International Restless Legs Syndrome Study Group Rating Research Articles

Cost-effectiveness of TOMAC therapy for medication-refractory restless legs syndrome: an updated analysis based on Extension study data

Aims Patients with medication-refractory restless legs syndrome (RLS) have limited therapeutic options available for symptom relief. Tonic motor activation (TOMAC) presents a novel, non-invasive therapy for this patient population. The aim of this study was to conduct an updated cost-effectiveness analysis of TOMAC therapy based on recently available longer-term follow-up data. Materials and Methods A previously published decision-analytic Markov model was utilized to project strategy-specific costs and outcomes over three-years and lifetime for TOMAC compared to status quo treatment (control). Cohort characteristics were based on 24-week clinical data from the extension cohort of the RESTFUL study, which included longer-term follow-up of RESTFUL completers who were assigned to continue or discontinue TOMAC use (TOMAC and control, respectively). The primary analysis outcome was the incremental cost-effectiveness ratio (ICER) in $ per quality-adjusted life year (QALY) gained, calculated using change in International RLS Study Group Rating Scale (IRLS) score as the effect measure. Extensive sensitivity analyses were performed. Results TOMAC treatment improved IRLS by 5.9 versus control, resulting in estimated utility improvement of +0.05. Over three-years and lifetime, TOMAC added 0.14 and 0.73 QALYs, at incremental costs of $6,751 and $27,440, resulting in projected ICERs of $47,609 and $37,823 per QALY gained, respectively. TOMAC was found to be cost-effective across all tested sensitivity analyses. Limitations and Conclusion The inclusion of longer follow-up data in the current analysis confirms earlier exploratory cost-effectiveness findings and suggest TOMAC therapy may provide a high-value treatment option for patients with medication-refractory RLS.

Efficacy and safety of TOMAC for treatment of medication-naïve and medication-refractory restless legs syndrome: A randomized clinical trial and meta-analysis

Objective/backgroundThere is a significant unmet need for safe and effective nonpharmacological therapies for restless legs syndrome (RLS). The objective was to evaluate the efficacy and safety of tonic motor activation (TOMAC) in patients with RLS. Patients/methodsA multicenter, randomized, participant-blinded, sham-controlled trial enrolled 45 adults with primary moderate-to-severe RLS who were either medication-naïve (n = 20) or medication-refractory (n = 25). Participants were 1:1 randomized to TOMAC (n = 22) or sham (n = 23) for two weeks and instructed to self-administer 30-min TOMAC sessions when they experienced RLS symptoms. The primary outcome was mean change in International RLS Study Group Rating Scale (IRLS) total score. A subsequent meta-analysis included the present trial and a previous randomized clinical trial that enrolled medication-naïve RLS patients. ResultsIRLS reduction was significantly greater for TOMAC than sham (TOMAC -6.59 vs. sham −2.17; mean difference (MD) = −4.42; 95 % confidence interval [CI] −1.57 to −7.26; p = 0.0040). Subgroup analysis showed similar IRLS mean difference for medication-refractory (MD = −4.50; p = 0.02) and medication-naïve (MD = −4.40; p = 0.08) cohorts, which was significantly different from sham only for the medication-refractory cohort. Meta-analysis of combined data from 33 medication-naïve RLS patients showed a significant reduction in mean IRLS score after two weeks for TOMAC compared to sham (MD = −4.30; 95 % CI -1.36 to −7.24; p = 0.004). ConclusionsThe present trial confirmed previous reports documenting efficacy and safety of TOMAC in refractory RLS and indicated similar effect sizes in refractory versus naïve subgroups. The meta-analysis demonstrated that TOMAC significantly improves RLS symptoms in naïve participants.

