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Objective We 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. Methods In 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). Results Six 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. Conclusions Rotigotine was effective and well-tolerated when used in routine clinical practice.

Background: Pancreatic polypeptide is released immediately after food ingestion. The release is operated by vagal-abdominal projections and has therefore been suggested as a test for vagal nerve integrity. Pathoanatomical and clinical studies indicate vagal dysfunction in early Parkinson's disease (PD). Methods: We assessed the postprandial secretion of pancreatic polypeptide and motilin in healthy controls (n = 18) and patients with idiopathic rapid-eye-movement sleep behavior disorder (iRBD, n = 10), a potential premotor stage of PD, as well as in drug-naive (n = 19) and treated (n = 19) PD patients. Results: The postprandial pancreatic polypeptide secretion showed a physiological pattern in all groups and even an enhanced response in drug-naive PD and iRBD. Motilin concentrations correlated with pancreatic polypeptide concentrations. Conclusions: Postprandial pancreatic polypeptide secretion is not a suitable test for vagal nerve integrity in PD. The unimpaired pancreatic polypeptide response in iRBD and PD might be explained by partially intact vagal-abdominal projections or compensatory mechanisms substituting a defective neuronal brain–gut axis. © 2012 Movement Disorder Society

Idiopathic REM sleep behavior disorder is a parasomnia characterized by dream enactment and is commonly a prediagnostic sign of parkinsonism and dementia. Since risk factors have not been defined, we initiated a multicenter case-control study to assess environmental and lifestyle risk factors for REM sleep behavior disorder.Cases were patients with idiopathic REM sleep behavior disorder who were free of dementia and parkinsonism, recruited from 13 International REM Sleep Behavior Disorder Study Group centers. Controls were matched according to age and sex. Potential environmental and lifestyle risk factors were assessed via standardized questionnaire. Unconditional logistic regression adjusting for age, sex, and center was conducted to investigate the environmental factors.A total of 694 participants (347 patients, 347 controls) were recruited. Among cases, mean age was 67.7 ± 9.6 years and 81.0% were male. Cases were more likely to smoke (ever smokers = 64.0% vs 55.5%, adjusted odds ratio [OR] = 1.43, p = 0.028). Caffeine and alcohol use were not different between cases and controls. Cases were more likely to report previous head injury (19.3% vs 12.7%, OR = 1.59, p = 0.037). Cases had fewer years of formal schooling (11.1 ± 4.4 years vs 12.7 ± 4.3, p0.001), and were more likely to report having worked as farmers (19.7% vs 12.5% OR = 1.67, p = 0.022) with borderline increase in welding (17.8% vs 12.1%, OR = 1.53, p = 0.063). Previous occupational pesticide exposure was more prevalent in cases than controls (11.8% vs 6.1%, OR = 2.16, p = 0.008).Smoking, head injury, pesticide exposure, and farming are potential risk factors for idiopathic REM sleep behavior disorder.

Background: Delayed gastric emptying is a non-motor symptom of Parkinson's disease. Few data exist on gastric emptying in early-stage Parkinson's disease. In idiopathic rapid-eye-movement sleep behavior disorder, a presumable pre-motor stage of Parkinson's disease, gastric emptying has not yet been investigated. Methods: Twenty healthy controls, 13 patients with idiopathic rapid-eye-movement sleep behavior disorder, and 39 patients with Parkinson's disease patients underwent standardized testing for gastric emptying with the 13C-octanoate breath test. Results: Gastric emptying was significantly delayed in drug-naive (P < .001) and in treated Parkinson's disease patients (P < .001), but normal in patients with idiopathic rapid-eye-movement sleep behavior disorder. Conclusions: Our study confirms delayed gastric emptying in drug-naive, early-stage Parkinson's disease. Normal gastric emptying in idiopathic rapid-eye-movement sleep behavior disorder might be explained by the fact that neurodegenerative changes in structures modulating gastric motility are not severe enough to cause a functional deficit that can be detected by the 13C-octanoate breath test. © 2011 Movement Disorder Society

Pain in the legs belongs to the five most frequent regional pain symptoms. Restless legs syndrome (RLS) presents a particular differential diagnosis for pain in the legs, which is characterized by a nocturnal urge to move the legs often associated with painful sensations in the legs. It is one of the most common neurological disorders and probably the leading cause of nocturnal pain in the legs. In this overview, the diagnosis and therapy of RLS as well as aspects of pain therapy of the disorder are presented. In addition, the differential diagnoses for exclusion of other specific causes of nocturnal pain in the legs are discussed.

