.6 ± 3.0 points in control group 1 (P < 0.0001). Considering an RBDSQ score of five points as a positive test result, we found a sensitivity of 0.96 and a specificity of 0.56. The RBDSQ poorly discriminated patients with the most challenging differential diagnoses such as sleepwalking or epilepsy. In control group 2, the mean RBDSQ score (2.02 ± 1.78) was significantly lower than in the RBD group (P < 0.0005), revealing a specificity of 0.92. Due to its high sensitivity, the RBDSQ appears to be particularly useful as a screening tool.

PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome

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, Pnominal/λ corrected = 5.91 × 10−10, odds ratio (OR) = 1.44; rs1975197, Pnominal/λ corrected = 5.81 × 10−9, OR = 1.31). This work identifies PTPRD as the fourth genome-wide significant locus for RLS.

Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial

BACKGROUND Continuous administration of a dopamine agonist could be used to treat patients with restless legs syndrome. Our aim was to investigate the efficacy of transdermal rotigotine in the treatment of idiopathic restless legs syndrome. METHODS In this randomised, double-blind, placebo-controlled trial, 458 patients with moderate-to-severe idiopathic restless legs syndrome (average baseline International Restless Legs Syndrome Study Group severity rating scale [IRLS] sum score of 28.1) were randomly assigned to receive transdermal rotigotine 1 mg over 24 h (n=115), 2 mg over 24 h (n=112), or 3 mg over 24 h (n=114), or to receive placebo (n=117). Study medication was delivered via patches, applied once a day for 6 months. Randomisation was done with a computer-generated randomisation list, stratified by centre. Primary efficacy outcomes were absolute change from baseline to end of maintenance in IRLS sum score and in the clinical global impressions (CGI) item 1 score, assessed by analysis of covariance in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00136045. FINDINGS Efficacy analyses were done on 112 patients in the 1 mg group, 109 in the 2 mg group, 112 in the 3 mg group, and 114 in the placebo group. Mean change in IRLS sum score from baseline at the end of the maintenance phase was -13.7 (SE 0.9) in the 1 mg group, -16.2 (0.9) in the 2 mg group, -16.8 (0.9) in the 3 mg group, and -8.6 (0.9) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Mean change in CGI item 1 score from baseline at the end of the maintenance phase was -2.09 (0.14) in the 1 mg group, -2.41 (0.14) in the 2 mg group, -2.55 (0.14) in the 3 mg group, and -1.34 (0.14) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Skin reactions, mostly mild or moderate, were seen in 145 (43%) of 341 patients who received rotigotine and in two (2%) of 117 who received placebo. Ten patients had serious adverse event that were deemed to be related to rotigotine: elevation of liver enzymes (one patient), worsening of tinnitus (one patient), non-response to anticoagulation (one patient), electrocardiogram changes (one patient), and application-site reactions (six patients). No admissions to hospital were needed for the application-site reactions, and they all resolved within a short time of patch removal without any other therapeutic intervention. The rate of typical dopaminergic side-effects in patients who received rotigotine was low; no signs of augmentation were noted. INTERPRETATION 24 h transdermal delivery of low-dose rotigotine could be used to relieve the night-time and daytime symptoms of restless legs syndrome. FUNDING Schwarz Biosciences.

Genome-Wide Association Study Identifies Novel Restless Legs Syndrome Susceptibility Loci on 2p14 and 16q12.1

Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10−11, OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10−19, OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 5′-end of TOX3 and the adjacent non-coding RNA BC034767.