Restless legs syndrome in patients with obstructive sleep apnea: Association between apnea severity and symptoms of depression, insomnia, and daytime sleepiness

ObjectiveTo determine if the prevalence and severity of restless legs syndrome (RLS) varies with apnea severity and analyze differences between the sexes in terms of comorbid RLS with symptoms of depression, insomnia, and daytime sleepiness in patients with obstructive sleep apnea (OSA). MethodsSymptoms of depression, insomnia, and daytime sleepiness were defined as Patient Health Questionnaire–9 score ≥10, Insomnia Severity Index score ≥15, and Epworth Sleepiness Scale score ≥11. Multivariate logistic and linear regression analyses were conducted. ResultsIn 707 adults with OSA (85.1% males), 16.1% (n = 114) had comorbid RLS. The prevalence of RLS was markedly lower in those with moderate and severe OSA than in those with mild OSA. Similarly, the odds of RLS significantly decreased with increasing apnea-hypopnea index. After controlling for age and sex, in patients with comorbid RLS, the International RLS Study Group Rating Scale scores were negatively correlated with apnea-hypopnea index and a nadir peripheral oxygen saturation during sleep. The presence of RLS was more likely to be associated with symptoms of depression, insomnia, and daytime sleepiness after controlling for confounding variables, but only in men. ConclusionsRLS is frequently noted in combination with OSA, with a female preponderance. The severities of OSA and RLS may be negatively associated. In patients with OSA, sex-related differences in terms of comorbid RLS with symptoms of depression, insomnia, and daytime sleepiness warrant further investigations.

Bilateral high-frequency noninvasive peroneal nerve stimulation evokes tonic leg muscle activation for sleep-compatible reduction of restless legs syndrome symptoms.

Restless legs syndrome (RLS) is a prevalent sleep disorder with limited treatment options. Bilateral high-frequency noninvasive peroneal nerve stimulation (NPNS) reduces RLS symptoms. Here, we sought to characterize the mechanism of action for NPNS and identify predictors of treatment response. We hypothesized that, similar to voluntary leg movements, NPNS reduces RLS symptoms by activating leg muscles. For 20 adults with moderate-severe RLS, we tested this hypothesis by recording surface electromyography (EMG) from the tibialis anterior leg muscle while administering NPNS at varying amplitudes to determine the minimum NPNS amplitude that evoked EMG activity (motor threshold) and maximal NPNS amplitude that was not distracting (therapeutic intensity level). Afterwards, participants self-administered NPNS (at the therapeutic intensity level) and sham control for 14 days, each in randomized order. Efficacy was defined as International RLS Study Group Rating Scale (IRLS) score difference for NPNS compared with sham. NPNS consistently activated leg muscles; NPNS evoked EMG activity at the therapeutic intensity level for 19 of 20 participants (mean TIL: 26.6 mA, mean MT: 18.3 mA). Evoked EMG activity was tonic (not phasic) and sustained over time. Evoked EMG activity predicted efficacy; participants with lower motor thresholds had greater IRLS improvement (r = .45, P = .046). NPNS treatment did not interfere with self-reported sleep onset (NPNS: 16% of nights; sham: 11%; P = .629) and frequently improved self-reported sleep onset (NPNS: 52% of nights; sham: 15%; P = .002). These results demonstrate that NPNS reduces RLS symptoms by activating afferent pathways, thereby generating tonic and sustained leg muscle activity without interfering with sleep. Registry: ClinicalTrials.gov; Name: Noninvasive Peripheral Nerve Stimulation for Restless Legs Syndrome; URL: https://clinicaltrials.gov/ct2/show/NCT04700683; Identifier: NCT04700683. Charlesworth JD, Adlou B, Singh H, Buchfuhrer MJ. Bilateral high-frequency noninvasive peroneal nerve stimulation evokes tonic leg muscle activation for sleep-compatible reduction of restless legs syndrome symptoms. J Clin Sleep Med. 2023;19(7):1199-1209.

Can calcitonin gene-related peptide monoclonal antibody improve migraine and restless legs syndrome?

