Working memory deficit in patients with restless legs syndrome: an event-related potential study

ObjectiveThe aim of this study was to investigate whether there is a working memory (WM) deficit in restless legs syndrome (RLS) patients, by studying the Sternberg WM task of event-related potential (ERP).MethodsThirteen drug-naive RLS patients and 13 healthy age-matched controls with no sleep disturbances participated in the present study. P300 ERP was recorded during Sternberg WM task using digits as mnemonic items. P300 amplitudes and reaction times were compared between groups (RLS vs control) considering brain regions (frontal, central, and parietal) and memory load sizes (two, three, and four) as within-subject factors. Clinical and sleep-related variables were correlated with P300 amplitude.ResultsThe reaction time in RLS patients was significantly longer than controls over all memory load sizes. The P300 amplitude at parietal regions in RLS patients was significantly lower than in controls regardless of memory load sizes, which was significantly negatively correlated with duration of RLS history in RLS patients.ConclusionOur study suggests that patients with severe RLS have WM deficits. Furthermore, negative correlation of P300 amplitudes with the duration of RLS illness suggests that cerebral cortical dysfunction in RLS patients results from repeated RLS symptom attacks.     

Transcranial direct current stimulation on primary sensorimotor area has no effect in patients with drug-naïve restless legs syndrome: a proof-of-concept clinical trial

ObjectiveTo evaluate the efficacy of transcranial direct current stimulation (tDCS) in people with drug-naïve restless legs syndrome (RLS).MethodsA two-week, double-blind, randomized, sham-controlled trial was performed. Thirty-three females with RLS were recruited. Participants received five sessions of tDCS using cathodal, anodal or sham stimulation. They were assessed at baseline (T0), three days (T1) and 13 days (T2) after the end of tDCS. Primary outcomes included the International RLS Group Rating Scale (IRLS) and the Clinical Global Impressions-Improvement (CGI-I). Secondary outcomes included the Patient Global Impression scale, the Pittsburgh Sleep Quality Index, the Medical Outcome Study sleep subscales, and the Beck Depression Inventory. Objective neurophysiological changes were assessed using event-related desynchronization/synchronization (ERD/ERS) of electroencephalography.ResultsThe changes in the IRLS scores, as well as the responder rate in the CGI-I scale, did not differ significantly among the groups. There was also no significant difference in any of the secondary outcome measures and ERD/ERS among the groups.ConclusionsTranscranial direct current stimulation with electrodes on the sensorimotor areas showed no significant effect in people with drug-naïve RLS.     

Open-label study of the long-term efficacy and safety of pramipexole in patients with Restless Legs Syndrome (extension of the PRELUDE study)

BACKGROUND AND OBJECTIVE: To demonstrate the long-term efficacy and safety of pramipexole for Restless Legs Syndrome (RLS) using physician and patient RLS ratings, along with subjective assays of sleep parameters, in a 26-week, open-label trial. PATIENTS AND METHODS: Among 107 Finnish adults with moderate to severe RLS, pramipexole initiated at 0.125 mg/day was titrated to a maximum 0.75 mg/day. Efficacy evaluations included the International RLS Study Group Rating Scale (IRLS), Patient Global Impression (PGI) scale, Clinical Global Impressions-Improvement (CGI-I) scale, Epworth Sleepiness Scale (ESS), and Short Form-36 (SF-36) Health Survey. Subjective Sleep Quality was assessed by patient ratings of sleep and morning tiredness. Safety was documented by Adverse Events reported in >5% of patients. RESULTS: The mean reduction in IRLS score was 73.5% (P<0.05). The IRLS responder rate, defined by score reduction of >or= 50%, was 81.3%. On the PGI scale, 89.7% of patients rated themselves as "very much" or "much" better. By CGI-I assessment, 94.8% of patients were considered either "very much" or "much" improved. Mean ESS score showed a modest but statistically significant reduction (P<0.05) within the normal range, indicating that long-term pramipexole did not increase daytime sleepiness. On the SF-36 all 8 domains showed improvement, 5 of them statistically significant (P<0.05) and 4 of these 5 (role-physical, bodily pain, vitality, and role-emotional) by >10 points on a 100-point scale. Subjective Sleep Quality also improved. The most frequent Adverse Events were influenza (17.8%), headache (15.0%), and fatigue (10.3%). CONCLUSION: Pramipexole is well tolerated and effective for long-term treatment of RLS.     

