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Background and Objectives: Restless legs syndrome (RLS) has been associated with anxiety, depression, insomnia, lifestyle factors and infections. We aimed to study the prevalence of symptoms of RLS during the COVID-19 pandemic versus pre-pandemic. We hypothesized that pre-existing RLS symptoms worsened and pandemic-related factors may have triggered new symptoms of RLS., Methods: Adults (≥18 years) from fifteen countries across four continents participated in an online survey between May and August 2020. The harmonized questionnaire included a validated single question on RLS with response alternatives from 1 to 5 on a scale from never to every/almost every evening or night. Other measures were the Insomnia Severity Index (ISI), measures of symptoms of anxiety (GAD-2) and depression (PHQ-2), and questions on different pandemic-related factors., Results: Altogether, 17 846 subjects (63.8 % women) were included in the final analyses. The mean age was 41.4 years (SD 16.1). During the pandemic, symptoms of RLS (≥3 evenings/nights per week) were more common 9.1 % (95 % CI 8.7-10.1) compared to 5.4 % (95 % CI 4.9-6.0) before the pandemic (P < 0.0001). Alltogether 1.3 % (95 % CI 1.1-1.6) respondents had new-onset symptoms (≥3 evenings/nights per week). Moderate-severe insomnia was strongly associated with RLS symptoms. The occurrences of new-onset RLS symptoms were 5.6 % (95 % CI 0.9-13.0) for participants reporting COVID-19 and 1.1 % (95 % CI 0.7-1.5) for non-COVID-19 participants. In the fully adjusted logistic regression model, the occurrence of new-onset RLS symptoms was associated with younger age, social restrictions and insomnia severity. In a similar analysis, RLS symptoms (≥3 evenings/nights per week) were associated with lower education, financial hardship, sleep apnea symptoms, use of hypnotics, insomnia severity, symptoms of depression and possible post-traumatic stress disorder., Discussion: Our findings indicate that RLS symptoms were more common during the pandemic than before. Usually, the prevalence of RLS increases with age. However, during the pandemic, new-onset symptoms of RLS were more common in younger age groups. This may be due to the pandemic-related factors being more pronounced in the younger compared to the older. The association between insomnia, psychiatric symptoms and RLS warrants clinical attention., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Markku Partinen reports financial support was provided by Signe and Ane Gyllenberg Foundation. Other from Takeda, personal fees and other from MSD, personal fees and other from Orion, personal fees and other from Umecrine, personal fees from Lundbeck, Other from Teva, outside the submitted work. Ilona Merikanto reports financial support was provided by Signe and Ane Gyllenberg Foundation. Courtney J. Bolstad reports financial support was provided by South Texas Veterans Healthcare System. Yuichi Inoue reports personal fees and other from Astellas Pharma, personal fees from Eisai, other from Idorsia Pharmaceuticals Japan, grants from Koike Medical, personal fees from Otsuka Pharmaceutical, grants from Philips Japan, outside the submitted work. Frances Chung – Dr. Chung reports grants from Ontario Ministry of Health Innovation Grant, grants from University Health NetworkFoundation, personal fees from Masimo Inc and Takeda Pharma, outside the submitted work; In addition, University Health Network has a patent STOP-Bang questionnaire pending. Thomas Penzel – Dr. Penzel reports personal fees from Jazz Pharmaceuticals, personal fees from Bayer Healthcare, personal fees from Neuwirth, personal fees from Löwenstein Medical, outside the submitted work; and Shareholder of The Siestagroup GmbH, Advanced Sleep Research GmbH, Nukute. Giuseppe Plazzi – Dr. Plazzi reports personal fees from UCB pharma, personal fees from Jazz pharmaceuticals, personal fees from Bioprojet, personal fees from Idorsia, personal fees from Takeda, outside the submitted work. YK Wing – personal fees from Eisai Co, Ltd, for delivering a lecture and sponsorship from Lundbeck HK Ltd and Aculys Pharma, Japan, outside the submitted work. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find new entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 individuals with RLS (cases) and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including three on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (r g  = 0.96). Locus annotation prioritized druggable genes such as glutamate receptors 1 and 4, and Mendelian randomization indicated RLS as a causal risk factor for diabetes. Machine learning approaches combining genetic and nongenetic information performed best in risk prediction (area under the curve (AUC) = 0.82-0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up and provided evidence that nonlinear interactions are likely relevant to RLS risk prediction., (© 2024. The Author(s).)