Patch application of the dopamine agonist rotigotine to patients with moderate to advanced stages of Restless Legs Syndrome: A double-blind, placebo-controlled pilot study

Efficacy and safety of the dopamine agonist rotigotine (RTG) was investigated in patients with moderate to severe idiopathic restless legs syndrome (RLS), including daytime symptoms. Three fixed doses of rotigotine (1.125 mg, 2.25 mg, and 4.5 mg) and placebo were applied by patches (size, 2.5 cm2 per 1.125 mg) in a double‐blind, randomized, parallel‐group, multicenter, 1‐week, proof‐of‐principle trial. The primary efficacy measure was the total score on the International Restless Legs Syndrome Scale (IRLS). Additionally, the RLS‐6 scale, the Clinical Global Impressions (CGI), and a sleep diary were used. Of 68 enrolled patients, 63 (mean age, 58±; 9 years; 64% women) were randomly assigned. RLS severity improved related to dose by 10.5 (1.125 mg RTG/die; P = 0.41), 12.3 (2.25 mg RTG/die; P = 0.18), and 15.7 points (4.5 mg RTG/die; P < 0.01) on the IRLS compared to placebo (8 points). According to the RLS‐6 scales, daytime symptoms significantly improved with all rotigotine doses. The CGI items supported the favorable efficacy of the 4.5‐mg dose. Skin tolerability of the patches and systemic side effects were similar between rotigotine and placebo. This pilot study suggests that continuous delivery of rotigotine by means of a patch may provide an effective and well‐tolerated treatment of RLS symptoms both during night and day.

Efficacy of pramipexole in restless legs syndrome: A six‐week, multicenter, randomized, double‐blind study (effect‐RLS study)

We evaluated the efficacy of pramipexole versus placebo in restless legs syndrome (RLS) for 6 weeks. Overall, 345 patients were randomly assigned in a 1:2 ratio to receive either placebo (n = 115) or pramipexole (n = 230) with a starting dose of 0.125 mg/day. The dose was individually optimized according to the Patient Global Impression (PGI) assessment, up to a maximum of 0.75 mg/day. The primary endpoint consisted of two assessments: the change from baseline in the International RLS Study Group Rating Scale (IRLS) and the proportion of patients with Clinical Global Impressions‐Improvement (CGI‐I) assessments of “much/very much improved” (CGI‐I responders) at week 6. Secondary endpoints included PGI and IRLS responder rates. Patient demographics and baseline characteristics were comparable between treatment groups. At baseline, mean IRLS scores were 24.9 (placebo) and 24.7 (pramipexole), representing severely affected patients. After 6 weeks, adjusted mean reductions (±SE) in IRLS score were 5.7 (±0.9) for placebo (median dose 0.47 mg/day) and 12.3 (±0.6) for pramipexole (median dose 0.35 mg/day; P < 0.0001). CGI‐I responder rates were 32.5% (placebo) and 62.9% (pramipexole) (P < 0.0001). For all secondary endpoints, pramipexole showed superior results. Pramipexole was well tolerated throughout the study.

A single-question screen for rapid eye movement sleep behavior disorder: A multicenter validation study†

Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia that is an important risk factor for Parkinsons disease (PD) and Lewy body dementia. Its prevalence is unknown. One barrier to determining prevalence is that current screening tools are too long for large‐scale epidemiologic surveys. Therefore, we designed the REM Sleep Behavior Disorder Single‐Question Screen (RBD1Q), a screening question for dream enactment with a simple yes/no response.

Effective cabergoline treatment in idiopathic restless legs syndrome

Objective: To assess the efficacy and safety of the dopamine agonist cabergoline (CAB) in patients with restless legs syndrome (RLS). Methods: Patients with moderate to severe RLS were randomized into four groups receiving placebo, 0.5 mg, 1 mg, or 2 mg CAB once daily in a double-blind, placebo-controlled, multicenter dose-finding trial followed by an open long-term extension trial of 47 weeks. Efficacy was assessed with the RLS-6 scales and International RLS Study Group severity scale (IRLS). Results: A total of 85 patients (age 56 ± 10 years, 71% females) were treated. Severity of RLS-6 scale symptoms during the night (the primary endpoint) was markedly improved by all CAB doses compared to placebo (placebo: −1.4 ± 3.1, 0.5 mg CAB: −4.2 ± 3.0 [p = 0.0082], 1.0 mg CAB: −4.0 ± 2.9 [p = 0.0040], 2.0 mg CAB: −4.8 ± 3.7 [p = 0.0026]). Similar results were found for the RLS severity at bedtime and during the day, IRLS, and satisfaction with sleep. A stable, clinically relevant improvement was achieved in all efficacy measures (severity during the night: change between last assessment and baseline: −5.6 ± 2.5, rate of remission: 71.2%) throughout 1 year with a mean CAB dose of 2.2 mg per day. During long-term treatment, 6 of 66 treated patients were affected (n = 2) or possibly affected (n = 4) by mild augmentation. Under CAB therapy up to 1 year, 11 of 85 patients discontinued treatment due to a drug-related adverse event. Conclusions: Cabergoline is an efficacious and well-tolerated option for the treatment of restless legs symptoms during the night and the day.

Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label extension study.

BACKGROUND Safety and efficacy of non-ergot dopamine agonists for the treatment of idiopathic restless legs syndrome have been shown in short-term trials. We did a prospective open-label extension of a 6-week, double-blind randomised trial to assess the safety, tolerability, and efficacy of rotigotine transdermal patch for up to 5 years in patients with restless legs syndrome. METHODS Patients (aged 18-75 years) with moderate-to-severe idiopathic restless legs syndrome were treated with once-daily rotigotine transdermal patch in 33 centres in Austria, Germany, and Spain between July 31, 2003, and April 15, 2009. The dose was titrated in weekly increments (up to 4 weeks) from 0·5 mg/24 h to a maximum of 4 mg/24 h, and was followed by up to 5 years of maintenance at the optimum dose. Primary safety outcomes included occurrence of adverse events and dropouts. Efficacy assessments were secondary and included the International Restless Legs Syndrome study group severity rating scale (IRLS). Augmentation of symptoms was assessed by means of standard diagnostic criteria and was confirmed by an international expert panel. All patients who received at least one dose of study drug were included in assessments. This study is registered with ClinicalTrials.gov, number NCT00498186. FINDINGS 295 patients entered the open-label study, of whom 126 (43%) completed 5 years of follow-up. 169 (57%) patients discontinued treatment, 89 (30%) because of adverse events and 31 (11%) because of lack of efficacy. 70 patients (24%) discontinued during year 1 of maintenance. The most common adverse events were application site reactions, which occurred in 37% (106/290) of patients in year 1, 17% (38/220) of patients in year 2, 14% (27/191) of patients in year 3, and in less than 6% of patients during year 4 (8/159) and year 5 (8/147). 56 patients (19%) discontinued because of application site reactions. Mean rotigotine dose was 2·43 mg/24 h (SD 1·21) after initial titration and 3·09 mg/24 h (1·07) at the end of maintenance. Of 89 patients who discontinued because of adverse events, 28 (31%) were on 4 mg/24 h rotigotine. Mean IRLS score of patients entering the open-label study was 27·8 (SD 5·9) at baseline of the double-blind trial. In patients who completed the maintenance period, mean IRLS score was reduced from a baseline score of 27·7 (SD 6·0) by a mean of 18·7 points (SD 9·5) to a score of 9·0 (SD 9·2) at the end of maintenance. 39% (48/123) of patients who completed the trial were classified as symptom free according to the IRLS. Clinically significant augmentation was recorded in 39 patients (13%), of whom 15 (5%) were receiving a dose of rotigotine within the range approved by the European Medicines Agency (EMA; 1-3 mg/24 h) and 24 (8%) were receiving 4 mg/24 h rotigotine. INTERPRETATION Rotigotine transdermal patch is generally well tolerated after 1 year and provides sustained efficacy for patients with moderate-to-severe restless legs syndrome at a stable dose for up to 5 years. Thus, rotigotine transdermal patch is an appropriate long-term treatment option for moderate-to-severe restless legs syndrome, a disorder that often requires lifelong treatment. FUNDING UCB BioSciences, on behalf of Schwarz Pharma, Ireland.