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Introduction: Restless Legs Syndrome (RLS), also known as Willis-Ekbom Disease (WED), is a sensorimotor disorder characterized by an uncontrollable urge to move the legs, typically accompanied by discomfort. Low iron levels, pregnancy, and age are some identified risk factors. RLS is treated using various pharmacological options, including dopamine agonists, benzodiazepines, anticonvulsants, opioids, and bupropion. Iron supplementation, particularly with intravenous Ferric carboxymaltose (FCM), has gained attention due to the role of iron deficiency in RLS pathophysiology. This meta-analysis evaluates the efficacy and safety of FCM in treating RLS symptoms. Materials and methods: A systematic review and meta-analysis were conducted following the PRISMA guidelines, using databases such as PubMed, Google Scholar, and Cochrane. Studies involving intravenous FCM in patients diagnosed with RLS were included. Statistical analysis was performed using Review Manager 5.4. Results: Seven studies involving 539 participants were analyzed. FCM significantly reduced IRLS scores (WMD = −5.77; 95% CI = [−8.85, −2.70]; p = 0.0002) and improved VAS and SF-36 scores compared to placebo. However, FCM did not significantly improve RLS quality of life scores. Adverse events were more common in the FCM group, particularly nausea, but no significant differences were found for severe adverse events. Conclusion: In conclusion, intravenous ferric carboxymaltose significantly reduces Restless Legs Syndrome symptoms, especially in patients with confirmed iron deficiency. The treatment appears generally well-tolerated, with adverse effects being manageable. However, further long-term studies are needed to fully assess the safety profile and confirm sustained symptom improvement in a broader population. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42024585233. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs, worsened in the evening, occurring at rest, and relieved temporarily by movement. Although its pathophysiology remains incompletely understood, oxidative stress has been suggested. Uric acid (UA) is a marker associated with oxidative stress, and its reduced levels pose a risk for certain neurodegenerative diseases. In this study, we aimed to assess serum UA concentrations in RLS patients to gain insights into its role in the etiopathogenesis of the condition.: This study involved 200 individuals. Serum UA levels were compared with clinical parameters. Disease severity was assessed, categorizing patients into "mild," "moderate," "severe," and "very severe" subgroups. Comparative analysis of UA levels was conducted between these subgroups and the control group. Patients exhibited a statistically significant reduction in UA levels compared to controls (p = 0.001; p < 0.01). No significant disparities in UA levels were observed among patients based on RLS scores (p > 0.05). The generalized linear model in which UA serves as the dependent variable revealed statistically significant associations with the "moderate" and "severe" stages of RLS, as well as age (p < 0.05). Additionally, a ROC curve analysis was executed to evaluate the potential of UA as a biomarker. The ROC analysis, focusing on the patient-control classification, revealed a statistically significant area under the curve (AUC = 0.848, p < 0.001). Our study supports the hypothesis implicating serum UA levels in RLS pathogenesis. Further understanding of UA and its physiological effects will clarify on its role in RLS pathophysiology. [ABSTRACT FROM AUTHOR]

Restless legs syndrome/Willis–Ekbom disease (RLS/WED) causes a strong urge to move legs while resting. Restless legs syndrome/WED is an often-inherited disease occurring in 3% to 10% of adult populations, increasing with age. Severity varies from mild disturbance of sleep to painful restless legs and arms, loss of sleep, fatigue, and risk of suicide. Dopaminergic drugs relieve symptoms, but cause augmentation, ie, initially helpful but later increase the burden of symptoms. Oral gabapentinoids and opioids are often added, but opioid tolerance and adverse effects are common. With the high prevalence and incomplete help from oral drugs, significant unmet needs exist for effective therapy for severe RLS/WED. Ongoing spinal intrathecal infusion of low-dose morphine is effective, but not generally recognized, as only 12 cases have been published since 2002. We report 7 patients suffering from severe RLS/WED, who had no relief from oral dopaminergic, gabapentinoid, or opioid drugs; they all had excellent relief during ongoing spinal intrathecal infusion of morphine at only 1 to 5 μg/h, ongoing for 1 to 21 years without need of higher doses of morphine.. We suggest that morphine may be transported with the cerebrospinal fluid reaching and readjusting malfunctioning dopamine neuronal systems in the brain and spinal cord. The effects last only as long as the infusion continues. A patient with RLS/WED and persistent genital arousal disorder (PGAD) was relieved of both RLS/WED and PGAD symptoms. These case reports suggest that intrathecal infusion of low-dose morphine is an effective treatment of severe RLS. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) is a disease from the spectrum of movement disorders, the prevalence of which increases significantly during pregnancy and is associated with poor sleep, a drop in daytime energy, and the development of psychological disorders during pregnancy and the postpartum period. The IRLSS scale was used to determine the presence of RLS symptoms. The total test sample that included the tested and control groups was (n=390) subjects. The examined group consisted of pregnant women (n=260), and the control group consisted of female students (n=130). In total, 260 pregnant women were monitored 6 months after pregnancy. Three measurements were performed, first in the third trimester of pregnancy, second two months after delivery, third 6 months after delivery, while one cross-sectional measurement was performed for the control group. The prevalence of RLS in pregnancy is highest in the third trimester and amounts to 26.5 %. In the postpartum period, a significant decrease in the prevalence of RLS was observed, measured two months after delivery (18.1 %). Postpartum, over time, a decrease in the prevalence of RLS was noticed, and six months after delivery it was (7.3 %), when it practically approached the prevalence of the control group (standard population) which was (6.2 %). The prevalence of RLS is highest during the third trimester of pregnancy and decreases after delivery so that 6 months after delivery it approaches the prevalence of the standard population. [ABSTRACT FROM AUTHOR]

Introduction and Purpose of Research: Restless Leg Syndrome (RLS) or Willis-Ekbom disease, is a common neurological disorder significantly impacting one’s sleep and quality of life. It often coexists with various health issues, including diabetes and cardiovascular diseases. Aim of study: The primary purpose of this research is to explore diverse therapeutic options for RLS which are tailored to individual patient needs. In order to understand the complex pathophysiology of the discussed disease, recent advancements are taken into account. Material and Methods of Research: The review is grounded in findings from 36 recent studies sourced through a systematic search of open-access databases, including PubMed and Google Scholar, focusing on literature published between 2004 and 2024. Results: Adequate and effective management of RLS include non-pharmacological interventions, such as physical activity, acupuncture, yoga and near-infrared light therapy, which can complement pharmacotherapy or prevail as the primary treatment form. Iron therapy emerges as vital for many patients. The correlation between iron metabolism and RLS symptoms requires further analysis and research. Pharmacological strategies involve dopaminergic medications, low-potency opioids, and benzodiazepines, with a target on minimizing side effects and dependency. Conclusion: RLS affects approximately 5-10% of the population, severely disrupting sleep and daily functioning. The condition constrains individualized management, integrating non-pharmacological forms of treatment with pharmacological therapies to improve patient outcomes and reduce dependence on medication.

IntroductionRestless Legs Syndrome (RLS), also known as Willis-Ekbom Disease (WED), is a sensorimotor disorder characterized by an uncontrollable urge to move the legs, typically accompanied by discomfort. Low iron levels, pregnancy, and age are some identified risk factors. RLS is treated using various pharmacological options, including dopamine agonists, benzodiazepines, anticonvulsants, opioids, and bupropion. Iron supplementation, particularly with intravenous Ferric carboxymaltose (FCM), has gained attention due to the role of iron deficiency in RLS pathophysiology. This meta-analysis evaluates the efficacy and safety of FCM in treating RLS symptoms.Materials and methodsA systematic review and meta-analysis were conducted following the PRISMA guidelines, using databases such as PubMed, Google Scholar, and Cochrane. Studies involving intravenous FCM in patients diagnosed with RLS were included. Statistical analysis was performed using Review Manager 5.4.ResultsSeven studies involving 539 participants were analyzed. FCM significantly reduced IRLS scores (WMD = −5.77; 95% CI = [−8.85, −2.70]; p = 0.0002) and improved VAS and SF-36 scores compared to placebo. However, FCM did not significantly improve RLS quality of life scores. Adverse events were more common in the FCM group, particularly nausea, but no significant differences were found for severe adverse events.ConclusionIn conclusion, intravenous ferric carboxymaltose significantly reduces Restless Legs Syndrome symptoms, especially in patients with confirmed iron deficiency. The treatment appears generally well-tolerated, with adverse effects being manageable. However, further long-term studies are needed to fully assess the safety profile and confirm sustained symptom improvement in a broader population.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42024585233.