Working memory load for faces modulates P300, N170, and N250r

We used event-related potential (ERP) methodology to examine neural activity associated with visual working memory (WM) for faces. There were two main goals. First, to extend previous findings of P300 load modulation to WM for faces. Second, to examine whether N170 and N250r are also influenced by WM load. Between one and four unfamiliar faces were simultaneously presented for memory encoding. After a 1-sec delay, a target face appeared, and participants had to judge whether this face was part of the previous face array. P300 amplitude decreased as WM load increased, and this P300 suppression was observed at both encoding and retrieval. WM load was also found to modulate other ERPs. The amplitude of the N170 elicited by the target face decreased with load, and this N170 decrease leveled off at load 2, reflecting the behavioral WM capacity of around two faces. In addition, the N250r, observed as an ERP difference for target faces that were present in the encoding array relative to target faces that were absent, was also reduced for higher WM loads. These findings extend previous work by showing that P300 modulation by WM load also occurs for faces. Furthermore, we show, for the first time, that WM load affects the N250r and the early visual N170 component. This suggests that higher visual areas play an important role in WM for faces.     

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

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

Low-dose pramipexole in the management of restless legs syndrome. An open label trial

Dopaminergic agents are considered the treatment of choice for restless legs syndrome (RLS); levodopa is the only substance licensed for this disorder in some European countries. However, in a substantial proportion of patients symptoms are not adequately controlled for a whole night due to the short half-life of levodopa or because symptom augmentation may develop. To further investigate the impact of pramipexole on the management of RLS we performed a short-term open label trial with pramipexole in 17 patients who were being insufficiently treated with levodopa or for whom pramipexole was primarily being considered because of the severity of the RLS symptoms. A single dose of 0.125-0.75 mg pramipexole (mean 0.3 +/- 0.2 mg) in the evening resulted in a significant improvement of subjective RLS symptoms as rated by the International RLS Study Group Severity Scale (IRLS scores: 29.8 +/- 4.7 baseline vs. 7.3 +/- 5.9 endpoint; p = 0.0001). Polysomnographic recordings showed a significant improvement of the periodic leg movements (PLM) index, PLM sleep arousal index, sleep-onset latency, total sleep time and sleep efficiency. All patients who had developed a worsening of RLS symptoms under levodopa recovered from daytime symptoms after their medication was switched to pramipexole. Since pramipexole was well tolerated, an ideal dosage to control RLS symptoms could be reached rapidly. Pramipexole has proven a suitable alternative in patients with moderate to severe RLS, particularly when their therapy has to be switched to a dopamine agonist.     

Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose-finding study--the PRELUDE study

BACKGROUND AND PURPOSE: To evaluate the effects of pramipexole (0.125-0.75 mg/d) on polysomnographic (PSG) measures and patient and clinician ratings of restless legs syndrome (RLS). PATIENTS AND METHODS: Patients (n=109) with moderate to severe RLS were randomized to placebo or fixed doses of pramipexole during a 3-week, double-blind, placebo-controlled, dose-finding study. RESULTS: In each pramipexole dose group, the periodic limb movements during time in bed index (PLMI) decreased significantly, compared with placebo (adjusted mean difference in log-transformed data: 0.125 mg, -1.54; 0.25 mg, -1.93; 0.50 mg, -1.89; and 0.75 mg, -1.52; P<0.0001). At all doses, International RLS Study Group Rating Scale (IRLS) scores were also significantly reduced, with the greatest adjusted mean reduction in the 0.50mg group (-17.01). At all but the lowest pramipexole dose, the percentage of responders (> or =50% reduction of IRLS score) was substantially higher than for placebo (61.9-77.3, vs 33.3%). In the pramipexole groups, 50.0-77.3% of patients rated their condition as 'much better' or 'very much better', compared with 38.1% of patients in the placebo group (P=0.0139 for the 0.50 mg dose). Clinical global impressions (CGI) scale ratings of 'much improved' or 'very much improved' were given to 61.9-86.4% of patients in the pramipexole groups, compared with 42.9% in the placebo group (P<0.05 for the 0.25, 0.50, and 0.75 mg groups). Pramipexole was well tolerated and did not produce somnolence at any dose. CONCLUSION: Pramipexole is effective and safe in the treatment of both objective and subjective facets of RLS.     

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.     

