Restless Legs Syndrome Study Research Articles

Prospective study of restless legs syndrome in a blood donors’ sample

Background and objectivesBlood donation is suggested to increase the risk of restless legs syndrome (RLS). This study aims to assess the prevalence of RLS in Spanish blood donors and determined its potential correlation with iron metabolism parameters. Materials and methodsProspective cohort study of 129 blood donors (54.3% men, 39.44 years ± 11.0) that underwent a physical examination, blood analysis (hemoglobin, ferritin, transferrin saturation index and soluble transferrin receptor) and a RLS screening questionnaire followed by a prospective follow-up study including a clinical phone interview. A multivariate logistic regression model was performed to examine the association between RLS and other variables. ResultsEighty-four (65.1%) participants were repeat blood donors (mean of 2.11 donations/year) at inclusion and 61 (47.4%) at follow-up (mean of 2.09 donations/year). Non-anemic iron deficiency (ferritin < 50 µg/l) was high in women p < 0.001 and in repeat donors (p = 0.003). The prevalence of RLS was 14.1% at inclusion increasing prospectively (19.5%; p = 0.065). On multivariate analysis, gender was the only variable significantly associated with a RLS diagnosis, being higher in women (OR 5.1; 95% CI 1.71–15.3; p = 0.003). ConclusionsDespite the high prevalence of non-anemic iron deficiency there was no association between ferritin, soluble transferrin receptor concentration values and RLS diagnosis. Gender was associated with RLS diagnosis regardless of other variables.

Clinical features, polysomnography, and genetics association study of restless legs syndrome in clinic based Chinese patients: A multicenter observational study

Study objectivesTo systemically describe the clinical features, polysomnography (PSG) finding, laboratory tests and single-nucleotide polymorphisms (SNPs) in a clinic based Chinese primary restless legs syndrome (RLS) population. MethodsThis observational study, conducted from January 2020 to October 2021 across 22 sleep labs in China, recruited 771 patients diagnosed with RLS following the 2014 RLSSG criteria. Clinical data, PSG testing, and laboratory examination and SNPs of patients with RLS were collected. A total of 32 SNPs in 24 loci were replicated using the Asian Screening Array chip, employing data from the Han Chinese Genomes Initiative as controls. ResultsIn this study with 771 RLS patients, 645 had primary RLS, and 617 has DNA available for SNP study. Among the 645 primary RLS, 59.7% were women. 33% had a family history of RLS, with stronger familial influence in early-onset cases. Clinical evaluations showed 10.4% had discomfort in body parts other than legs. PSG showed that 57.1% of RLS patients had periodic leg movement index (PLMI) of >5/h and 39.1% had PLMI >15/h, respectively; 73.8% of RLS patients had an Apnea-Hypopnea Index (AHI) > 5/h, and 45.3% had an AHI >15/h. The laboratory examinations revealed serum ferritin levels <75 ng/ml in 31.6%, and transferrin saturation (TSAT) of <45% in 88.7% of RLS patients. Seven new SNPs in 5 genes showed a significant allelic association with Chinese primary RLS, with one previously reported (BTBD9) and four new findings (TOX3, PRMT6, DCDC2C, NOS1). ConclusionsChinese RLS patients has specific characters in many aspects. A high family history with RLS not only indicates strong genetic influence, but also reminds us to consider the familial effect in the epidemiological study. Newly developed sequencing technique with large samples remains to be done.

Clinical features, polysomnography, and genetics association study of Restless Legs syndrome in a Chinese population: a multicenter observational study

Clinical features, polysomnography, and genetics association study of Restless Legs syndrome in a Chinese population: a multicenter observational study

Genetic Association Studies in Restless Legs Syndrome: Risk Variants & Ethnic Differences.