Sleep disturbances after ischaemic stroke include alterations of sleep architecture, obstructive sleep apnea, restless legs syndrome, daytime sleepiness and insomnia. Our aim was to explore their impacts on functional outcomes at month 3 after stroke, and to assess the benefit of continuous positive airway pressure in patients with severe obstructive sleep apnea. Ninety patients with supra-tentorial ischaemic stroke underwent clinical screening for sleep disorders and polysomnography at day 15 ± 4 after stroke in a multisite study. Patients with severe obstructive apnea (apnea-hypopnea index ≥ 30 per hr) were randomized into two groups: continuous positive airway pressure-treated and sham (1:1 ratio). Functional independence was assessed with the Barthel Index at month 3 after stroke in function of apnea-hypopnea index severity and treatment group. Secondary objectives were disability (modified Rankin score) and National Institute of Health Stroke Scale according to apnea-hypopnea index. Sixty-one patients (71.8 years, 42.6% men) completed the study: 51 (83.6%) had obstructive apnea (21.3% severe apnea), 10 (16.7%) daytime sleepiness, 13 (24.1%) insomnia, 3 (5.7%) depression, and 20 (34.5%) restless legs syndrome. Barthel Index, modified Rankin score and Stroke Scale were similar at baseline and 3 months post-stroke in the different obstructive sleep apnea groups. Changes at 3 months in those three scores were similar in continuous positive airway pressure versus sham-continuous positive airway pressure patients. In patients with worse clinical outcomes at month 3, mean nocturnal oxygen saturation was lower whereas there was no association with apnea-hypopnea index. Poorer outcomes at 3 months were also associated with insomnia, restless legs syndrome, depressive symptoms, and decreased total sleep time and rapid eye movement sleep., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Restless legs syndrome (RLS) is a common neurological sensorimotor disorder that impairs sleep, mood and quality of life. RLS is defined by an urge to move the legs at rest that increases in the evening and at night, and is frequently associated with metabolic and cardiovascular diseases. Symptoms frequency, age at RLS onset, severity, familial history and consequences of RLS vary widely between patients. A genetic susceptibility, iron deficiency, dopamine deregulation, and possible hypo-adenosinergic state may play a role in the pathophysiology of RLS. Polysomnographic recordings found often periodic leg movements during sleep and wakefulness in patients with RLS. RLS can be classified as primary or comorbid with major diseases: iron deficiency, renal, neurological, rheumatological and lung diseases. First-line treatments are low-dose dopamine agonists, and alpha-2-delta ligands depending on the clinical context, and second/third line opiates for pharmacoresistant forms of RLS. Augmentation syndrome is a serious complication of dopamine agonists and should be prevented by using the recommended low dose. Despite an increase in knowledge, RLS is still underdiagnosed, poorly recognized, resulting in substantial individual health burden and socioeconomic coast, and education is urgently needed to increase awareness of this disabling disorder., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Symptoms of restless legs syndrome are relieved by movement. Whether a cognitive task decreases sensory discomfort remains understudied. We aimed to assess the frequency of patients with restless legs syndrome who report decreased sensory discomfort during cognitive activities, and quantify this decrease during a cognitive task. Three-hundred and fifty-eight consecutive adults with restless legs syndrome (age 55.17 ± 14.62 years; 55.87% women; 27.65% treated) answered the question: "Does the intensity of your restless legs syndrome symptoms decrease when you perform activities other than moving your legs?" rated on a nine-point Likert scale (from fully-agree to totally-disagree). A subgroup of 65 consecutive drug-free patients underwent an 80-min suggested immobilisation test at 20:00 hours to quantify legs discomfort on a visual analogue scale before polysomnography, including 40 patients performing a cognitive task (balloon analogue risk task) from the 60 to 80 min. A total of 130 (36.3%) patients reported a decrease, 158 (44.1%) no decrease, and 70 (19.5%) uncertain changes in severity of restless legs syndrome symptoms during cognitive activities, with a similar proportion whether treated or not. Patients experiencing a decrease had less severe restless legs syndrome symptoms. In the suggested immobilisation test, mixed-effect regression models showed that legs discomfort decreased in patients performing the cognitive task while it continued to increase in those without task, with a larger difference in patients reporting a self-reported decrease in restless legs syndrome during cognitive activities. In conclusion, one-third of patients reported a self-reported decrease of restless legs syndrome symptoms during cognitive activities, this improvement in restless legs syndrome was confirmed during a sustained cognitive task. Cognitive strategies could be implemented for the management of restless legs syndrome., (© 2022 European Sleep Research Society.)

Background and Objectives: To explore the first coronavirus disease 2019 (COVID-19) lockdown effect on sleep symptoms in patients with narcolepsy, idiopathic hypersomnia (IH), and restless legs syndrome (RLS)., Methods: Between March and May 2020, a sample of adult patients regularly followed up in a Reference Hospital Sleep Unit (299 with narcolepsy, 260 with IH, and 254 with RLS) was offered an online survey assessing their sleep-wake habits, daily activities, medication intake, and validated scales: International RLS Study Group questionnaire, Narcolepsy Severity Scale (NSS), IH Severity Scale (IHSS), Epworth Sleepiness Scale (ESS), Insomnia Severity Index, Beck Depression Inventory-II, and European Quality of Life (QoL) scale. The survey was proposed once, and the questions were answered for the prelockdown (recall of the month before the confinement) and the lockdown (time of study) periods., Results: Overall, 331 patients completed the survey (response rate 40.7%): 102 with narcolepsy, 81 with IH, and 148 with RLS. All patients reported later bedtimes, with reduced differences for time in bed (TIB) and total sleep time (TST) over 24 hours between weekdays and weekends. Patients with narcolepsy spent more TIB and increased TST overnight, with more daytime napping. They had more awakenings, higher ESS scores, lower QoL, and no NSS changes. Patients with IH also increased their TIB, TST overnight and 24 hours on weekdays. Nocturnal sleep latency and the number of awakenings increased but with no change in ESS, QoL, and IHSS scores. Patients with RLS reported longer nocturnal sleep latency, more awakenings, more naps, decreased TIB, and TST overnight. RLS severity increased while QoL decreased. A significant portion of patients reported disease worsening during the lockdown (narcolepsy: 39.4%, IH: 43.6%, and RLS: 32.8%), and some patients stopped or lowered their medication (narcolepsy: 22.5%, IH: 28%, and RLS: 9.5%)., Discussion: During the lockdown, all patients reported later bedtimes; those with narcolepsy and IH extended their sleep duration unlike patients with RLS. These changes were often associated with negative consequences on QoL. In the current context of recurrent COVID-19 waves, the recent development of teleconsultations should enable physicians to monitor patients with chronic sleep disorders more closely and to recommend optimized sleep schedules and duration, in order to prevent psychological problems and improve their QoL., (© 2022 American Academy of Neurology.)