Depressive Storungen sind eine haufige Komorbiditat beim Restless-legs-Syndrom (RLS). Vergleichbare Pravalenzraten von Begleitdepressionen finden sich zwar auch bei anderen Erkrankungen, die Assoziation zwischen RLS und Depression ist jedoch durch die RLS-bedingten erheblichen Schlafstorungen besonders komplex. Klinisch von Bedeutung ist zudem, dass verfugbare Daten, uberwiegend aus Fallberichten, zeigen, dass eine Vielzahl antidepressiver Medikamente die RLS-Symptomatik verstarken kann. Eine komorbide Depression beeinflusst den Therapieerfolg der Grunderkrankung und sollte deshalb berucksichtigt werden. Bislang gibt es keine systematischen Untersuchungen und daher keine evidenzbasierten Empfehlungen zur pharmakologischen Therapie von depressiven Symptomen bei RLS. In der vorliegenden Ubersicht werden die klinische Relevanz von depressiven Storungen bei RLS und die Auswirkung einer antidepressiven Behandlung auf die RLS-Symptomatik diskutiert sowie ein Therapiealgorithmus (Evidenzklasse C) zur Behandlung einer komorbiden Depression bei RLS vorgestellt.

Background Although the diagnosis of restless legs syndrome (RLS) is largely based on the presence of the four essential criteria, no validated diagnostic questionnaire exists for use in epidemiological studies or clinical practice.

Long-term efficacy and tolerability data are not yet available for patch formulations of dopamine agonists in restless legs syndrome.Efficacy and safety of rotigotine (0.5-4mg/24h), 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.Of 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+/-1.2mg/24h with 4mg/24h (40.6%) being the most frequently applied dose; 14.8% were sufficiently treated with 0.5 or 1.0mg/24h. The IRLS total score improved by ?17.4+/-9.9 points between baseline and end of Year 1 (p0.001). The other measures of severity, sleep satisfaction and quality of life supported the efficacy of rotigotine (p0.001 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.Rotigotine 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.

Background: Patients suffering from Parkinson’s disease (PD) often complain about painful sensations. Recent studies detected increased subjective pain sensitivity and increased spinal nociception, which appeared to be reversible by dopaminergic treatment. Possibly, reduced descending pain inhibition contributes to this finding. Objective: Subjective pain thresholds as well as nociceptive reflex thresholds were investigated to isolate potential loci of the pathophysiological changes within the pain pathway. In addition, the diffuse noxious inhibitory control (DNIC) system as one form of descending control was assessed. Method: 15 patients with PD and 18 controls participated in the study. Electrical and heat pain thresholds as well as the nociceptive flexion reflex (NFR) thresholds were determined. Thereafter, the electrical pain thresholds were measured once during painful heat stimulation (conditioning stimulation) and twice during innocuous stimulation (control stimulation). Results: Patients with PD exhibited lower electrical and heat pain thresholds as well as lower NFR thresholds. Suppression of the electrical pain thresholds during painful heat stimulation (conditioning stimulation) compared with control stimulation did not differ significantly between the groups. No differences in the thresholds between patients with PD with and without clinical pain were seen. Conclusions: Finding the NFR threshold to be decreased in addition to the decreased electrical and heat pain thresholds indicates that the pathophysiological changes either already reside at or reach down to the spinal level. Reduced activation of the DNIC system was apparently not associated with increased pain sensitivity, suggesting that DNIC-like mechanisms do not significantly contribute to clinical pain in PD.

In a pilot placebo-controlled study, low dosages of 0.5-2mg/24h rotigotine showed a dose-dependent beneficial effect in restless legs syndrome (RLS) patients.Efficacy and safety of the dopamine agonist rotigotine, formulated as a once-daily transdermal system (patch), was investigated for five fixed dosages and compared to placebo in patients with idiopathic RLS in a double-blind, randomized, parallel-group, multicenter, six-week dose-finding trial. Primary efficacy measure was the total score of the International RLS Severity Scale (IRLS); in addition, the RLS-6 scales and the Clinical Global Impressions (CGI) were administered.Of 371 enrolled patients, 341 patients (mean age 58+/-10years, 67% females) were randomized. The IRLS total score improved between baseline and end of the six-week treatment period by -10.6 (0.5mg/24h rotigotine; patch area 2.5cm2), -15.1 (1mg/24h; 5cm2), -15.7 (2mg/24h; 10cm2), -17.5 (3mg/24h; 15cm2), and -14.8 (4mg/24h, 20cm2) as compared to placebo (-9.2). The hierarchical statistical test procedure demonstrated superiority of rotigotine over placebo for 4mg/24h, 3mg/24h, 2mg/24h, and 1mg/24h, with p-values of 0.0013,0.0001, 0.0003, and 0.0004, respectively. Only the 0.5mg/24h dose was not different compared to placebo (p=0.2338). The CGI and the RLS-6 severity items supported the efficacy of the rotigotine doses beyond 0.5mg/24h. The most frequent side effects were application site reactions and nausea and tended to be more frequent with higher doses.This dose-finding trial identified the range for a maintenance dose of rotigotine from 1mg/24h to 3mg/24h. The lowest dose was ineffective and, with the highest dose, no additional benefit was observed.