A method to switch from oral dopamine agonists to rotigotine in patients with restless legs syndrome and mild augmentation

BackgroundWe examined the short- and long-term efficacy and tolerability of a cross-titration algorithm from oral dopamine agonists to the rotigotine transdermal patch in patients dissatisfied with their restless legs syndrome (RLS) treatment, predominantly with mild augmentation.MethodsPatients with RLS (n = 20) were recruited at a single site. The cross-titration consisted of decreasing oral dopaminergic agents (ropinirole by 1 mg or pramipexole by 0.25 mg) and increasing rotigotine by 1 mg every two days. Efficacy and adverse events (AEs) were assessed at one, three, six and 12 months after the switch.ResultsPatients had moderate–severe RLS symptoms at the baseline (mean international restless legs syndrome (IRLS) score 19.4 ± 5.5); 85% had augmentation and 45% reported afternoon RLS symptoms. The baseline mean pramipexole equivalent dose was 0.6 ± 0.3 mg. At Week 5, 85% (17/20) had successfully switched from their oral dopamine agonist to rotigotine (mean dose 2.5 ± 0.6 mg; change in IRLS score: −6.7 ± 8.4, p = 0.002); 14 patients were CGI-I responders (much or very much improved). Three patients withdrew due to lack of efficacy. Twelve months after cross-titration, 10 patients continued on rotigotine, of whom four required either higher doses of rotigotine or supplemental RLS medication compared with their optimal Week 5 dose; five patients withdrew due to AEs and two due to lack of efficacy.ConclusionA cross-titration to rotigotine was efficacious after five weeks in 70% of patients dissatisfied with RLS treatment, most of whom had mild augmentation. At one year following the medication switch, 50% had discontinued rotigotine due to lack of continued efficacy or side effects.     

Clinical characteristics of restless legs syndrome in end‐stage renal failure and idiopathic RLS patients

This study was done to identify the clinical characteristics of uremic restless legs syndrome (RLS). Consecutive uremic RLS patients (n = 15) and idiopathic RLS patients (iRLS; n = 20) were evaluated. The groups were compared with respect to their clinical course, subjective symptoms [using the Pittsburgh Sleep Quality Index (PSQI) and the International Restless Legs Syndrome Severity Scale (IRLS)], polysomnographic (PSG) variables, the results of the suggested immobilization test (SIT), and the drug doses used to treat RLS. The duration of the disorder was significantly shorter in the uremic RLS group than in the iRLS group. The PSQI and IRLS scores before treatment were higher in the uremic RLS group than in the iRLS group. The periodic leg movement index (PLM index) on PSG and the SIT index were also higher in the uremic RLS group (P < 0.001, respectively). The bromocriptine equivalent dose of dopaminergic agonists used to treat RLS was significantly higher in the uremic RLS group (P < 0.001). Uremic RLS appears to deteriorate faster and to become more severe than iRLS. Moreover, uremic RLS patients appear to have a decreased response to dopaminergic agonists. © 2007 Movement Disorder Society     

Adult ADHD and working memory: Neural evidence of impaired encoding

ObjectivesTo investigate neural and behavioural correlates of visual encoding during a working memory (WM) task in young adults with and without Attention-Deficit/Hyperactivity Disorder (ADHD).MethodsA sample of 30 college students currently meeting a diagnosis of ADHD and 25 typically developing students, matched on age and gender, performed a delayed match-to-sample task with low and high memory load conditions. Dense-array electroencephalography was recorded. Specifically, the P3, an event related potential (ERP) associated with WM, was examined because of its relation with attentional allocation during WM. Task performance (accuracy, reaction time) as well as performance on other neuropsychological tasks of WM was analyzed.ResultsNeural differences were found between the groups. Specifically, the P3 amplitude was smaller in the ADHD group compared to the comparison group for both load conditions at parietal–occipital sites. Lower scores on behavioural working memory tasks were suggestive of impaired behavioural WM performance in the ADHD group.ConclusionsFindings from this study provide the first evidence of neural differences in the encoding stage of WM in young adults with ADHD, suggesting ineffective allocation of attentional resources involved in encoding of information in WM.SignificanceThese findings, reflecting alternate neural functioning of WM, may explain some of the difficulties related to WM functioning that college students with ADHD report in their every day cognitive functioning.     

