A dose-ranging study of pramipexole for the symptomatic treatment of restless legs syndrome: Polysomnographic evaluation of periodic leg movements and sleep disturbance

Objective: To evaluate, both polysomnographically and by subjective scales, the efficacy and safety profile of pramipexole for restless legs syndrome (RLS) via a 3-week, double-blind, placebo-controlled, parallel-group, dose-ranging study.Methods: At baseline and after 3 weeks, periodic limb movements (PLM) and sleep parameters were assessed by polysomnography, and patients self-assessed their sleep disturbance and overall RLS severity using the international RLS study group rating scale (IRLS). Four pramipexole doses were evaluated: 0.125, 0.25, 0.50, and 0.75 mg/d. Data from 107 patients were included in the intent-to-treat (ITT) analysis.Results: For pramipexole recipients, the primary outcome measure, PLM per hour in bed asleep or awake (the PLM index, or PLMI), decreased by a median of ?26.55 to ?52.70 depending on dosage group, vs. ?3.00 for placebo (p < 0.01 or ?0.001 for each group vs. placebo; Wilcoxon–Mann–Whitney test). Improvements in the secondary endpoints of PLM while asleep and while awake were also significantly superior for pramipexole. At 3 weeks, all pramipexole doses reduced the median for PLM while asleep to levels considered normal (<5 PLM/h). Except for delta-sleep time and awakenings/arousals, sleep parameters remained unchanged or favored pramipexole. Median sleep latency was reduced by ?5.00 to ?11.75 min in the pramipexole groups, vs. ?2.00 for placebo (p < 0.05 for all groups except 0.25 mg/d). Median total sleep time increased by 25.75–66.75 min, vs. 25.50 (p < 0.05 for 0.50 mg/d), and median time in stages 2–4/rapid eye movement (REM) sleep increased by 37.00–68.00 min, vs. 26.75 (p < 0.05 for 0.50 mg/d). By subjective IRLS ratings, all pramipexole doses were significantly superior to placebo. Safety analysis demonstrated no dose-dependent increase in adverse events, and no drug-related increase in daytime somnolence was observed.Conclusions: Pramipexole is effective and well tolerated in RLS, most notably among objective measures, for reducing PLM and decreasing sleep latency. Although other sleep parameters showed lesser, usually insignificant change, patients’ subjective ratings of RLS severity and sleep disturbance were significantly improved (p ? 0.0023).     

Efficacy and safety of pramipexole in Japanese patients with primary restless legs syndrome: A polysomnographic randomized,double-blind,placebo-controlled study

ObjectiveTo evaluate the efficacy of pramipexole on polysomnographic measures, patient ratings and a clinical rating in Japanese patients with primary restless legs syndrome (RLS).MethodsPatients with moderate to severe RLS having periodic limb movements in bed index (PLMI) ? 5 were randomly assigned to receive pramipexole or placebo in a 6-week, double-blind, placebo-controlled study with forced titration from 0.125 to 0.75 mg/day. Both polysomnography (PSG) and the suggested immobilization test (SIT) were performed at baseline and 6 weeks after starting treatment.ResultsThe analysis of covariance of log-transformed PLMI showed that the adjusted means at the end of study were significantly smaller in the pramipexole group than in the placebo group (p = 0.0019). In all patients, variables on SIT did not show any differences between the two groups, whereas a significant improvement was shown in the pramipexole group compared with the placebo group for patients with a SIT-PLM index at baseline ? 15. Pramipexole group showed a significant reduction in the International Restless Legs Syndrome Study Group rating scale (IRLS; p = 0.0005), a significant improvement in both Patient Global Impression (PGI; p < 0.0001) and Clinical Global Impressions (CGI-I; p = 0.0488), and a significantly greater mean reduction in the Pittsburgh Sleep Quality Index (PSQI; p = 0.0016), when compared with those of placebo group at week 6.ConclusionsPramipexole is highly efficacious in the reduction of PLMI and in the improvement of subjective severity of RLS and subjective sleep disturbance caused by the disorder.     