Data from a survey of 6,620 Parkinson's disease patients were examined for correlation of freezing with age, sex, duration, subjective severity of Parkinson's disease, and antiparkinsonian medication. Forty-seven percent of the patients reported experiencing freezing regularly. Logistic regression analysis showed that freezing was significantly associated with a longer disease duration and a more advanced stage of the disease. Freezing episodes were more likely in men than in women and in patients taking, in addition to levodopa, Entacapone, Amantadine, or dopamine agonists. Finally, patients considering tremor as their main symptom reported freezing less frequently. Common antiparkinsonian drugs given in combination with levodopa were not negatively correlated with freezing. The results underline the necessity to develop appropriate countermeasures against this phenomenon, which is widely known to cause significant impairment of patients' quality of life and—as our data also showed—may cause traffic accidents in licensed patients. © 2007 Movement Disorder Society

Gutachterliche Fragestellungen bei Patienten mit einem Restless-Legs-Syndrom (RLS) nehmen stetig zu. Darum hat die “AG Motorik und Schlaf” der DGSM erstmals Empfehlungen zur Begutachtung und sozialmedizinischen Einschatzung des RLS erarbeitet. Im Folgenden werden die spezifischen Empfehlungen zur Beurteilung des RLS im Rahmen gutachterlicher Verfahren zusammengefasst (aus [5]). Diese Konsensusleitlinie soll eine Grundlage zur Vereinheitlichung und Qualitatssicherung in der Begutachtung des RLS darstellen und nicht in individuelle Begutachtungen eingreifen.

We developed and validated a standardized test procedure to evaluate the accuracy of the supportive diagnostic criterion "response to dopaminergic treatment" in restless legs syndrome (RLS). Forty-eight patients who fulfilled at least three of the four essential criteria for RLS, thus including uncertain clinical cases for a nonexpert, were recruited. Patients received a preliminary diagnosis of RLS or non-RLS. All patients underwent a polysomnography (PSG) and were then asked to perform the diagnostic L-DOPA test at home, which consisted in the application of one single dose of 100/25 mg L-DOPA/benserazide and a subsequent observational period of 2 hours. Before, and in 15-minute intervals after, drug intake, the patients rated the severity of the "symptoms in the legs" and the "urge to move the legs" using a 100-mm visual analogue scale. Considering a 50% improvement as a positive test result, we found a sensitivity of 88% ("symptoms in the legs") and 80% ("urge to move the legs") with a specificity of 100% for both test items. A rate of 90% or 83% of all patients could be correctly diagnosed by the L-DOPA test. Both scales were able to predict the response to dopaminergic agents in the subsequent course of the treatment by 100%. The periodic leg movements arousal index as assessed by polysomnography was less appropriate for the prediction of the correct diagnosis. We recommend the L-DOPA test for diagnostic decision making in all patients with an unclear RLS diagnosis according to the essential diagnostic criteria of the International RLS Study Group.

The term ‘sleep attack’ is used in patients with Parkinson's disease (PD) to designate a sudden onset of sleep (SOS) without any prior sleepiness. Clinically, sleep attacks can be distinguished from unintended sleep episodes, i.e. SOS with prior sleepiness. This study aimed to assess the prevalence of SOS and to identify its predictors in patients with sleep-disordered breathing (SDB). A total of 114 consecutive patients with the clinical suspicion of obstructive sleep apnoea syndrome (OSAS) and a respiratory disturbance index (RDI) of >5/h were examined using a questionnaire and polysomnography (PSG). Altogether 57.7% reported SOS, with 5.2% of the total population describing exclusively sleep attacks. SOS was observed in both patients with obstructive sleep apnoea-hypopnoea (OSAH) or increased upper airway resistance (UAR). Increased scores on the Epworth Sleepiness Scale (ESS) were the best predictor of SOS. Logistic regression showed a possible association of SOS with a low PLMS index, while no definite effect was observed for other PSG parameters. Our data show that SDB is frequently associated with SOS. Future studies should address in more detail whether SDB patients with sleep attacks pose an increased accident risk.