BackgroundA significant association between migraine and restless legs syndrome (RLS) has been reported, and their coexistence is not uncommon. We report a patient with concomitant migraine and RLS who showed improvement of both migraine and RLS symptoms after treatment with galcanezumab, a calcitonin gene-related peptide (CGRP) monoclonal antibody. Case presentationA 47-year-old woman had been treated in our outpatient headache clinic for migraine without aura. She had RLS since childhood and had been treated with dopamine agonists and α2δ ligands. Over the past 2 months, the patient suffered from frequent migraine headaches and worsening RLS symptoms, despite ongoing treatment. Therefore, galcanezumab was started. After 1 month, the number of headache days decreased from 20 to 4, and her score on the International RLS Study Group Rating Scale improved from 38 to 10. Her photo/phono/osmo-phobia were also markedly improved. The efficacy of galcanezumab for both headache and RLS was sustained over 5 months. ConclusionWe report a case of improvement of both migraine and RLS after treatment with CGRP monoclonal antibody. Additional studies are needed to clarify how CGRP antagonism affects RLS symptoms in patients with migraine and RLS comorbidity.

Evaluation of affective temperament profile and levels of depressive symptoms and anxiety in patients with restless legs syndrome.

Restless legs syndrome (RLS) is a sleep-related sensorimotor disorder associated with mood and anxiety disorders. Although affective temperaments are considered subclinical manifestations of mood disorders (MDs), to date, no previous research has explored the relationship between affective temperaments and RLS. We aimed to evaluate affective temperaments, depressive symptoms, and anxiety among newly diagnosed, drug-naive patients with RLS. Additionally, our study identified possible associations between clinical variables and affective temperaments, depressive symptoms, and anxiety profiles in this group. The study included 74 patients with RLS and 90 healthy volunteers. All participants performed the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire, Beck Depression Inventory, and Hamilton Anxiety Inventory. Temperament, depression, and anxiety scores in patients with RLS were significantly higher than those in healthy controls (p ≤ 0.05). Linear regression analysis showed that anxious temperament scores were positively related to longer disease duration (β = 0.658, p = 0.000), whereas disease severity (as measured by the International RLS Study Group Rating Scale) (β = 0.447, p = 0.006) and lower educational status (β = - 0.803, p = 0.008) correlated with the anxiety profile. Results suggested that higher scores on the affective temperament, depression, and anxiety scales indicate subclinical MDs and psychiatric comorbidities in RLS. Therefore, exploring the predictors of mood and anxiety disorders in patients with RLS may improve treatment strategies and clinical outcomes.

Pramipexole in peritoneal dialysis patients with restless legs syndrome (RLS): a protocol for a multicentre double-blind randomised controlled trial

IntroductionRestless legs syndrome (RLS) is a common neurological sensorimotor disorder among patients with end stage renal disease. This clinical trial aimed to provide evidence on the efficacy and safety of...

Correlation of Anaemia and Restless Legs Syndrome in Elderly: A Cross-sectional Study

Introduction: Restless Legs Syndrome (RLS) also known as Willis Ekbom Disease (WED) which manifests as a neurologic disorder among patients with anaemia, particularly with iron deficiency anaemia. Aim: To find the association of anaemia with RLS in the elderly population. Materials and Methods: In this cross-sectional study, 100 patients of age ≥60 years were enrolled and categorised into mild, moderate, and severe anaemia as per World Health Organisation (WHO) criteria. Every participant was enquired about RLS via a questionnaire based on the International RLS Study Group Rating Scale (IRLSSGRS) for its Severity and for the diagnosis (Essential clinical criteria for the diagnosis of RLS). Results: The study showed that patients with anaemia had a statistically significant correlation with RLS (p=0.04) and severity of RLS (p=0.032). Serum ferritin levels too showed a statistically significant correlation with RLS (p=0.032). Conclusion: Patients with severe anaemia and lower serum ferritin levels were more prone to RLS and had more RLS severity.

Prevalence and Risk Factors of Restless Legs Syndrome in Hemodialysis Patients.