Background: Whether depression and suicide thoughts relate to restless legs syndrome (RLS) or comorbidities associated with RLS remain unclear., Objectives: To determine frequency of depressive symptoms and suicidal thoughts in patients with RLS and their change after RLS treatment, associated clinical and polysomnographic factors, and current major depressive episode (MDE) frequency and suicide risk in RLS., Methods: Overall, 549 untreated patients with RLS and 549 age-, sex-, and education level-matched controls completed a standardized evaluation, including the Beck Depression Inventory-II that has one item on suicide thoughts. Patients underwent a polysomnographic recording and completed the Urgency, Premeditation, Perseverance, Sensation Seeking Impulsive Behavior scale. In a subgroup of 153 patients, current MDE and suicide risk were assessed with the face-to-face Mini-International Neuropsychiatric Interview (MINI). A subgroup of 152 patients were evaluated in untreated and treated conditions., Results: The frequency of depressive symptoms (32.5%) and suicidal thoughts (28%) was 10-fold and 3-fold higher, respectively, in patients with RLS than controls. Current MDE (10.5%) and suicidal risk (19.9%) (MINI) were also high. Moderate-to-severe depressive symptoms were associated with young age, female sex, insomnia symptoms, and urgency dimension. The suicide risk was associated with depression, impulsiveness, and RLS severity. RLS treatment improved depressive symptoms but not suicidal thoughts., Conclusion: The rate of depressive symptoms, depression, and suicidal thoughts/risk was higher in patients with RLS, with key associations with insomnia symptoms, urgency dimension, and RLS severity. These results emphasize the importance of detecting these symptoms in current practice and of evaluating their change after treatment, especially in young women, to improve RLS management. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Restless legs syndrome (RLS) is a common sensorimotor disorder characterized by an urge to move that appears during rest or is exacerbated by rest, that occurs in the evening or night and that disappears during movement or is improved by movement. Symptoms vary considerably in age at onset, frequency and severity, with severe forms affecting sleep, quality of life and mood. Patients with RLS often display periodic leg movements during sleep or resting wakefulness. RLS is considered to be a complex condition in which predisposing genetic factors, environmental factors and comorbidities contribute to the expression of the disorder. RLS occurs alone or with comorbidities, for example, iron deficiency and kidney disease, but also with cardiovascular diseases, diabetes mellitus and neurological, rheumatological and respiratory disorders. The pathophysiology is still unclear, with the involvement of brain iron deficiency, dysfunction in the dopaminergic and nociceptive systems and altered adenosine and glutamatergic pathways as hypotheses being investigated. RLS is poorly recognized by physicians and it is accordingly often incorrectly diagnosed and managed. Treatment guidelines recommend initiation of therapy with low doses of dopamine agonists or α 2 δ ligands in severe forms. Although dopaminergic treatment is initially highly effective, its long-term use can result in a serious worsening of symptoms known as augmentation. Other treatments include opioids and iron preparations., (© 2021. Springer Nature Limited.)

Objectives: To compare the clinical features of autonomic dysfunction using the SCOPA-AUT questionnaire in untreated patients with restless legs syndrome (RLS) with controls, to identify factors associated with more severe autonomic symptoms, and to assess the effect of medication in patients., Methods: The SCOPA-AUT questionnaire that evaluates cardiovascular, gastrointestinal, urinary, thermoregulatory, pupillomotor, and sexual dysfunctions was completed by 409 consecutive untreated patients with RLS (54.1 ± 14.5 y.o; 265 women) and 331 controls (59.0 ± 17.0; 161 women). Clinical and polysomnographic data were assessed in all patients. A subgroup of 57 patients were evaluated a second time after treatment (mostly dopaminergic agonist) after an interval of 0.88 ± 1.42 year., Results: Compared to controls, untreated patients with RLS were younger, more often women, obese, with increased cardiovascular diseases (CVD). The SCOPA-AUT total score was higher in patients than controls in unadjusted and adjusted models. Patients had more autonomic symptoms in all subdomains of the scale (except for sexual dysfunction in men). These results were confirmed in a subgroup of 259 cases and age-sex-matched controls. Female gender, obesity, RLS severity, diabetes mellitus, CVD, sleepiness, insomnia and depressive symptoms but neither periodic legs movements during sleep (PLMS) nor objective sleep parameters were associated with high scores. Despite RLS and PLMS improvement, medication did not change total and subdomain scores., Conclusions: Patients with RLS have frequent and large spectrum of autonomic symptoms, without effect of PLMS, sleep fragmentation and medication. These results suggest a global autonomic dysfunction in RLS that should be assessed more systematically in severe patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Restless legs syndrome (RLS) is one of the most common neurological disorders. It describes an irresistible urge to move the legs, mostly manifested in the evening and at night, which can lead to severe sleep disturbance. As part of the European Brain Council (EBC)-led Value-of-Treatment project, this study aimed at capturing the socioeconomic impact of RLS related to the inadequate diagnosis and treatment across different European healthcare settings. The economic burden of RLS was estimated using the published EBC framework of analysis in three separate European Union healthcare systems (France, Germany, and Italy). The RLS care pathway was mapped to identify the unmet needs of patients. Based on specific patient stories, the economic impact of correctly diagnosing RLS and changing between inadequate and target treatment was calculated using appropriate scenario analysis. RLS proved to be a significant personal and social burden, when epidemiological data, high prevalence of RLS, and its need for treatment are combined. By looking at the savings emerging from the provision of optimal care management (timely and correct diagnosis, evidence-based therapy, avoidance of therapy-related complications such as augmentation), the authors foresee substantial economic savings with the achievement of adequate diagnosis and treatment of RLS. Education about RLS is urgently needed for all subspecialties involved in RLS patient care as well as the general public. Equally important, the search for new causal treatment strategies should be intensified to reduce suffering and substantial societal cost., (© 2020 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: The objective of this study was to assess the rotigotine effect on the nocturnal blood pressure (BP) dip by 24-hour ambulatory BP monitoring and on endothelial function in patients with restless legs syndrome (RLS) compared with placebo., Methods: In this double-blind, placebo-controlled trial, 76 adult patients with moderate to severe RLS and periodic legs movements in sleep index ≥10/hour were randomized to rotigotine at optimal dose of 3 mg per day or placebo for 6 weeks. A total of 6 patients had a major protocol deviation. Polysomnography, ambulatory BP monitoring, and endothelial function were assessed at baseline and end point. The primary outcome was the between-group difference in the percentage of BP nondipper profiles at end point. The main secondary outcomes were the mean BP dip, periodic legs movements in sleep index, and endothelial function., Results: Of the 70 patients (age, 59.4 ± 11.40; 43 women) randomized to rotigotine (n = 34) and placebo (n = 36), 66 (33 rotigotine, 33 placebo) completed the study. The percentage of BP nondippers at end point was higher in the placebo than in the rotigotine group (systolic BP, 72.22% vs 47.06%; diastolic BP, 47.22% vs 20.59%; P < 0.05). Mean BP dip at end point was higher in the rotigotine than in the placebo group (systolic BP, 11.24 ± 6.15 vs 6.12 ± 7.98; diastolic BP, 15.12 ± 7.09 vs 9.36 ± 10.23; P < 0.05). Endothelial function was comparable between the groups. No significant safety concerns were reported with similar incidences of adverse events between groups., Conclusion: Rotigotine increased the percentage of BP dipper profiles and the BP dip in patients with RLS. Future studies should assess whether this change is associated with a reduction in the long-term cardiovascular risk in RLS. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