Treatment standards or guidelines have been developed for most features of Parkinson's disease (PD). However, data on the actual treatment that is put into practice are scarce. In 2000, a nationwide survey on the topic of sudden onset of sleep (SOS) in PD was initiated among the members of the German patient support group (deutsche Parkinson-Vereinigung, dPV). A part of this mailed questionnaire survey covering the antiparkinsonian and concomitant medication of the participants is presented here. This study analyses data sets from more than 6,500 PD patients. The mean dopaminergic dose was equivalent to 599 +/- 387 mg levodopa/die. The most frequently administered drugs were levodopa (94.2 %), dopamine agonists (DA) (71.7 %), amantadine (40.1 %), selegiline (27.6 %), entacapone (20.4 %), budipine (12.3 %), and anticholinergics (11.8 %). Costs of pharmacotherapy were estimated to be approximatelyeuro399 million/year in Germany. PD drug therapy in general strongly depended on age, disease duration, and the level of care. The treatment guidelines were apparently not consistently followed underlining the need for their continuous propagation throughout the medical community. In addition our data suggest that non-motor symptoms in PD are not adequately treated and that concomitant sedative medication contributes to the occurrence of SOS.

Cerebrospinal fluid (CSF) and blood obtained from 22 untreated or scarcely treated patients with moderate to severe restless legs syndrome (RLS; mean age, 58.6 +/- 13 years) and 11 control subjects (mean age, 56.6 +/- 12.9 years) were investigated for biogenic amines between 6:00 and 8:00 PM. We did not find any significant differences in the CSF concentrations of homovanillic acid, 3-ortho- methyl-dopa, levodopa, 5-hydroxytryptophan, 5-hydroxyindoleacetic acid, tetrahydrobiopterin, dihydrobiopterin, 5-methyltetrahydrofolate, and neopterin. In addition, serotonin in whole blood and plasma activity of aromatic amino acid decarboxylase were all normal. Our results suggest that dopaminergic and serotonergic release is not substantially affected in RLS.

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.

Die selbstberichtete Pravalenz von Tagesmudigkeit und Schlafstorungen bei Parkinson-Patienten vor und seit ihrer Erkrankung sollte abgeschatzt und auf Zusammenhange zueinander uberpruft werden. Ferner sollte erhoben werden, worauf die Patienten diese Symptome attribuieren und wie diese mit der Menge an Tagschlaf korreliert sind. Ein Fragebogen zu Schlafstorungen, Schlafverhalten, Tagesmudigkeit etc. wurde an 12 000 Parkinson-Patienten verschickt. Bei einer Rucklaufquote von 63% konnten die Daten von 6620 Patienten analysiert werden. Die Pravalenz von Tagesmudigkeit (35% vs. 71%) und Schlafstorungen (23% vs. 76%) war akut signifikant hoher als vor der Parkinson-Krankheit (P

The relationship between Restless Legs Syndrome (RLS) and Parkinson's disease (PD) is still controversial. Most genetic, pathological, and imaging data argue against a close association of these two disorders. Still, many studies reported an increased prevalence of RLS in PD patients. These studies are difficult to interpret because the current diagnostic criteria for RLS have not been validated in PD patients. Although many PD patients suffer from motor restlessness due to parkinsonism and may thus mimic RLS, the risk for (secondary) RLS in PD patients is probably slightly increased. This review provides an overview of the current pertinent literature and discusses the possible association between RLS and PD.

