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Background: Iron supplementation is the most commonly considered treatment option for children with restless legs syndrome (RLS) or periodic limb movement disorder (PLMD); however, there is a scarcity of evidence on the effectiveness of intravenous preparations. In this study, we evaluated the effectiveness and tolerability of intravenous ferric carboxymaltose (IV FCM) on clinical symptoms and iron indices in children with RLS or PLMD., Methods: This was a single-center retrospective data analysis. Children with a diagnosis of RLS or PLMD, who underwent a single infusion of IV FCM, were included. Clinical Global Impression (CGI) Scale scores, serum ferritin, and serum iron profile at baseline and after eight weeks post infusion were obtained. Adverse effects were assessed., Results: Thirty-nine children received IV FCM, 29 with RLS and 10 with PLMD. Pre-infusion CGI-Severity revealed moderate illness, with post-infusion CGI-Improvement between "very much improved" and "much improved". Ferritin increased from 14.6 μg/L±7.01 to 112.4 μg/L±65.86 (p < 0.00001), together with improvements in iron, total iron binding capacity, and transferrin levels from baseline to post-treatment. When compared to children with RLS, those with PLMD had a similar improvement in clinical symptoms and laboratory parameters. Seven subjects (14.3%) experienced one or two adverse events; all were mild., Conclusions: Children with RLS and PLMD responded to IV iron supplementation with improvement in both clinical severity and laboratory parameters. Treatment was well tolerated. Although larger, randomized-controlled trials are needed, IV FCM appears to be a promising alternative to oral iron supplementation for the treatment of pediatric RLS or PLMD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Intravenous ferric carboxymaltose (FCM) has been shown to be efficacious in treating restless legs syndrome (RLS) symptoms in non-anemic patients. The aim of this study was to evaluate the effectiveness of FCM in treating RLS symptoms in patients who also had an iron deficiency anemia (IDA)., Methods: This is a randomized, double-blinded, placebo-controlled study. Subjects with RLS and IDA were enrolled. Subjects received an infusion of either 1500 mg FCM or placebo in Phase I. The primary outcomes were a change-from-baseline at week six on the International Restless Legs Syndrome Study Group scale (IRLS). Phase II of the study involved long-term (52 weeks) follow-up, for those who responded to treatment in the prior phase, with the potential for further treatment if symptoms returned., Results: We enrolled 29 RLS patients with IDA (15 FCM and 14 placebo). At week six post-infusion, FCM compared to placebo group showed significant improvement from baseline in IRLS score (-13.47 ± 7.38 vs. 1.36 ± 3.59). Among secondary outcome variables, quality of sleep showed significant improvement from baseline in the FCM group. 61% of subjects remained off RLS medications at the Phase II, week-52 endpoint. There were no serious adverse events observed in the study., Conclusion: The study showed significant efficacy and safety of FCM 1500 mg treatment both in the short term (6 weeks) and long term (52 weeks) in RLS patients with IDA., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This study reports on an epigenetic biomarker for restless leg syndrome (RLS) developed using whole genome DNA methylation data. Lymphocyte-derived DNA methylation was examined in 15 subjects with and without RLS (discovery cohort). T-tests and linear regressions were used followed by a principal component analysis (PCA). The principal component model from the discovery cohort was used to predict RLS status in a peripheral blood (N = 24; including 12 cases and 12 controls) and a post-mortem neural tissue (N = 71; including 36 cases and 35 controls) replication cohort as well as iron deficiency anemia status in a publicly available dataset (N = 71, 59 cases with iron deficiency anemia, 12 controls). Using receiver-operating characteristic analysis the optimum biomarker model - that included 49 probes - predicted RLS status in the blood-based replication cohort with an area under the curve (AUC) of 87.5% (confidence interval = 71.9%-100%). In the neural tissue samples, the model predicted RLS status with an AUC of 73.4% (confidence interval = 61.5%-85.3%). An AUC of 83% was found for predictions of iron deficiency anemia. Thus, the blood-based biomarker model reported here and built with epigenome-wide data showed reasonable replicability in lymphocytes and neural tissue samples. A limitation of this study is that we could not determine the metabolic or neurobiological pathways linking epigenetic changes with RLS. Further research is needed to fine-tune this model for prospective predictions of RLS and to enable translation for clinical use., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Restless sleep is a frequent complaint in clinical practice and has been reported in the medical literature since the 1970s. Most often, it has been described in association with specific sleep or medical conditions. However, more recently, publications have emerged that describe a disorder characterized by restless sleep as the core feature. To assess this further, the International Restless Legs Syndrome Study Group (IRLSSG) appointed a task force composed of international sleep experts., Methods: A committee of 10 sleep clinicians developed a set of 16 consensus questions to review, conducted a comprehensive literature search, and extensively discussed potential diagnostic criteria. The committee recommendations were reviewed and endorsed by the IRLSSG Executive Committee., Results: Based on the medical literature and expert clinical experience, the task force found sufficient evidence to formulate diagnostic criteria for a clinical entity designated "restless sleep disorder" (RSD). Eight essential criteria were agreed upon, which include a complaint of restless sleep, observed large body movements during sleep, video-polysomnographic documentation of 5 or more large body movements/hour, occurrence at least three times a week for at least three months, clinically significant impairment, and differentiation from other conditions that might secondarily cause restless sleep. However, the current evidence limits application to ages 6-18 years. Diagnostic coding, addition to existing diagnostic nosologies, and name selection are discussed., Conclusions: Consensus diagnostic criteria for RSD have been developed, which are intended to improve clinical practice and promote further research., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Significant benefit of intravenous ferric carboxymaltose (FCM) treatment for restless legs syndrome (RLS) has been well-established. However, no clinical indicators predicting treatment response of RLS have been established. This study aimed to determine factors predicting outcome of clinical FCM treatment of RLS patients., Methods: Data were retrospectively reviewed from all patients who received FCM treatment for RLS from April 2016 to April 2019. These data included: detailed history, international RLS scale score (IRLS), questionnaires, comorbidity, and previous RLS medication use. Morning fasting serum iron, ferritin, and total iron-binding capacity were measured before and at four weeks after treatment. RLS patients with possible secondary RLS were identified by reviewing the medical histories. This included patients with iron deficiency anemia, lumbosacral radiculopathy, and gastrectomy. Primary RLS included those with no indication of secondary medical factors contributing to RLS. Treatment response was assessed using the IRLS and clinical ratings at four weeks after FCM administration. Patients with a greater than 40% decrease in IRLS were classified as responders., Results: The study comprised 164 patients with IRLS and clinical ratings obtained before and at four weeks after intravenous (IV) iron. Treatment responses differed considerably between diagnostic groups of RLS. Percentage responding was: 64.7% (66 of 102) for patients with primary RLS, 90.9% (10 of 11) with gastrectomy, 91.3% (21 of 23) with iron deficiency anemia and 39.3% (11 of 28) with lumbosacral radiculopathy. When responders were compared to non-responders in primary RLS patients, responders had significantly lower serum iron (80.5 ± 26.7 vs. 95.8 ± 30.5 μg/dL, p = 0.022) and percentage transferrin saturation (%TSAT) (25.4 ± 9.6 vs. 30.5 ± 10.5%, p = 0.026) in females, but not males. Logistic regression controlling for major subject variables showed that %TSAT significantly predicted response. (odds ratio [OR]: 0.955, confidence interval: 0.913-0.998, p = 0.040)., Conclusion: Intravenous FCM in moderate to severe RLS patients is beneficial as a first-line or add-on treatment, particularly for patients with compromised peripheral iron state. Overall, lower %TSAT predicted better chance of responding to the IV iron treatment especially for females., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Brain iron deficiency (BID), especially for the substantia nigra (SN), without peripheral iron deficiency (ID) has been well documented as a ubiquitous finding for restless legs syndrome (RLS) patients. This close association suggests the biology of RLS BID can produce RLS symptoms. Association, however, cannot establish such a direct relationship. Instead, the BID of RLS could be experimentally produced to determine if it then produces significant RLS-like biological or behavioral features. Forward genetics approach led to identification from the BXD strains the BXD40 females (BXD40f) as a putative animal model for the RLS BID. The BXD40f on an iron-sufficient diet have a lower iron in the VMB (containing the SN) during the active but not inactive period. This was not found for the other BXD strains evaluated. The BXD40f on an ID diet uniquely have even greater reduced VMB but not peripheral iron, matching the RLS BID pathophysiology. A prior report found that the BXD40f on an iron-sufficient diet had an RLS-like behavior of increased activity occurring