Purpose: To estimate incidence rates of suicidal ideation and behavior following treatment initiation with gabapentinoids or dopamine agonists (DAs) in patients with newly diagnosed early‐onset idiopathic restless legs syndrome (RLS) and to examine suicidal behavior risk, comparing between those receiving gabapentinoids and DAs. Methods: A new user retrospective cohort study using MarketScan claims data from 2012 to 2019 was conducted. Exposures were monotherapy gabapentinoids or DAs initiated within 60 days of new RLS diagnosis. Three varying outcome measures of suicidality were examined and incidence rates were calculated for each. A log‐binomial regression model the estimated relative risk (RR) of the outcomes with gabapentinoids. Propensity score weighting adjusted for baseline covariates, including age, substance use disorders, hyperlipidemia, antipsychotic use, hypnotic/sedative use, and mood stabilizer use, which were most imbalanced before weighting. Results: The cohort included 6672 patients, with 4986 (74.7%) initiating a DA and 1686 (25.3%) initiating a gabapentinoid. Incidence rates for all outcome measures were higher in the gabapentinoid group (suicidality: 21.6 vs. 10.7 per 1000 person‐years; suicidality with self‐harm: 23.0 vs. 11.1 per 1000 person‐years; overdose‐ and suicide‐related events: 30.0 vs. 15.5 person‐years). Associated risk of suicidality (adjusted RR, 1.27 [95% CI, 0.86–1.88]); suicidality with self‐harm (adjusted RR, 1.30 [95% CI, 0.89–1.90]); or overdose‐ and suicide‐related events (adjusted RR, 1.30 [95% CI, 0.93–1.80]) was not significant with gabapentinoids. Conclusions: Incidence rates for suicidal ideation and behavior were higher among the gabapentinoid group, although increased risk was not detected after adjustment. A possible signal cannot be ruled out given limitations of the data and rarity of the outcome. [ABSTRACT FROM AUTHOR]

Background: Restless Leg Syndrome (RLS) is frequently associated with Chronic Kidney Disease (CKD), often under diagnosed and inadequately treated. Hence, this study aimed to ascertain the prevalence of CKD-induced RLS, exploring associated factors, pharmacotherapy and its impact on patients' quality of life. Materials and Methods: An observational prospective study conducted at Dhiraj General Hospital, Vadodara, from November 2022 to March 2023 included 246 CKD patients. Screening for RLS symptoms led to further evaluation and treatment in the Neurology department. Patients were re-evaluated after one month to assess treatment outcomes. Results: Analysis of 246 patients revealed a 6.91% prevalence of RLS in CKD. Factors contributing to RLS included anemia, advanced CKD stages and prolonged dialysis. Female gender emerged as a CKD risk factor. Pramipexole, Syndopa and Ropirinole effectively treated RLS in CKD patients. Conclusion: RLS substantially diminishes the quality of life in end-stage renal disease patients. Identification and management of contributing factors hold promise for improving outcomes and quality of life in CKD patients with RLS. [ABSTRACT FROM AUTHOR]

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Purpose: This study aimed to (1) evaluate in patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) the presence of sleep disorders such as hypersomnia, fatigue, risk of apnea, and the presence of restless legs syndrome/Willis-Ekbom disease (RLS/WED); (2) evaluate quality of sleep in patients with MS and NMOSD; and (3) correlate them with clinical and imaging data. Methods: The study was cross-sectional and was carried out in the sector of demyelinating diseases of the neurology service of HUGV-UFAM, Manaus, Brazil, from January 2017 to December 2020. Results: Our sample consisted of 60 patients, 41 with MS and 19 with NMOSD. We found that patients with MS and NMOSD have poor sleep quality (65%) and hypersomnia (53% in MS; 47% in NMOSD), but low risk of apnea by STOP-BANG. The frequency of RLS/WE found was 14% in MS, and 5% in NMOSD. No correlation existed between sleep quality, number of relapses, and sleep quality for the Expanded Disability Status Scale (EDSS), i.e., fatigue/illness duration. Conclusion: Patients with MS and NMOSD have poor sleep quality, excessive sleepiness, and are at low risk for OSA, yet the frequency of RLS/WED is like that of the general population. There does not seem to be a significant difference between these sleep disorders in these demyelinating diseases of the CNS. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) has an increased estimated prevalence in patients with Parkinson's disease (PS). RLS frequently mimics symptoms intrinsic to PD, such as motor restlessness, contributing to making its diagnosis challenging in this population. We report the case of a patient with new-onset RLS following subthalamic deep-brain stimulation (DBS-STN). We assessed symptoms using suggested immobilization test (SIT) with both DBS-STN activated and switched off. A 59-year-old man with idiopathic PD developed disabling RLS following DBS-STN at age 58, with PD onset at 50 manifesting as left arm tremor. Despite improved motor symptoms during the month following surgery, the patient experienced left leg discomfort at rest, transiently alleviated by movements due to an irrepressible urge to move, and worsened at night. Symptoms had no temporal relationship with oral dopa-therapy and disappeared when DBS-STN was deactivated. A 1 h SIT assessed motor behavior with irrepressible urge to move, as well as sensory symptoms by visual analog scale. After 30 m DBS-STN was switched off followed by the appearance of tremor in the left arm while both motor and sensory symptoms of RLS disappeared in the left leg. The mechanisms of DBS-STN's impact on RLS remain controversial. We hypothesize the DBS-STN to induce in our patient a hyperdopaminergic tone. DBS-induced and DBS-ameliorated RLS represent interesting conditions to further understand the pathophysiology of RLS. Moreover, the present observation suggests that SIT can be a valuable tool to assess RLS in PD patients before and after DBS-STN in future prospective studies. • Deep brain stimulation may induce restless legs syndrome in Parkinson's patients. • Suggested immobilization test helps identify restless legs in Parkinson's patients. • Suggested immobilization test aids in distinguishing dyskinesia from restless legs. • A hyperdopaminergic tone may drive pathophysiology of restless legs syndrome. [ABSTRACT FROM AUTHOR]

Abstract Background and objective Restless legs syndrome/Willis-Ekbom Disease (RLS/WED) is one of the most prevalent sleep disorders. There are contradicting data about the effectiveness of magnesium and vitamin B6 in alleviating the symptoms of this condition. Therefore, this study aimed to assess the efficacy of magnesium and vitamin B6 in alleviating the symptoms of RLS/WED. Methods A single-blind study was conducted on individuals with this illness for at least three months. Randomly, 75 patients were assigned into three groups: magnesium, vitamin B6, and placebo. The experimental group received daily doses of 40 mg vitamin B6 or 250 mg magnesium oxide. While others in the control group merely received a placebo. Patients’ disease severity and sleep quality were evaluated three times using standard questionnaires (at the beginning of the study, one and two months after therapy). Utilizing SPSS22 software and the ANOVA, t-test, and repeated measure tests, statistical analysis was conducted. Results The mean and standard deviation of sleep quality and disease severity at the beginning of the trial and throughout the first month following the intervention did not differ statistically between the three groups. In the second month following the intervention, the mean and standard deviation of sleep quality and disease severity were significantly different (P = 0.001). Conclusion Taking magnesium and vitamin B6 supplements can reduce the severity of symptoms of RLS/WED patients and improve their sleep quality.