The validity of the PAM-RL device for evaluating periodic limb movements in sleep and an investigation on night-to-night variability of periodic limb movements during sleep in patients with restless legs syndrome or periodic limb movement disorder using this system

BackgroundThe status of night-to-night variability for periodic limb movements in sleep (PLMS) has not been clarified. With this in mind, we investigated the validity of PLMS measurement by actigraphy with the PAM-RL device in Japanese patients with suspected restless legs syndrome (RLS) or periodic limb movement disorder (PLMD) and the night-to-night variability of PLMS among the subjects.MethodsForty-one subjects (mean age, 52.1 ± 16.1 years) underwent polysomnography (PSG) and PAM-RL measurement simultaneously. Thereafter, subjects used the PAM-RL at home on four more consecutive nights.ResultsThe correlation between PLMS index on PSG (PLMSI-PSG) and PLM index on PAM-RL (PLMI-PAM) was 0.781 (P < .001). When the PLMSI cutoff value on PSG was set at 15 episodes per hour, the cutoff value for predicting this PLMSI level was 16.0 episodes per hour. When the condition was set to the level in which the mean interclass correlation coefficient reached ⩾0.9, the number of required nights for repeated measurements was 26 nights for subjects with PLMI of <15 episodes per hour and three nights for those with PLMI ⩾15 episodes per hour on PAM-RL.ConclusionsPAM-RL is thought to be valuable for assessing PLMS even in Japanese subjects. Recording of PAM-RL for three or more consecutive nights may be required to ensure the screening reliability of a patient with suspected pathologically frequent PLMS.     

Elevated C-reactive protein is associated with severe periodic leg movements of sleep in patients with restless legs syndrome

BackgroundRestless legs syndrome (RLS) is a common sleep disorder in which urges to move the legs are felt during rest, are felt at night, and are improved by leg movement. RLS has been implicated in the development of cardiovascular disease. Periodic leg movements (PLMs) may be a mediator of this relationship. We evaluated systemic inflammation and PLMs in RLS patients to further assess cardiovascular risk.Methods137 RLS patients had PLM measurements taken while unmedicated for RLS. Banked plasma was assayed for high sensitivity C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha).ResultsMean (SD) PLM index was 19.3 (22.0). PLMs were unrelated to TNF-a and IL-6, but were modestly correlated with log CRP (r(129) = 0.19, p = 0.03). Those patients with at least 45 PLMs/h had an odds ratio of 3.56 (95% CI 1.26–10.03, p = 0.02, df = 1) for having elevated CRP compared to those with fewer than 45 PLMs/h. After adjustment for age, race, gender, diabetes, hypertension, hyperlipidemia, inflammatory disorders, CRP-lowering medications, and body mass index, the OR for those with ?45 PLMs/h was 8.60 (95% CI 1.23 to 60.17, p = 0.03, df = 10).ConclusionsPLMs are associated with increased inflammation, such that those RLS patients with at least 45 PLMs/h had more than triple the odds of elevated CRP than those with fewer PLMs. Further investigation into PLMs and inflammation is warranted.     

One year open-label safety and efficacy trial with rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome

BackgroundLong-term efficacy and tolerability data are not yet available for patch formulations of dopamine agonists in restless legs syndrome.MethodsEfficacy and safety of rotigotine (0.5–4 mg/24 h), formulated as a once-daily transdermal system (patch), were investigated in an open extension (SP710) of a preceding 6-week placebo-controlled trial (SP709, 341 randomized patients) in patients with idiopathic restless legs syndrome. For efficacy assessment the international RLS severity scale (IRLS), the RLS-6 scales, the clinical global impressions (CGI) and the QoL-RLS questionnaire were administered. In addition, long-term tolerability and safety were assessed.ResultsOf 310 patients who finished the controlled trial, 295 (mean age 58 ± 10 years, 66% females) with a mean IRLS score of 27.8 ± 5.9 at baseline of SP709 were included. We report results after one year of this ongoing long-term trial. Two hundred twenty patients (retention rate = 74.6%) completed the 12-month follow-up period. The mean daily dose was 2.8 ± 1.2 mg/24 h with 4 mg/24 h (40.6%) being the most frequently applied dose; 14.8% were sufficiently treated with 0.5 or 1.0 mg/24 h. The IRLS total score improved by −17.4 ± 9.9 points between baseline and end of Year 1 (p < 0.001). The other measures of severity, sleep satisfaction and quality of life supported the efficacy of rotigotine (p < 0.001 for pre-post-comparisons of all efficacy variables). The tolerability was described as “good” or “very good” by 80.3% of all patients. The most common adverse events were application site reactions (40.0%), which led to withdrawal in 13.2%. Further relatively frequent adverse events were nausea (9.5%) and fatigue (6.4%). Two drug-related serious adverse events, nausea and syncope, required hospitalization. Symptoms of augmentation were not reported by the patients.ConclusionRotigotine provided a stable, clinically relevant improvement in all efficacy measures throughout one year of maintenance therapy. The transdermal patch was safe and generally well tolerated by the majority of patients. Comparable to any transdermal therapy, application site reactions were the main treatment complication.     