only in the last part of the active period that was not present in the other strains without the low VMB iron. This increased activity matches the circadian pattern of symptoms in RLS patients with increased urge or drive to move in the last part of the day. This study asks first: if you decrease the VMB iron by an iron deficient diet do the RLS-like behaviors worsen; and second will the dopaminergic treatments effective for RLS also reduce the worsened RLSlike behaviors., Methods: In sum, 13 BXD40f mice post weaning were randomly assigned for 100 days to either a iron-sufficient diet (n = 6) or an ID diet (N = 7). They were then evaluated for 24-h activity in their home cage using implanted G2 EMitter telemetry device. At 3 h before the end of the active period IP doses were given every other day of either: saline (vehicle only), 12.5 mg levodopa, 25 mg levodopa, 0.5 mg quinpirole, or 1 0.0 mg quinpirole., Results: The ID compared to irons-sufficient diet produced earlier onset of the RLS-like behavior matching the earlier onset of symptoms with increasing severity of RLS. The dopaminergic treatments significantly reduced the RLS-like behavior. Added analyses of the RLS-like behaviors as decreased resting times showed similar results to activity increases., Conclusions: These data demonstrate both that The BXD40f provide a useful animal model of RLS and also strongly support the hypothesis that the biology of RLS BID can produce RLS symptoms., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The primary symptoms of Restless Legs Syndrome (RLS) are circadian-dependent, leading to increased activity or decreased rest, especially at night. The primary pathology in RLS is brain iron insufficiency despite normal systemic iron stores. Natural variances in brain and peripheral iron concentrations across recombinant inbred (RI) murine strains provide a biological model of RLS. The question is whether these RI mice strains show a behavioral analog to circadian-dependent clinical phenotype of RLS., Methods: The home cage activity of eight female RI strains was measured over a 72-h period. The ratio of the average activity in the last 2 h of the active period relative to that in the total 12-h active period (late active period activity ratio, LAPAR) was the primary outcome variable. The relation of average LAPAR scores to measures of ventral midbrain (VMB) iron was evaluated across strains in this study., Results: RI strain 40 (LAPAR = 1.28) and RI strain 21 (LAPAR = 1.02) were the only strains to show an increased activity in the last part of the active period. ANOVA showed the increased activity was significantly greater during the last 2 h compared to the preceding 10 h of the active phase only for the RI strain 40. Average LAPAR across the eight strains did not significantly correlate with the VMB iron content (r = -0.27, p < 0.10) but did correlate with changes in VMB iron with iron deficiency (r = 0.71, p < 0.05) and diurnal change in VMB iron (r = 0.65, p < 0.05)., Conclusion: The female RI strain 40 mice exhibited a distinct end-of-active-period behavior analogous to circadian-dependent clinical phenotype of RLS., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Resting-state brain connectivity has been shown to differ for Restless Legs Syndrome (RLS) compared to healthy control (CON) groups. This study evaluates the degree these RLS-CON differences are changed by concurrent treatment., Methods: Resting-state functional MRIs were obtained from 32 idiopathic RLS patients during the morning asymptomatic period and 16 age and gender-matched CON subjects. Of the 32 RLS patients, 16 were drug-naïve (DN-RLS), and 16 were regularly drug-treated using a dopamine agonist (DT-RLS). Various assessments of disease characteristics were also performed. The primary purpose was to assess the replicability of prior results and the effects of treatment on these differences between controls and untreated RLS patients. Resting-state connectivity was analyzed by a seed-based method using the bilateral ventral-posterolateral nuclei (VPLN) in the thalamus., Results: In the DN-RLS group, compared to the CON group, three areas (the bilateral lingual gyri and right middle temporal gyrus) were replicated. The three replicated areas did not significantly differ for DT-RLS compared to DN-RLS. DT-RLS compared to DN-RLS had significantly higher thalamic connectivity for the left uvula, right tuber, left anterior insula, and right declive., Conclusions: Thalamic connectivity to the bilateral lingual gyri and right middle temporal gyrus is a replicable finding in DN-RLS that was not affected by dopamine agonist treatments. Other changes in thalamic connectivity were altered by dopamine agonist treatment. These treatment effects may be pertinent to the known treatment benefits of a dopamine agonist on RLS symptoms., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: The International Restless Legs Study Group (IRLSSG) has developed the IRLS (International Restless Legs Syndrome Severity Scale) and validated it as a clinician/researcher administered scale to be used when both patient and examiner are present. The IRLSSG recognized the need for a self-completing scale that can be used economically in clinical practice and in large population-based studies. In this study the validity and the reliability of the IRLS as a self-administered scale (sIRLS) is assessed., Methods: Established RLS patients were recruited by eight centers in four countries and consented to participate in this study. The validity of the sIRLS was assessed by patients completing the sIRLS before a clinician administered the IRLS. The reliability of the sIRLS was assessed by patients completing the sIRLS again, two weeks after the first one, provided no change had occurred., Results: Overall, 173 patients were recruited and 164 of them were included in the analyses. The sIRLS showed satisfactory scaling assumptions and no relevant floor or ceiling effect. One factor explained 61.3% of the variance. Cronbach's alpha was 0.93 and the item homogeneity index was 0.59. Intraclass correlation coefficient between the sIRLS and the IRLS was 0.94. The sIRLS standard error of measurement was 3.61 (½ SD at baseline = 4.11). The results mostly overlapped those of the IRLS analyzed in parallel., Discussion: The sIRLS is a reliable, valid and precise instrument that showed tight association with the IRLS. These findings support the use of the sIRLS for self-evaluation of RLS severity. The responses obtained on the sIRLS and the IRLS scale varied slightly. Therefore, we recommend that either the sIRLS or the IRLS scale be used as the only scale for serial measures over time., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We assessed corticomotor excitability in the primary motor cortex (M1) of participants with moderate-to-severe restless legs syndrome (RLS) symptoms using transcranial magnetic stimulation (TMS) in relation to the clinical and sleep aspects of the disease. Thirty-five participants (20 F; mean age: 59.23 ± 1.66 years; range: 42-78 years) affected by primary RLS (off medications) and 31 age-matched controls (19 F; mean age: 57.90 ± 1.50 years; range: 43-79 years) underwent TMS following two nights of polysomnography (PSG). Paired-pulse TMS measures [short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI), and intracortical facilitation (ICF)] of the dominant M1 hand and M1 leg muscles were collected and analyzed in relation to clinical features of RLS and PSG. We found decreased corticomotor excitability in M1 hand , whereas it was increased in M1 leg , which was greater in patients with more severe RLS. Participants with RLS with a history of dopamine-agonist-induced symptom augmentation showed decreased LICI (reduced inhibition) compared to nonaugmented participants with RLS for M1 leg . None of the TMS measures (M1 hand or M1 leg ) correlated with the PSG parameters. This study shows hyperexcitability in M1 leg , and this appears related to RLS disease severity and decreased excitability in M1 hand . The results provide new insight into the complex neurobiology of RLS, particularly in more advanced stages of the disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Restless Legs Syndrome (RLS) is characterized by uncomfortable nocturnal sensations in the legs making sedentary activities and sleep difficult, and is thus linked with psychosocial distress. Due to the symptomatology and neurobiology of RLS (disrupting brain iron and dopamine) it is likely that RLS associates with poorer health-related quality of life (HRQL) and depressive disorder. The objective of this study was to investigate the RLS-HRQL and the RLS-depressive disorder links in a generally healthy population that is not biased by medications., Methods: Complete data, including the Cambridge-Hopkins RLS questionnaire, the 12-item short-form standardized health survey (SF-12), the Major Depression Inventory (MDI), body mass index, smoking status, alcohol consumption, and education were available for 24,707 participants enrolled in the Danish Blood Donor Study from May 1, 2015 to February 1, 2017. Information on quality of sleep was available for all RLS cases. T-tests and multivariable logistic regression models were applied to examine the associations of RLS and MDI scores, and the physical and mental component scores (PCS and MCS) of SF-12, respectively. Analyses were conducted separately for men and women., Results: RLS associated with poorer MCS and poorer PCS. Moreover, Participants with RLS were more likely to classify with depressive disorder. Poor quality of sleep was associated with depressive disorder and poorer MCS among RLS cases, and with poorer PCS in female RLS cases., Conclusion: Thus, we demonstrated that RLS is associated with a significantly lower HRQL and a higher prevalence of depressive disorder among otherwise healthy individuals., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: There have been four randomized, placebo-controlled, double-blinded studies of intravenous (IV) iron in Restless Legs Syndrome (RLS), all of which delivered a final total dose of 1000 mg of iron. The purpose