Background and objective: Restless legs syndrome/Willis-Ekbom Disease (RLS/WED) is one of the most prevalent sleep disorders. There are contradicting data about the effectiveness of magnesium and vitamin B6 in alleviating the symptoms of this condition. Therefore, this study aimed to assess the efficacy of magnesium and vitamin B6 in alleviating the symptoms of RLS/WED. Methods: A single-blind study was conducted on individuals with this illness for at least three months. Randomly, 75 patients were assigned into three groups: magnesium, vitamin B6, and placebo. The experimental group received daily doses of 40 mg vitamin B6 or 250 mg magnesium oxide. While others in the control group merely received a placebo. Patients' disease severity and sleep quality were evaluated three times using standard questionnaires (at the beginning of the study, one and two months after therapy). Utilizing SPSS22 software and the ANOVA, t-test, and repeated measure tests, statistical analysis was conducted. Results: The mean and standard deviation of sleep quality and disease severity at the beginning of the trial and throughout the first month following the intervention did not differ statistically between the three groups. In the second month following the intervention, the mean and standard deviation of sleep quality and disease severity were significantly different (P = 0.001). Conclusion: Taking magnesium and vitamin B6 supplements can reduce the severity of symptoms of RLS/WED patients and improve their sleep quality. [ABSTRACT FROM AUTHOR]

Background and objective: Restless legs syndrome/Willis-Ekbom Disease (RLS/WED) is one of the most prevalent sleep disorders. There are contradicting data about the effectiveness of magnesium and vitamin B6 in alleviating the symptoms of this condition. Therefore, this study aimed to assess the efficacy of magnesium and vitamin B6 in alleviating the symptoms of RLS/WED. Methods: A single-blind study was conducted on individuals with this illness for at least three months. Randomly, 75 patients were assigned into three groups: magnesium, vitamin B6, and placebo. The experimental group received daily doses of 40 mg vitamin B6 or 250 mg magnesium oxide. While others in the control group merely received a placebo. Patients' disease severity and sleep quality were evaluated three times using standard questionnaires (at the beginning of the study, one and two months after therapy). Utilizing SPSS22 software and the ANOVA, t-test, and repeated measure tests, statistical analysis was conducted. Results: The mean and standard deviation of sleep quality and disease severity at the beginning of the trial and throughout the first month following the intervention did not differ statistically between the three groups. In the second month following the intervention, the mean and standard deviation of sleep quality and disease severity were significantly different (P = 0.001). Conclusion: Taking magnesium and vitamin B6 supplements can reduce the severity of symptoms of RLS/WED patients and improve their sleep quality. [ABSTRACT FROM AUTHOR]

Introduction: This guideline establishes clinical practice recommendations for treatment of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) in adults and pediatric patients., Methods: The American Academy of Sleep Medicine (AASM) commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths based on a systematic review of the literature and an assessment of the evidence using the grading of recommendations assessment, development, and evaluation methodology. The task force provided a summary of the relevant literature and the certainty of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations., Good Practice Statement: The following good practice statement is based on expert consensus, and its implementation is necessary for the appropriate and effective management of patients with RLS., 1. In all patients with clinically significant RLS, clinicians should regularly test serum iron studies including ferritin and transferrin saturation (calculated from iron and total iron binding capacity). Testing should ideally be administered in the morning avoiding all iron-containing supplements and foods at least 24 hours prior to blood draw. Analysis of iron studies greatly influences the decision to use oral or intravenous (IV) iron treatment. Consensus guidelines, which have not been empirically tested, suggest that supplementation of iron in adults with RLS should be instituted with oral or IV iron if serum ferritin ≤ 75 ng/mL or transferrin saturation < 20%, and only with IV iron if serum ferritin is between 75 and 100 ng/mL. In children, supplementation of iron should be instituted for serum ferritin < 50 ng/mL with oral or IV formulations. These iron supplementation guidelines are different than for the general population., 2. The first step in the management of RLS should be addressing exacerbating factors, such as alcohol, caffeine, antihistaminergic, serotonergic, antidopaminergic medications, and untreated obstructive sleep apnea., 3. RLS is common in pregnancy; prescribers should consider the pregnancy-specific safety profile of each treatment being considered., Recommendations: The following recommendations are intended as a guide for clinicians in choosing a specific treatment for RLS and PLMD in adults and children. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. The recommendations listed below are ranked in the order of strength of recommendations and grouped by class of treatments within each PICO (Patient, Intervention, Comparator, Outcome) question. Some recommendations include remarks that provide additional context to guide clinicians with implementation of this recommendation., Adults With Rls: 1. In adults with RLS, the AASM recommends the use of gabapentin enacarbil over no gabapentin enacarbil (strong recommendation, moderate certainty of evidence)., 2. In adults with RLS, the AASM recommends the use of gabapentin over no gabapentin (strong recommendation, moderate certainty of evidence)., 3. In adults with RLS, the AASM recommends the use of pregabalin over no pregabalin (strong recommendation, moderate certainty of evidence)., 4. In adults with RLS, the AASM recommends the use of IV ferric carboxymaltose over no IV ferric carboxymaltose in patients with appropriate iron status (see good practice statement for iron parameters) (strong recommendation, moderate certainty of evidence)., 5. In adults with RLS, the AASM suggests the use of IV low molecular weight iron dextran over no IV low molecular weight iron dextran in patients with appropriate iron status (see good practice statement for iron parameters) (conditional recommendation, very low certainty of evidence)., 6. In adults with RLS, the AASM suggests the use of IV ferumoxytol over no IV ferumoxytol in patients with appropriate iron status (see good practice statement for iron parameters) (conditional recommendation, very low certainty of evidence)., 7. In adults with RLS, the AASM suggests the use of ferrous sulfate over no ferrous sulfate in patients with appropriate iron status (see good practice statement for iron parameters) (conditional recommendation, moderate certainty of evidence)., 8. In adults with RLS, the AASM suggests the use of dipyridamole over no dipyridamole (conditional recommendation, low certainty of evidence)., 9. In adults with RLS, the AASM suggests the use of extended-release oxycodone and other opioids over no opioids (conditional recommendation, moderate certainty of evidence)., 10. In adults with RLS, the AASM suggests the use of bilateral high-frequency peroneal nerve stimulation over no peroneal nerve stimulation (conditional recommendation, moderate certainty of evidence)., 11. In adults with RLS, the AASM suggests against the standard use of levodopa (conditional recommendation, very low certainty of evidence)., Remarks: levodopa may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation)., 12. In adults with RLS, the AASM suggests against the standard use of pramipexole (conditional recommendation, moderate certainty of evidence)., Remarks: pramipexole may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation)., 13. In adults with RLS, the AASM suggests against the standard use of transdermal rotigotine (conditional recommendation, low certainty of evidence)., Remarks: transdermal rotigotine may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation)., 14. In adults with RLS, the AASM suggests against the standard use of ropinirole (conditional recommendation, moderate certainty of evidence)., Remarks: ropinirole may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation)., 15. In adults with RLS, the AASM suggests against the use of bupropion for the treatment of RLS (conditional recommendation, moderate certainty of evidence)., 16. In adults with RLS, the AASM suggests against the use of carbamazepine (conditional recommendation, low certainty of evidence)., 17. In adults with RLS, the AASM suggests against the use of clonazepam (conditional recommendation, very low certainty of evidence)., 18. In adults with RLS, the AASM suggests against the use of valerian (conditional recommendation, very low certainty of evidence)., 19. In adults with RLS, the AASM suggests against the use of valproic acid (conditional recommendation, low certainty of evidence)., 20. In adults with RLS, the AASM recommends against the use of cabergoline (strong recommendation, moderate certainty of evidence)., Special Adult Populations With Rls: 21. In adults with RLS and end-stage renal disease (ESRD), the AASM suggests the use of gabapentin over no gabapentin (conditional recommendation, very low certainty of evidence)., 22. In adults with RLS and ESRD, the AASM suggests the use of IV iron sucrose over no IV iron sucrose in patients with ferritin < 200 ng/mL and transferrin saturation < 20% (conditional recommendation, moderate certainty of evidence)., 23. In adults with RLS and ESRD, the AASM suggests the use of vitamin C over no vitamin C (conditional recommendation, low certainty of evidence)., 24. In adults with RLS and ESRD, the AASM suggests against the standard use of levodopa (conditional recommendation, low certainty of evidence)., Remarks: levodopa may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation)., 25. In adults with RLS and ESRD, the AASM suggests against the standard use of rotigotine (conditional recommendation, very low certainty of evidence)., Remarks: rotigotine may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation)., Adults With Plmd: 26. In adults with PLMD, the AASM suggests against the use of triazolam (conditional recommendation, very low certainty of evidence)., 27. In adults with PLMD, the AASM suggests against the use of valproic acid (conditional recommendation, very low certainty of evidence)., Children With Rls: 28. In children with RLS, the AASM suggests the use of ferrous sulfate over no ferrous sulfate in patients with appropriate iron status (see good practice statement for iron parameters) (conditional recommendation, very low certainty of evidence)., Citation: Winkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2025;21(1):137-152., (© 2025 American Academy of Sleep Medicine.)