Genetic association studies have not produced consistent results in restless legs syndrome (RLS). To conduct a systematic review on genetic association studies in RLS to highlight the common gene variants and ethnic differences. We conducted Pubmed, Embase, and Cochrane search using terms "Genetic association studies" and "restless legs syndrome" for candidate gene-based studies. Out of the initial 43 studies, 18 case control studies (from 2012 to 2022) were included. Thirteen studies including 10794 Caucasian subjects (4984 RLS cases and 5810 controls) and five studies involving 2009 Asian subjects (796 RLS cases and 1213 controls) were tabulated and analyzed. In addition, three Genome-Wide Association Studies (GWAS) in Asians and Europeans/Caucasians were included for comparisons. In the Asian population, gene variants in BST1, SNCA Rep1, IL1B, BTBD9, and MAP2K5/SKOR1 increased the risk of RLS (odds ratio range 1.2-2.8). In Caucasian populations, examples of variants that were associated with an increased risk of RLS (odds ratio range 1.1-1.9) include those in GABRR3 TOX3, ADH1B, HMOX1, GLO1, DCDC2C, BTBD9, SKOR1, and SETBP1. Based on the meta-analysis of GWAS studies, the rs9390170 variant in UTRN gene was identified to be a novel genetic marker for RLS in Asian cohorts, whereas rs113851554 in MEIS1 gene was a strong genetic factor among the >20 identified gene variants for RLS in Caucasian populations. Our systemic review demonstrates that multiple genetic variants modulate risk of RLS in Caucasians (such as MEIS1 BTBD9, MAP2K5) and in Asians (such as BTBD9, MAP2K5, and UTRN).

Chronic inflammation markers and cytokine-specific autoantibodies in Danish blood donors with restless legs syndrome

Restless Legs Syndrome (RLS) is a neurological sensorimotor disorder negatively impacting sufferers’ quality of sleep and health-related quality of life. The pathophysiology of RLS is poorly understood and research focusing on the link between RLS and inflammation has been limited. Our study aimed to investigate whether chronic inflammation markers C-reactive protein (CRP) and soluble urokinase-type plasminogen activator receptor (suPAR), as well plasma levels of five different cytokine-specific autoantibodies (c-aAb), i.e. modulators of inflammation, associate with RLS in otherwise healthy individuals. CRP, suPAR and c-aAb were measured in plasma samples of participants from the Danish Blood Donor Study in 2010. Returning donors between 2015 and 2018 completed the validated Cambridge-Hopkins RLS-questionnaire for RLS assessment, resulting in datasets with RLS assessment and values for CRP (N = 3564), suPAR (N = 2546) and c-aAb (N = 1478). We performed logistic regression models using the CRP, suPAR or c-aAb as the independent variable and RLS status as the dependent variable, adjusted for appropriate covariates. Our study indicates that a high concentration of CRP is associated with RLS, while an increased probability of experiencing frequent RLS symptoms in those with an elevated plasma suPAR level appears to be mediated through lifestyle factors. We additionally report that a high titer of autoantibodies specific against the cytokine interferon-alpha was associated with RLS. Our results support the existence of links between systemic inflammation and RLS, though further RLS studies on CRP, suPAR and c-aAb in larger cohorts are warranted to confirm our findings and further reveal the hitherto underexplored links between RLS and inflammation.

The relationship between chronic kidney disease and restless legs syndrome and its effective factors. A case-control study.

I Restless legs syndrome (RLS), is a neurological disorder in which persons feel uncomfortable, especially at night, in the limbs and needs to move their legs. This condition worsens with rest. The aim of this study was to evaluate the frequency of restless legs syndrome in patients with renal insufficiency. In this case-control study, 180 patients with chronic kidney disease (90 hemodialysis patients and 90 non-dialysis patients) who referred to the nephrology clinic and dialysis ward of Imam Reza Hospital in Tabriz, were investigated. Data collection was done through a questionnaire form which was based on the criteria of the International Association for the Study of Restless Legs Syndrome. Among 180 patients in studied, 92 (51.7%) cases were male and 88 (48.3%) cases were female. The mean age of patients was 60.4 ± 17.2. So, 90 non-dialysis patients and 90 hemodialysis patients were evaluated. Of all the hemodialysis patients studied, 33 (37%) patients had restless legs syndrome, and among the non-dialysis patients, only 16 (18%) patients had restless legs syndrome. The frequency of restless legs syndrome is significantly higher in patients undergoing hemodialysis (P=0.001). There was also a meaningful difference about the frequency of restless legs syndrome among the male (77%) patients than females (23%) (P=0.001). A significant percentage (27%) of patients with renal failure suffer from restless legs syndrome and the hemodialysis patients are more involved in this disease, which needs more importance. Also, based on our findings in this study, men have a high probability of a conflict of restless legs syndrome than women

Tools for the Assessment of Pediatric Restless Legs Syndrome.