of this study was to evaluate effects of a lesser total dose (500 mg of iron)., Methods: Subjects with idiopathic RLS were enrolled in a randomized, double-blinded, placebo-controlled study. Subjects received either 500 mg ferric carboxymaltose (FCM) or placebo as a single infusion (Phase I). Subjects who were previously on medication were off any RLS medications for at least two weeks prior to baseline assessment. The primary outcome variable was a change-from-baseline at week six on the International RLS Severity Scale (IRLSS) and a subject-completed Visual Analog Scale of Severity (VAS). Phase II of the study involved long-term (30 weeks) follow-up after completing the six week efficacy phase., Results: At week six post infusion, FCM, compared to placebo recipients, showed no significantly greater change-from-baseline for both primary outcome measures (IRLSS scale, FCM 500 mg vs. placebo: -8.3 ± 7.5 vs. -4.8 ± 8.7, p = 0.100; VAS, FCM 500 mg vs. placebo: -23.4 ± 24.1 vs. -13.3 ± 23.1, p = 0.077). None of the secondary outcome variables showed a significant difference at week six. Seven (21.9%) of the 32 subjects treated with iron in Phase I remained free from further RLS medications at 30 weeks. No serious adverse effects were found in this study., Conclusions: This study did not show significant benefit from a single 500 mg FCM treatment for RLS symptoms. The two previous, well-controlled, trials of 1000 mg FCM showed significant treatment benefits which suggested that there may have been a clinically relevant total dose required to achieve a clinical response., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Restless legs syndrome (RLS) patients compared to controls have been found to have abnormal patterns in the default mode network (DMN) in the morning when symptom threshold is the highest and symptoms are least likely to occur. If these morning abnormalities in DMN are pertinent to disease expression, then similar or further detectable differences may be expected on a nighttime assessment when RLS symptom threshold is at its lowest. The purpose of this study was to elucidate the potential neural mechanisms underlying the circadian aspect of RLS symptom expression by assessing diurnal changes in DMN., Methods: Fifteen drug-naïve subjects with idiopathic RLS and 15 age- and gender-matched healthy subjects had fMRI scans in the morning and evening. The DMN patterns were compared both for differences between morning and evening and between RLS and controls., Results: RLS patients compared to the healthy controls showed significant differences in morning and evening DMN. In particular, RLS patients showed consistent increased connectivity in the parietal lobule in both the morning and evening. In contrast, connectivity in the thalamus was increased in the morning and reduced in the evening. In addition, there were negative correlations between thalamic connectivity and the Korean versions of the international RLS scale and the quality-of-life subscore., Conclusions: The results indicated diurnal disturbances of the DMN in RLS subjects are consistent with both the circadian rhythm and severity of RLS. The circadian expression of RLS may relate to changes in arousal cortical-activation thresholds occurring with diurnal changes in the thalamic circuits of the DMN., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Brain iron deficiency has been implicated in the pathophysiology of RLS, and current RLS treatment guidelines recommend iron treatment when peripheral iron levels are low. In order to assess the evidence on the oral and intravenous (IV) iron treatment of RLS and periodic limb movement disorder (PLMD) in adults and children, the International Restless Legs Syndrome Study Group (IRLSSG) formed a task force to review these studies and provide evidence-based and consensus guidelines for the iron treatment of RLS in adults, and RLS and PLMD in children., Methods: A literature search was performed to identify papers appearing in MEDLINE from its inception to July 2016. The following inclusion criteria were used: human research on the treatment of RLS or periodic limb movements (PLM) with iron, sample size of at least five, and published in English. Two task force members independently evaluated each paper and classified the quality of evidence provided., Results: A total of 299 papers were identified, of these 31 papers met the inclusion criteria. Four studies in adults were given a Class I rating (one for IV iron sucrose, and three for IV ferric carboxymaltose); only Class IV studies have evaluated iron treatment in children. Ferric carboxymaltose (1000 mg) is effective for treating moderate to severe RLS in those with serum ferritin <300 μg/l and could be used as first-line treatment for RLS in adults. Oral iron (65 mg elemental iron) is possibly effective for treating RLS in those with serum ferritin ≤75 μg/l. There is insufficient evidence to make conclusions on the efficacy of oral iron or IV iron in children., Conclusions: Consensus recommendations based on clinical practice are presented, including when to use oral iron or IV iron, and recommendations on repeated iron treatments. New iron treatment algorithms, based on evidence and consensus opinion have been developed., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Restless legs syndrome (RLS) is a neurological sensorimotor disorder characterized by uncomfortable sensations in the legs. RLS often occurs as a comorbid condition. Besides an increased risk of iron deficiency, blood donors are considered to be generally healthy. Blood donors are therefore an ideal population for studying factors associated with RLS occurrence, herein the role of iron. It is suggested that RLS is linked to sex, age, low socioeconomic status, unhealthy lifestyle, and iron deficiency. The objective of this study is therefore to estimate the RLS prevalence and identify associated biological, sociodemographic, economic, and lifestyle factors in a population of blood donors., Methods: A total of 13,448 blood donors enrolled in the Danish Blood Donor Study from May 2015 to May 2016. RLS cases were identified using the validated Cambridge-Hopkins RLS-questionnaire. Logistic regression models were applied to assess the relationship between RLS and data on socially related factors collected using questionnaires and population registers., Results: In this study, 7.2% women and 4.5% men were classified with RLS. RLS was associated with: female sex, high age, smoking, frequent alcohol consumption, and low education. RLS-related symptoms were associated with obesity, parity and donation intensity three years prior to inclusion among women. RLS was not related to: reduced plasma ferritin, employment status, and income., Conclusions: RLS is a frequent disorder in otherwise healthy individuals. The associations discovered in this study can be utilized in preventing or reducing RLS symptoms., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: At high altitude, prevalence of restless legs syndrome has been found to be greater than expected in small population-based studies, which did not use validated tools for identification of RLS. However, it is not known as to whether this increased prevalence is associated with altitude or increased risk factors for RLS in these populations or errors in identification of RLS., Method: This population based, door-to-door study was conducted at low altitude (400 m above sea level) and high altitudes (1900-2000 m and 3200 m above sea level) using random stratified sampling in Himalayan and sub-Himalayan region of India. Subjects between 18 and 84 years were screened for restless-legs-syndrome using the validated Cambridge-Hopkins RLS diagnostic questionnaire. Medical comorbidities were ascertained from their medical records. Their anthropometric measurements were obtained and wake resting oxygen saturation was monitored using finger pulse-oximeter. Physical activity during leisure time was evaluated by using the Goldin leisure time exercise questionnaire., Results: A total of 1689 subjects were included. Average age of the included subjects was 35.2 years; 55.2% were women. RLS was identified in 9.4% subjects with higher prevalence among women (13.6% women vs. 4.1% men; P < 0.001). RLS was significantly more prevalent at higher altitudes (12.2% at 1900-2000 m and 11.8% at 3200 m) compared to low altitude (2.5% at 400 m). The low altitude prevalence matched that reported in prior studies of RLS in India. Subjects with medical disorders sometimes related to RLS (eg, peripheral neuropathy, COPD, varicose veins and anemia) also had higher prevalence of RLS. Binary logistic regression controlling for female gender, number of pregnancies, peripheral neuropathy, varicose veins, anemia showed that high altitude independently significantly increased the likelihood of RLS (OR: 5.4, 95% CI: 2.8, 10.4)., Conclusion: RLS is about five times more prevalent at high than low altitudes even when controlling for effects of other medical conditions associated with increased risk of RLS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In this article, we review the original findings from MRI and autopsy studies that demonstrated brain iron status is insufficient in individuals with restless legs syndrome (RLS). The concept of deficient brain iron status is supported by proteomic studies from cerebrospinal fluid (CSF) and from the clinical findings where intervention with iron, either dietary or intravenous, can improve RLS symptoms. Therefore, we include a section on peripheral iron status and how peripheral status may influence both the RLS symptoms and treatment strategy. Given the impact of iron in RLS, we have evaluated genetic data to determine if genes are directly involved in iron regulatory pathways. The result was negative. In fact, even the HFE mutation C282Y could not be shown to have a protective effect. Lastly, a consistent finding in conditions of low iron is increased expression of proteins in the hypoxia pathway. Although there is lack of clinical data that RLS patients are hypoxic, there are intriguing observations that environmental hypoxic conditions