Effectiveness and tolerability of rotigotine transdermal patch for the treatment of restless legs syndrome in a routine clinical practice setting in Germany

ObjectiveWe aimed to assess effectiveness and tolerability of rotigotine in patients with moderate to severe idiopathic restless legs syndrome (RLS) under daily practice conditions in Germany.MethodsIn this 3-month noninterventional study, effectiveness was assessed using RLS-6 (primary variables were symptom severity when falling asleep [item 2] and during the night [item 3]). Data were collected at baseline and at the end of treatment. Safety assessments included adverse events (AEs).ResultsSix hundred and eighty-four patients were treated with rotigotine and 418 (61%) completed the study. The full analysis set (FAS) comprised 564 patients (106 de novo; 458 pretreated [454 had complete rotigotine dosing data]). Mean rotigotine dose of longest duration was 2.4 ± 1.4 mg/24 h. Rotigotine improved all RLS-6 items (mean change from baseline [item 2], −2.4 ± 3.6; [item 3], −2.7 ± 3.4), with the most pronounced improvement observed in daytime symptoms while at rest (item 4, −2.9 ± 3.2). AEs were typical of dopaminergic treatment and transdermal administration. De novo patients generally started rotigotine on 1 mg/24 h (85% [90/106]) and pretreated patients on 1 (50% [227/454]) or 2 mg/24 h (40% [183/454]). Most patients who were pretreated with levodopa (57%), pramipexole (84%), or ropinirole (78%) monotherapy discontinued these medications on initiation of rotigotine.ConclusionsRotigotine was effective and well-tolerated when used in routine clinical practice.     

Sertraline and periodic limb movements during sleep: an 8-week open-label study in depressed patients with insomnia

BackgroundPrevious studies have reported that selective serotonin reuptake inhibitors (SSRIs) might induce or exacerbate periodic limb movements during sleep (PLMS). However, most of these studies were retrospective and cross-sectional studies with small sample sizes on a selective SSRI, fluoxetine. Because different SSRIs have different pharmacologic profiles, it was not certain if other SSRIs also might lead to PLMS.MethodsData were taken from an open-label 8-week trial of sertraline in depressive patients with insomnia (n = 31). Depressed patients were administered sertraline 50 mg at 8:00 am on the first day, and the dosage was subsequently titrated up to a maximum of 200 mg daily during the 8-week trial. All participants were tested by repeated polysomnography (PSG) (baseline, first day, 14th day, 28th day, and 56th day). Periodic leg movements (PLM) were visually counted and the PLM index (PLMI) was calculated. PLMS was defined as PLMI ⩾5, and significant PLMS was defined as PLMI ⩾15.ResultsCompared with baseline (PLMI, 3.6 ± 1.5), all PLMI indices increased on the immediate administration of sertraline on the first day (PLMI, 5.1 ± 3.9). From the 14th day onward, PLMI became stable and significantly higher than baseline and the first day (8.7 ± 3.1 on the 14th day, 8.3 ± 3.7 on the 28th day, and 8.5 ± 3.6 on the 56th day; F[11.81]; P = .003). The clinical responses and PSG characteristics continuously improved during the 8-week trial. The PLMS group (PLMI ⩾5) had a higher arousal index (AI) than the non-PLMS group on the 14th day (9.4 ± 5.5 vs 5.2 ± 3.7; t test, 4.22; P = .03) and the 56th day (8.1 ± 5.5 vs 4.3 ± 3.7; z score, 3.11; P = .04); albeit, there was no significant clinical disturbances in the PLMS group.ConclusionsPLMS were increased during sertraline treatment, but only a few of the PLMS reached the significant level. This effect of sertraline on PLMS might be dosage dependent. Although the sertraline-induced PLMS did not seem to cause significant clinical disturbance, the PLMS group (PLMI ⩾5) had a higher AI than the non-PLMS group. Thus clinicians should pay more attention to PLMS during SSRI antidepressant treatment.     