BackgroundThere are only a few of the questionnaires for the diagnosis, severity and quality of life of adult Restless Legs Syndrome (RLS) that have been utilized in children. Even fewer of these types of instruments have been developed specifically for Pediatric RLS.MethodsThis article is a review of instruments used in adult RLS, their applicability to children and of instruments specifically developed for childhood RLS.ResultsA single question for the diagnosis of RLS has been validated for adults and utilized in one epidemiology study of adolescents with RLS. The Pediatric Emory RLS questionnaire has been developed as a diagnostic instrument for childhood RLS, utilized in two studies of RLS in children, but not yet validated. The IRLS (International Restless Legs Scale), the CGI (Clinical Global Impression), and the RLS-6, which have been validated for determining adult RLS severity, were administered without difficulty in one therapeutic study of adolescent RLS. In addition, the IRLS has also been utilized in another 5 studies of childhood and adolescent RLS. The pediatric Restless Legs Syndrome Severity Scale (P-RLS-SS) has been developed for use in children but not yet validated. A modification of the P-RLS-SS based upon rating the severity of the 4 diagnostic criteria for RLS has been developed for children but not yet validated. There are no Quality of Life scales developed for Pediatric RLS. However, 3 separate studies utilized the general Peds Quality of Life Inventory (PedsQL) in RLS children and adolescents and one of these studies also employed the general Sleep Behavior Questionnaire (SBQ) and yet another of these studies also employed the Pediatric Symptom checklist (PSC).DiscussionThere is a need for the development and validation of instruments specific to Pediatric RLS. Meanwhile, we recommend the use of the Pediatric RLS instruments that have been developed and we recommend use of the adult scales in adolescent RLS where language barriers are not a problem. If adult scales are used in younger children, we recommend that they be administered in conjunction with an ongoing discussion between the parent and the child during the scale administration.

Restless legs syndrome and arterial stiffness in pre-dialysis chronic kidney disease

Despite plenty of restless legs syndrome (RLS) studies conducted with hemodialysis patients, it has been scarcely studied in patients with predialysis chronic kidney disease (CKD). In the present study, we aimed to investigate the frequency of RLS in patients with nondialysis chronic kidney disease and explore the relationship between RLS with sleep quality, depression, pulse wave velocity (PWV), and clinical parameters. This cross-sectional study included 259 stage 3–5 predialysis CKD patients. The diagnosis of RLS was defined according to the diagnostic criteria defined by the international RLS study group. Beck depression inventory (BDI) was employed to assess depression while Pittsburgh Sleep Quality Index (PSQI) was employed to assess sleep quality. 41 patients (16%) were diagnosed with RLS. BDI and PSQI scores of patients with RLS were significantly higher than those without RLS (p = 0.01, p = 0.03, respectively). Pulse wave velocity (PWV) was significantly lower in patients with RLS (8.0 ± 1.8) than those without RLS (8.6 ± 1.9) (p = 0.05). Decrease in PWV and increase in BDI score demonstrated by multivariate analysis were shown as independent predictors of RLS development (ExpB = 1.266, p = 0.02 and ExpB = 0.957, p = 0.007 and p = 0.04, respectively). RLS is a significant problem in predialysis CKD patients and depression, and poor sleep quality is typical in these patients. Arterial stiffness is lower in these patients and any factors related to the pathophysiology of RLS might play important roles in modulating atherosclerosis.

The Frequency of Restless Legs Syndrome in Patients with Multiple Sclerosis and Its Related Factors

: Restless Legs Syndrome (RLS) is a type of sensory-motor disorder characterized by pain, discomfort, numbness and tingling. This study was conducted to compare the prevalence of RLS in Multiple Sclerosis (MS) patients and healthy controls. Eighty-four patients with MS were selected as the case group and 84 healthy volunteers with no underlying diseases as the controls. The data collection tools included a demographic questionnaire, a scale about the disease details and a diagnostic questionnaire for RLS. A total of 45.8% of the MS patients and 22.9% of the healthy subjects had restless legs syndrome and a significant difference was observed between the two groups in this regard. In the study of RLS among MS patients, age correlated significantly with the incidence of this syndrome, and although the difference in the duration of disease was not significant, the mean duration of MS was higher in the patients with RLS. Among the MS patients with RLS, 26.31% had a family history of RLS. Also, the MS patients suffered from RLS approximately three times more than the healthy group.