worsen RLS symptoms; in this chapter we review very compelling data for activation of hypoxic pathways in the brain in RLS patients. In general, the data in RLS point to a pathophysiology that involves decreased acquisition of iron by cells in the brain. Whether the decreased ability is genetically driven, activation of pathways (eg, hypoxia) that are designed to limit cellular uptake is unknown at this time; however, the data strongly support a functional rather than structural defect in RLS, suggesting that an effective treatment is possible., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Restless legs syndrome (RLS) is a complex disorder that involves sensory and motor systems. The major pathophysiology of RLS is low iron concentration in the substantia nigra containing the cell bodies of dopamine neurons that project to the striatum, an area that is crucial for modulating movement. People who have RLS often present with normal iron values outside the brain; recent studies implicate several genes are involved in the syndrome. Like most complex diseases, animal models usually do not faithfully capture the full phenotypic spectrum of "disease," which is a uniquely human construct. Nonetheless, animal models have proven useful in helping to unravel the complex pathophysiology of diseases such as RLS and suggesting novel treatment paradigms. For example, hypothesis-independent genome-wide association studies (GWAS) have identified several genes as increasing the risk for RLS, including BTBD9. Independently, the murine homolog Btbd9 was identified as a candidate gene for iron regulation in the midbrain in mice. The relevance of the phenotype of another of the GWAS identified genes, MEIS1, has also been explored. The role of Btbd9 in iron regulation and RLS-like behaviors has been further evaluated in mice carrying a null mutation of the gene and in fruit flies when the BTBD9 protein is degraded. The BTBD9 and MEIS1 stories originate from human GWAS research, supported by work in a genetic reference population of mice (forward genetics) and further verified in mice, fish flies, and worms. Finally, the role of genetics is further supported by an inbred mouse strain that displays many of the phenotypic characteristics of RLS. The role of animal models of RLS phenotypes is also extended to include periodic limb movements., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: There have been three randomized, placebo-controlled, double-blind studies of intravenous iron in restless legs syndrome (RLS), with differing outcomes. The one positive study used ferric carboxymaltose (FCM) at a total dose of 1000 mg. The purpose of this study was to replicate and extend the findings from the prior FCM study., Methods: Non-anemic, idiopathic RLS patients were enrolled in a randomized, double-blinded, placebo-controlled study and received either 1000 mg FCM or placebo as a single infusion (phase I). Subjects were off any RLS medications for at least two weeks prior to baseline assessment. The primary outcome variable was change from baseline at week 6 on the International Restless Legs Syndrome Severity (IRLSS) scale and a subject-completed, visual analog scale (VAS) of severity. Phase II of the study involved long-term (30 weeks) follow-up after completion of the six-week efficacy phase., Results: At week 6 postinfusion, FCM compared to placebo recipients showed significantly greater change from baseline for both primary outcome measures (IRLSS scale, -11.9 ± 8.04 vs -7.88 ± 5.89, p = 0.03; VAS, -40.6 ± 22.7 vs -21.3 ± 20.0, p = 0.001). None of the secondary outcome variables showed a significant difference at week 6. After six weeks of treatment, the FCM group had 19 (59.4%) responders, of which 12 had IRLSS scores <10 ("remitters"). Twelve (37.5%) of the 32 subjects treated with iron in phase I remained free of further RLS medications at 30 weeks. There were no serious adverse events observed in this study., Conclusion: Two studies now support the value of FCM treatment both in the short term (six weeks) and long term (30 weeks) for improving RLS symptoms., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: The unusual sensations of restless legs syndrome/Willis-Ekbom disease (RLS/WED) are induced by rest or a low arousal state with a circadian variation in the threshold for induction. It has been suggested that the emergence of RLS/WED symptoms relates to abnormal brain functions dealing with internally generated stimuli. The purpose of this study was to investigate the changes in the default mode network (DMN) in RLS/WED subjects., Methods: Sixteen drug-naïve, idiopathic, RLS/WED subjects, and 16 age-matched and gender-matched healthy subjects were scanned in an asymptomatic resting state. A comparison of the DMN was conducted between the two groups. Resting state functional magnetic resonance imaging (MRI), Korean versions of the International RLS scale, and other sleep questionnaires were used., Results: The results showed reductions in the DMN connectivity in the left posterior cingulate cortex, the right orbito-frontal gyrus, the left precuneus, and the right subcallosal gyrus of the RLS/WED subjects. The DMN connectivity was increased in sensory-motor-associated circuits, which included the right superior parietal lobule, the right supplementary motor area, and the left thalamus. In addition, the connectivity between the DMN and thalamus was negatively correlated with that in the orbito-frontal gyrus and the subcallosal gyrus in the subjects., Conclusions: The results showed disturbances of the DMN in RLS/WED subjects that influence the thalamic relay sensory-motor-associated circuit. These findings may underscore the fact that RLS/WED subjects have disturbances in default mode network functions involving internal stimuli in the resting state. This may be related to compensatory changes to maintain resting., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: Altered brain iron homeostasis with regional iron deficiency has been previously reported in several studies of restless legs syndrome (RLS) patients. Inconsistencies still exist, however, in the reported iron changes in different brain regions and different RLS phenotypes. The purpose of this study was to assess differences in brain iron concentrations between RLS patients and healthy controls and their relation to severity of disease and periodic limb movement during sleep (PLMS)., Methods: Assessment of brain iron was done using quantitative magnetic susceptibility measurement, which has been shown to correlate well with the tissue iron content in brain's gray matter. Thirty-nine RLS patients and 29 age-matched healthy controls were scanned at 7 T. Magnetic susceptibilities in substantia nigra (SN), thalamus, striatum, and several iron-rich gray matter regions were quantified and compared with related clinical measures., Results: Compared with healthy controls, RLS patients showed significantly decreased magnetic susceptibility in the thalamus and dentate nucleus. No significant difference was found in the SN between RLS patients and healthy controls, but a significant correlation was observed between magnetic susceptibility in SN and the PLMS measure., Conclusions: Using quantitative magnetic susceptibility as an in vivo indicator of brain iron content, the present study supports the general hypothesis of brain iron deficiency in RLS and indicates its possible link to PLMS., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) in conjunction with the European Restless Legs Syndrome Study Group (EURLSSG) and the RLS Foundation (RLS-F) to develop evidence-based and consensus-based recommendations for the prevention and treatment of long-term pharmacologic treatment of dopaminergic-induced augmentation in restless legs syndrome/Willis-Ekbom disease (RLS/WED). The Task Force made the following prevention and treatment recommendations: As a means to prevent augmentation, medications such as α2δ ligands may be considered for initial RLS/WED treatment; these drugs are effective and have little risk of augmentation. Alternatively, if dopaminergic drugs are elected as initial treatment, then the daily dose should be as low as possible and not exceed that recommended for RLS/WED treatment. However, the physician should be aware that even low dose dopaminergics can cause augmentation. Patients with low iron stores should be given appropriate iron supplementation. Daily treatment by either medication should start only when symptoms have a significant impact on quality of life in terms of frequency and severity; intermittent treatment might be considered in intermediate cases. Treatment of existing augmentation should be initiated, where possible, with the elimination/correction of extrinsic exacerbating factors (iron levels, antidepressants, antihistamines, etc.). In cases of mild augmentation, dopamine agonist therapy can be continued by dividing or advancing the dose, or increasing the dose if there are breakthrough night-time symptoms. Alternatively, the patient can be switched to an α2δ ligand or rotigotine. For severe augmentation the patient can be switched either to an α2δ ligand or rotigotine, noting that rotigotine may also produce augmentation at higher doses with long-term use. In more severe cases of augmentation an opioid may be considered, bypassing α2δ ligands and rotigotine., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: Periodic leg movements in sleep (PLMS) are generally evaluated by the number of events per hour during sleep, but this is an unstable measure with marked nightly variability and also fails to assess the basic periodicity that essentially characterizes these movements. The inter-movement interval (IMI) evaluates a putative biological process producing the period of PLMS. By contrast, the actual number of PLMS reflects the expression of this biological process that would likely be affected by multiple factors, particularly those disrupting sleep. Thus, this study tests the hypothesis that measurement of IMI duration should be more stable over nights in comparison to any measure based on counting the number of movements. IMI approximates a