普拉克索治疗原发性不宁腿综合征的疗效和安全陛观察

目的 观察普拉克索对我国原发性不宁腿综合征(RLS)患者的治疗效果以及可能发生的不良反应. 方法 选择自2009年5月至11月在哈尔滨医科大学第二附属医院神经内科就诊的10例中到重度原发性RLS患者,给予普拉克索0.125～0.75mg/d,每日睡前2～3h顿服,持续治疗6周.利用国际RLS研究小组的RLS严重程度量表(mLS)、临床总体印象改善量表(CGI-I)、患者总体印象量表(PGI)和Epworth嗜睡量表(ESS)对患者治疗前后的RLS症状严重程度和嗜睡程度进行评估.并对结果进行统计学分析,同时记录不良反应.结果 (1)治疗后患者的IRLS评分较治疗前平均降低73.7%,比较差异有统计学意义(P<0.05),9例患者IRLS评分降低在50%以上;(2)治疗结束时,8例患者PGI评估选择"很好"或"非常好",9例患者CGI-I评估为"明显改善"或"非常明显改善";(3)患者ESS评分在治疗后较治疗前平均降低3.80±1.75,比较差异有统计学意义(P<0.05);(4)1例患者在治疗末期加量至0.5mg/d时出现轻度恶心,胃区不适,治疗结束停药2 d后症状自行消失;(5)1例患者首次用药后双下肢感觉异常和睡眠障碍即有明显改善.结论 为期6周的临床实验表明,在每日口服剂量为0.125～0.75 mg时,普拉克索对于我国原发性RLS的治疗是安全有效的.     

Working memory function in post-traumatic stress disorder: An event-related potential study

ObjectivePrevious studies using event-related potentials (ERPs) in post-traumatic stress disorder (PTSD) have demonstrated reduced P3 amplitude during target detection and working memory (WM) processes. This study investigated effects of psychotropic medication (primarily antidepressants) on these ERP components.MethodsERPs were recorded from 26 scalp sites in 34 PTSD patients (20 unmedicated, 14 medicated) with age- and gender-matched controls during a WM paradigm that involved detection of target letters on a visual display.ResultsAs expected, PTSD patients showed a reduced amplitude P3wm component during WM updating and a reduced and delayed target P3 component. Contrary to expectation, these ERP effects were most apparent in the medicated subgroup of PTSD patients. The medicated PTSD subgroup showed a trend towards reduced P3wm amplitude compared with controls and a significant amplitude reduction and delay of target P3 component, while there was little difference between the non-medicated PTSD subgroup and controls. Neither ERP nor behavioural measures were related to Clinician Administered PTSD Scale (CAPS) symptom severity measures.ConclusionsThese results are consistent with research that suggests antidepressant medication may impair working memory performance.SignificanceThe present study illustrates the importance of monitoring medication effects on cognitive performance during clinical efficacy studies.     

Open-label study of the efficacy and safety of intravenous ferric carboxymaltose in pregnant women with restless legs syndrome

ObjectiveThe objective of this study was to test the efficacy and safety of intravenous ferric carboxymaltose (FCM) in pregnant women with restless legs syndrome (RLS) and iron deficiency or anemia. The open-label pilot study (exploratory) was performed at the University Hospital of Zürich and the Neurocenter of Southern Switzerland (Lugano).Patient and MethodsNineteen women in the third trimester of pregnancy with moderate-to-severe RLS and serum ferritin levels <35 µg/l or hemoglobin (Hb) < 11.0 g/dl were included in the study. RLS was graded according to the International Restless Legs Syndrome (IRLS) Study Group rating scale. All participants had a score of ≥20 or had RLS ≥3 times/week. Based on the Hb levels, 500 or 700 mg of FCM was administered over 20 min. The primary end point was a ≥ 50% reduction in the mean IRLS score one week after FCM infusion. The secondary end points included periodic limb movements (PLMs; assessed using nocturnal foot actigraphy), sleep quality (assessed using the Pittsburgh Sleep Quality Index), and safety.ResultsThe IRLS score decreased from 23 ± 7 (baseline) to 13 ± 7 (P <0.01), whereas the PLM index decreased from 35 ± 26 (baseline) to 25 ± 20 (P <0.001). Significant improvement in sleep quality was also reported (P <0.029), and treatment was well tolerated. Three serious adverse events were reported, but they were considered unrelated to treatment.ConclusionsThese data provide promising evidence on the safety and efficacy of FCM for moderate-to-severe RLS in pregnant women with iron deficiency or anemia. Therefore, a future placebo-controlled study is warranted.     