Restless legs syndrome in end-stage renal disease: Clinical characteristics and associated comorbidities

BackgroundDespite being frequently described in patients with end-stage renal disease (ESRD), clinical characteristics and comorbidities in association with restless legs syndrome (RLS) are still to be confirmed.ObjectivesThe aim of this study was to investigate clinical factors associated with RLS in ESRD patients in hemodialysis.MethodsThis is a cross-sectional study of 400 patients on hemodialysis, evaluating RLS, clinical features and other sleep abnormalities.ResultsOut of 400, 86 patients presented RLS (21.5%; mean age 48.8 ± 13.8 y), being more frequent in females (p < 0.005). Forty-eight individuals (12% mean age 50.7 ± 13.1 y) had moderate/severe RLS, 14 reported symptoms prior to hemodialysis, 13 described family history of RLS, and eight described symptoms as disturbing during dialysis. RLS cases showed lower hemoglobin (p < 0.005), poorer quality of sleep (Pittsburgh Sleep Quality Index >5, p = 0.002), higher scores on the Beck Depression Inventory Scale (p < 0.005), greater scores on the Charlson Comorbidity Index (p = 0.01) and the Epworth Sleepiness Scale (p = 0.001) and higher risk of obstructive sleep apnea (OSA; Berlin questionnaire, p = 0.01). Hypertension was more frequent in cases with moderate/severe RLS (p = 0.01) and remained after controlling for the risk of OSA (p = 0.02).ConclusionIn ESRD patients in hemodialysis, RLS is present in 21.5%; 16% report symptoms prior to hemodialysis and a family history of RLS. Symptoms are disturbing during hemodialysis in 9% of cases. RLS is associated with lower hemoglobin, worse sleep quality, excessive daytime sleepiness, depressive symptoms and higher risk of OSA. Hypertension is associated with moderate/severe RLS.     

Augmentation in the treatment of restless legs syndrome with transdermal rotigotine

ObjectiveTo assess the risk of augmentation under treatment with the transdermally delivered dopamine agonist rotigotine for restless legs syndrome (RLS).MethodsExperts in RLS augmentation retrospectively reviewed data from two double-blind, placebo-controlled 6-month trials (745 rotigotine and 214 placebo subjects, NCT00136045 and NCT00135993) and from two open-label 1-year trials (620 rotigotine subjects, NCT00498108 and NCT00263068). All study visits were systematically evaluated applying the Max Planck Institute (MPI) criteria for the diagnosis of both augmentation and clinically relevant augmentation.ResultsMPI criteria for augmentation were met on at least one visit by 8.2% of all subjects in the double-blind trials with 12 subjects meeting the criteria for clinically relevant augmentation: 11 under rotigotine (1.5%) and one under placebo treatment. In the open-label trials, 9.7% of all subjects met the MPI criteria for augmentation and 2.9% met the criteria for clinically relevant augmentation. None of the patients treated with rotigotine for up to 1.5 years (double-blind plus open-label trial) discontinued prematurely owing to augmentation. Neither could dose-dependency or a time pattern for clinically relevant augmentation episodes be detected.ConclusionsOur analyses suggest that the risk for clinically relevant augmentation for the duration of up to 18 months of rotigotine treatment is low.     

Prevalence and clinical characteristics of restless legs syndrome in diabetic peripheral neuropathy: comparison with chronic osteoarthritis