log-normal distribution. This study, therefore, tests the hypothesis that the means of the log IMI are more stable from night 1 (N1) to night 2 (N2) sleep recordings compared with measures of the number of PLMS., Methods: PLMS/h and IMI were measured for two consecutive nights of full sleep recordings for 29 restless legs syndrome (RLS) patients not being treated and 22 healthy controls without RLS. N1-N2 difference between nights was measured as percent of average for the nights., Results: Mean log IMI showed little nightly variability (mean ± SD for RLS: 3.6% ± 3.7, controls: 7.1% ± 7.0) significantly less p < 0.001) in comparison to PLMS/h (mean ± SD for RLS: 43.2 ± 37.1, controls: 63.7 ± 40.8). The IMI nightly variability was also significantly better than that for the periodicity index. IMI also varied considerably between individuals., Conclusion: Mean log IMI is a remarkably stable measure across nights within a subject and shows differences between subjects that may have clinical and biological significance. Because of this consistency, the mean log IMI should be considered as one standard measure of PLMS alongside the PLMS index., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background and Purpose: A Matrix Laboratory (MATLAB) script (MATPLM1) was developed to rigorously apply World Associations of Sleep Medicine (WASM) scoring criteria for periodic limb movements in sleep (PLMS) from bilateral electromyographic (EMG) leg recordings. This study compares MATPLM1 with both standard technician and expert detailed visual PLMS scoring., Methods and Subjects: Validation was based on a 'macro' level by agreement for PLMS/h during a night recording and on a 'micro' level by agreement for the detection of each PLMS from a stratified random sample for each subject. Data available for these analyses were from 15 restless leg syndrome (RLS) (age: 61.5 ± 8.5, 60% female) and nine control subjects (age: 61.4 ± 7.1, 67% female) participating in another study., Results: In the 'micro' analysis, MATPLM1 and the visual detection of PLMS events agreed 87.7% for technician scoring and 94.4% for expert scoring. The technician and MATPLM1 scoring disagreements were checked for 36 randomly selected events, 97% involved clear technician-scoring error. In the 'macro' analysis, MATPLM1 rates of PMLS/h correlated highly with visual scoring by the technician (r(2) = 0.97) and the expert scorer (r(2) = 0.99), but the technician scoring was consistently less than MATPLM1: median (quartiles) difference: 10 (5, 23). There was little disagreement with expert scorer [median (quartile) difference: -0.3 (-2.4, 0.3)]., Conclusions: The MATPLM1 produces reliable scoring of PLMS that matches expert scoring. The standard visual scoring without careful measuring of events tends to significantly underscore PLMS. These preliminary results support the use of MATPLM1 as a preferred method of scoring PLMS for EMG recordings that are of a good quality and without significant sleep-disordered breathing events., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Restless legs syndrome (RLS) is a common disorder, with several known genetic risk factors, yet the actual genetic causes are unclear., Methods: Whole-exome sequencing (WES) was performed in seven RLS families, focusing on six known genetic loci: MEIS1, BTBD9, PTPRD, MAP2K5/SKOR1, TOX3, and rs6747972. Genotyping using specific TaqMan assays was performed in two case-control cohorts (627 patients and 410 controls), and in a familial cohort (n = 718)., Results: WES identified two candidate GLO1 variants (within the BTBD9 locus), p.E111A and the promoter variant c.-7C>T, both co-segregated with the disease in four families. The GLO1 p.E111A variant was associated with RLS in the French-Canadian cohort (odds ratio, OR = 1.38, p = 0.02), and demonstrated a similar trend in the US cohort (OR = 1.26, p = 0.09, combined analysis OR = 1.28, p = 0.009). However, the original genome-wide association study (GWAS) marker, BTBD9 rs9357271, had stronger association with RLS (OR = 1.84, p = 0.0003). Conditional haplotype analysis, controlling for the effect of the BTBD9 variant rs9357271, demonstrated that the association of GLO1 p.E111A turned insignificant (p = 0.54). In the familial cohort, the two GLO1 variants were not associated with RLS. Other variants in the SKOR1 (p.W200R and p.A672V) and PTPRD (p.R995C, p.Q447E, p.T781A, p.Q447E, and c.551-4C > G) genes, did not co-segregate with the disease., Conclusions: The GLO1 variations studied here are not the source of association of the BTBD9 locus with RLS. It is likely that the genetic variants affecting RLS susceptibility are located in regulatory regions., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: The complaint of pain has largely been ignored in the diagnostic criteria for restless legs syndrome (RLS). The purpose of this study was to investigate the prevalence of painful symptoms in RLS, and to compare sleep-related characteristics between the patients who experienced the painful symptoms and those who did not., Methods: The patients with RLS were retrospectively screened from July 2011 to December 2013 at a tertiary-care sleep center. For classifying those with pain and those without pain, more than three specialists separately observed the patients' reports and complaints of symptoms, and the final decision was made through consensus. The demographics and clinical characteristics, including sleep, psychiatric-related scales, and polysomnographic data were reviewed for the study., Results: One hundred and sixty patients with RLS were selected, and 23.8% of them reported painful symptoms of RLS. Patients with RLS who experienced painful sensations were found to have lower ferritin levels, more severe RLS symptoms, anxiety and depressive symptoms, and a lower quality of life. The polysomnography data found that patients with RLS who experienced painful sensations had a longer latency to sleep onset and a lower periodic limb movement index (PLMI) (p <0.05)., Conclusions: Patients who experienced painful sensations had more severe RLS symptoms and a trend toward lower PLMI during sleep. According to these results, an inference can be made that painful sensations may be one important point in determining the severity of RLS., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objectives: Iron deficiency anemia (IDA) engenders restless legs syndrome (RLS, aka Willis-Ekbom disease). Intravenous (IV) iron can rapidly reverse IDA and would be expected to similarly reverse RLS caused by IDA. This is the first consecutive case series evaluating the effects of IV iron therapy on RLS occurring with IDA (RLS-IDA)., Methods: RLS-IDA patients were evaluated before and 7-12 months after a 1000-mg IV infusion of low-molecular-weight iron dextran (INFeD(@)) using validated questionnaires and standardized telephone interview. Patients were classified as respondent versus nonrespondent for RLS improvement., Results: Follow-up data were obtained on 42 (70%) of 60 consecutive RLS-IDA patients. The symptoms of RLS were reduced in 76% (32/42) with 47% (20/42) showing an extended response lasting >6 months. The response did not relate to age or gender, but tended to be less among African-Americans than Whites (40% (2/5) vs. 81% (30/37), p = 0.078). White respondents versus nonrespondents had higher hemoglobin levels after treatment (12.1 vs. 11.3 g/dl, p = 0.03)., Conclusions: RLS-IDA is reduced after administration of IV iron in most cases, but the 24% failing to respond was higher than expected. The nonrespondents all showed below-normal hemoglobin levels (<12.5 g/dl) suggesting a failure of adequate treatment of the iron deficiency. IV iron treatment of the RLS with IDA likely requires ensuring more than minimally adequate body iron stores to support iron delivery to the brain. For some, this may require a dose higher than the customary 1000-mg IV iron used for the treatment of either IDA or RLS alone., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: In 2003, following a workshop at the National Institutes of Health, the International Restless Legs Syndrome Study Group (IRLSSG) developed updated diagnostic criteria for restless legs syndrome/Willis-Ekbom disease (RLS/WED). These criteria were integral to major advances in research, notably in epidemiology, biology, and treatment of RLS/WED. However, extensive review of accumulating literature based on the 2003 NIH/IRLSSG criteria led to efforts to improve the diagnostic criteria further., Methods: The clinical standards workshop, sponsored by the WED Foundation and IRLSSG in 2008, started a four-year process for updating the diagnostic criteria. That process included a rigorous review of research advances and input from clinical experts across multiple disciplines. After broad consensus was attained, the criteria were formally approved by the IRLSSG executive committee and membership., Results: Major changes are: (i) addition of a fifth essential criterion, differential diagnosis, to improve specificity by requiring that RLS/WED symptoms not be confused with similar symptoms from other conditions; (ii) addition of a specifier to delineate clinically significant RLS/WED; (iii) addition of course specifiers to classify RLS/WED as chronic-persistent or intermittent; and (iv) merging of the pediatric with the adult diagnostic criteria. Also discussed are supportive features and clinical aspects that are important in the diagnostic evaluation., Conclusions: The IRLSSG consensus criteria for RLS/WED represent an international, interdisciplinary, and collaborative effort intended to improve clinical practice and promote further research., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Restless legs syndrome (RLS) is a primary sensory disorder with a secondary motor component (e.g., urge to move), and the thalamus is known to play a central role in RLS. The purpose of our study was to explore the intrinsic changes in the thalamocortical circuit in RLS patients using a resting-state functional magnetic resonance imaging (fMRI) paradigm., Methods: Resting-state fMRIs were obtained in the morning from 25 idiopathic RLS patients