Initial clinical results from the compression therapy for restless leg syndrome (REST) Study: Use of a novel wearable intermittent LEG compression device for RLS

Initial clinical results from the compression therapy for restless leg syndrome (REST) Study: Use of a novel wearable intermittent LEG compression device for RLS

Genetic Association Study of Restless Legs Syndrome in Chinese Population

Backgrounds: Several recent case-control studies have suggested some candidate genes being responsible for causing the restless legs syndrome (RLS). However, the association between those genes and the risk for RLS among the Asian population has not been well investigated. Objectives: The aim of the study was to investigate the genetic risk factors of RLS among the Chinese Population. Methods: A total of 158 RLS patients and 229 controls were recruited and the diagnosis of RLS was based on the criteria of International RLS Study Group. Polymer chain reaction and sequencing were used to detect 14 single nucleotide polymorphisms (SNPs) in 9 genetic loci (heme oxygenase 1 [HMOX1], HMOX2, vitamin D3 [1, 25-dihydroxyvitamin D3] receptor gene [VDR], interleukin 17A [IL17A], IL1B, NOS1, alcohol-dehydrogenase [ADH1B], gamma-aminobutyrate acid receptors[GABRR3] and GABRA4). Results: Among 14 selected SNPs, the frequency of IL1B rs1143634C allelic variant was lower in RLS patients than that in controls. Moreover, after adjustment for age and sex, rs731236 of VDR were found associated with increased risk of RLS in the dominant model. However, none of those results survived Bonferroni correction. The effects of HMOX1 and HMOX2 gene on developing RLS were not seen after the inclusion of RLS patients with a low ferritin level. Conclusions: Our study failed to replicate the association between 9 candidate genetic loci (HMOX1, HMOX2, VDR, IL17A, IL1B, NOS1, ADH1B, GABRR3 and GABRA4) and RLS in the Chinese population.

Caenorhabditis elegans and its applicability to studies on restless legs syndrome.

Restless legs syndrome (RLS) is a common neurological disorder in the United States. This disorder is characterized by an irresistible urge to move the legs, although the symptoms vary in a wide range. The pathobiology of RLS has been linked to iron (Fe) deficiency and dopaminergic (DAergic) dysfunction. Several genetic factors have been reported to increase the risk of RLS. Caenorhabditis elegans (C. elegans) is a well-established animal model with a fully sequenced genome, which is highly conserved with mammals. Given the detailed knowledge of its genomic architecture, ease of genetic manipulation and conserved biosynthetic and metabolic pathways, as well as its small size, ease of maintenance, speedy generation time and large brood size, C. elegans provides numerous advantages in studying RLS-associated gene-environment interactions. Here we will review current knowledge about RLS symptoms, pathology and treatments, and discuss the application of C. elegans in RLS study, including the worm homologous genes and methods that could be performed to advance the pathophysiology RLS.

Treatment of restless legs syndrome: Evidence-based review and implications for clinical practice (Revised 2017)§.

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.

Prospective study of restless legs syndrome and total and cardiovascular mortality among women.

We prospectively examined whether women with physician-diagnosed restless legs syndrome (RLS) had a higher risk of total and cardiovascular disease (CVD) mortality relative to those without RLS. The current study included 57,417 women (mean age 67 years) from the Nurses' Health Study without cancer, renal failure, and CVD at baseline (2002). Main outcomes were total and CVD mortality. We used the Cox proportional hazards model to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and CVD-specific mortality based on RLS status, adjusting for age, presence of major chronic diseases, and other potential confounders. We documented 6,448 deaths during 10 years of follow-up. We did not observe a significant association between presence of physician-diagnosed RLS and high risk of total mortality (adjusted HR 1.15, 95% CI 0.98-1.34). When cause-specific mortality was studied, participants with RLS had a significantly higher risk of CVD mortality (adjusted HR 1.43, 95% CI 1.02-2.00) relative to those without RLS after adjustment for potential confounders. Longer duration of RLS diagnosis was significantly associated with a higher risk of CVD mortality (p for trend = 0.04). Excluding participants with common RLS comorbidities strengthened the association between RLS and total (adjusted HR 1.43, 95% CI 1.03-1.97) and CVD mortality (adjusted HR 2.27, 95% CI 1.21-4.28). However, we did not find a significant association between RLS and mortality due to cancer and other causes. Women with RLS had a higher CVD mortality rate, which may not be fully explained by common co-occurring disorders of RLS.