Introduction: This systematic review provides supporting evidence for the accompanying clinical practice guideline on the treatment of restless legs syndrome and periodic limb movement disorder., Methods: The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine. A systematic review was conducted to identify studies that compared the use of pharmacological or nonpharmacological treatment to no treatment to improve patient-important outcomes. Statistical analyses were performed to determine the clinical significance of using various interventions to treat restless legs syndrome and periodic limb movement disorder in adults and children. The Grading of Recommendations Assessment, Development, and Evaluation process was used to assess the evidence for making recommendations., Results: The literature search resulted in 3,631 studies out of which 148 studies provided data suitable for statistical analyses. The task force provided a detailed summary of the evidence along with the certainty of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations., Citation: Winkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med . 2025;21(1):153-199., (© 2025 American Academy of Sleep Medicine.)

Summary: Questionnaires for restless legs syndrome have rarely been validated against face‐to‐face interviews in the general population. We aimed to validate the modified Norwegian, seven‐item Cambridge‐Hopkins restless legs syndrome questionnaire and a single diagnostic question for restless legs syndrome. We also aimed to stratify validity at 65 years of age. Among a random sample of 1,201 participants from the fourth wave of the Trøndelag Health Study, 232 (19%) agreed to participate, out of whom 221 had complete data for analyses. Participants completed the questionnaires for restless legs syndrome immediately before attending a face‐to‐face interview using the latest diagnostic criteria. We calculated sensitivity, specificity, and Cohen's kappa statistic (κ) of questionnaire‐ versus interview‐based diagnoses. We found acceptable validity of the seven‐item modified Cambridge‐Hopkins diagnostic questionnaire for restless legs syndrome (κ = 0.37, 95% confidence interval [CI] 0.23–0.51) and good validity of the single diagnostic question (κ = 0.47, 95% CI 0.35–0.58). We also found good validity through the combination of modified Cambridge‐Hopkins diagnostic questionnaire for restless legs syndrome items 2 and 5, while item 1 or 2 alone showed only acceptable validity. The single diagnostic question was significantly more valid among those aged <65 years (κ = 0.60 versus κ = 0.26). Both single‐ and two‐item questionnaire‐based diagnoses overestimated interview‐based restless legs syndrome prevalence. The seven‐item modified Cambridge‐Hopkins diagnostic questionnaire for restless legs syndrome will be useful for epidemiological studies although low sensitivity may cause underestimation of true restless legs syndrome prevalence in the general population, especially among elderly. Brief questionnaire‐based diagnoses of up to three items seem best utilised as an initial screen. Future studies should identify brief and even more valid questionnaire‐based diagnoses for restless legs syndrome in order to estimate prevalence accurately in large epidemiological studies. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the relationship between Willis-Ekbom Disease/Restless Legs Syndrome and iron deficiency anemia in older people with dementia. Methods: A cross-sectional study was conducted with 70 older people diagnosed with dementia and restless leg syndrome in a Psychogeriatric outpatient clinic in a city in the interior of São Paulo, Brazil. The older people filled in instruments of sociodemographic characterization, measures to evaluate the Restless Legs Syndrome, neuropsychiatric symptoms, sleep quality, sleepiness and cognition. Blood data were also collected levels of creatinine, ferritin, red blood cells, hemoglobin and hematocrit, the latter collected in the patients' medical records. Results: The sample consists mostly of older people with mixed dementia (i.e., Alzheimer's disease + Vascular Dementia), with 39% of female patients and mean age of 77.80 years (9.36). This study identified a frequency of 15.7% of Restless Legs Syndrome. Patients with the syndrome present more frequency of neuropsychiatric symptoms, worse sleep quality, higher index of body mass and lower levels of ferritin (p <.05). Conclusions: A frequency of 15.7% was identified for restless leg syndrome among patients with dementia. In addition, patients with the syndrome have ferritin deficiency. [ABSTRACT FROM AUTHOR]

Objective/background: Restless legs syndrome (RLS) is a complex condition associated with circadian rhythm that disrupts sleep and can cause multisystemic consequences. This study assesses pharmacotherapy treatment initiation, estimates annual treatment prevalence, and assesses treatment patterns for early-onset idiopathic RLS.Methods: We used the MarketScan Commercial Claims Database from 2012 to 2019 to conduct a new user retrospective cohort study. Annual treatment prevalence was calculated from a cross-sectional sample. Newly diagnosed adults with early-onset (18-44 years) idiopathic RLS who initiated on and off-label gabapentinoids, dopamine agonists, or levodopa/carbidopa were included. Among monotherapy users who had one year of insurance enrollment, treatment patterns (single fill, continuous use of initiated therapy, switching, and add-on therapy) were examined and mean time on the initial treatment (as a measure of persistence) was calculated.Results: In total, 6, 828 patients were initiated on monotherapy treatment for early-onset idiopathic RLS in which 4,638 met all inclusion criteria. In 2019, annual prevalence of monotherapy treatment of diagnosed patients for ropinirole was 171.3/1,000 patients; 85.0/1,000 patients for pramipexole; and 132.1/1,000 patients for gabapentin. Overall, 22.3% (n = 1,033) of patients maintained their initiated pharmacotherapy for the entire year. Rotigotine had the longest persistence (mean 185.4 [161.4 SD] days) but this user group was the smallest (n = 29). Gabapentin enacarbil, pregabalin, and rotigotine use was low (2.8% total).Conclusion: Ropinirole, pramipexole, and gabapentin were initiated most often for early-onset idiopathic RLS. FDA-approved agents for RLS, including gabapentin enacarbil and rotigotine, were used less frequently. In general, persistence was low for all RLS study drugs examined. [ABSTRACT FROM AUTHOR]