ObjectiveThe current study aimed to investigate the prevalence and risk factors of restless legs syndrome (RLS) in patients undergoing hemodialysis, as well as the mortality and risks of cardiovascular and cerebrovascular events.MethodsA total of 354 hemodialysis patients from four hospitals were enrolled. RLS was diagnosed using the International RLS Study Group (IRLSSG) criteria. The patients were evaluated face-to-face using the IRLSSG rating scale, Epworth Sleepiness Scale (ESS), Hamilton Anxiety Scale, Hamilton Depression Scale, and Pittsburgh Sleep Quality Index (PSQI). The patients were followed up for 9 months. Death was considered an endpoint event. The cardiovascular and cerebrovascular events were investigated.ResultsThe prevalence of RLS in hemodialysis patients was 40.7% and was associated with factors such as duration of hemodialysis, hypersensitive C-reactive protein, hyperparathyroidism, glycosylated serum protein, and erythropoietin treatment. The scores of the PSQI, ESS, and Hamilton Depression Scale in the RLS group were significantly higher than those in the non-RLS group (p < 0.05). During follow-ups, the incidence rate of cardiovascular diseases was 18.8% in the RLS group and 8.6% in the non-RLS group (p < 0.005). The IRLSSG rating scores were significantly higher in RLS patients with kidney transplantation failure compared with those without transplantation (p < 0.05).ConclusionThe prevalence of RLS was high in hemodialysis patients. The risk factors of RLS included duration of hemodialysis, hypersensitive C-reactive protein, hyperparathyroidism, glycosylated serum protein, and erythropoietin treatment. RLS affected sleep quality and emotion and increased the risk of cardiovascular diseases in hemodialysis patients. RLS was more severe in patients with kidney transplantation failure compared with those without transplantation.

Restless Legs Syndrome in Aircrew.

INTRODUCTION: Restless legs syndrome (RLS) is characterized by an uncomfortable sensation on the legs, which causes the urge to move the legs. The main cause is unknown but there are many risk factors, including geographical properties and high altitude. Our objective was to explore the frequency of RLS in aircrew.METHODS: There were 301 Turkish aircrew who were admitted to Istanbul Medipol University Hospital Neurology Department for periodic examinations and 272 healthy (non-aircrew) subjects included in the study. The International RLS Study Group's Questionnaire and the International RLS Study Group Rating Scale (IRLSSGRS) were used to evaluate RLS. The participants filled the RLS questionnaire and then both groups were divided into two subgroups as having RLS or not. The subjects years in the profession, average flight duration in a month, daily sleep duration, smoking, and coffee consumption were recorded. None of the subjects had previously been diagnosed with RLS.RESULTS: The frequency of RLS was 6.7% in the aircrew group and 7.9% in the control group, and there was no significant difference between the two groups. Age, gender, daily duration of sleep, smoking, coffee consumption, family history of RLS, being a pilot or a flight attendant, years in profession, and monthly flight hours were similar in aircrew with and without RLS.DISCUSSION: The RLS frequency in aircrew was similar to that of the control group. We can conclude flying at high altitude wasnt a risk factor for RLS.Düz OA, Yilmaz NH, Olmuscelik O. Restless legs syndrome in aircrew. Aerosp Med Hum Perform. 2019; 90(11):934937.

Screening questions for the diagnosis of restless legs syndrome in hemodialysis.

BackgroundRestless legs syndrome (RLS) is common in end-stage renal disease and is associated with reduced health-related quality of life. Simple and accurate screening instruments are needed since RLS is underdiagnosed and treatable. We examined the operating characteristics of screening questions and a disease-specific measurement tool for the diagnosis of RLS in hemodialysis.MethodsWe conducted a cohort study of prevalent adult hemodialysis patients in Hamilton, Canada. The diagnosis of RLS was made using the 2012 Revised International Restless Legs Syndrome Study Group (IRLSSG) criteria. All participants received three screening instruments: (i) a single screening question for RLS derived from a nondialysis population; (ii) a single question from the Edmonton Symptom Assessment System (ESAS); and (iii) the IRLSSG Rating Scale (IRLS). All instruments were compared with the reference standard using logistic regression from which receiver operating characteristics curves were generated. Cutoffs associated with maximum performance were identified.ResultsWe recruited 50 participants with a mean (SD) age of 64 (12.4) years, of whom 52% were male and 92% were on three times weekly hemodialysis. Using the reference standard, 14 (28%) had a diagnosis of RLS. The single screening question for RLS had an area under the receiver operating curve (AUROC) of 0.72 with a sensitivity of 85.7% and specificity of 58.3%. An ESAS cutoff of ≥1 had the highest AUROC at 0.65 with a sensitivity of 79% and specificity of 56%. An IRLS cutoff of ≥20 had the highest AUROC at 0.75 with a sensitivity of 71% and specificity of 81%.ConclusionIRLS had better specificity than the single question or ESAS for the diagnosis of RLS.