who were not using RLS medications and 25 controls. Resting-state connectivity was analyzed by a seed-based method using Analysis of Functional NeuroImages (AFNI) software with the bilateral thalami (ventroposterolateral nucleus [VPLN]). The connectivity characteristics of RLS patients were compared to those of the controls., Results: We found that RLS patients showed reduced thalamic connectivity with the right parahippocampal gyrus, right precuneus, right precentral gyrus, and bilateral lingual gyri; however, the right superior temporal gyrus, bilateral middle temporal gyrus, and right medial frontal gyrus showed enhanced connectivity with the thalamus. RLS severity was negatively correlated with connectivity between the thalamus and right parahippocampal gyrus (r = -0.414; P = .040)., Conclusions: Our results suggest that the characteristics of the connectivity changes may reflect the pathways involved in producing RLS symptoms and indicate that RLS patients may have deficits in controlling and managing sensory information, which supports the act of viewing RLS as a disorder disrupting somatosensory processing., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective and Background: Individuals with restless legs syndrome (RLS) (Willis-Ekbom disease [WED]) usually have periodic leg movements (PLMs). The suggested immobilization test (SIT) measures sensory and motor features of WED during wakefulness. Surface electromyogram (EMG) recordings of the anterior tibialis (AT) are used as the standard for counting PLMs. However, due to several limitations, leg activity meters such as the PAM-RL were advanced as a potential substitute. In our study, we assessed the validity of the measurements of PLM during wakefulness (PLMW) in the SIT for PAM-RL using both default and custom detection threshold parameters compared to AT EMG., Methods: Data were obtained from 39 participants who were diagnosed with primary WED and who were on stable medication as part of another study using the SIT to repeatedly evaluate WED symptoms over 6-12 months. EMG recordings and PAM-RL, when available, were used to detect PLMW for each SIT. Complete PAM-RL and polysomnography (PSG) EMG data were available for 253 SITs from that study. The default PAM-RL (dPAM-RL) detected leg movements based on manufacturer's noise (resting) and signal (movement) amplitude criteria developed to accurately detect PLM during sleep (PLMS). The custom PAM-RL (cPAM-RL) similarly detected leg movements except the noise and movement detection parameters were adjusted to match the PAM-RL data for each SIT., Results: The distributions of the differences between either dPAM-RL or cPAM-RL and EMG PLMW were strongly leptokurtic (Kurtosis >2) with many small differences and a few unusually large differences. These distributions are better described by median and quartile ranges than mean and standard deviation. Despite an adequate correlation (r=0.66) between the dPAM-RL and EMG recordings, the dPAM-RL on average significantly underscored the number of PLMW (median: quartiles=-13: -51.2, 0.0) and on Bland-Altman plots had a significant magnitude bias with greater underscoring for larger average PLMW/h. There also was an adequate correlation (r=0.70) between cPAM-RL and EMG but with minimal underscoring of PLMW (median quartiles=0.0; -20, 10) and no significant magnitude bias. Two scorers independently scoring 13% of the SITs showed an adequate interscorer reliability of 0.96-0.98., Conclusions: Our study confirms our expectation that measuring PLMW in a SIT using dPAM-RL is not valid and that adjustments to the detection threshold criteria are required. The PAM-RL, using parameters customized for each SIT provided a valid and reliable measure of PLMW with minimal magnitude bias compared to the AT EMG recordings., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: The prevalence of restless legs syndrome (RLS) in patients with peripheral neuropathy has been reported to be higher than that of the general population in some studies, which suggests an association between neuropathy and RLS, but not all studies show increased RLS with neuropathy. These differences may reflect adequacy of the diagnosis, effects of chronic pain complicating the diagnosis, or population differences. Moreover, if there is increased risk for RLS with neuropathy, it may reflect consequences of the chronic pain rather than other aspects of diabetes mellitus (DM). Therefore, we investigated the effects of diagnosis rigor on the estimated prevalence of RLS in patients with diabetic peripheral neuropathy (DPN) and those with chronic leg pain from osteoarthritis (OA), and then we compared the RLS prevalence in these two populations with each other and with population prevalence for Korea., Methods: Our study is a prospective case-control study of 199 patients with DPN and 220 patients with OA. After evaluating the presence of RLS in these subjects using the diagnostic criteria of the International RLS Study Group, we confirmed the diagnosis of RLS through face-to-face interviews using the 18-item Hopkins Diagnostic Questionnaire, which removes RLS mimics; and through independent examinations by two neurologists., Results: Of the 199 subjects with DPN, 44 (22%) appeared to have RLS from their answers on the 4-item RLS diagnostic questionnaire compared to 8 (3.6%) of 220 subjects with OA. However, the prevalence of RLS in the DPN group dropped to 16 (8%) subjects but stayed at 8 (3.6%) OA subjects when using the Hopkins Telephone Diagnostic Interview (HTDI) adapted for clinical interview. The RLS prevalence determined by HTDI remained significantly higher (P=.042) in the DPN group compared to the OA group and was twice that reported for the general Korean population (8% vs 3.9%). Among subjects with DPN, those with RLS were older (68.06±8.43years vs 62.46±11.05years; P=.049) and had higher pain scores (visual analog scale [VAS], 4.69±2.52 vs 2.72±2.12; P=.002). The quality of sleep (MOS [Medical Outcomes Study] sleep scale) and health-related quality of life (QoL) (total score on the 36-Item Short-Form Health Survey [SF-36]) showed no significant difference between the two groups., Conclusions: The prevalence of RLS in patients with DPN cannot be accurately assessed with only the four diagnostic criteria interview, but the prevalence was higher than expected for Koreans from the general population prevalence and also was higher than occurred with OA patients with chronic leg pains when accurately assessed with a structured interview. Chronic leg pain from OA does not significantly complicate RLS diagnosis, and chronic pain itself does not explain the increased RLS prevalence in diabetic neuropathy., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) to develop evidence-based and consensus-based recommendations for the long-term pharmacologic treatment of restless legs syndrome/Willis-Ekbom disease (RLS/WED). The Task Force reviewed the results of all studies of RLS/WED treatments with durations of 6 months or longer presented at meetings over the past 2 years, posted on Web sites of pharmaceutical companies, or published in peer-reviewed journals, asking the questions, "What is the efficacy of this treatment in patients with RLS/WED?" and "What is the safety of this treatment in patients with RLS/WED?" The Task Force developed guidelines based on their review of 61 papers meeting inclusion criteria, and using a modified evidence-grading scheme. Pregabalin has been established as effective for up to 1 year in treating RLS/WED (Level A evidence). Pramipexole, ropinirole, and rotigotine have been established as effective for up to 6 months in treating RLS/WED (Level A). The following drugs have been established as probably effective (Level B) in treating RLS/WED for durations ranging from 1 to 5 years: gabapentin enacarbil, pramipexole, and ropinirole (1 year); levodopa (2 years); and rotigotine (5 years). Because of associated safety concerns, pergolide and cabergoline should not be used in the treatment of RLS/WED unless the benefits clearly outweigh the risks. Other pharmacologic therapies have insufficient evidence to support their long-term use in treating RLS/WED. The IRLSSG Task Force also developed consensus-based strategies for the prevention and treatment of complications (such as augmentation, loss of efficacy, excessive daytime sleepiness, and impulse control disorders) that may develop with the long-term pharmacologic treatment of RLS/WED. The use of either a dopamine-receptor agonist or α2δ calcium-channel ligand is recommended as the first-line treatment of RLS/WED for most patients, with the choice of agent dependent on the patient's severity of RLS/WED symptoms, cognitive status, history, and comorbid conditions., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Various techniques used to assess brain iron concentrations have demonstrated the presence of low iron stores in patients with restless legs syndrome (RLS). Previous open-label and randomized studies generally support the value of iron treatment for RLS symptoms. Only one of these studies assessed iron therapy response to changes in brain iron status. The current study was designed to assess the effect of iron therapy on RLS symptoms and on CSF measures of brain iron status., Methods: Idiopathic RLS patients drawn from the Korean population received four weekly intravenous (IV) doses of 250 mg low-molecular weight iron dextran for a total dose of 1g. One week after the last dose, any subject on RLS medication tapered off the RLS medications. Blood and CSF samples were taken to measure iron parameters at baseline and again, three weeks after the last dose. We have been following their response to the drug for two years after treatment., Results: Twenty-five patients (age 55.2 ± 9.3, 18 female) enrolled in this study without serious adverse reactions. Seventeen of the 25 patients (68%) showed moderate or complete improvement of all RLS symptoms after treatment based on the Korean-translated versions of the International RLS Severity scale (K-IRLS). Changes in the K-IRLS did not correlate significantly with changes in CSF ferritin. The response