Background and purpose: Stroke‐related restless legs syndrome (sRLS) secondary to ischemic lesions is an emerging entity and an interesting condition, but there are limited available data to help us further understand its underlying pathways. In this study, we characterized sRLS clinically, neuroanatomically and functionally. Methods: Consecutive patients hospitalized in the Stroke Unit of the University Hospital of Strasbourg were assessed clinically and electrophysiologically for sRLS characteristics. They underwent brain magnetic resonance imaging for the neuroanatomical study of involved structures, and received functional evaluations with 18F‐FDG (2‐deoxy‐2‐[fluorine‐18]fluoro‐D‐glucose) positron emission tomography (PET) for glucose consumption, 123I‐FP‐CIT ([123]I‐2beta‐carbometoxy‐3beta‐[4‐iodophenyl]‐N‐[3‐fluoropropyl]nortropane) single‐photon emission computed tomography for dopamine reuptake and PET with 18F‐FDOPA ((3,4‐dihydroxy‐6‐[18]F‐fluoro‐l‐phenylalanine) for presynaptic dopaminergic synthesis. Results: Sixteen patients with sRLS, eight women and eight men, aged 41–81 years, were included. The clinical characteristics of sRLS and idiopathic RLS were similar. Most patients presented with bilateral and symmetric de novo RLS. Eight patients had infarction in the lenticulostriate area (middle cerebral artery and internal carotid arteria). The body of the caudate nucleus was most commonly affected. Seven patients had sRLS secondary to ventral brainstem infarction (perforating branches of the basilar arteria) affecting the pons in six patients and the medulla oblongata in one patient. Both the corticospinal tract and the cortico‐pontocerebellar fibres were lesioned in all patients with brainstem stroke. One patient had infarction in the left posterior cerebellar vermis and occipital area (posterior cerebral artery and superior cerebellar artery). Isotopic explorations showed a significantly increased dopaminergic tone in the striatum ipsilateral to lenticulostriate infarction. Dopamine fixation was normal in patients with stroke outside of the lenticulostriate area. Conclusions: Clinicians should be aware of the characteristics of sRLS for the appropriate diagnosis and treatment of this condition. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is one of the most common neurological disorders that significantly affects quality of life and sleep. It manifests itself in involuntary movements of the lower limbs due to the feeling of discomfort and restlessness that patients feel in their lower limbs. RLS is of great interest to the experts in various fields of medicine, especially to neurologists, general practitioners, internists and psychiatrists. Numerous clinical conditions and diseases play a role in the pathophysiology of RLS. Some of them are pregnancy, some kidney and stomach diseases, iron deficiency and some disorders of the metabolism. Moreover, iron is a very important micronutrient in the human body. It is involved in many metabolic processes and, in addition to RLS, it is also associated with other diseases such as hemochromatosis and anemia. This neurological disorder has wide therapeutic choices, which include lifestyle changes, dopaminergic agonists, opioids and iron therapy. Many non-anemic patients with RLS showed reduced levels in brain iron levels compared to healthy control groups in several research. The best course of treatment for this group of patients is iron supplementation. Oral iron supplementations are the first choice of therapy for patients with low serum ferritin levels. However, when serum ferritin levels are normal or high or when oral iron is not tolerated, intravenous iron is a better choice. There are many intravenous iron formulations, but low molecular weight dextran and ferric carboxymaltose have very efficient effects on the treatment of RLS.

Background and Aims: The data on the prevalence of the Restless Legs Syndrome/Willis -Ekbom disease (RLS/WED) in the population of teenagers is scarce. The aim of this study was to determine RLS/WED occurrence in adolescents, its diagnostic accuracy, family history, clinical characteristics and impact on everyday functioning.Material and Methods: A group of 2379 pupils (aged 13-18 y.o.) from 6 randomly selected secondary schools in Gdańsk, Poland were screened for RLS/WED with the use of a questionnaire. In order to verify the diagnosis and perform additional tests (neurological examination, psychological evaluation, biochemical blood tests, demographic questionnaire, International RLS rating scale/IRLSS, Epworth daytime sleepiness scale). all of the respondents with RLS/WED suspicion and their parents were asked for a consultation by a child neurologist. Both children and parents with RLS/WED diagnosis were tested with actigraphy at home for at least two consecutive nights.Results: Two thousand and ninety seven students (88,15%) filled the questionnaire correctly (1171 girls and 926 boys, 56% and 44%). Sixty four respondents were suspected of having RLS/WED (3,1%), however, 36 of them were diagnosed as RLS/WED-mimics (mainly positional discomfort). Finally, 21 (1%) were diagnosed with definite idiopathic RLS/WED. The average age of symptom onset was 10.96 years. The severity was moderate in the most of the cases (61.9%) and the course of the disease was intermittent in all of them. Family history was positive in 80%. Abnormal actigraphy (PLMS index >5/h) was present in 80%. Blood level of ferritin was low (<50 ng/ml) in 85%. Excessive daytime sleepiness and school problems affected almost half of them. The presence of RLS/WED symptoms was associated with disrupted sleep, behavioral problems (irritability, aggression, hyperactivity), attention deficit and lowered mood. No correlation between RLS/WED and attention deficit hyperactivity disorder (ADHD), nocturnal enuresis or primary headaches was found. Thirty eight percent of the patients sought medical help, but none of them obtained proper diagnosis nor treatment of RLS/WED.Conclusions: In this study restless legs syndrome affected 1% of Polish teenagers, in the majority of cases was idiopathic and associated with positive family history. It affected sleep and everyday functioning. Neurological consultation is essential to avoid false positive diagnoses of RLS/WED in teenagers. [ABSTRACT FROM AUTHOR]

Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a sleep disorder characterized by sensorimotor symptoms such as unpleasant sensations before sleep, akathisia, and periodic limb movements during sleep. It is also closely related to hyperarousal and is often accompanied by insomnia. Although the mechanism is not clear, the understanding of etiology and pathophysiology has greatly expanded through recent advances in genetic and neurobiological research. The most important pathophysiology of RLS/WED is brain iron deficiency. Such iron deficiency in the brain is caused by complex interactions between several genetic factors and various environmental factors, including comorbidities. Iron deficiency in the brain results in dysfunction of several neurotransmitters. A decrease in adenosine activity appears first, followed by an increase in the activity of glutamate and dopamine. A decrease in adenosine activity and an increase in glutamate activity stimulate the brain arousal system, resulting in hyperarousal. In addition, overproduction of dopamine and glutamate leads to dysfunction of the cortical-striatal-thalamic circuit, resulting in symptoms such as akathisia and periodic limb movements during sleep. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the relation between systemic iron parameters (SIP) and substantia nigra (SN) iron deposits, as assessed by transcranial sonography (TCS) in restless legs syndrome (RLS).Methods: We conducted a cross-sectional study in RLS patients, from whom blood samples with SIP were obtained, consisting of total iron-binding capacity (TIBC), serum ferritin, hemoglobin, transferrin saturation (TSAT), serum iron, and serum transferrin. TCS was performed over the SN, and the substantia nigra echogenicity index (SNEI) was determined according to established methods. Symptom severity was evaluated using the international restless legs scale (IRLS). A Spearman correlation was performed.Results: A total of 167 patients were studied. Correlations between SNEI and SIP were as follows: serum ferritin (R = 0.0422; n.s.), TSAT (R = 0.0883; n.s.), TIBC (R = -0.1091; n.s.), serum transferrin (R = -0.0420; n.s.), hemoglobin (R = 0.0185; n.s.), serum iron (R = 0.0389; n.s.). No correlation was found with age and IRLS (R = 0.1375; n.s. and R = 0.0880, n.s., respectively).Conclusions: SIP are not correlated with SN iron content in RLS, quantified by means of TCS. TCS of the SN might be a more valid estimate and could be useful in the evaluation of RLS patients. [ABSTRACT FROM AUTHOR]

Elisabeth Ruppert1–31Sleep Disorders Center - CIRCSom, Department of Neurology, Hôpital Civil, 67091 Strasbourg, France; 2Faculty of Medicine, University of Strasbourg, 67000 Strasbourg, France; 3Institute for Cellular and Integrative Neurosciences, CNRS - UPR 3212, University of Strasbourg, 67000 Strasbourg, FranceAbstract: This literature review focuses on restless arms syndrome (RAS), an upper limb variant of restless legs syndrome (RLS). RLS, also known as Willis-Ekbom disease, is a frequently occurring neurological disorder characterized by an irresistible urge to move the lower limbs often accompanied by unpleasant sensations in the legs, worsened at rest and in the evening, improved by movement. Extension of leg restlessness to the upper limbs is frequently reported in typical patients who had RLS only in the legs and usually occurs later in the course of RLS, restlessness remaining most invalidating in the lower limbs. In RAS, the arms are predominantly affected with little or no involvement of the legs. Cases of restless shoulders syndrome or periodic arm movements without arm restlessness were not considered. A total of 9 articles with 10 cases were included and analyzed for the adherence to the five essential diagnostic criteria of the International RLS Study Group (IRLSSG) classification, as well as for the additional supportive features. All of the reported cases were classified as having definite RAS. The clinical history and disease evolution of two previously reported patients were completed and updated. Overall, the clinical picture of RAS does not differ from that of RLS, except for the symptoms localization on the upper limbs. Underlying mechanisms of the spread of RLS to upper limb restlessness and of RAS remain unknown. Whether RAS is a phenotypic variant of RLS or a separate entity needs further investigations. RAS likely remains underdiagnosed and according to IRLSSG diagnostic criteria RAS should be considered when RLS-like symptoms are present in one or both arms, especially when they have a circadian pattern and are improved by movement and dopaminergic therapy. Clinicians should be aware of this rare condition, especially as treatment using dopaminergic agonists proves to be very efficient.Keywords: RLS variant, RLS equivalent, restless upper limb, restlessness of upper extremities, Willis-Ekbom disease, periodic arm movements