Deep brain stimulation improves restless legs syndrome in patients with Parkinson disease

To study the effect of subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with Parkinson disease (PD) and moderate to severe restless legs syndrome (RLS) on their RLS symptoms. Patients undergoing STN DBS surgery for PD completed the International RLS Study Group Rating Scale (IRLS) and RLS Quality of Life (QoL) questionnaires preoperatively and postoperatively at 6 months, 1 year, and 2 years. The primary outcome measure was IRLS sum score and subscales (severity and impact) and the secondary measure was RLS QoL scores. Differences among the mean scores over time were analyzed using mixed model regression. Twenty-two patients were enrolled. The preoperative IRLS sum scores were 19.59 ± 6.95, severity subscale 12.91 ± 4.33, impact subscale 4.45 ± 2.72, and transformed RLS QoL score 68.30 ± 20.26. The differences between preoperative and averaged postoperative scores were IRLS sum score -7.80, severity subscale -5.50, impact subscale -1.20, and RLS QoL 4.73. The overall F tests demonstrated differences among the times for the means of the IRLS sum and subscales: p < 0.05. There were no correlations between RLS symptoms improvement and PD motor symptoms improvement or reduction in PD medications. Half of the patients had at least 50% improvement and 27% had resolution of their RLS symptoms (IRLS = 0). STN DBS significantly decreased RLS symptoms in patients with PD despite a decrease in dopaminergic treatment. This improvement was sustained over a 2-year period. This study provides Class IV evidence that for patients with PD and moderate to severe RLS, STN DBS improves RLS symptoms.

Polysomnographic findings in restless legs syndrome (RLS) patients with severe augmentation

Background and objectivesAugmentation can occur frequently in restless legs syndrome (RLS) patients treated with dopaminergic agents. Video-polysomnographic (PSG) data from augmented RLS patients are scant. The aim of this study was to evaluate PSG findings in augmented RLS patients and compare them with those of non-augmented RLS patients. Patients and methodsValid PSG data were analyzed from 99 augmented and 84 non-augmented RLS inpatients who underwent one night PSG. ResultsBoth patient groups showed a high subjective burden of RLS symptoms. The mean scores on the International RLS Study Group Rating Scale (IRLS) were significantly higher in the group with augmentation than in the group without. The periodic leg movement index (PLMI) was increased in both groups, mostly on account of the PLM in wakefulness (PLMW). Both groups presented a reduced sleep efficiency and an increased sleep latency. The levodopa equivalent dose (LED) was significantly higher in the augmented group. ConclusionsOur study confirms that RLS patients with augmentation have disturbed sleep due to high amount of leg movements and fragmented sleep. Overall, however, polysomnographic characteristics were not different between insufficiently treated RLS and severely augmented RLS patients, implying that augmentation could represent a severe form of RLS and not a different phenomenon.