BackgroundThe prevalence of restless legs syndrome (RLS) in patients with peripheral neuropathy has been reported to be higher than that of the general population in some studies, which suggests an association between neuropathy and RLS, but not all studies show increased RLS with neuropathy. These differences may reflect adequacy of the diagnosis, effects of chronic pain complicating the diagnosis, or population differences. Moreover, if there is increased risk for RLS with neuropathy, it may reflect consequences of the chronic pain rather than other aspects of diabetes mellitus (DM). Therefore, we investigated the effects of diagnosis rigor on the estimated prevalence of RLS in patients with diabetic peripheral neuropathy (DPN) and those with chronic leg pain from osteoarthritis (OA), and then we compared the RLS prevalence in these two populations with each other and with population prevalence for Korea.MethodsOur study is a prospective case-control study of 199 patients with DPN and 220 patients with OA. After evaluating the presence of RLS in these subjects using the diagnostic criteria of the International RLS Study Group, we confirmed the diagnosis of RLS through face-to-face interviews using the 18-item Hopkins Diagnostic Questionnaire, which removes RLS mimics; and through independent examinations by two neurologists.ResultsOf the 199 subjects with DPN, 44 (22%) appeared to have RLS from their answers on the 4-item RLS diagnostic questionnaire compared to 8 (3.6%) of 220 subjects with OA. However, the prevalence of RLS in the DPN group dropped to 16 (8%) subjects but stayed at 8 (3.6%) OA subjects when using the Hopkins Telephone Diagnostic Interview (HTDI) adapted for clinical interview. The RLS prevalence determined by HTDI remained significantly higher (P = .042) in the DPN group compared to the OA group and was twice that reported for the general Korean population (8% vs 3.9%). Among subjects with DPN, those with RLS were older (68.06 ± 8.43 years vs 62.46 ± 11.05 years; P = .049) and had higher pain scores (visual analog scale [VAS], 4.69 ± 2.52 vs 2.72 ± 2.12; P = .002). The quality of sleep (MOS [Medical Outcomes Study] sleep scale) and health-related quality of life (QoL) (total score on the 36-Item Short-Form Health Survey [SF-36]) showed no significant difference between the two groups.ConclusionsThe prevalence of RLS in patients with DPN cannot be accurately assessed with only the four diagnostic criteria interview, but the prevalence was higher than expected for Koreans from the general population prevalence and also was higher than occurred with OA patients with chronic leg pains when accurately assessed with a structured interview. Chronic leg pain from OA does not significantly complicate RLS diagnosis, and chronic pain itself does not explain the increased RLS prevalence in diabetic neuropathy.     

PLM detection by actigraphy compared to polysomnography: a validation and comparison of two actigraphs

ObjectiveTo compare periodic leg movement (PLM) counts obtained with polysomnography (PSG) to those obtained from actigraphy with two devices (Actiwatch and PAM-RL).MethodsTwenty-four patients underwent full night actigraphy with Actiwatch from both legs and simultaneous PSG. Out of these patients, 10 had additional actigraphy with PAM-RL. Bilateral and unilateral PLM indices (PLMI) for both actigraphs were calculated for time in bed and compared to polysomnographic PLMI. Additionally, a comparison between the two different actigraphs was performed.ResultsPLMI obtained with Actiwatch were significantly lower than those obtained with PSG (21.2 ± 25.6/h versus 34.4 ± 30.7/h; p < 0.001), whereas the PLMI from PAM-RL were significantly higher than in PSG (63.6 ± 39.3/h versus 37.0 ± 33.5/h; p = 0.009). In direct comparison, Actiwatch gave significantly lower PLMI than the PAM-RL (p = 0.005). The correlations between Actiwatch and PSG (rho = 0.835, p < 0.001), PAM-RL and PSG (rho = 0.939, p < 0.001), and Actiwatch and PAM-RL (rho = 0.915, p < 0.001) were significant. Unilateral actigraphy compared to standard PSG gave less consistent findings. When comparing different settings of the PAM-RL, manual threshold setting resulted in PLMI that were no longer different from PSG (p = 0.074), in contrast to the default threshold setting.ConclusionsThe Actiwatch underestimated and the PAM-RL overestimated PLMI compared to PSG. Whereas PLMI obtained with two actigraphs and PSG were highly correlated, they differed in mean values. Therefore, PSG, actigraphy and also the different actigraphs cannot be interchanged in longitudinal studies, and actigraphy should not be used for diagnostic decision making based on PLM indices. The best approximation to PSG PLMI was achieved by using manual threshold setting with the PAM-RL.     

Sleep disorders and daytime sleepiness in children with attention-deficit/hyperactivity disorder: A two-night polysomnographic study with a multiple sleep latency test