Background: Randomized controlled trials (RCTs) are the cornerstone of modern medical research, and their reporting may not always be optimal. The Consolidated Standards of Reporting Trials (CONSORT) statement is an evidence-based means to improve the quality of RCTs’ reporting by providing a checklist of recommended items.The aim of this study was to assess the reporting quality of published RCTs on the restless legs syndrome (RLS), based on a checklist arising from the CONSORT statement. Methods: Medical electronic databases were searched for RCTs involving patients with RLS. Inclusion criteria were follows: articles must have been published in English and RLS patients must have been randomized into a minimum of two treatment cohorts of different medicinal orientations. CONSORT-recommended items were marked as “reported” or “not reported,” and an overall CONSORT compliance metric was calculated. Comparisons among different time periods, CONSORT-endorsing and non-endorsing, and different levels of impact factor journals were made. Results: Fifty-four eligible trials, published in 21 different scientific journals, were found. The average CONSORT compliance score was 56.6% (23.68–84.21%). CONSORT-endorsing journals had a mean CONSORT compliance of 58.47%, whereas non-endorsing journals had a mean CONSORT compliance of 50.4%. The median CONSORT compliance for articles published in low- (IF7) journals was 52.63, 56.57, and 59.21%, respectively. Only 14 of the 38 CONSORT items (36.8%) were reported in >75% of the articles. Discussion: This study shows that the reporting of RLS-related RCTs is suboptimal, regardless of the time period, the quality of the publishing journal, and the endorsing or non-endorsing of the CONSORT statement.

Restless legs syndrome is a sensorimotor disorder that significantly affects quality of life. This study explored the experience of people living with restless legs syndrome. Focus groups were analysed thematically resulting in five themes. Participants described disempowerment in managing symptoms, difficulty coping and poor understanding of the condition. Participants tried many therapies with little relief and were unable to monitor treatment effects. Concerns with healthcare services were common. Feeling understood provided validation and empowerment. Healthcare providers can help people with restless legs syndrome by improving restless legs syndrome awareness, providing psychosocial support and education, and assisting people to monitor treatment effects. [ABSTRACT FROM AUTHOR]

Background: Restless legs syndrome (RLS) is prevalent in patients with chronic obstructive pulmonary disease (COPD). No large population-based cohort study has assessed the relationship. We evaluated the incidence of RLS among COPD patients by sociodemographic status (SES) and comorbidity using insurance claims data of Taiwan.Methods: From the database, we established a cohort consisting of 77,831 individuals aged ≥ 20 years newly diagnosed with COPD from 2000 to 2013. We also identified same number of individuals without COPD as the comparison cohort, frequency matched by sex, age and index year. Both cohorts were followed up to the end of 2013 to estimate the incidence and hazard ratio (HR) of developing RLS.Results: The incidence of RLS was 2.2-fold higher in COPD patients than in those free of COPD (6.67 and 3.08 per 10,000 person-years), with an adjusted HR (aHR) 1.68 (95% CI 1.41-2.01) after controlling for covariates. The incidence rates in both cohorts increased with age and higher in low socioeconomic group. The risk of RLS increased further among COPD patients with additional comorbidities. Compared to those without COPD and comorbidity, the aHR was 7.93 (95% CI 1.11-57.8) for those with iron deficiency, 3.95 (96% CI 1.92-8.13) with Parkinson's disease, 2.85 (95% CI 1.05-7.72) with polyneuropathy, or 1.81 (95% CI 1.14-2.87) with diabetes.Conclusion: Patients with COPD are at an increased risk of developing RLS regardless of gender, age and occupation. The COPD patients with comorbidities should be particularly cautious about the RLS risk. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Restless legs syndrome (RLS) is a frequent comorbid condition associated with distinct unrelated diseases. While the incidence of RLS has not been definitively confirmed, RLS-like symptoms have been reported in a section of Asian population who also had hyperthyroidism. The prevalence of RLS is generally low in Asian populations. Under these circumstances, we hypothesized that in a population where RLS is common, such as in Brazil, RLS could manifest as a comorbid ailment alongside Graves’ disease, a common hyperthyroid condition. METHODS: In a cross-sectional survey, 108 patients who presented with Graves' disease were analyzed for restless legs or associated symptoms. RESULTS: Twelve patients (11.1%) displayed symptoms of RLS prior to the incidence of Graves’ disease. These patients experienced worsening of the symptoms during their hyperthyroid state. Six patients (5.6%) developed RLS, consequent upon the incidence of Graves’ disease as per the consensus of the panel of the experts. Fifteen patients (13.9%) also presented with RLS-like symptoms without any discernible circadian feature of the syndrome. CONCLUSION: Our findings confirm that Graves’ disease might trigger restless legs-like symptoms, while the condition of hyperthyroidism could also be complicated by definite RLS.

There is evidence of a higher prevalence of restless legs syndrome/Willis-Ekbom disease (RLS/WED) in individuals with spinocerebellar ataxia type 3 (SCA3), although the factors underlying this association remain unknown. The present study aimed to determine the prevalence of RLS/WED in SCA3 patients and to investigate which factors of SCA3 patients are associated with presence of RLS/WED. From February to August of 2006, we carried out clinical interviews in 40 controls and 40 SCA3 patients, diagnosed and followed up at Faculty of Medicine of Ribeirão Preto, University of São Paulo. Twenty-seven SCA3 patients were submitted to a detailed clinical protocol, electroneuromyography, blood work up, polysomnography (PSG), suggested immobilization test (SIT), and magnetic resonance image (MRI). RLS/WED was found in 27.5% of SCA3 patients and 2.5% of normal controls (p = 0.003). The factors related to RLS/WED in SCA3 patients were female gender, age at start of the symptoms of ataxia after 30 years, presence of peripheral neuropathy, and documented iron deficiency. Among SCA3 patients, those with RLS showed higher values of maximal discomfort level and discomfort level sum compared to non-RLS individuals on SIT. There is a relation between RLS/WED and SCA3, which seems to be resultant of different factors whose identification could improve the quality of assistance to those patients as well as to promote a better comprehension of the pathophysiology of both RLS/WED and SCA3. [ABSTRACT FROM AUTHOR]

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Objective: To evaluate the incidence of iron overload and anaphylaxis following intravenous (IV) iron treatment of restless legs syndrome (RLS).Methods: A total of 58 consecutive RLS patients, meeting clinical requirements for IV iron treatment according to current IRLSSG guidelines were recruited. IV iron treatment consisted of two 500 mg infusions of ferric carboxymaltose (FCM) administered five days apart. During each of the three follow-up visits we obtained blood samples, substantia nigra echogenity index (SNEI) by means of transcranial sonography (TCS), and assessed the severity of RLS symptoms (IRLS scale). "Iron overload risk" was defined as transferrin saturation (TSAT) > 45% on two consecutive follow-up visits. In patients who had a reduction in systemic iron levels following treatment, an additional 500 mg of FCM was administered when feasible. In such cases an additional two follow-up visits were performed.Results: Among the total sample, only 2/58 participants met criteria for iron overload risk. They had no evidence of liver damage and did not require additional treatment. Among the 21 patients receiving an additional 500 mg infusion after, only one patient was diagnosed with iron overload risk. Among these three patients, only one was a hemochromatosis gene carrier. No anaphylaxis or other side-effects were reported.Conclusions: In real-life clinical conditions, the risk of iron overload is low when IV FCM is administered according to the safety limits defined in the current RLS treatment guidelines. However, a close clinical follow-up with periodic blood sampling for iron status, is needed. [ABSTRACT FROM AUTHOR]