Impact of sleep-related complaints on depressive symptoms in patients with restless legs syndrome

OBJECTIVE: Restless legs syndrome (RLS) is a distressing sensorimotor disorder with a 5% to 10% prevalence in the United States and Western Europe. The nocturnal occurrence of symptoms often leads to severe sleep disturbances. RLS has been reported to be associated with depression and anxiety. The aim of the present study was to investigate the relationship between RLS symptom severity, sleep disturbances, and depressive symptoms. METHOD: Questionnaire data from 100 consecutive patients with idiopathic RLS who had been investigated in our Sleep Disorders Unit from April 1999 to December 2004 were evaluated. Patients were untreated regarding RLS, depression, or sleep disturbances. Severity of RLS was assessed with the International RLS Study Group rating scale (IRLS). Depressive symptoms and subjective sleep quality were determined using the Beck Depression Inventory (BDI) and the Pittsburgh Sleep Quality Index (PSQI), respectively. RESULTS: IRLS scores indicated moderate-to-severe RLS symptoms in the population studied (mean +/- SD IRLS score = 23.6 +/- 6.7). The mean +/- SD BDI score was 9.3 +/- 5.6, with highest values on the "reduced sleep," "loss of energy," and "work difficulties" items, indicating predominating somatic symptoms of depression. Fourteen patients had a BDI score of 15 to 20 ("mild depression"), and 3 patients had a BDI score of 20 to 30 ("mild to moderate depression"). Overall, patients estimated their sleep quality as moderately impaired (mean +/- SD PSQI score = 10.9 +/- 3.7). Severity of RLS correlated with the impairment of subjective sleep quality (r = 0.281, p = .007) but not with self-rated depressive symptoms (r = 0.119, p = .237). CONCLUSION: RLS patients scored high on the somatic items of the BDI, particularly on those related to sleep disturbance, but not on the other items that mostly address cognitive symptoms. Our results indicate that RLS might be associated with some features of depression but not with the full spectrum of a depressive disorder. The relationship between the 2 disorders should be investigated in further studies.     

Treatment of restless legs syndrome/Willis-Ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis

ObjectivesRecent animal models of restless legs syndrome (RLS) suggest that brain iron deficiency is associated with a hypoadenosinergic state, with downregulation of adenosine A₁ receptors (A1R) in the striatum and cortex. We hypothesized that an increase in extracellular adenosine induced by inhibitors of adenosine transporters, such as the non-selective ENT1/ENT2 inhibitor dipyridamole, would result in an improvement in RLS symptoms.MethodsIn a prospective two-month open-label, non-placebo controlled clinical trial, 15 untreated idiopathic RLS patients began treatment with 100 mg dipyridamole (with uptitration to 400 mg if necessary). Multiple Suggested Immobilization Tests and polysomnography were performed at baseline and at eight weeks. Severity was assessed at four and eight weeks using the IRLS, and the CGI scales. The primary endpoint was therapeutic response (50% improvement in IRLS total score).ResultsThirteen patients completed the study. IRLS score improved from a mean (±S.D.) of 23.4 ± 4.6 at baseline to 10.7 ± 4.5 at eight weeks. Six out of 13 patients were full responders and four were partial responders. The mean (±S.D.) effective dose of dipyridamole at eight weeks was 281.8 ± 57.5 mg/day. Sleep variables also improved, and the mean (±S.D.) periodic leg movement index decreased from 26.7 ± 7.2 to 4.3 ± 1.9. Dipyridamole was generally well tolerated. Main side effects were abdominal cramps, diarrhea, dizziness, and flushing.ConclusionsThese preliminary results suggest that dipyridamole has significant therapeutic effects on both sensory and motor symptoms, as well as sleep. In addition, it provides evidence that hypoadenosinergic mechanisms play a central role in RLS.Classification of evidenceThe study provides class III evidence supporting the therapeutic effects of dipyridamole in RLS.     

Relationship of periodic leg movements and severity of restless legs syndrome: a study in unmedicated and medicated patients.