ObjectiveTo evaluate sleep macrostructure, sleep disorders incidence and daytime sleepiness in attention-deficit/hyperactivity disorder (ADHD) affected children compared with controls.MethodsThirty-one patients (26 boys, 5 girls, mean age 9.3 ± 1.7, age range 6–12 years) with ADHD diagnosed according to DSM-IV criteria, without comorbid psychiatric or other disorders, as never before pharmacologically treated for ADHD. The controls were 26 age- and sex-matched children (22 boys, 4 girls, age range 6–12 years, mean age 9.2 ± 1.5). Nocturnal polysomnography (PSG) was performed for two nights followed by the multiple sleep latency test (MSLT).ResultsNo differences between the two groups comparing both nights were found in the basic sleep macrostructure parameters or in the time (duration) of sleep onset. A first-night effect on sleep variables was apparent in the ADHD group. Occurrence of sleep disorders (sleep-disordered breathing [SDB], periodic limb movements in sleep [PLMS], parasomnias) did not show any significant differences between the investigated groups. A statistically significant difference (p = 0.015) was found in the trend of the periodic limb movement index (PLMI) between two nights (a decrease of PLMI in the ADHD group and an increase of PLMI in the control group during the second night). While the mean sleep latency in the MSLT was comparable in both groups, children with ADHD showed significant (sleep latency) inter-test differences (between tests 1 and 2, 1 and 4, 1 and 5, p < 0.01).ConclusionAfter the inclusion of adaptation night and exclusion of psychiatric comorbidities, PSG showed no changes in basic sleep parameters or sleep timing, or in the frequency of sleep disorders (SDB, PLMS) in children with ADHD compared with controls, thus not supporting the hypothesis that specific changes in the sleep macrostructure and sleep disturbances are connected with ADHD. A first-night effect on sleep variables was apparent only in the ADHD group. Though we found no proof of increased daytime sleepiness in children with ADHD against the controls, we did find significant vigilance variability during MSLT in the ADHD group, possibly a sign of dysregulated arousal.     

A randomized,double-blind, 6-week,dose-ranging study of pregabalin in patients with restless legs syndrome

ObjectiveThis study evaluated the dose-related efficacy and safety of pregabalin in patients with idiopathic restless legs syndrome (RLS).MethodsThis six-arm, double-blind, placebo-controlled, dose–response study randomized patients (N = 137) with moderate-to-severe idiopathic RLS in an equal ratio to placebo or pregabalin 50, 100, 150, 300, or 450 mg/day. The dose–response was characterized using an exponential decay model, which estimates the maximal effect (E_max) for the primary endpoint, the change in the International Restless Legs Study Group Rating Scale (IRLS) total score from baseline to week 6 of treatment. Secondary outcomes included Clinical Global Impressions-Improvement Scale (CGI-I) responders, sleep assessments, and safety.ResultsThe separation of treatment effect between placebo and pregabalin began to emerge starting at week 1 which continued and increased through week 6 for all dose groups. The IRLS total score for pregabalin was dose dependent and well characterized for change from baseline at week 6. The model estimated 50% (ED₅₀) and 90% (ED₉₀) of the maximal effect in reducing RLS symptoms that occurred at pregabalin doses of 37.3 and 123.9 mg/day, respectively. A higher proportion of CGI-I responders was observed at the two highest doses of pregabalin (300 and 450 mg/day) versus placebo. Dizziness and somnolence were the most common adverse events and appeared to be dose-related.ConclusionsIn this 6-week phase 2b study, pregabalin reduced RLS symptoms in patients with moderate-to-severe idiopathic RLS. The symptom reduction at week 6 was dose-dependent with 123.9 mg/day providing 90% efficacy. Pregabalin was safe and well tolerated across the entire dosing range.     

Increased prevalence of nocturnal smoking in restless legs syndrome (RLS)

ObjectiveWe investigated the prevalence of nocturnal smoking (NS) in patients with RLS.MethodsOne hundred RLS patients living in Emilia-Romagna (Northern Italy) and 100 matched controls, randomly selected from the general population, underwent interviews for the presence of nocturnal smoking and for obsessive-compulsive traits, depression, excessive daytime sleepiness (EDS) and subjective sleep quality.ResultsNS was more prevalent in RLS patients than controls (lifetime prevalence: 12% vs. 2%, P = 0.012). Patients with NS had more frequently Sleep-Related Eating Disorders (SRED) than patients without NS (83.3% vs. 26.1%, P = 0.0002). Pathological and borderline Maudsley Obsessive-Compulsive Inventory (MOCI) values as well as pathological values at the Beck Depression Inventory (BDI) increased from controls to RLS patients without NS to RLS patients with NS (P = 0.005 and P = 0.01, respectively).ConclusionsWe demonstrate an increased prevalence of NS in patients with RLS, in many cases associated with increased SRED. NS may be associated with psychopathological traits in RLS and may be relevant in the management of RLS patients.     