Sleep disturbances in restless legs syndrome

Background/Aim. Resteless legs syndrome (RLS) is chronical neurological disorder characterized by urge to move legs that is usually accompanied by unpleasant sensations in the lower extremities. Sleep disturbance is one of the main accompanying symptoms of RLS which exists in approximatelly 90% of patients. Impairment of sleep is related to daily sleepiness, depressive and anxiety disorders. The aim of this study was to detect frequency and characterisitics of sleep-related symptoms in patients with RLS, and its impairrment to daily sleepiness, fatique, anxiety and depression. Methods. We have examinated 94 patients with RLS. The diagnose of RLS was based on questionnaire with 4 specific questions according to the International Restless Legs Syndrome Study Group (IRLSSG) criteria updated in 2003. Severity of symptoms was astimated with IRLSSG Rating Scale, depression and anxiety with Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS) and sleepiness with Epworth Sleepiness scale (ESS). We astimated sleep characteristics and disturbances with specific questionnaire. Results. In our study 79.9% of patients had sleep-related symptoms. Average sleep duration was 6.50 ? 1.42 hours, with average frequency of awakening 2.34 ? 1.69 times per night. Average ESS score was 5.12 ? 4.08 (0?17). Patients with more severe symptoms had higher degree of sleepiness (p = 0.005). Patients with higher symptoms frequency, significantly more often had sleep disturbance (p = 0.016), tiredness and daily sleepiness (p = 0.001). Daily sleepiness (ESS) also significantly correlates with depression (p &lt; 0.05) and anxiety (p = 0.012). Conclusion. Our results confirm that sleep disturbances are one of the key accompanying symptoms of RLS which cause daily sleepiness, tiredness, depression and anxiety. Therefore, their early recognition and appropriate treatment must be a priority in RLS patients.

Pharmacokinetics of rotigotine transdermal system in adolescents with idiopathic restless legs syndrome (Willis–Ekbom disease)

ObjectiveTo investigate the pharmacokinetics (PK) of rotigotine transdermal system in adolescents with moderate-to-severe idiopathic restless legs syndrome (RLS). MethodsThis multicenter, open-label, dose-escalation study enrolled patients ≥13 to <18 years of age. Rotigotine transdermal patches were applied daily and up-titrated weekly: 0.5, 1, 2, 3 mg/24 h. Blood samples were collected on the final day of each dose step. Primary PK variables were the apparent total body clearance (CL/f; L/h) and volume of distribution at steady state (VSS/f; L) of unconjugated rotigotine for each dose step, calculated for the PK per-protocol set (PKPPS). Other PK, safety, and efficacy variables (International RLS Study Group Rating Scale [IRLS]; Clinical Global Impressions Item 1 [CGI-1]) were assessed. ResultsOf 24 patients who received rotigotine, 23 completed all dose steps and 17 formed the PKPPS. Least-squares mean (95% confidence interval) CL/f and VSS/f values were broadly similar across all dose steps (CL/f: 0.5 mg/24 h: 676.86 [408.50–1121.51]; 1 mg/24 h: 671.72 [459.11–982.80]; 2 mg/24 h: 937.56 [658.50–1334.89]; 3 mg/24 h: 1088.77 [723.47–1638.53]; VSS/f: 5403.16 [2850.67–10,241.17]; 6220.79 [3842.05–10,072.28]; 7114.01 [4547.88–11,128.07]; 6037.92 [3598.36–10,131.41]). Among 23 patients with efficacy data, mean IRLS and CGI-1 scores improved at each dosage level. Adverse events reported by ≥3 patients were nausea (seven) and application site reactions (four). ConclusionsKey PK properties of rotigotine in adolescent patients with moderate-to-severe idiopathic RLS were comparable to those previously observed in adults. Rotigotine improved RLS symptoms and was well tolerated. ClinicalTrials.gov: NCT01495793.

Effect of Gabapentin Enacarbil on Individual Items of the International Restless Legs Study Group Rating Scale and Post-sleep Questionnaire in Adults with Moderate-to-Severe Primary Restless Legs Syndrome: Pooled Analysis of 3 Randomized Trials