The association between restless legs syndrome (RLS) and iron homeostasis remains unclear. We compared serum hepcidin and ferritin levels in patients with RLS and controls, and assessed their relationships with RLS phenotype, drug intake, and history of augmentation syndrome. 102 drug-free RLS patients (age 58.9 [24.5-77.2], 63 females) and 73 controls (age 56.8 [23.46-76.6], 45 females) underwent a polysomnography recording. Hepcidin levels were quantified by ELISA. 34 RLS patients had a second assessment after starting dopaminergic drugs. Ferritin level was low (< 50 µg/l) in 14.7% of patients and 25% of controls, with no between-group differences in the mean values. Hepcidin levels were higher in patients even after adjustment for confounding factors, and excluding participants with low ferritin levels. Ferritin and hepcidin levels were comparable before and after treatment, and between patients with (n = 17) and without history of augmentation. Ferritin and hepcidin levels correlated with age, body mass index, and periodic leg movements. Higher hepcidin levels were associated with older age, older age at RLS onset, less daytime sleepiness and familial RLS. In conclusion, serum hepcidin levels but not ferritin were higher in RLS patients regardless of treatment and history of augmentation. Serum hepcidin may be a more relevant biomarker of RLS than ferritin.

Objectives: To investigate whether cerebrospinal fluid (CSF) and serum ferritin levels differ between patients with narcolepsy type 1 (NT1) comorbid with restless legs syndrome (RLS) or periodic leg movements during sleep (PLMS), and patients with NT1 or controls without comorbid RLS or PLMS., Methods: Sixty-six drug-free patients with NT1 (44 males, age 38.5 years [14-81]) were enrolled, including 20 with RLS, 18 with PLMS index ≥15/h (six with both RLS and PLMS). Thirty-eight drug-free patients (12 males, age 22.5 years [12-61]) referred for sleepiness complaint, but without central hypersomnia, RLS, PLMS were included as controls. Clinical, electrophysiological and biological (CSF/serum ferritin, orexin [ORX]) data were quantified., Results: NT1 patients with and without RLS did not differ for age, gender, and body mass index (BMI). No between-group differences were found for CSF ferritin, ORX, and serum ferritin levels. No CSF ferritin, ORX, and serum ferritin level differences were found between NT1 patients with and without PLMS, or with RLS or PLMS versus not. CSF-ferritin levels were not different between NT1 and controls in adjusted analyses. CSF-ferritin levels in the whole population correlated positively with age, serum-ferritin, BMI, negatively with ORX, but not with PLMS index. In NT1, CSF-ferritin levels correlated with age and serum-ferritin but not with PLMS., Conclusion: The absence of CSF ferritin deficiency in NT1 with comorbid RLS or PLMS indicates normal brain iron levels in that condition. This result suggests that the frequent association between RLS, PLMS, and NT1 is not based on alterations in brain iron metabolism, a pathophysiological mechanism involved in primary RLS., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: To investigate the relationship between sensory discomfort/motor component and cardiovascular autonomic response by continuous beat-to-beat blood pressure monitoring (CBPM) during the suggested immobilization test (SIT) in patients with restless legs syndrome (RLS)., Methods: Thirty-two drug-free patients with primary RLS (10 men; mean age 60.29 ± 10.81 years) and 17 healthy controls (2 men; mean age 58.82 ± 11.86 years) underwent a 1-hour SIT starting at 8 pm with concomitant CBPM to measure the heart rate (HR) and systolic/diastolic blood pressure (SBP, DBP). In all subjects, the presence of sensory discomfort and motor component during the SIT (S-SIT+ and M-SIT+, respectively) was quantified. Mixed regression models were used to compare the SBP, DBP, and HR profiles during the SIT by taking into account the repeated measures (6 time periods of 10 minutes)., Results: In patients with S-SIT+ (n = 17), SBP (p < 0.0001), DBP (p = 0.0007), and HR (p = 0.03) increased during the SIT compared with other patients and controls. Seventeen patients had M-SIT+ (none among healthy controls). Classifying patients in 4 groups in function of the presence/absence of the SIT sensory and motor components revealed that SDB and DBP increased throughout the SIT in patients with S-SIT+, independently of the motor component (p < 0.0001 and p = 0.0008 for SBD; p < 0.0001 and p = 0.01 for DBP in the S-SIT+/M-SIT- and S-SIT+/M-SIT+ groups, respectively)., Conclusion: During the SIT, BP concomitantly increased only in patients with RLS and sensory discomfort, with or without motor component. This highlights the link between evening sensory RLS symptoms, autonomic activation, and potential long-term cardiovascular consequences., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Restless legs syndrome (RLS) is frequently comorbid with hypertension and cardiovascular diseases; however this relationship and underlying mechanisms remain controversial. After clinical evaluation, 84 drug-free patients with primary RLS (53 women; mean age 55.1 ± 12.3 years) and 76 controls (47 women; mean age 52.2 ± 15.3 years) underwent 24-hour ambulatory blood pressure (BP) and polysomnographic monitoring, and peripheral arterial tonometry to assess endothelial function for 61 patients and 69 controls. Hypertension was diagnosed in 11.9% of patients with RLS based on office measurement, and in 46.4% on the 24 h recording, with nighttime hypertension, two times more frequent than daytime hypertension. Periodic limb movement during sleep (PLMS), markers of sleep fragmentation, and systolic and mean BP non-dipping profile were more frequent among patients. BP non-dipping status was associated with older age, later RLS onset and diagnosis, RLS severity and higher sleep fragmentation. The mean 24-hour, daytime and nighttime BP values, the frequency of hypertension and the endothelial function were comparable between groups. However, both systolic and diastolic BP trajectories over a 24-hour period differed between groups. In conclusion, patients with RLS exhibit a 24-hour BP deregulation with increased frequency of systolic non-dipping profiles that could worsen the risk for CVD morbidity and mortality.