Background: Restless Legs Syndrome, a potentially disabling sleep disorder, also known as Willis-Ekbom disease (RLS/WED), may be caused by loss of inhibitory modulation of descending central motor pathways, structural changes in the somatosensory cortex, abnormal connectivity between motor and sensory areas, as well as by subtle abnormalities in white matter micro-organization.Objective: To compare diffusion-tensor imaging (DTI) metrics in areas associated with sensory or motor function, as well as sensorimotor integration, between subjects with primary mild-to-severe RLS/WED and controls.Methods: DTI metrics were assessed in 38 subjects with RLS/WED (14 mild to moderate, 24 severe to very severe) and 24 healthy age-matched controls with whole-brain Tract Based Spatial Statistics (TBSS), Region-of-interest (ROI) and probabilistic tractography based analyses. The ROIs corresponded to the corticospinal tract (CST) at the level of the cerebral peduncle; the superior, middle and inferior cerebellar peduncles. Subgroup analyses were made according to the severity of RLS/WED symptoms. The corticospinal tract was evaluated with probabilistic tractography. We also explored associations between significant findings and severity of symptoms with the Spearman's correlation coefficient.Results: TBSS analysis revealed decreased axial diffusivity (AD) in the left posterior thalamic radiation in RLS/WED. In subjects with severe RLS/WED, AD was reduced in the left posterior corona radiata and this reduction was negatively correlated with severity of symptoms. ROI-based analysis showed that radial diffusivity (RD) was increased in the superior cerebellar peduncles of individuals with severe RLS/WED. Tractography did not show between-group or subgroup differences.Conclusions: Our results are consistent with subtle white matter changes, prominently in RLS/WED subjects with more severe symptoms, in areas related to sensory or motor function, as well as to sensorimotor integration, compared to controls. These findings support the hypothesis, raised by prior pathophysiological studies, of defective integration within these networks. [ABSTRACT FROM AUTHOR]

Le syndrome des jambes sans repos ou syndrome de Willis–Ekbom est une pathologie sensorimotrice fréquente, plus souvent rencontrée chez la femme que chez l'homme. Il est caractérisé par des impatiences des membres inférieurs, c'est-à-dire le besoin impérieux de bouger les jambes, survenant le soir ou en début de nuit, majorées par le repos et soulagées par l'activité motrice. On distingue classiquement les formes précoces ou primaires survenant chez des adultes jeunes ayant des antécédents familiaux et les formes comorbides ou secondaires survenant chez des sujets plus âgés ayant des pathologies associées comme une carence martiale, une insuffisance rénale chronique ou certaines pathologies neurologiques (centrales ou périphériques). Les conséquences cliniques peuvent être majeures, en particulier, les troubles du sommeil induits par les impatiences sont au centre des plaintes des patients. La physiopathologie du syndrome des jambes sans repos reste incomplètement comprise. Elle repose probablement sur une anomalie du métabolisme de la dopamine liée à une carence en fer intracérébral chez des sujets prédisposés génétiquement. C'est pourquoi le traitement du syndrome des jambes sans repos, outre des règles hygiéno-diététiques et d'hygiène de sommeil, inclut une supplémentation en fer en cas de carence martiale avérée éventuellement associée à un traitement pharmacologique de fond. Ce traitement de fond repose, pour les formes sévères à très sévères, sur l'utilisation d'agonistes dopaminergiques, d'antiépileptiques ou d'opioïdes, molécules dont les effets secondaires sont nombreux, raison pour laquelle chaque indication devra être discutée de façon personnalisée. Restless legs syndrome, also called Willis–Ekbom disease, is a frequent sensorimotor disease, more often encountered in women than men. It is characterized by an urge to move legs, during the evening or the beginning of the night, increased by rest and relieved by movement. Two forms are classically distinguished: primary restless legs syndrome occurring in young adults with family history and secondary forms occurring in older adults with comorbidities such as iron deficiency, chronic renal failure or neurological diseases (affecting central or peripheral nervous system). The clinical impact of the urge to move the legs may be major, including in particular sleep disorders which can profoundly alter the quality of life. Pathophysiology of restless legs syndrome still remains partially understood and probably relies on dopamine metabolism abnormality secondary to cerebral iron deficiency in genetically susceptible patients. That's why, besides nutritional and sleep hygiene advices, treatment of restless legs syndrome includes iron supplementation if there is an iron deficiency. Pharmacological treatment, for severe to very severe forms, includes use of dopamine agonists, antiepileptic drugs or opioids. These medications have numerous side effects and each prescription has to be individually customized for each patient. [ABSTRACT FROM AUTHOR]

Purpose of review: The main purpose of this manuscript is to review the existing clinical evidence about when iron replacement therapy should be initiated for RLS/WED, and how it should be administered (oral vs. intravenous). Recent findings: Our knowledge of the pathophysiology of restless legs syndrome/Willis-Ekbom (RLS/WED) continues to grow, revealing the existence of brain iron deficiency as the most well-known biological alteration behind this disorder. Since iron replacement therapy in RLS/WED is one of the first-line available treatments, its indication should be considered periodically, at both the beginning and during the follow-up. Summary: There is more and more evidence sustaining that the proper use of iron replacement therapy may lead to a reduction in symptomatic drug requirements, and therefore minimize the risk of complications that may result from their long-term use. For all the above, treatment paradigms for RLS/WED, previously based on symptomatic drugs, are changing, giving iron replacement therapy the importance it merits. Thus, it is essential for neurologists to be updated on why, when, and how to use iron in RLS/WED. [ABSTRACT FROM AUTHOR]

Objective Restless Legs Syndrome (RLS) is a common neurological disorder that affects patients’ sleep, emotional state and daily life negatively. In this study it was aimed to determine the sleep quality, daytime sleepiness and depression frequency in patients with RLS and their relation with duration and severity of illness. Materials and Methods In our center, 41 patients with primary RLS diagnosis were included in the study. Patients were divided into groups as mild, moderate, severe and very severe, according to the RLS severity scale of the International Restless Legs Syndrome Study Group. Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Beck Depression Inventory were filled in by all the patients, including identity and sociodemographic data with illness information. Statistical analysis was performed among groups divided according to disease severity. Depressive symptoms of the disease duration and its relation with sleep problems were investigated. Results In this study 41 patients, 30 (73.2%) female, 11 (26.8%) male, were included. Of the patients participating in the study, 2 patients (4.9%) had mild RLS while 7 (17.1%) were very severely ill. Fourteen patients (34.1%) had moderate disease and 18 (43.9%) had severe disease. Bad sleep quality was found in 68.3% (n=28) of patients with RLS, excessive daytime sleepiness in 14.6% (n=6) severe depression in 7.3% (n=3) and totally 29.3% of patients (n=12) depressive symptoms were observed. As the severity of illness increased, sleep quality deteriorated and depressive symptoms increased (p

Restless-Legs-Syndrome (RLS), also known as Willis-Ekbom disease, is a sleep- and rest related disorder characterized by the unpleasant urge to move the legs. Pharmacological therapy is mainly based on dopamine-agonists and delta-2-alpha calcium channel ligands. Also, randomized-controlled-trials (RCTs) reported effectiveness of oral oxycodone (in combination with naloxone), and intrathecal opioids have also been administered for this indication. In the case reported here, a patient with advanced pancreatic cancer was referred to an acute palliative care unit for the treatment of cancer-related pain. Yet, in thorough exploration of her symptom burden, the patient reported that she felt her quality of life had been predominantly limited by symptoms other than cancer pain. Her medical history and neurological examination revealed that these symptoms were most obviously caused by severe RLS. In the years before, pharmacological therapies with dopamine-agonists and delta-2-alpha calcium channel ligands were initiated, but failed to relieve the RLS. In the palliative care ward, intravenous morphine was successfully titrated to treat her cancer pain. Concurrently, the patient also experienced almost complete relief from her RLS-symptoms and an increase in quality of life. The amelioration of her RLS-symptoms continued after morphine therapy was switched from intravenous to oral administration. Even after the patient was dismissed to home care and opioid rotation to transdermal fentanyl, symptom control of RLS remained excellent. To our knowledge, this is the first report of successfully treating RLS with intravenous and oral morphine. Since morphine is more easily available worldwide and the cost of morphine therapy is substantially lower compared to oxycodone/naloxone, comparisons to morphine may be an intriguing option for future RCTs.