The severity range of restless legs syndrome (RLS) and augmentation in a prospective patient cohort: Association with ferritin levels

ObjectivesThe aim of the study was to prospectively examine all patients with a diagnosis of RLS consulting a sleep disorders clinic and to assess RLS severity and augmentation and their associations, including ferritin levels.MethodsPatients were stratified into patients with RLS as ancillary diagnosis, RLS sufferers without current augmentation and RLS sufferers with current augmentation. Work-up included RLS severity scales and blood biochemical variables including indices of iron metabolism.ResultsIn an 18-month period, 302 patients with RLS (183 women, 119 men; mean age, 59.1 ± 13.7 years) were recruited. RLS was considered idiopathic in 291 patients (96.4%). Most patients (240, 79.5%) were RLS sufferers, whereas the remaining 62 (20.5%) had RLS as ancillary diagnosis. Nineteen out of 162 patients treated with dopaminergic agents (11.7%) had current augmentation. Almost one-third of all patients (31.1%) had ferritin levels <50 μg/l. Patients with an ancillary diagnosis of RLS had higher ferritin levels than RLS sufferers without current augmentation. The lowest ferritin levels were present in RLS sufferers with current augmentation 132.8 ± 98.0 μg/l vs. 100.6 ± 84.5 μg/l vs. 55.8 ± 43.6 μg/l; p = 0.002). Patients with augmentation did not differ from non-augmented patients regarding age, gender, RLS etiology, presence of previous augmentation, or any other documented comorbidity (p > 0.05).ConclusionThe severity spectrum of RLS in this clinical cohort ranged from the ancillary diagnosis of RLS to augmented RLS. There was an inverse correlation between RLS severity and ferritin levels. Patients with current augmentation had the lowest ferritin levels. Our data further strengthen a putative role of low iron stores as a potential aggravator of idiopathic RLS. Moreover, low ferritin might represent a potential biomarker of RLS augmentation under dopaminergic therapy.     

Effect of pramipexole on RLS symptoms and sleep: a randomized, double-blind, placebo-controlled trial

BackgroundPatients with Restless Legs Syndrome (RLS) often seek treatment because of sleep problems related to nocturnal symptoms. Our goal was to test the ability of pramipexole to improve sleep in RLS patients and to reconfirm its efficacy for primary RLS symptoms.MethodsAdults with moderate or severe RLS were randomized to receive placebo or pramipexole (flexibly titrated from 0.25 to 0.75 mg), 2–3 h before bedtime for 12 weeks. The co-primary outcome measures were change in Medical Outcomes Study (MOS) sleep disturbance score and International RLS Study Group Rating Scale (IRLS) score at 12 weeks.ResultsThe intent-to-treat population included 357 patients: 178 received pramipexole and 179 received placebo. At 12 weeks, the adjusted mean change from baseline was greater for pramipexole (vs. placebo) for IRLS score (−13.4 ± 0.7 vs. −9.6 ± 0.7) and MOS sleep disturbance score (−25.3 ± 1.5 vs. −16.8 ± 1.5) (p ⩽ 0.0001; ANCOVA). Responder rates (clinical and patient global impression and IRLS) were also significantly higher in the pramipexole group. RLS-QOL score was improved over placebo at Week 12 (p < 0.01) as were MOS sleep adequacy (p = 0.0008) and quantity (p = 0.08) scores. Nine percent of patients in each group withdrew because of adverse events.ConclusionsPramipexole is effective and well-tolerated for RLS and related sleep disturbance.     

Autonomic complaints in patients with restless legs syndrome

BackgroundData regarding autonomic function in restless legs syndrome (RLS) are limited to heart rate and blood pressure changes in cases with periodic limb movements (PLMS).MethodsWe compared autonomic symptoms of 49 subjects with RLS vs 291 control subjects using the Scales for Outcome in Parkinson disease-Autonomic (SCOPA-AUT) questionnaire, consisting of 23 items in six domains scored from 0 to 3. The total score and domain scores were transformed to 0–100 points. Subjects with neurodegenerative disorders (i.e., dementia, Parkinsonism) were excluded.ResultsThe RLS group was younger (mean ± standard deviation, 77.9 ± 8.0 vs 80.5 ± 7.9 years; P = .03) and included more women (84% vs 69%; P = .04). The mean SCOPA-AUT total score was higher in the RLS group compared with the control group (20 ± 11 vs 16 ± 9; P = .005). Additionally the RLS group had abnormalities in gastrointestinal, cardiovascular, and pupillomotor domains. When comparing the percentage of subjects with any complaint on individual questions (score of ⩾1), the RLS group had a greater number of subjects with sialorrhea, constipation, early abdominal fullness, lightheadedness when standing, and heat intolerance.ConclusionsAutonomic complaints, especially gastrointestinal, cardiovascular, and oversensitivity to light, were significantly increased in subjects with RLS. Causes for autonomic dysfunction in RLS require further investigation.     