Study Objective: The association between restless legs syndrome (RLS), periodic leg movements during sleep (PLMS) and iron deficiency has been reported in children with attention-deficit/hyperactivity disorder (ADHD); however little is known in adults. The aim of this study was to assess frequencies of RLS, PLMS and other leg movements (LM) and iron deficiency and their relationships with ADHD phenotype in adults with ADHD., Methods: Two hundred adults with ADHD (112 males, median age 31 years) were evaluated on lifetime ADHD symptoms and sleep characteristics. RLS was diagnosed according to standard criteria. Serum ferritin levels were measured, with iron deficiency defined as <50 ng/mL. A subgroup of 48 ADHD patients with RLS, 48 ADHD without RLS and 48 controls underwent a polysomnography to record sleep, LM, and PLMS., Results: RLS was diagnosed in 33.0%, associated with earlier onset of ADHD, hyperactive presentation and more severe lifetime ADHD symptoms. Iron deficiency was found in 35.5% with higher frequency in patients with RLS. LM were more frequent in ADHD patients, with higher LM periodicity levels in those with comorbid RLS in comparison to controls. However, PLMS index did not differ between groups. Patients with ADHD and RLS had higher frequency of iron deficiency than other groups., Conclusions: In a large sample of adults with ADHD, we individualized a subgroup characterized by earlier and severe ADHD symptoms, RLS, higher LM during sleep and iron deficiency. This endophenotype may reflect a different neurobiological mechanism that remains to be further studied., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Augmentation syndrome is one of the most severe complications of RLS. It is characterised by a worsening of treated symptoms; principally an increase in the severity of symptoms and an earlier onset time. Augmentation syndrome occurs primarily with dopaminergic treatments. It is crucial for the patient to be sufficiently well informed to prevent its occurrence and the prescription of too high doses of dopaminergic agonists avoided. In the presence of augmentation syndrome confirmed using the diagnostic criteria, the specialist treating the restless legs syndrome should quickly modify the patient's treatment. In this article, our expert group proposes a practical strategy for the diagnosis, prevention and treatment of augmentation syndrome., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: To better understand the role of iron homeostasis dysregulation in restless legs syndrome, we compared serum hepcidin and ferritin levels in drug-free patients with primary restless legs syndrome and healthy controls and studied the relationship between hepcidin level and restless legs syndrome severity., Methods: One hundred and eight drug-free patients with primary restless legs syndrome (65 women; median age, 61.5 years) and 45 controls (28 women; median age, 53.9 years) were enrolled. Inclusion criteria were: normal ferritin level (>50 ng/mL) and absence of iron disorders, chronic renal or liver failure, and inflammatory or neurological diseases. Each subject underwent a thorough clinical examination and a polysomnography assessment. Serum hepcidin-25 was quantified using a validated mass spectrometry method. Restless legs syndrome severity was evaluated according to the International Restless Legs Syndrome Study Group., Results: Despite no group difference between normal ferritin levels and demographic features, serum hepcidin level and hepcidin/ferritin ratio were higher in patients than in controls. Hepcidin level and hepcidin/ferritin ratio, but not ferritin level, were positively correlated with periodic leg movements during sleep and wakefulness in the whole sample. Hepcidin level seem to be associated with restless legs syndrome severity in a complex U-shaped relationship, without relationship with age at restless legs syndrome onset, positive family history, sleep and depressive symptoms, genetic background, and polysomnographic measurements. No relationship was found between ferritin level and restless legs syndrome severity., Conclusion: In drug-free patients with primary restless legs syndrome, hepcidin level is higher than in controls and may be associated with restless legs syndrome clinical severity. This result emphasizes the complex peripheral iron metabolism deregulation in restless legs syndrome, opening potential perspectives for a personalized approach with a hepcidin antagonist. © 2018 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Parkinson's disease (PD) and restless legs syndrome (RLS) may be clinically and/or etiologically related, yet this association is under debate. Single-nucleotide polymorphisms (SNPs) in the TOX3 gene locus were implicated in both RLS and PD genome-wide association studies (GWASs), suggesting a potential pleiotropy. Two case-control cohorts including 644 PD patients, 457 RLS patients, and 945 controls were genotyped for one known RLS-related SNP (rs3104767) and one PD-related SNP (rs4784226) in the TOX3 locus. The associations between genotype and PD and RLS risk were tested using multivariate regression models. The allele frequencies of RLS-related SNP rs3104767 in RLS patients and controls were 0.35 and 0.43, respectively (OR 0.70, p = 0.0007). Regression model suggested that this association is derived by homozygous carriage of rs3104767 (adjusted p = 0.008). A nominal association was observed for homozygous carriers of the rs3104767 SNP in PD (OR 1.62, 95% CI 1.05-2.54, p = 0.034), i.e., with an opposite direction of effect on RLS and PD, but this was not significant after Bonferroni correction. However, data from published GWASs of RLS and PD, and from the PDgene database, further supported these inverse associations. Our results confirm the association between the TOX3 SNP rs3104767 and RLS and suggest that TOX3 variants are involved in both RLS and PD, but with different or even opposite effects. Studies in larger populations of different ethnicities are required to further refine the TOX3 locus is involved in RLS and PD.

Background: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets., Methods: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10 -8 ) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest., Findings: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1)., Interpretation: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations., Funding: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Y. Dauvilliers déclare des liens ponctuels (activité d’expertise, conférences, prise en charge lors de congrès) avec UCB Pharma, Jazz, Bioprojet, Theranexus, Avadel, Actelion, Takeda, GSK.