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

Background Rotigotine is a unique dopamine agonist with activity across D1 through D5 receptors as well as select adrenergic and serotonergic sites. This study reports the 2-year follow-up safety and efficacy data of an ongoing open-label multicenter extension study (NCT00498186) of transdermal rotigotine in patients with moderate to severe restless legs syndrome (RLS). Methods Patients received a once-daily patch application of an individually optimized dose of rotigotine between 0.5 mg/24 h to 4 mg/24 h. Safety assessments included adverse events (AEs) and efficacy was measured by the International RLS Study Group Severity Rating Scale (IRLS), RLS-6 scales and Clinical Global Impression (CGI). Quality of life (QoL) was measured by QoL-RLS. Results Of 310 patients who completed a 6-week placebo-controlled trial (SP709), 295 (mean age 58 ± 10 years, 66% females) were included in the open-label trial SP710. 64.7% (190/295 patients) completed the 2-year follow-up; 29 patients discontinued during the second year. Mean daily rotigotine dose after 2 years was 2.93 ± 1.14 mg/24 h with a 2.9% dose increase from year 1. Rotigotine was generally well tolerated. The rate of typical dopaminergic side effects, nausea and fatigue, was low (0.9% and 2.3%, respectively) during the second year; application site reactions were frequent but lower than in year 1 (16.4% vs. 34.5%). The IRLS total score improved from baseline of SP709 (27.8 ± 5.9) by 17.2 ± 9.2 in year 2 completers. Similar improvements were observed in RLS-6 scales, CGI scores and QoL-RLS. The responder rate in the CGI change item 2 ("much" and "very much" improved) was 95% after year 2. Conclusions Transdermal rotigotine is an efficacious and well-tolerated long-term treatment option for patients with moderate to severe RLS with a high retention rate during 2 years of therapy. Trial registration NCT00498186

Restless legs syndrome (RLS) is characterized by a distressing, irresistible need or urge to move the legs. It often co-exists with an uncomfortable, though not usually painful, sensation in the legs. Although clear diagnostic criteria and effective treatment options exist, RLS is generally underdiagnosed and under-treated. RLS patients often suffer from sleep disturbances that may severely disrupt normal life functioning. Furthermore, it is one of the most common neurological disorders. In this communication, we provide a systematic review of the literature on health-related quality of life (HRQoL) and health economic issues in patients suffering from RLS. RLS has a considerable impact on the HRQoL of patients, which is comparable to other neurological and chronic diseases. The most important factors contributing to the impairment of HRQoL are the severity of RLS symptoms and the associated sleep disturbances. Although little work has been published on cost-of-illness of RLS, available studies suggest that a considerable economic burden is caused by RLS. Because of the large number of patients requiring treatment and the considerable increase in the number of treatment studies performed in recent years, as well as approval of several drugs for this indication, we assume a considerable increase in treatment frequency. Very few of the RLS treatment options, however, have been evaluated for their cost-effectiveness, and further research is needed on both quality-of-life issues and the economic impact of RLS.

Background: The primary characteristics of restless legs syndrome (RLS), including severe sleep disorders, restlessness in the evening and discomfort while at rest, have substantial impact on normal daily activities. Because of the high prevalence of RLS in the general population, it is necessary to evaluate the economic impact of RLS. Objective: To determine the health economic burden of patients with RLS in Germany. Methods: A total of 519 RLS patients (mean age: 65.2–11.1 years) in different stages of disease were recruited in five health centres (university hospitals, district hospitals and office-based neurologists) by applying the diagnostic criteria of the International Restless Legs Syndrome Study Group. A questionnaire was administered that assessed healthcare resource consumption as well as socioeconomic, demographic, clinical and health status. In addition, the International RLS severity scale (IRLS), Epworth Sleepiness Scale (ESS), EQ-5D and Beck Depression Inventory (BDI) were addressed in the assessment. Direct and indirect costs (€, year 2006 values) were derived from various German economic resources and calculated from the perspective of the healthcare and transfer payment providers. Results: We calculated average total costs over the 3-month observation period. It was determined that average total costs were €2090 for this period. The average direct medical and non-medical costs from the perspective of the health insurance provider were determined to be €780, with €300 attributed to drug costs and €354 to hospitalization costs. Average total indirect costs amounted to h1308 and were calculated based on productivity loss, using the human capital approach. As cost-driving factors we identified disease severity according to the IRLS (p < 0.01) and ESS (p < 0.04). Health-related quality of life was determined to be substantially affected by RLS; the mean EQ-5D visual analogue scale (VAS) was 55.6, considerably lower than that of the agematched general population. Conclusion: RLS places a notable financial burden on society as well as on patients and their families. More detailed studies are needed to evaluate the health economic impact of this disorder.