Relation of the International Restless Legs Syndrome Study Group rating scale with the Clinical Global Impression severity scale,the restless legs syndrome 6-item questionnaire,and the restless legs syndrome-quality of life questionnaire

BackgroundThe SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life questionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To provide clinical context for the IRLS and to guide the choice of assessment scales for RLS studies, our post hoc analysis of SP790 data evaluated associations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and RLS-QoL.MethodsScale associations were analyzed at baseline and at the end of maintenance (EoM) using data from the safety set (rotigotine and placebo groups combined [n = 458]). Changes from baseline to EoM in IRLS score vs comparator scale scores also were analyzed.ResultsThere was a trend towards increasing IRLS severity category with increasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation coefficients showed correlations between IRLS and comparator scale scores at baseline and EoM as well as correlations for change from baseline to EoM.ConclusionCorrelations between the IRLS and comparator scales were substantial. These data indicate that the IRLS is clinically meaningful. The IRLS and CGI-1 are generally sufficient to evaluate the overall severity and impact of RLS symptoms in clinical trials.     

Insomnia symptoms,objectively measured sleep,and disease severity in chronic obstructive pulmonary disease outpatients

BackgroundSleep disturbances are known to have a negative impact on a range of clinical outcomes in chronic obstructive pulmonary disease (COPD). We examined the associations of insomnia symptoms and objectively measured sleep parameters to a composite score for body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index (a multidimensional index of COPD severity), arterial blood gases, nocturnal respiratory disturbances, periodic limb movements (PLM), psychologic distress, pain, age, and sex.MethodsThe sample comprised 73 COPD outpatients (mean age, 63.6 years; standard deviation {SD}, 7.5; range 47–85 years; 41.1% women). Insomnia symptoms were measured with the Bergen Insomnia Scale (BIS) and sleep efficiency (SE), slow-wave sleep (SWS), and total sleep time (TST) were assessed with clinical polysomnography (PSG).ResultsBODE index was positively associated with composite BIS score (P = .040). Patients with more severe COPD presented more complaints of nonrestorative sleep compared to patients with less severe COPD (P = .010). In multivariate analysis, the composite BIS score was independently associated with PLM (P < .001), nocturnal respiratory disturbances (P = .001), pain (P = .031), and psychologic distress (P = .044) but not with the BODE index. Objectively measured sleep variables were not associated with any of the health-related variables.ConclusionInsomnia symptoms in COPD patients result from a wide range of health-related factors. More severe COPD may be associated with a subjective experience of nonrestorative sleep but not with objectively measured sleep variables.     

Reliability and validity of two self-administered questionnaires for screening restless legs syndrome in population-based studies

BackgroundA reliable and valid questionnaire for screening restless legs syndrome (RLS) is essential for determining accurate estimates of disease frequency. In a 2002 NIH-sponsored workshop, experts suggested three mandatory questions for identifying RLS in epidemiologic studies. We evaluated the reliability and validity of this RLS-NIH questionnaire in a community-based sample and concurrently developed and evaluated the utility of an expanded screening questionnaire, the RLS-EXP.MethodsThe study was conducted at Kaiser Permanente of Northern California and the Stanford University Sleep Clinic. We evaluated test–retest reliability in a random sample of subjects with prior physician-assigned RLS (n = 87), subjects with conditions frequently misclassified as RLS (n = 31), and healthy subjects (n = 9). Validity of both instruments was evaluated in a random sample of 32 subjects, and in-person examination by two RLS specialists was used as the gold standard.ResultsFor the first three RLS-NIH questions, the kappa statistic for test–retest reliability ranged from 0.5 to 1.0, and sensitivity and specificity was 86% and 45%, respectively. For the subset of five questions on RLS-EXP that encompassed cardinal features for diagnosing RLS, kappas were 0.4–0.8, and sensitivity and specificity were 81% and 73%, respectively.ConclusionsSensitivity of RLS-NIH is good; however, the specificity of the instrument is poor when examined in a sample that over-represents subjects with conditions that are commonly misclassified as RLS. Specificity can be improved by including separate questions on cardinal features, as used in the RLS-EXP, and by including a few questions that identify RLS mimics, thereby reducing false positives.