Objective: The association between restless legs syndrome (RLS), cardiovascular diseases (CVD) and hypertension is inconsistent. This case-control study examined i) the association between primary RLS, CVD and hypertension by taking into account many potential confounders and ii) the influence of RLS duration, severity and treatment, sleep and depressive symptoms on CVD and hypertension in primary RLS., Methods: A standardized questionnaire to assess the RLS phenotype, history of CVD and hypertension, sleep and depressive symptoms, drug intake and demographic/clinical features was sent to the France-Ekbom Patients Association members. A CVD event was defined as a self-reported history of coronary heart disease, heart failure, arrhythmia or stroke. Hypertension was also self-assessed. Current treatment for hypertension and arrhythmia also defined underlying hypertension and arrhythmia. Controls without RLS and without consanguinity were chosen by the patients., Results: 487 patients with primary RLS (median age 71 years; 67.4% women) and 354 controls (68 years, 47.7% women) were included. Most of the patients (91.7%) were treated for RLS, especially with dopaminergic agonists. The median age of RLS onset was 45 years. CVD and hypertension were associated with RLS in unadjusted association, but not after adjustment for age, sex and body mass index. Patients with RLS and with CVD and/or hypertension were significantly older, with hypercholesterolemia, sleep apnea and older age at RLS and at daily RLS onset compared with patients without CVD and/or hypertension. No significant difference was found for other RLS features, ferritin levels, daytime sleepiness, insomnia and depressive symptoms., Conclusion: Despite some limitations in the design of this study, we found that most of the treated patients for primary RLS had no association with CVD and hypertension after controlling for key potential confounders. Comorbid CVD or hypertension was associated with cardiovascular risk factors, but not with RLS features except for older age at onset.

Restless Legs Syndrome (RLS) is a genetically complex neurological disorder in which overlapping genetic risk factors may contribute to the diversity and heterogeneity of the symptoms. The main goal of the study was to investigate, through analysis of heart rate variability (HRV), whether in RLS patients the MEIS1 polymorphism at risk influences the sympathovagal regulation in different sleep stages. Sixty-four RLS patients with periodic leg movement index above 15 per hour, and 38 controls underwent one night of video-polysomnographic recording. HRV in the frequency- and time- domains was analyzed during nighttime sleep. All RLS patients were genotyped, and homozygotes for rs2300478 in the MEIS1 locus were used for further analysis. Comparison of the sympathovagal pattern of RLS patients to control subjects did not show significant differences after adjustments for confounding factors in frequency-domain analyses, but showed an increased variability during N2 and N3 stages in time-domain analyses in RLS patients. Sorting of RLS patients according to MEIS1 polymorphism reconfirmed the association between MEIS1 and PLMS, and showed a significant increased sympathovagal balance during N3 stage in those homozygotes for the risk allele. RLS patients should be considered differently depending on MEIS1 genotype, some being potentially at risk for cardiovascular disorders.

Background: Restless legs syndrome (RLS) has been associated with insomnia, decreased quality of life, and increased morbidity and mortality in end-stage renal disease. This randomized controlled trial investigated effects of rotigotine in patients with RLS and end-stage renal disease., Study Design: Double-blind placebo-controlled study., Setting & Participants: Adults with moderate to severe RLS (International RLS Study Group Rating Scale [IRLS] ≥ 15) and Periodic Limb Movement Index (PLMI) ≥ 15 who were receiving thrice-weekly hemodialysis enrolled from sites in the United States and Europe., Intervention: Following randomization and titration (≤21 + 3 days) to optimal-dose rotigotine (1-3mg/24 h) or placebo, patients entered a 2-week maintenance period. Polysomnography was performed at baseline and the end of maintenance., Outcomes & Measurements: Primary efficacy outcome: reduction in PLMI, assessed by ratio of PLMI at end of maintenance to baseline. Secondary/other outcomes (P values exploratory) included mean changes from baseline in PLMI, IRLS, and Clinical Global Impression item 1 (CGI-1 [severity of illness]) score., Results: 30 patients were randomly assigned (rotigotine, 20; placebo, 10); 25 (15; 10) completed the study with evaluable data. Mean (SD) PLMI ratio (end of maintenance to baseline) was 0.7±0.4 for rotigotine and 1.3±0.7 for placebo (analysis of covariance treatment ratio, 0.44; 95% CI, 0.22 to 0.88; P=0.02). Numerical improvements were observed with rotigotine versus placebo in IRLS and CGI-1 (least squares mean treatment differences of -6.08 [95% CI, -12.18 to 0.02; P=0.05] and -0.81 [95% CI, -1.94 to 0.33; P=0.2]). 10 of 15 rotigotine and 2 of 10 placebo patients were CGI-1 responders (≥50% improvement). Hemodialysis did not affect unconjugated rotigotine concentrations. The most common adverse events (≥2 patients) were nausea (rotigotine, 4 [20%]; placebo, 0); vomiting (3 [15%]; 0); diarrhea (1 [5%]; 2 [20%]); headache (2 [10%]; 0); dyspnea (2 [10%]; 0); and hypertension (2 [10%]; 0)., Limitations: Small sample size and short duration., Conclusions: Rotigotine improved periodic limb movements and RLS symptoms in the short term among ESRD patients requiring hemodialysis in a small-scale study. No dose adjustments are necessary for hemodialysis patients., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

While sleep disturbances are frequent in renal disease patients, no studies have examined prospectively the associations between sleep disturbances and kidney function decline in community-dwelling elderly subjects.Glomerular filtration rates (eGFRs) were estimated at baseline and at 11-year follow-up. A glomerular filtration decline over the follow-up period was defined as a percentage decline greater than or equal to the cut-off value of the highest tertile of kidney function decline (22%) in 1105 subjects. Excessive daytime sleepiness (EDS) and insomnia complaints were self-rated at baseline. Restless legs syndrome (RLS) and its age at onset were assessed at study end-point. An ambulatory polysomnography recording was performed during the follow-up in 277 subjects. Apnoea-hypopnoea index (AHI), periodic limb movements during sleep (PLMS) and total sleep time were analysed.An increased risk of eGFR decline was associated with EDS (OR 1.67, 95% CI 1.18-2.34) and RLS (OR 1.98, 95% CI 1.18-3.30) independently of potential confounders including cardiovascular risk factors. Among insomnia complaints, a borderline association with eGFR decline was found for early morning awakening only. High AHI (≥30 events·h(-1)) and short total sleep time (<6 h), but not PLMS were linked to eGFR decline in crude associations, but only AHI remained significantly associated after multi-adjustments.EDS, RLS and AHI constitute independent risk factors for kidney glomerular function decline., (Copyright ©ERS 2016.)