to IV iron could not be predicted by patients' demographics, or by blood or CSF iron baseline characteristics. RLS symptom improvement started between one and six weeks after treatment and the treatment benefits lasted from one month to 22 months. Fourteen patients, (56%) completely stopped all medications, for a mean duration of 31.3 ± 33.1 weeks. These results are comparable to those from a prior study with high molecular weight dextran., Conclusions: Intravenous low-molecular weight iron dextran produced significant improvement of RLS symptoms in a majority of patients without any significant adverse effects. Serious anaphylaxis occurs with high molecular weight, but rarely, if ever, with this low molecular weight dextran. Given apparent comparable efficacy the low molecular weight and not the high molecular weight iron dextran, should be considered for RLS treatment. Although changes in CSF ferritin were seen following therapy, these changes were not related to clinical improvements., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: There have been few quality of life (QoL) studies of patients with restless legs syndrome (RLS) in Asian countries. We studied the QoL of patients with RLS and compared it to normal controls and patients with hypertension, type 2 diabetes, or osteoarthritis in Korea., Methods: A total of 215 RLS patients (141 female; mean age 51.7 ± 13.5) were enrolled. All patients completed the questionnaires, including all the Korean versions of SF-36, RLS QoL, the International RLS Severity scale (IRLS), the Pittsburgh Sleep Quality Index (PSQI), and the Beck Depression Inventory-2 (BDI-2). These results were compared with the scores from normal controls (N=214) and from patients with hypertension (196), uncomplicated type 2 diabetes (185), or osteoarthritis of the knee (177)., Results: The SF-36 QoL in patients with RLS was lower than that of the normal controls, and even lower than patients with hypertension or diabetes, but higher than those with osteoarthritis. The SF-36 Qol of RLS patients showed a significantly negative correlation with the severity of RLS symptoms(r=-0.430, p<0.001) and the severity of depression (r=-0.565, p<0.001), but was not significantly related to gender, age, or age-of-symptom onset (early or late-onset). Step-wise multiple regression identified three factors related to SF-36 QoL: depression (46.5% of RLS had responses on BDI-2 indicating depression) (β=-.899, p<0.001), RLS symptom severity (K-IRLS) (β=-.718, p<0.001), and gender (female) (β=-6.128, p=0.007)., Conclusions: These findings show that RLS has a considerable impact on the QoL of Koreans, which is comparable with studies of western countries. The QoL impairment relates to the degree of depression with RLS for Koreans., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: Intravenous (IV) iron has been used as a treatment to reduce Restless Legs Syndrome (RLS) symptoms, but two double-blinded trials of a frequently prescribed IV iron formulation, iron sucrose, failed to show lasting efficacy. This study evaluates efficacy and safety of a new IV iron formulation (ferric carboxymaltose, FCM) with molecular properties that may make iron more available for uptake to the brain than iron sucrose does., Methods: In this 28-day, multi-centre, randomised, placebo-controlled trial 46 RLS patients were discontinued from all RLS treatment. Twenty-four received 500 mg FCM in two doses 5 days apart and 22 received a matching placebo. At day 28, those on placebo were given a single 1000 mg IV FCM and those not responding to initial treatment were given a third dose of 500 mg FCM. Patients were followed up for 24 weeks or until needing added RLS treatment., Results: FCM significantly improved primary and secondary outcomes compared to placebo: International Restless Legs Syndrome study group severity scale (IRLS) average (SD) decrease of 8.9 (8.52) versus 4.0 (6.11), p=0.040; Clinical Global Inventory of Change (CGI-1) very much or much improved 48.3% versus 14.3%, p=0.004. Quality of life was also significantly improved. Of the 24 with initial iron treatment 45% responded and 29% remitted (IRLS ≤ 10) at day 28, and 25% continued free of other RLS medications at 24 weeks after treatment. The single 1000 mg dose on day 28 produced the same degree of treatment response as the divided dose, but the added 500 mg dose for those not responding to the initial treatment showed little benefit. There were no significant adverse events., Conclusions: IV FCM provided a safe and effective treatment for RLS that lasted for at least 24 weeks for some patients. Larger studies are needed to confirm these results., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: There has been recent interest in characterizing potential abnormalities of pain processing in patients with sleep disorders such as Restless Legs Syndrome (RLS). The aim of this study was to evaluate psychophysical responses to noxious heat and pressure stimuli in both treated and untreated RLS patients, compared to matched controls., Methods: This study is a cross-sectional group comparison of RLS patients with matched controls. A total of 31 patients (15 treated, 16 untreated) with a confirmed diagnosis of RLS were compared to 18 controls with no history of RLS or related sleep disorders., Results: RLS patients (both treated and untreated) demonstrated reduced pain thresholds and reported greater clinical pain relative to controls. Moreover, RLS patients demonstrated enhanced temporal summation of heat pain (p<.05), which may reflect aberrant central nervous system facilitation of pain transmission. Both treated and untreated RLS patients reported disrupted sleep relative to controls, and mediation analyses suggested that the reduced pain thresholds in RLS were attributable to sleep disturbance. However, the effect of RLS on the magnitude of temporal summation of heat pain was independent of sleep disturbance., Conclusions: These findings suggest that central nervous system pain processing may be amplified in RLS, perhaps partially as a consequence of sleep disruption. RLS patients, even those whose symptoms are managed pharmacologically, may be at elevated long-term risk for the development or maintenance of persistent pain conditions. Further studies in larger samples could help to improve the prospects for pain management in RLS patients., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Restless legs syndrome (RLS) is a neurological disorder characterized by a strong urge to move the legs and has been shown in many studies with abnormally low brain iron. Iron deficiency is associated with hypomyelination in brains of animals. Therefore we hypothesized that a myelin deficit should be present in the brains of patients with RLS., Methods: We performed Western blot analysis on myelin isolated from RLS (n=11) and control (n=11) brain tissue obtained at autopsy for the expression of the integral myelin proteins, myelin basic protein (MBP), and proteolipid protein (PLP) and the oligodendrocyte specific enzyme 3'5'-cyclic nucleotide phosphohydrolase (CNPase). To expand the postmortem findings to in vivo, we analyzed the brains of RLS patients (n=23) and controls (n=23) using voxel-based morphometry (VBM)., Results: The expression of MBP, PLP and CNPase in the myelin from RLS was decreased by approximately 25% (p<0.05) compared to controls. The amounts of transferrin (Tf) and H-ferritin (H-Frt) in the myelin fraction were also significantly decreased in RLS compared to controls. The imaging analysis revealed significant small decreases in white matter volume in RLS patients compared to controls in the corpus callosum, anterior cingulum and precentral gyrus., Conclusion: A decrease in myelin similar to that reported in animal models of iron deficiency was found in the brains of individuals with RLS. The evidence for less myelin and loss of myelin integrity in RLS brains, coupled with decreased ferritin and transferrin in the myelin fractions, is a compelling argument for brain iron insufficiency in RLS. These data also indicate the need to look beyond the sensorimotor symptoms that typically define the syndrome and its assumed relation to the dopaminergic system. Understanding the full range of RLS pathology may help us better understand the complex, intermittent nature and diversity of the clinical features of RLS and expand our consideration of treatment options for RLS., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: Assess the rate of augmentation as it occurs during standard long-term dopaminergic treatment of RLS, potential risk factors or predictors of augmentation, the relationship between treatment duration and augmentation, and the clinical impact of augmentation on subjects' health outcomes., Methods: Two hundred sixty-six patients with dopamine-treated RLS completed a one-time online survey. All subjects were recruited by their PCP/neurologist and were 18 or older. Augmentation was assessed using NIH guidelines and an augmentation classification system was developed through this research., Results: Overall, 20% of the patients were classified as having definitive or highly suggestive clinical indications of augmentation. Five factors were considered likely to reflect increased risk of developing augmentation, including more frequent RLS symptoms pre-treatment, greater discomfort with RLS symptoms before treatment, and longer treatment duration. RLS augmentation occurred at a rate of about 8% each year for at least the first 8 years of dopamine treatment. Subjects reporting definite or highly suggestive clinical indicators of augmentation had an average IRLS score of 23.6, indicating generally inadequate treatment with generally poor clinical outcomes. Only 25% of the patients reported no indications of augmentation and they were the only group to show on average a low (<15) IRLS score and good clinical outcomes., Conclusions: As currently used, long term dopaminergic treatment for an average ± SD of 2.7 ± 2.4 years produced significant augmentation problems in at least 20% of the patients and only 25% of the patients were totally free of this problem. It is important