Introduction: Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is a sleep-related sensory-motor disorder associated with poor sleep quality and impaired daily functioning. In patients affected by chronic RLS/WED, a pharmacological therapy is recommended. International guidelines suggest to start the treatment with a α2δ calcium channel ligand in most cases, unless contraindicated., Areas Covered: The present review is based on an extensive Internet and PubMed search from 1986 to 2024. Our purpose is to describe the absorption, distribution, metabolism, and toxicology (ADMET) of the α2δ ligands, with common consideration for the therapeutic class, specificities of different compounds, efficacy, and safety in relation to other treatment options., Expert Opinion: α2δ ligands are quite similar in their ADMET profiles, sharing most of the pharmacokinetics and potential adverse effects. However, we highlight the linear kinetic of gabapentin enacarbil and pregabalin, differently from gabapentin. α2δ ligands are safe and effective for the treatment of RLS/WED. Additional benefits can be obtained in comorbid insomnia, chronic pain syndromes, history of impulse control disorder, and comorbid anxiety. The use of α2δ ligands is associated with poor risk of augmentation. We still need new long-term safe and effective treatments, which could be developed along with our knowledge of RLS/WED pathophysiology.

Objective: To analyze changes in substantia nigra (SN) iron deposits, assessed by quantitative transcranial sonography (TCS), to obtain and compare substantia nigra echogenicity indices (SNEI) at baseline and after intravenous (IV) iron therapy in patients with restless legs syndrome (RLS)/Willis-Ekbom disease (WED).Methods: A total of 30 consecutive subjects diagnosed with RLS/WED were recruited and underwent IV iron treatment. The SNEI, total daily dose of dopamine equivalents, and International Restless Legs Syndrome Rating Scale (IRLS) scores were obtained at baseline and following IV iron administration. Comparative statistics were performed by means of nonparametric testing.Results: The sample was stratified into two groups according to the median baseline SNEI and the grade of SN hypoechogenicity: severely hypoechogenic (HE) (n = 13) and moderately HE (n = 17). Following IV iron, the increase in SNEI among severely HE subjects was 19% (0.038 ± 0.046 cm2; P < 0.01), whereas in moderately HE subjects it was 10% (0.021 ± 0.069 cm2; P = 0.28). Among severely HE subjects, the average reduction in IRLS following IV iron was 10 ± 7.12 points (P < 0.01), in contrast to 1.85 ± 9.85 (not significant) among moderately HE subjects. Finally, we quantified the percentage of patients in each group who were able to reduce by ≥30% their total daily dopaminergic requirements (TDR) after IV iron, with a 57.14% reduction in the severely HE group vs 25% in the moderately HE group (P = 0.1). Three of 30 subjects (17%) were able to completely cease all dopaminergic treatment.Conclusion: Intravenous iron caused changes in SNEI in both groups of patients, reflecting an increase in brain iron stores. However, the increase in SNEI was greater in patients previously defined as severely HE. Furthermore, RLS/WED symptoms also improved more in severely HE subjects, and there was a greater reduction in TDR. This study highlights the role of TCS in quantifying brain iron deposits and in predicting which patients will likely benefit from IV iron. [ABSTRACT FROM AUTHOR]

Background/objective: Restless legs syndrome (RLS) is a neurological disorder with a strong genetic susceptibility. A painful RLS sub-phenotype has been described previously but the neurobiological basis for this phenotypic variant remains unknown. This study investigated whether any of the six initially discovered genomic loci associating with RLS (BTBD9, MEIS1, PTPRD, MAP2K5/SKOR1, TOX3, and an intergenic region on chromosome 2), were more strongly associated with complaints of painful versus non-painful RLS.Methods: RLS patients (N = 199; Age = 53.1 ± 16.8; 100% Caucasians; 57% women) diagnosed clinically were genotyped for known variants associating with RLS. Definition of painful RLS required that subjects selected "painful" from a list of 14 adjectives to describe their RLS sensory experience and answered positively to a separate question that queried specifically as to whether they perceived their RLS sensations as painful. Genotype association tests employed logistic regression analyses with assumption of an additive genetic model. Analyses were performed using PLINK software v1.07.Results: We identified two RLS patient subgroups: a painful (n = 41) and non-painful (n = 158). Among 10 tested SNPs, only rs3104767 (related to the TOX3 gene locus) was more associated with painful RLS. The minor allele T of SNP rs3104767 was associated with an increased risk of RLS being perceived as painful with an OR of 1.67 [CI = (1.01-2.74); p = 0.049]. Notably, this minor T allele associated with pain sensation in RLS patients in this study was the non-risk allele for RLS in the original RLS genome wide association study, but a similar trend was observed in a recent Parkinson disease sample study.Conclusion: This study might suggest the TOX3 gene variant as a potential genetic substrate for the painful RLS sub-phenotype. This was an exploratory small study and correction for multiple comparisons would have rendered the results not significant. Therefore, the above findings require replication in larger clinical as well as population-based samples of RLS subjects. [ABSTRACT FROM AUTHOR]

Background: Periodic limb movements in sleep (PLMS) are repetitive movements usually of the legs strongly associated with Restless-legs syndrome (RLS), which appear more frequently in males, older age and other sleep disturbances, such as sleep-disordered breathing (SDB). Patients with Parkinson's disease (PD) suffer from various sleep disturbances including REM sleep behavior disorder, RLS and PLMS. Although a dopaminergic pathophysiology of PLMS is discussed, no systematic data on PLMS side-to-side distribution in PD and its correlation with asymmetry of motor symptoms are available. Objective: This study aimed at elucidating PLMS asymmetry in correlation to that of motor symptoms in PD compared to SDB and RLS. Methods: Cross-sectional, retrospective analysis of two polysomnography (PSG) recordings per patient scoring PLMS separately for both legs. Results: Of 105 patients (44 PD, 44 age- and sex-matched SDB and 17 RLS patients) PLMS measures (number of PLM, PLM-Index, PLM-arousal index) showed significant side-to-side differences in all disease entities in both PSGs (P < 0.001; Wilcoxon rank test). PLM-Index asymmetry (PLM-I difference of >5/h between both sides) was observed less frequently in PD (34% of patients) compared to RLS (77% , P < 0.05) and SDB (59% , P < 0.05; χ2 test). In asymmetric PD patients, predominant side of PLMS was more stable than in SDB and RLS comparing the two PSGs, but we did not detect an agreement between PLMS predominant side with that of motor symptoms in PD patients. Conclusions: Only the minority of PD patients shows asymmetric PLMS distribution with relatively high night-to-night stability but no correlation with motor symptom asymmetry. [ABSTRACT FROM AUTHOR]

Purpose: This review (Part II of a series on sleep disorders) presents an update of the characteristics, epidemiology, assessment, and latest management of insomnia, restless legs syndrome (Willis‐Ekbom disease; RLS/WED), and narcolepsy. Insomnia, the most common sleep disorder and most prevalent of all psychological health disorders, is a problem of difficulty initiating and maintaining sleep and early morning awakenings. RLS/WED is characterized by a crawling sensation or urge to move the legs in the evening and nighttime. Narcolepsy is a sleep disorder that commonly results in chronic daytime sleepiness and cataplexy. Nonpharmacological management, which includes education, cognitive behavioral therapy, and complementary therapy, is used as primary or adjunctive to pharmacotherapy for the treatment of these disorders. Methods: This narrative review utilized medical databases such as PubMed to identify relevant English‐language original and systematic review articles predominantly from peer‐reviewed journals from 2012 to 2019. However, as background, findings from classic articles prior to 2012 were also included. Clinical Relevance: Assessment of sleep problems, excessive sleepiness, and difficulty performing activities or being productive should be routine in the care of all patients. Utilization of behavioral interventions, including cognitive behavioral therapy, in addition to education and sleep hygiene, can promote sleep quality. Management of insomnia, RLS/WED, and narcolepsy should include helping patients adjust to treatment, managing cataplexy triggers in narcolepsy, and initiating strategies to live with chronic illness to improve quality of life. [ABSTRACT FROM AUTHOR]