OBJECTIVE: To evaluate the relationship of the severity of restless legs syndrome (RLS) as assessed by a subjective, patient-rated scale (International RLS Study Group Rating Scale, IRLS), and of periodic leg movements in sleep (PLMS) as an objective parameter, in two different patient populations. METHODS: Data of 200 unmedicated patients with idiopathic RLS were evaluated. Group 1 (n=100) consisted of selected patients participating in the Pergolide European Australian RLS (PEARLS) study. Group 2 (n=100) represented an outpatient RLS population investigated in a Sleep Disorders Center. Additionally, Group 1 was also evaluated after a 6 week double-blind treatment period, where 47 patients received pergolide and 53 patients placebo. RESULTS: In unmedicated patients, IRLS scores correlated with the PLMS-arousal index (r=0.22, p=0.033) but not with the PLMS index in Group 1 while no correlation was found in Group 2. The change of the IRLS score under treatment in Group 1 correlated significantly both with the change of the PLMS index (r=0.42, p<0.001) and the change of the PLMS-arousal index (r=0.38, p<0.001). CONCLUSIONS: The IRLS adequately reflects treatment changes of PLMS indices. In unmedicated patients, the IRLS correlates with PLMS indices probably only in selected RLS populations with predefined PSG criteria and high PLM activity. SIGNIFICANCE: The IRLS is an appropriate subjective rating scale for measuring treatment effects in RLS.     

Cabergoline compared to levodopa in the treatment of patients with severe restless legs syndrome: results from a multi-center, randomized, active controlled trial.

We report the first large-scale double-blind, randomly assigned study to compare two active dopaminergic therapies for Restless Legs Syndrome (RLS), the dopamine agonist cabergoline (CAB) and levodopa/benserazide (levodopa). Patients with idiopathic RLS were treated with fixed daily doses of 2 or 3 mg CAB or 200 or 300 mg levodopa for 30 weeks. Efficacy was assessed by changes in the IRLS (International RLS Severity Scale) and by time to discontinuation of treatment due to loss of efficacy or augmentation. 361 of 418 screened patients (age 58 +/- 12 years, 71% females) were randomly assigned and treated (CAB: n = 178; levodopa: n = 183) in 51 centers of four European countries. Baseline IRLS total score was 25.7 +/- 6.8. The baseline-adjusted mean change from baseline to week 6 in IRLS sum score was d = -16.1 in the CAB group and d = -9.5 in the levodopa group (d = -6.6, P < 0.0001). More patients in the levodopa group (24.0%) than in the CAB group (11.9%, P = 0.0029, log-rank test) discontinued because of loss of efficacy (14.2% vs. 7.9%, P = 0.0290) or augmentation (9.8% vs. 4.0%, P = 0.0412). Adverse events (AEs) occurred in 83.1% of the CAB group and in 77.6% of the levodopa group. In both groups, most frequent AEs were gastrointestinal symptoms (CAB: 55.6%, levodopa: 30.6%, P < 0.0001). This first large-scale active controlled study in RLS showed superior efficacy of cabergoline versus levodopa after a 30-week long-term therapy. Tolerability was found more favorable with levodopa than with cabergoline.     

Meta-analysis of the efficacy and tolerability of pramipexole versus ropinirole in the treatment of restless legs syndrome

OBJECTIVE: In the absence of comparative trials a meta-analysis was performed to compare the efficacy and tolerability of the non-ergot derived dopamine agonists, pramipexole and ropinirole, in restless legs syndrome (RLS). METHODS: Frequentist fixed and random-effects models were pre-specified for the direct comparisons and a Bayesian approach for the indirect comparison. Efficacy outcomes included the mean change from baseline in the International RLS Study Group Rating Scale (IRLS) score and the percentage of responders on the clinical global impressions - improvement scale (CGI-I). Safety outcomes included the incidence of withdrawal and adverse events. RESULTS: The direct meta-analysis confirmed superior efficacy for both treatments versus placebo for the IRLS (pramipexole: -5.45; 95% CI: -7.70; -3.20; ropinirole: -3.16; 95% CI: -4.26; -2.05) and the CGI-I (pramipexole: OR=2.98; 95% CI: 2.08; 4.26; ropinirole: OR=1.99; 95% CI: 1.52; 2.60). Placebo comparisons showed a significantly higher incidence of nausea for pramipexole (p<0.01), whereas nausea, vomiting, dizziness, and somnolence were significantly higher for ropinirole (all p<0.01). The indirect comparison showed with a probability of > or = 95%, a superior reduction in the mean IRLS score (-2.33; 95% credibility interval [CrI]: -4.23; -0.41), higher CGI-I response rate (OR=1.50; 95% CrI: 0.97; 2.32) and significantly lower incidence of nausea, vomiting, and dizziness for pramipexole compared to ropinirole. CONCLUSION: Differences in efficacy and tolerability favouring pramipexole over ropinirole can be observed. These findings should be further confirmed in head-to-head clinical trials.