for physicians to carefully screen patients for changes in RLS symptoms for as long as they are on dopamine agents, with particular attention paid to those patients who present with the most severe RLS symptoms prior to treatment initiation. Given the marked increase in suffering with augmentation, a method for early detection and intervention would be an important contribution to the effective management and treatment of RLS., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Restless legs syndrome (RLS) is a chronic disease, which is managed with palliative medications that are likely to be required for a patient's lifetime. It is, therefore, important to know the long-term consequences of these treatments. Currently, the most commonly prescribed treatment for RLS is one of the dopamine (DA) agonists. Most of what we understand about efficacy and side effects of the DA agonists are, however, derived from relatively short-term studies. This is particularly a problem since these medications produce in some patients a significant increase or augmentation of RLS symptoms known to occur during the first 2 years of treatment and perhaps even later in treatment. The primary aim of this study was to determine the long-term efficacy (10-year) for commonly used RLS medication types: dopaminergic agonists and opioids., Methods: Records of all RLS patients treated in one tertiary care center with pramipexole, pergolide or methadone during the years 1997-2007 were reviewed. The duration and reason for any discontinuation of treatment and medication doses were recorded., Results: Annual rates for discontinuing treatment persisted for up to 10 years of treatment and were fairly constant after the first year at 9% for pramipexole, 8% for pergolide, and 0% for methadone. Similarly, annual augmentation rates were fairly constant after the first year and persisted for up to 10 years at 7% for pramipexole, 5% for pergolide, and 0% for methadone. The percentage continuing on the treatment medication for over 5 years was 58% for pramipexole and 35% for pergolide., Conclusions: The DA agonists appear to have a limited period of clinical utility for many patients. Severe augmentation, while not common in any 1 year, can develop even after years on the medication. Methadone, in contrast, shows neither augmentation nor major problems with continued efficacy after the first year of treatment., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Pramipexole is an effective treatment for restless legs syndrome (RLS), but no controlled studies have lasted >12 weeks., Methods: RLS patients (N=331) with pretreatment serum ferritin >30 ng/mL were randomly assigned to take double-blind optimized pramipexole (0.125-0.75 mg/d) or placebo for 26 weeks. The primary efficacy endpoint was change in International RLS Study Group Rating Scale (IRLS) score. Other endpoints assessed global change, symptoms, and QoL. Patients maintained symptom diaries. Cases meeting predefined criteria for suspected augmentation were reviewed by a blinded expert panel, which used a predefined algorithm., Results: Among 321 patients providing post-baseline data, of whom 234 completed 26 weeks, pramipexole was more effective than placebo by multiple endpoints, including an adjusted mean IRLS score change of -13.7 vs. -11.1 (p=0.0077) and an IRLS responder rate (≥50% score reduction) of 58.6% vs. 42.8% (p=0.0044). Efficacy showed considerable country-to-country variability. Six-month incidence of confirmed augmentation was 9.2% for pramipexole and 6.0% for placebo. The rate increased with treatment duration for pramipexole but not placebo. Treatment-related adverse events (AEs) were more likely for pramipexole than for placebo, but discontinuation due to AEs was less likely., Conclusions: During a 6-month period, pramipexole was effective, safe, and generally well tolerated. Because risk of augmentation may have increased over 6 months, it should be studied in longer trials. Beginning or mild augmentation is difficult to distinguish from natural RLS fluctuation, at least in a non-iron-deficient population., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: To develop a questionnaire to measure Pediatric Restless Legs Syndrome (P-RLS) symptoms and impact for use in clinical research., Methods: Questionnaire items were developed based on open-ended, qualitative interviews of 33 children and adolescents diagnosed with definite RLS (ages 6-17 years) and their parents. The draft questionnaire was then tested through cognitive debriefing interviews with 21 of the same children/adolescents and 15 of their parents. This involved the children and parents answering the draft items and then interviewing them about the child's ability to understand and interpret the questionnaire. Expert clinicians provided clinical guidance throughout., Results: Draft severity questions were generated to measure the four-symptom and four-impact domains identified from the concept elicitation interviews: RLS sensations, move/rub due to RLS, relief from move/rub, pain, and impact of RLS on sleep, awake activities, emotions, and tiredness. RLS descriptions, symptoms, and impact were compared between those who had comorbid attention-deficit/hyperactivity disorder and those who did not. Revisions to several questions were made based on the cognitive debriefing interviews and expert clinician review, resulting in a severity scale with 17 morning and 24 evening items. Caution regarding self-administration in children ages 6-8 years is recommended. To complement the child/adolescent measures, a separate parent questionnaire was also developed., Conclusions: The P-RLS-SS was constructed based on detailed input from children and adolescents with RLS, their parents, and clinical experts, thus providing a scale with strong content validity that is intended to be comprehensive, clinically relevant, and important to patients. Validation of this scale is recommended.

Background: Abrupt discontinuation of heavy marijuana (MJ) use is associated with self-reports of sleep difficulty. Disturbed sleep is clinically important because MJ users experiencing sleep problems may relapse to MJ use to improve their sleep quality. Few studies have used polysomnography (PSG) to characterize changes in sleep architecture during abrupt abstinence from heavy MJ use., Methods: We recorded PSG measures on nights 1, 2, 7, 8, and 13 after abrupt MJ discontinuation in 18 heavy MJ users residing in an inpatient unit., Results: Across abstinence, Total Sleep Time (TST), Sleep Efficiency (SEff), and amount of REM sleep declined, while Wake after Sleep Onset (WASO) and Periodic Limb Movements (PLM) increased. Furthermore, quantity (joints/week) and duration (years) of MJ use were positively associated with more PLMs., Conclusion: The treatment of sleep disturbance is a potential target for the management of cannabis use disorders since poor sleep could contribute to treatment failure in heavy MJ users.

Objective: This study was designed to evaluate the associated risk of RLS with pregnancy in relation to the family history and the age of symptom onset of RLS., Methods and Subjects: Data from a prior RLS family history study in which 1019 subjects (527 males, 492 females) were interviewed, provided a diagnosis and characterization of RLS and determination of pregnancy status on which the current study analysis was undertaken., Results: In the family members of RLS probands, the prevalence of RLS was significantly higher for parous women than for nulliparous women (49.5% vs. 33.7%, OR=1.92, 95% CI=1.16-3.19) or for men (49.5% vs. 30.0%, OR 2.29, 1.69-3.10), but no different for nulliparous women compared to men (33.7% vs. 30.0%, OR 1.19, 0.72-1.96). When only those whose RLS started at or after age 30 were considered, similar differences occurred. These differences were not observed among family members of control probands., Conclusions: These data indicate pregnancy has a major impact on the risk of developing RLS for those with a family history of RLS. This pregnancy effect appears to account for most of the gender differences often reported in overall RLS prevalence data., (Copyright 2009 Elsevier B.V. All rights reserved.)

Background: Restless legs syndrome (RLS) is a medical condition with established neuropathology and genetic associations. Significant questions have, however, recently been raised about its true prevalence, medical significance and the degree to which it is under or over-diagnosed. This study therefore aimed to determine its prevalence, morbidity and adequacy of diagnosis based on physician evaluations of their own patients in primary care practice., Methods: Screening questionnaires were completed by adult patients attending 62 primary care practices across six western European countries within a one-week period. Patients screening positive for significant RLS symptoms were clinically evaluated for RLS by their physician. Physicians also classified the degree RLS affected the patient's health and well-being. Patients independently completed the SF-36 Quality of Life and Medical Outcomes Study (MOS) sleep questionnaires., Results: Ten thousand five hundred and sixty-four patients completed the screening questionnaire; 804 responded positively to RLS symptoms and 630 of these were subsequently evaluated by their physician. The physicians diagnosed RLS in 365 patients. Ninety-one percent of these had not been previously diagnosed with RLS. In this cohort of adult primary care patients (without or with prorating for missed interviews) the estimated prevalence for diagnosed RLS was 3.5% or 4.4% and for medically-significant RLS 2.1% or 2.7%. A moderate to high degree of RLS negative impact on health related strongly to a lower vitality subscale on the SF-36 and short sleep times (5.2-5.4h) with more sleep disturbance on the MOS sleep scale., Conclusion: RLS in these western European countries is a common, clinically-significant medical condition that, despite all the publicity, remains largely undiagnosed. RLS evaluation is particularly recommended for patients complaining of insomnia., (Copyright 2009 Elsevier B.V. All rights reserved.)