Background Restless legs syndrome (RLS) is a common neurological condition. We investigated the prevalence of RLS in patients suffering from unpleasant sensations in the legs. Methods We included 16,543 patients consulting one of 312 primary care practices in Germany on November 8, 2007. All patients filled out a self-assessment questionnaire. Patients who reported suffering from unpleasant sensations in the legs were then assessed by the physician. Main outcome measures were the overall prevalence of unpleasant sensations in the legs and the prevalence of RLS; the most common differential diagnoses in the subpopulation suffered from unpleasant leg sensations. Results Out of all participating patients 7704 (46.6%) suffered from unpleasant sensations in the legs and 1758 (10.6%) were diagnosed with RLS according to the four essential clinical criteria. Among patients with unpleasant leg sensations, the prevalence of RLS was considerably higher (22.7%) than in the total population. The most common differential diagnoses were osteoarthritis (21.5%), disc lesion (19.2%), varicose veins (18.8%) and muscle cramps (14.6%). Of the patients with RLS 53.4% had already consulted their physician about their leg problems in the past. Still, only 20.1% of the RLS patients had received the correct diagnosis. Comorbidity rates were significantly increased in RLS patients compared to patients suffering from leg symptoms of other origin. Conclusions This study showed a high prevalence of RLS in primary care patients with unpleasant sensations in the legs. Thus, in patients presenting with these symptoms the diagnosis of RLS should routinely be considered.

Only in the last three decades, the restless legs syndrome (RLS) has been examined in randomized controlled trials. The Movement Disorder Society (MDS) commissioned a task force to perform an evidence-based review of the medical literature on treatment modalities used to manage patients with RLS. The task force performed a search of the published literature using electronic databases. The therapeutic efficacy of each drug was classified as being either efficacious, likely efficacious, investigational, nonefficacious, or lacking sufficient evidence to classify. Implications for clinical practice were generated based on the levels of evidence and particular features of each modality, such as adverse events. All studies were classed according to three levels of evidence. All Level-I trials were included in the efficacy tables; if no Level-I trials were available then Level-II trials were included or, in the absence of Level-II trials, Level-III studies or case series were included. Only studies published in print or online before December 31, 2006 were included. All studies published after 1996, which attempted to assess RLS augmentation, were reviewed in a separate section. The following drugs are considered efficacious for the treatment of RLS: levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin. Drugs considered likely efficacious are rotigotine, bromocriptine, oxycodone, carbamazepine, valproic acid, and clonidine. Drugs that are considered investigational are dihydroergocriptine, lisuride, methadone, tramadol, clonazepam, zolpidem, amantadine, and topiramate. Magnesium, folic acid, and exercise are also considered to be investigational. Sumanirole is nonefficacious. Intravenous iron dextran is likely efficacious for the treatment of RLS secondary to end-stage renal disease and investigational in RLS subjects with normal renal function. The efficacy of oral iron is considered investigational; however, its efficacy appears to depend on the iron status of subjects. Cabergoline and pergolide (and possibly lisuride) require special monitoring due to fibrotic complications including cardiac valvulopathy. Special monitoring is required for several other medications based on clinical concerns: opioids (including, but not limited to, oxycodone, methadone and tramadol), due to possible addiction and respiratory depression, and some anticonvulsants (particularly, carbamazepine and valproic acid), due to systemic toxicities.

Background Restless Legs Syndrome (RLS) has a substantial impact on normal daily activities. Because of the high prevalence it is necessary to evaluate the impact on the health-related quality of life (HRQoL). Objective To assess health-related quality of life in patients with RLS. Methods A total of 519 patients (327 female patients; mean age: 64.2 y) were recruited in five different German centers according to the diagnostic criteria of the International RLS Study Group. Patients were either interviewed or completed a mailed questionnaire. The questionnaire consisted of an evaluation of the sociodemographic, clinical and health-related status. HRQoL was evaluated with the EuroQoL (EQ-5D). In addition, the IRLS scale, the MOS Sleep Scale, the Epworth Sleepiness Scale, and the BDI were applied as clinical rating scales. Results HRQoL is substantially affected by RLS. The mean EQ-5D-VAS was 55.6 and considerably lower compared to the general population. It was found to be as low as in other chronic neurological disorders such as Parkinson’s disease and stroke. From different factors investigated by uni- and multivariate analyses, severity of RLS and depressive symptoms had the most significant impact on HRQoL. Additionally, sleep deficits, the duration of the disease and net household income were identified as predictors for different EQ-5D outcome scores. Conclusions RLS considerably affects HRQoL. Further comparative studies are necessary to evaluate the effect of disease symptoms on HRQoL and their change due to medication.