Purpose of Review: Much recent progress has been made in understanding restless legs syndrome (RLS), focusing mainly on genetic predisposition and dysregulation of iron metabolism and the dopaminergic system. We provide in this review an update of the most recent scientific advances on the pathophysiology of primary RLS., Recent Findings: Genome-wide association studies identified six genetic variants including MEIS1 and BTBD9 with potential relationships with iron. Brain iron level is low in RLS and neuropathological studies have shown significant decreases in dopamine D2 receptors in the putamen that correlated with RLS severity, and increased tyrosine hydroxylase in the substantia nigra. An overly activated dopaminergic system was reported in both animal and cell models of iron insufficiency thus suggesting that in at least a subgroup of RLS patients altered iron metabolism plays a role in the disorder. Also, dysregulation of iron uptake and storage within brain microvessels was recently reported and might play a role in a subgroup of RLS patients., Summary: RLS is a genetically heterogeneous complex trait with high prevalence but large phenotype variability. Current theories of RLS pathophysiology emphasize brain iron deficiency with abnormal dopaminergic consequences, together with a strong underlying genetic background.

Study Objectives: To assess whether the frequency of impulse control disorders (ICDs), addictive behaviors, impulsivity, and impairment of decision-making task performance under ambiguous and risky conditions were present in patients with restless legs syndrome (RLS) and whether changes could be related to dopaminergic medications., Design: Case-control prospective study., Setting: Academic Sleep Disorders Center., Participants: Of the 149 participants, there were 39 who were drug free with primary RLS, 50 who were taking dopamine agonists (DA), and 60 control subjects. Participants were assessed with a clinical interview screening for ICDs, augmentation syndrome, impulsivity, depression, and addictive behaviors. All participants completed two decision-making tasks, one under an ambiguous condition (Iowa Gambling Task) and the other under a risky condition (Game of Dice Task). Drug-free patients with RLS underwent 1 night of polysomnography recording., Measurements and Results: Seventy percent of patients were treated with pramipexole (median dose, 0.36 mg), and 30% with ropinirole (median dose, 0.75 mg). Median duration of DA intake was 11 mo (range, 1-72 mo). No differences were found on impulsivity scores, ICDs, and substance addiction between drug-free patients or those taking DA, or control subjects. Patients with RLS reported more depressive symptoms than control subjects, but without differences between patients taking or not taking DA. Drug-free and treated patients demonstrated reduced performances on the Iowa Gambling Task but not on the Game of Dice Task compared to control subjects, with no differences between patients taking medications and those who were not. No association was found between decision-making task performances, or polysomnographic and clinical variables., Conclusion: Impulse control disorders, impulsivity, and substance addiction were infrequent in drug-free patients with restless legs syndrome or those treated with a low dose of dopamine agonists. However, patients with restless legs syndrome, either drug free or taking dopamine agonists, had preferences toward risky choices on the Iowa Gambling Task, which led to negative consequences in the long run, a condition potentially leading to further development of impulse control disorders.

Introduction: Models of dopaminergic function in restless legs focus on central dopaminergic neurons. Domperidone, a peripheral dopamine blocker that cannot cross the blood-brain barrier, is commonly used in Parkinson's disease. After encountering a case of restless legs syndrome that dramatically worsened with domperidone, we assessed whether Parkinson's patients may have exacerbation of restless legs with domperidone., Methods: From two Parkinson's disease cohorts, we assessed restless legs prevalence according to standard criteria, in patients taking vs. not taking domperidone. Regression analysis was performed, adjusting for age, sex, disease duration, UPDRS, dopaminergic medications and other medications., Results: One hundred eighty four patients were assessed, of whom 46 (25%) had restless legs. Thirteen out of twenty seven (48%) patients on domperidone had restless legs compared to 33/157 (21%) without (p = 0.010). Other medications were not associated with restless legs., Conclusion: This unexpected finding suggests that dopaminergic neurons outside of the blood-brain barrier may be important in restless legs syndrome pathophysiology., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Diagnosis of restless leg syndrome (RLS) in Parkinson's disease (PD) is difficult because of clinical confounds. The suggested immobilization test (SIT) is validated for diagnosis of primary RLS. This study evaluated the usefulness of the SIT for diagnosis of RLS in PD. We compared SIT scores, as well as polysomnography measures in 50 patients with PD (25 with RLS, 25 without), 25 patients with primary RLS, and 25 age/sex matched controls. Mean leg discomfort score was increased in patients with PD and RLS compared to PD without RLS, and also in patients with primary RLS compared to controls. Leg discomfort was significantly higher at the end of the test in patients with RLS compared to patients without RLS. Intensity of leg discomfort was similar between patients with RLS, with or without PD. Using a mean leg discomfort cutoff of 11, we showed sensitivity of 91% and specificity of 72% for RLS diagnosis in PD during symptomatic time intervals. Periodic leg movements index during the SIT did not differ between groups. Periodic leg movements index during sleep and wakefulness was increased in patients with primary RLS compared to controls, but did not differ between patients with PD, with and without RLS. The sensory SIT is a simple test that may help diagnose RLS in patients with PD., (Copyright © 2012 Movement Disorder Society.)

We compared periodic and non-periodic leg movements during sleep and polysomnography in patients with narcolepsy with cataplexy (NC) with or without restless legs syndrome (RLS) with matched idiopathic RLS (iRLS) and control subjects. We enrolled 100 patients with NC: 17 having RLS were compared with 34 sex- and age-matched patients without RLS and with 17 normal controls and 17 iRLS subjects. Periodic leg movements were highest in iRLS and lowest in controls, with those in NC with RLS very close to iRLS, but higher than those in NC without RLS. The periodicity indexes showed the highest value in iRLS followed by NC with or without RLS and, finally, by controls. The inter-leg movement intervals peaked between 10 and 50 s in NC with RLS and in iRLS, the former did not display the nocturnal gradual decrease of periodic leg movements typical of iRLS. Periodic leg movements during sleep and polysomnography displayed specific features in RLS and NC, respectively, with NC with RLS showing an intermediate pattern. Even if RLS is only detected by targeted interview in NC, its frequency and impact on night-time sleep architecture and continuity suggest that this condition should be routinely searched for in NC., (© 2011 European Sleep Research Society.)

Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10(-11), OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10(-19), OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 5'-end of TOX3 and the adjacent non-coding RNA BC034767., Competing Interests: The authors have declared that no competing interests exist.

The dopamine system is implicated in reward-based decision making with explicit information (decision making under risk) and implicit probabilities (decision making under ambiguity). Although the pathophysiology of restless legs syndrome (RLS) is not yet fully understood, the genetic factors, iron status, and dopaminergic system are thought to play a role. RLS provides an opportunity to test the dopaminergic hypothesis in a drug-free population and to characterize reward processing using decision-making paradigms. We investigated impulsivity, impulse control disorders, and decision making in 50 untreated patients with primary RLS compared with 60 sex- and age-matched normal controls using one night of polysomnography recording, a structured psychiatric interview, and questionnaires (RLS Severity Scale, Beck Depression Inventory, and Urgency Premeditation Perseverance Impulsive Behavior Scale). Subjects performed the Iowa Gambling Task to assess decision making under ambiguity and the Game of Dice Task to assess decision making under risk. Patients with RLS showed selective changes in decision making on the Iowa Gambling Task and normal decision making on the Game of Dice Task compared with controls. Patients with RLS had greater depressive symptoms than controls, but no difference was found in impulsivity, impulse control disorders, or addictive behaviors. Clinical and polysomnographic variables were unrelated to decision-making performance. Results indicate reduced decision-making performance under ambiguity in drug-free patients with RLS. From a clinical perspective, when using dopaminergic medication to treat RLS, patients with abnormal baseline behaviors should be closely monitored., (© 2010 Movement Disorder Society.)

Study Objectives: To investigate the occurrence of restless legs syndrome (RLS) in narcolepsy with cataplexy (NC)., Design: A case-control study assessing the frequency of comorbidity of RLS and NC in three European sleep disorder centers., Patients: Three sleep research centers recruited 184 NC patients and 235 age-matched controls., Interventions: N/A., Measurements and Results: NC patients and controls underwent a face-to-face interview investigating demographics, medical and drug history, sleep habits, and sleep disorders, in particular RLS based on the 4 international criteria and on a frequency > or =2 times/week, with a detailed description of RLS symptoms when present. RLS was significantly more prevalent among NC patients (14.7%) than in controls (3.0%). The age at onset of RLS in NC patients fits with the age at onset in idiopathic RLS, and RLS appeared more than 10 years after NC onset. Unlike idiopathic RLS, RLS in NC subjects was not more prevalent in women and was less familial (15.4% of cases). Lastly, NC patients with RLS showed a moderate disease severity and an almost daily occurrence of symptoms, which were also diurnal in 35% of cases. Older age, higher blood ferritin levels, and sleep paralysis seem to have a predictive value for RLS in NC. The higher ferritin levels indicate that different pathophysiological mechanisms underlie secondary RLS associated with NC., Conclusions: This study highlights the association between RLS and NC. The nature of this association is still investigational, but it does indicate that RLS must be addressed in the evaluation and management of nocturnal sleep impairment in NC patients.

Restless legs syndrome (RLS) is characterized by an unpleasant sensation in the lower limbs and an urge to move, occurring during periods of rest, in the evening and during the night and improved by movement. There are two different phenotypes of RLS: an early-onset form, starting before 36 years old with mostly a familial history, being mostly severe and highly genetically determined, with a high dependence to iron brain levels; a delayed-onset form, starting after 36 years old, mostly secondary, without familial history, with a rapid evolution in two or three years, and with frequent low ferritine serum levels. The primary form of RLS is associated with a familial history in 40 to 92 % of the patients. Monozygotic twins have a 54 to 83 % concordance rate for RLS phenotype. Linkage association studies have identified eight loci involved in the familial transmission of the disease. Genetic association studies have identified allelic variants responsible for a 50 % increased risk to develop RLS in the general population. Proteins coded by some implicated genes are involved in the development of spinal motor neurons and spinal dorsal horns, and in brain iron homeostasis., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Objective: To determine the distribution of age-at-onset in a large cohort of patients with restless legs syndrome (RLS) and to compare clinical and polysomnographic characteristics of patients with early and late age-at-onset of RLS., Methods: Two hundred and fifty patients with RLS were studied. Information on age-at-onset, etiology, familial history and symptoms severity of RLS was obtained. Age-at-onset density functions were determined from bootstrap methods and kernel density estimators., Results: Age-at-onset showed a significant bimodal distribution with a large peak occurring at 20 years of age and a smaller peak in the mid-40s. Early- and late-onset RLS could be separated with a cut-off at 36 years of age. Distributions of age-at-onset differed as a function of presence/absence of a familial history and etiology of RLS. Age-at-onset clearly differentiated patients with a primary RLS (early onset) from those with secondary RLS. Finally, early-onset RLS was associated with increased RLS severity with higher indices of periodic leg movements in sleep (PLMS) associated with microarousals and periodic leg movements during wakefulness (PLMW)., Conclusions: Early- and late-onset RLS could be distinguished depending on familial history and etiology of RLS. Our data suggest that different pathological processes are involved in these two groups, the early-onset group being highly genetically determined.

Gamma-hydroxybutyrate (GHB) has re-emerged as a major treatment for narcolepsy. As dopaminergic transmission is clearly involved in the pathophysiology of restless legs syndrome (RLS), and GHB reduces dopamine release, one may hypothesize that RLS may occur in narcolepsy in the presence of GHB. We report a case of narcolepsy with a severe occurrence of typical RLS with GHB, symptoms never previously experienced by the subject and reversible after withdrawal.