Genetics of restless legs syndrome

At the outset of genetic studies in restless legs syndrome (RLS), the disorder was assumed to be a classical monogenic disorder that runs in families. However, years of family studies did not reveal any causally-related genes or genetic variants. The advent of high-throughput genotyping technology led to a change; genome-wide association studies in large case−control samples became feasible, which led to the identification of first genetic risk variants for RLS. Variants detected by this approach are common ones, which that individually confer only a minor increase in risk of disease. Overall, the currently known risk variants in six genomic loci account for only a small proportion of the genetically determined susceptibility to RLS. Additional risk loci and individual variants remain to be discovered. First studies indicate that rare genetic variants are also important contributors in RLS. These are expected to have a larger impact on the phenotype and may thus prove to be excellent candidates for functional studies and, in the long-term, targets for developing therapeutics or preventive measures. To enable their discovery, large-scale studies including tens of thousands of affected individuals may be needed. Next-generation sequencing technologies such as whole exome or whole genome sequencing will be essential for this endeavor. Even though the number of known risk variants is still limited, they have been indispensable in terms of deciphering the underlying pathophysiology of RLS, providing the molecular starting points for animal models and in vitro studies to understand disease mechanisms. In addition, genetic risk variants can be valuable tools for disentangling the phenotypic complexity observed in RLS. Testing RLS risk variants for associations with periodic limb movements (PLMs) identified a significant role of some of the variants and suggested PLMs as an endophenotype in RLS. Further advances in genetics research in RLS will be driven by large-scale sequencing projects and the identification of additional common, but also rarer risk variants with larger effects on disease risk. Another uncharted territory in RLS research epigenetic effect on gene activity. Overall, genetic studies continue to hold great potential for understanding biology of the disease.

Brain iron deficiency in idiopathic restless legs syndrome measured by quantitative magnetic susceptibility at 7 tesla

ObjectivesAltered brain iron homeostasis with regional iron deficiency has been previously reported in several studies of restless legs syndrome (RLS) patients. Inconsistencies still exist, however, in the reported iron changes in different brain regions and different RLS phenotypes. The purpose of this study was to assess differences in brain iron concentrations between RLS patients and healthy controls and their relation to severity of disease and periodic limb movement during sleep (PLMS). MethodsAssessment of brain iron was done using quantitative magnetic susceptibility measurement, which has been shown to correlate well with the tissue iron content in brain's gray matter. Thirty-nine RLS patients and 29 age-matched healthy controls were scanned at 7 T. Magnetic susceptibilities in substantia nigra (SN), thalamus, striatum, and several iron-rich gray matter regions were quantified and compared with related clinical measures. ResultsCompared with healthy controls, RLS patients showed significantly decreased magnetic susceptibility in the thalamus and dentate nucleus. No significant difference was found in the SN between RLS patients and healthy controls, but a significant correlation was observed between magnetic susceptibility in SN and the PLMS measure. ConclusionsUsing quantitative magnetic susceptibility as an in vivo indicator of brain iron content, the present study supports the general hypothesis of brain iron deficiency in RLS and indicates its possible link to PLMS.

Restless legs syndrome does not affect 3-year mortality in hemodialysis patients

ObjectiveUremic restless legs syndrome (RLS) has been related to an enhanced mortality of hemodialysis (HD) patients. In the general population studies of this association have yielded inconsistent results. The aim of the present study was to re-evaluate the relationship of RLS and mortality in HD patients. MethodsWe recorded the 3-year mortality in 579 HD patients after assessment for RLS symptoms. This population has been previously evaluated for the prevalence of RLS, according to the essential criteria of the International RLS Study Group. Mortality data were acquired from the national end-stage renal disease registry. Survival probability was calculated by the Kaplan–Meier method and analyzed by the log-rank test. For multivariate survival analysis, we implemented a Cox regression model. ResultsDuring the 3-year follow-up, we documented 118 deaths. Mortality was 15.6% in patients with RLS and 22.3% in patients without RLS (p = 0.079). According to the Cox regression analysis, there was no significant association between RLS and 3-year mortality, either in an age- and gender-adjusted model (hazard ratio [HR] = 0.772, 95% confidence interval [CI] = 0.488–1.219, p = 0.267) or in a multivariate adjusted model (HR = 0.667, 95% CI = 0.417–1.069, p = 0.092). ConclusionDiagnosis of RLS according to the essential criteria of the International RLS Study Group does not seem to influence the 3-year mortality in HD patients. Our findings are in contrast to those in some previous reports, and reinforce the need for further studies of RLS and mortality in HD.