PurposeFew studies have investigated restless legs syndrome (RLS) treatment effects on individual International RLS Study Group Rating Scale (IRLS) items. We assessed the effects of gabapentin enacarbil (GEn) on individual IRLS items and their correlation with sleep disturbances in adults with moderate-to-severe primary RLS. MethodsData were pooled from the randomized, double-blind, placebo-controlled, 12-week studies of XP052, XP053, and XP081 for adults who received GEn (600 or 1200 mg) or placebo once daily. Adults had primary RLS, IRLS total score ≥15, and RLS symptoms >15 days during the month before screening and for ≥4 of the 7 consecutive evenings at baseline. End points included mean change from baseline to week 12 in individual IRLS and post-sleep questionnaire (PSQ) items. For IRLS items, least squares mean treatment differences were calculated from a mixed model for repeated measures. For PSQ items, Cochran–Mantel–Haenszel row mean scores tests with integer scoring were used. Correlations between IRLS and PSQ items were assessed by Spearman’s rank coefficients. Safety profile outcomes included treatment-emergent adverse events (TEAEs) and serious TEAEs. FindingsThe modified intent-to-treat population included 671 patients (GEn 600 mg = 161; GEn 1200 mg = 266; placebo = 244). GEn significantly improved mean [SE] differences versus placebo for all IRLS items at week 12, including severity of sleep disturbance (GEn 600 mg, −0.4 [0.10]; GEn 1200 mg, −0.4 [0.09]), daytime tiredness (−0.4 [0.09]; −0.4 [0.08]), RLS severity (−0.4 [0.10]; −0.3 [0.08]), impact on daily affairs (−0.3 [0.07]; −0.3 [0.07]), and mood disturbance (−0.2 [0.07]; −0.3 [0.06]); all P<0.001). For PSQ items, significant (P<0.01) improvements occurred with both GEn doses versus placebo at week 12. The correlations between IRLS and PSQ items for change from baseline to week 12 were moderate to strong, and all correlations were significant (P<0.001). The most frequent TEAEs were somnolence (GEn 600 mg, 20%; GEn 1200 mg, 23%; placebo, 5%) and dizziness (GEn 600 mg, 14%; GEn 1200 mg, 22%; placebo, 5%). ImplicationsGEn significantly improved individual IRLS items and sleep disturbance versus placebo. Correlations between IRLS and PSQ items were moderate to strong. This was not a formal meta-analysis and was not powered to compare the GEn doses. Nevertheless, our study finds that the benefits of GEn extend to individual IRLS items and supports the importance of sleep quality in RLS treatment. ClinicalTrials.gov identifiers: NCT00298623, NCT00365352, and NCT01332305.

Rotigotine in Hemodialysis-Associated Restless Legs Syndrome: A Randomized Controlled Trial.

Restless legs syndrome (RLS) has been associated with insomnia, decreased quality of life, and increased morbidity and mortality in end-stage renal disease. This randomized controlled trial investigated effects of rotigotine in patients with RLS and end-stage renal disease. Double-blind placebo-controlled study. Adults with moderate to severe RLS (International RLS Study Group Rating Scale [IRLS]≥ 15) and Periodic Limb Movement Index (PLMI)≥ 15 who were receiving thrice-weekly hemodialysis enrolled from sites in the United States and Europe. Following randomization and titration (≤21+ 3 days) to optimal-dose rotigotine (1-3mg/24 h) or placebo, patients entered a 2-week maintenance period. Polysomnography was performed at baseline and the end of maintenance. Primary efficacy outcome: reduction in PLMI, assessed by ratio of PLMI at end of maintenance to baseline. Secondary/other outcomes (P values exploratory) included mean changes from baseline in PLMI, IRLS, and Clinical Global Impression item 1 (CGI-1 [severity of illness]) score. 30 patients were randomly assigned (rotigotine, 20; placebo, 10); 25 (15; 10) completed the study with evaluable data. Mean (SD) PLMI ratio (end of maintenance to baseline) was 0.7±0.4 for rotigotine and 1.3±0.7 for placebo (analysis of covariance treatment ratio, 0.44; 95% CI, 0.22 to 0.88; P=0.02). Numerical improvements were observed with rotigotine versus placebo in IRLS and CGI-1 (least squares mean treatment differences of-6.08 [95% CI,-12.18 to 0.02; P=0.05] and-0.81 [95% CI,-1.94 to 0.33; P=0.2]). 10 of 15 rotigotine and 2 of 10 placebo patients were CGI-1 responders (≥50% improvement). Hemodialysis did not affect unconjugated rotigotine concentrations. The most common adverse events (≥2 patients) were nausea (rotigotine, 4 [20%]; placebo, 0); vomiting (3 [15%]; 0); diarrhea (1 [5%]; 2 [20%]); headache (2[10%]; 0); dyspnea (2 [10%]; 0); and hypertension (2 [10%]; 0). Small sample size and short duration. Rotigotine improved periodic limb movements and RLS symptoms in the short term amongESRD patients requiring hemodialysis in a small-scale study. No dose adjustments are necessary for hemodialysis patients.