The European Restless Legs Syndrome (RLS) Study Group (EURLSSG) is an association of European RLS experts who are actively involved in RLS research. A major aim of the Study Group is the development and continuous improvement of standards for diagnosis and treatment of RLS. Several members developed study designs and evaluation methods in investigator-initiated trials early in the 1990s, and all members have since contributed to many pivotal and nonpivotal drug trials for the treatment of RLS. The recommendations on clinical investigations of pharmacological treatment of RLS patients summarize the group's expertise and knowledge acquired through clinical trials. The recommendations primarily address how to plan and conduct confirmatory, randomized clinical studies in patients with idiopathic RLS. Advice is presented for the diagnosis of RLS and clinical and polysomnographic inclusion and exclusion criteria. Primary and secondary endpoints for an evaluation of efficacy are based on a critical description of validated methods for both short- and long-term trials, also in special populations (children, pregnant women, elderly patients). The recommendations include the assessment of augmentation. Finally, general issues including the evaluation of safety and tolerability, as well as specific neurological and cardiovascular risks and sleep attacks/daytime somnolence, are discussed. The aim of these recommendations is to support research groups or pharmaceutical companies in the design of optimized study protocols.

Study Objectives: Previously, we found a significant association between the dopamine D2 receptor gene polymorphism Taq IA and sudden onset of sleep in patients with Parkinson disease. Here we evaluated the association between the preprohypocretin (-909T/C), (-22C/T), and (-20C/A) polymorphisms and sudden onset of sleep in the same population of patients with Parkinson disease. Design: We conducted an association study analyzing the distribution of preprohypocretin polymorphisms in Germanic, caucasian Parkinson disease patients with and without sudden onset of sleep, matched according to drug therapy, disease duration, sex, and age. Setting: Movement disorders section at a university hospital. Participants: 132 Parkinson disease patients with sudden onset of sleep and 132 Parkinson disease patients without sudden onset of sleep. Interventions: Blood samples were taken from each participant and used for DNA extraction. Polymorphisms were analyzed by established polymerase chain reaction protocols or direct sequencing. Measurements and Results: The variant allele T of the (-909T/C) preprohypocretin polymorphism was more commonly found in Parkinson disease patients with sudden onset of sleep. Statistical analysis showed that there were significant differences in the genotype (P = .024) and allele (P = .018) distribution between both groups. For heterozygous and homozygous carriers of allele T, the genotype relative-risk estimates for the presence of sudden onset of sleep were 2.01 (95% confidence interval: 0.76-5.34) and 2.81 (95% confidence interval: 1.09-7.25), respectively. Conclusions: Our results show a significant association between the (-909T/C) preprohypocretin polymorphism and sudden onset of sleep in Parkinson disease. However, we could not demonstrate any interaction between the Taq IA and (-909T/C) polymorphisms with respect to the occurrence of sudden onset of sleep, suggesting that multiple genetic factors may contribute to the pathogenesis of this phenomenon.

BACKGROUND AND PURPOSE: Sudden onset of sleep (SOS) was recently reported in patients with Parkinson's disease (PD) under dopaminergic treatment. Here, we investigated as to what extent SOS is found in patients with restless legs syndrome (RLS), who are frequently treated with dopaminergic drugs, and controls. PATIENTS AND METHODS: A questionnaire survey on SOS was administered to 156 RLS patients and 126 controls. RESULTS: While no significant difference between RLS patients and controls was detected in Epworth sleepiness scale (ESS) scores (P=0.76), the prevalence of SOS was higher in RLS patients (32.7%) than in controls (19.8%) (P=0.02). Significant predictors of SOS in RLS were ESS score (odds ratio (OR) 16.4), male sex (OR 4.6), duration of night-time sleep (OR 3.0), and age (OR 2.9), while no association was observed for duration or severity of the disease. Patients on dopaminergic therapy usually featured a lower risk of SOS than untreated patients. Falling asleep while driving was reported by 14.6% of all RLS patients with a driver's license and associated with increased risk of accident (OR 7.1). CONCLUSIONS: RLS patients who are untreated, male, and elderly should be assessed for the presence of SOS. In contrast to PD, dopaminergic drugs may reduce the risk of SOS in RLS. The possible benefit of the drugs should be investigated particularly in male patients. Language: en