An epidemiologic study of restless legs syndrome among Chinese children and adolescents.

To determine the prevalence of restless legs syndrome (RLS) in Chinese children and adolescents as well as the impact of the disorder on 8-11 and 12-17 years old. This population-based study was conducted in five primary schools and seven high schools, which were randomly selected in Henan province, China. A total of 6792 students aged 8-17 years old were given a questionnaire that included the adult diagnostic criteria of RLS proposed by the International Restless Legs Study Group. Subjects who answered "yes" to all four questions were selected for a face-to-face interview to confirm RLS diagnosis. Individuals with definite RLS were then administered another questionnaire to survey RLS symptoms and perceived consequences. The prevalence of definite RLS in Chinese children and adolescents was 2.2 % (141/6437), with a prevalence of 1.8 % in the 8-11 years old age group and 2.4 % in the 12-17 years old age group. RLS was found to be more prevalent in females (2.7 %) than in males (1.7 %) (P = 0.008), and the prevalence of RLS was determined to increase with age. Sleep disturbance was the most common symptom of RLS in children and adolescents. Various consequences were attributed to RLS, with participants reporting that they dreaded the arrival of evening/night most frequently, followed by the description that RLS had a negative impact on mood. These data suggest that RLS is prevalent in Chinese children and adolescents, and that those affected by this disorder suffer from disruptions to sleep and daytime function.

Rotigotine in the treatment of primary restless legs syndrome: A meta-analysis of randomized placebo-controlled trials.

The aim of this study was to summarize the efficacy and tolerability of rotigotine in the treatment of primary restless legs syndrome (RLS). PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for English-language randomized controlled trials (RCTs) that assessed the effectiveness of rotigotine for RLS. The pooled mean change from baseline in International RLS (IRLS) Study Group Rating Scalescore and relative risk (RR) of response based on the Clinical Global Impression-Improvement (CGI-I) scale score were applied to evaluate the outcomes. The pooled proportions of adverse events (AEs) were also estimated. Six RCTs were included. The meta-analysis showed a favorable effectiveness of rotigotine versus placebo on RLS [mean change on IRLS score: mean difference (MD)=-4.80; 95% confidence interval (CI): -5.90 to -3.70; P<0.00001 and RR of response on CGI-I was 2.19; 95% CI: 1.86 to 2.58, P<0.00001]. The most common AEs were application site reactions, nausea, headache and fatigue. In general, rotigotine was well-tolerated in patients with primary RLS. Based on the findings from the meta-analysis, rotigotine was more significantly efficacious in the treatment of RLS than placebo. Nevertheless, long-term studies and more evidence of comparisons of rotigotine with other dopamine agonists are needed.

Blood cis-eQTL analysis fails to identify novel association signals among sub-threshold candidates from genome-wide association studies in restless legs syndrome.

Restless legs syndrome (RLS) is a common neurologic disorder characterized by nightly dysesthesias affecting the legs primarily during periods of rest and relieved by movement. RLS is a complex genetic disease and susceptibility factors in six genomic regions have been identified by means of genome-wide association studies (GWAS). For some complex genetic traits, expression quantitative trait loci (eQTLs) are enriched among trait-associated single nucleotide polymorphisms (SNPs). With the aim of identifying new genetic susceptibility factors for RLS, we assessed the 332 best-associated SNPs from the genome-wide phase of the to date largest RLS GWAS for cis-eQTL effects in peripheral blood from individuals of European descent. In 740 individuals belonging to the KORA general population cohort, 52 cis-eQTLs with pnominal<10−3 were identified, while in 976 individuals belonging to the SHIP-TREND general population study 53 cis-eQTLs with pnominal<10−3 were present. 23 of these cis-eQTLs overlapped between the two cohorts. Subsequently, the twelve of the 23 cis-eQTL SNPs, which were not located at an already published RLS-associated locus, were tested for association in 2449 RLS cases and 1462 controls. The top SNP, located in the DET1 gene, was nominally significant (p<0.05) but did not withstand correction for multiple testing (p = 0.42). Although a similar approach has been used successfully with regard to other complex diseases, we were unable to identify new genetic susceptibility factor for RLS by adding this novel level of functional assessment to RLS GWAS data.