Relationship between prevalence and severity of restless legs syndrome and anemia in patients with systemic lupus erythematosus.

Our aim was to evaluate the relationship between the prevalence and severity of restless legs syndrome (RLS) and the anemia in patients with systemic lupus erythematosus (SLE). This was a case-control study which was conducted at the rheumatology clinic of a university affiliated hospital, including 62 patients with SLE and 62 age- and sex-matched healthy controls. The patients were divided into two groups in terms of their hemoglobin levels. The criterion for anemia was hemoglobin level lower than 12 g/dL in females and 13 g/dL in males. Nineteen patients (30.6%) in the patient group were diagnosed with RLS, and International RLS Study Group Rating Scale (IRLSSG-RS) score was 10.7 ± 9.5 (median:10.0 [range:0.0-30.0]). Three subjects (4.8%) in the control group had RLS, and the IRLSSG-RS score was 0.7 ± 3.3 (median:0.0 [range:0.0-18.0]). The prevalence of RLS and the IRLSSG-RS score were higher in the patient group than those in the control group (P < 0.001). Ten SLE patients (50%) with anemia had RLS, and their IRLSSG-RS score was 14.5 ± 9.9 (median:21.0 [range:11.0-30.0]). Nine SLE patients (21.4%) without anemia had RLS and their IRLSSG-RS was 9.0 ± 8.9 (median:21.0 [range:11.0-24.0]). Significant differences were present in the prevalence of RLS and the IRLSSG-RS score between SLE patients with and without anemia (P = 0.024, P = 0.044, respectively). The present study demonstrated that the prevalence of RLS was higher in patients with SLE than that of the normal population. Results of this study also suggested that anemia was associated with higher frequency of and more severe RLS in patients with lupus.

Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study

AimThe aim of this study is to assess the effect of switching to rotigotine transdermal patch on severity of restless legs syndrome (RLS) in patients who experienced acute augmentation with previous oral dopaminergics. MethodsIn this 13-month observational study, adults with moderate-to-severe RLS and augmentation were switched to rotigotine per the physician’s independent decision. Assessments included Clinical Global Impression severity score (CGI-1); (primary), treatment regimen for switching (secondary), RLS-6, International RLS Study Group Rating Scale (IRLS), and augmentation severity rating scale (ASRS). ResultsA total of 99 patients received rotigotine, of whom 46 completed observational period, and 43 were assessed for effectiveness. A total of 5 patients switched to rotigotine after a >1-day drug holiday, 23 switched overnight, 9 had an overlapping switch, and 6 received ongoing oral dopaminergics with rotigotine for ≥28 days. Of the 99 patients, 57 took concomitant RLS medications (excluding switching medications) on at least 1 day. At the final visit, median change in CGI-1 (Hodges–Lehman estimate [95% CI]) was −2.0 (–2.5, −1.50); 37 of the 43 patients improved by ≥1 CGI-1 category, and 16 of 43 were responders (≥50% improvement). RLS-6 and IRLS scores also improved. Patients had median ASRS of 0 at the final visit indicating “no worsening/occurrence of augmentation.” ASRS item 1 showed a shift in mean time of symptom onset (24-h clock) from 12:38 (baseline) to 18:25 (final visit). Most common reasons for withdrawal of rotigotine were adverse events (26 patients) and lack of efficacy (14 patients). ConclusionsSwitching from oral therapies to rotigotine was effective in improving RLS symptoms in 37 of the 43 patients (from the original population of 99 patients) who remained in the study over 13 months. Clinical trial registrationClinicalTrials.govNCT01386944.

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.