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

Pain sensitivity was assessed in 11 patients (age 60 +/- 10 years) with 'primary' restless leg syndrome (RLS) (disease duration 18 +/- 15 years) and 11 age- and gender-matched healthy control subjects. Stimulus-response functions for pricking pain were obtained with seven calibrated punctate mechanical stimulators activating Adelta-high threshold mechano-nociceptors. Stimuli at the foot were significantly more painful than at the hand in both patients and healthy control subjects both in the morning and evening. Generally, pin-prick pain ratings in RLS patients were significantly elevated, by a factor of 5.3 in the upper limb and by a factor of 6.4 in the lower limb indicating a significant generalized static hyperalgesia more pronounced in the lower limb. In contrast, pain to light touch (allodynia = dynamic mechanical hyperalgesia) as tested by a battery of three gentle tactile stimuli was never reported. Acute single-dose dopaminergic treatment with 100 mg levodopa + 25 mg benserazide, 90 min prior to the evening measurements, largely resolved patients' RLS symptoms, but had no effect on pin-prick pain. Static hyperalgesia to pin-prick, however, was significantly reversed (median reduction -74%) by long-term individually tailored dopaminergic treatment. Our study shows that patients with RLS exhibit a profound static mechanical hyperalgesia to pin-prick stimuli, but no dynamic mechanical hyperalgesia (allodynia). This type of hyperalgesia is probably mediated by central sensitization to Adelta-fibre high-threshold mechanoreceptor input, a hallmark sign of the hyperalgesia type of neuropathic pain. The reduction of hyperalgesia in RLS patients by long-term dopaminergic treatment suggests that the pathophysiology of RLS includes disturbed supraspinal pain modulation involving the basal ganglia and/or descending dopaminergic pathways.

CSF hypocretin-1 levels at 6 pm did not significantly differ between patients with restless legs syndrome (RLS) and control subjects as measured by direct radioimmunoassay and after acid extraction. The authors did not observe significant differences between early onset and late onset RLS. Hypocretin-1 levels did not correlate with RLS severity or polysomnographic measures. These results contrast with previous findings reporting significantly increased CSF hypocretin-1 in the late evening and mostly in early onset RLS.

Ralf Kohnen1, Heike Benes2, Birgit Hogl3, Birgit Hogl3, Julia Hulsmann1, Wolfgang Oertel4, Karin Stiasny-Kolster5, Claudia Trenkwalder6. 1ReSearch Pharmaceutical Services & University of Erlangen-Nuremberg, Germany; 2Somni bene Institute for Medical Research and Sleep Medicine Schwerin & University of Rostock, Germany; 3University Hospital for Neurology, Sleep Laboratory and Special Outpatient Department for Sleep Disorders, Austria; 4Philipps-University Marburg, Clinic for Neurology, Germany; 5Somnomar Institute for Medical Research and Sleep Medicine, Germany; 6Paracelsus-Elena Hospital, Center of Parkinsonism and Movement Disorders & Neurophysiology Department, University of Goettingen, Germany

Background Restless legs syndrome (RLS) is a neurological disorder with a lifetime prevalence of 3-10%. in European studies. However, the diagnosis of RLS in primary care remains low and mistreatment is common. Methods The current article reports on the considerations of RLS diagnosis and management that were made during a European Restless Legs Syndrome Study Group (EURLSSG)-sponsored task force consisting of experts and primary care practioners. The task force sought to develop a better understanding of barriers to diagnosis in primary care practice and overcome these barriers with diagnostic and treatment algorithms. Results The barriers to diagnosis identified by the task force include the presentation of symptoms, the language used to describe them, the actual term "restless legs syndrome" and difficulties in the differential diagnosis of RLS. Conclusion The EURLSSG task force reached a consensus and agreed on the diagnostic and treatment algorithms published here.

Susanne Knake1, Johannes T Heverhagen2, Katja Menzler1, Boris Keil2, WolfgangH Oertel1, Karin Stiasny-Kolster11Department of Neurology, Center of Nervous Diseases, 2Department of Radiology, Philipps University, Marburg, GermanyAbstract: Using a T2* gradient echo magnetic resonance imaging (MRI) sequence, regional T2 signal intensity (SI) values, a surrogate marker for T2 values, were determined in 12 regions of interest (substantia nigra, pallidum, caudate head, thalamus, occipital white matter, and frontal white matter bilaterally) and in two reference regions (cerebrospinal fluid and bone) in 12 patients suffering from moderate to severe idiopathic restless legs syndrome (RLS; mean age 58.5 ± 8.7 years) for 12.1 ± 9.1 years and in 12 healthy control subjects (mean age 56.8 ± 10.6 years). Iron deposits shorten T2 relaxation times on T2-weighted MRI. We used regional T2* SI to estimate regional T2-values. A T2-change ratio was calculated for each region of interest relative to the reference regions. We did not find significant differences in any of the investigated brain regions. In addition, serum measures involved in iron metabolism did not correlate with T2 SI values. We could not replicate earlier findings describing reduced regional brain iron concentrations in patients with RLS. Our results do not support the view of substantially impaired regional brain iron in RLS.Keywords: restless legs syndrome, pathophysiology, iron, MRI, substantia nigra