EKBOM KA.
Restless legs syndrome.
Neurology. 1960 Sep;10:868-73. doi: 10.1212/wnl.10.9.868.
Abstract/Text
Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JAG.
Genetics of restless legs syndrome: An update.
Sleep Med Rev. 2018 Jun;39:108-121. doi: 10.1016/j.smrv.2017.08.002. Epub 2017 Aug 31.
Abstract/Text
A major role of genetic factors in the risk of developing restless legs syndrome (RLS) is supported by the high frequency of positive family history of RLS in patients affected with this disease, and the higher concordance rates in monozygotic twins compared with dizygotic ones in twin studies. In this review we have focused on those reports describing inheritance patterns of RLS, genetic anticipation, the results of studies performed on positivity of family history of RLS, twin studies, linkage studies in familial RLS, genome-wide association studies (GWAS), exome sequencing studies, and case-control association studies on candidate genes in RLS. Although to date the causative gene(s) has(ve) not been definitively identified, a number of variants of several genes, most of them through GWAS, have been associated with RLS risk, the strongest candidates being variants of PTPRD, BTBD9, and MEIS1 genes. Despite results of several recent case-control association studies which have suggested a possible contribution of heme-oxygenase 1 (HMOX1) rs2071746 and vitamin D3 receptor (VDR) rs731236 variants, or the presence of allele 2 of the complex microsatellite repeat Rep1 within the alpha-synuclein (SNCA) gene promoter in modifying the risk for RLS, these studies need to be replicated in further studies involving different populations.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Trenkwalder C, Allen R, Högl B, Clemens S, Patton S, Schormair B, Winkelmann J.
Comorbidities, treatment, and pathophysiology in restless legs syndrome.
Lancet Neurol. 2018 Nov;17(11):994-1005. doi: 10.1016/S1474-4422(18)30311-9. Epub 2018 Sep 21.
Abstract/Text
Restless legs syndrome, also known as Willis-Ekbom disease, is a common neurological condition whose manifestation is affected by complex environmental and genetic interactions. Restless legs syndrome can occur on its own, mostly at a young age, or with comorbidities such as cardiovascular disease, diabetes, and arterial hypertension, making it a difficult condition to properly diagnose. However, the concept of restless legs syndrome as being two entities, primary or secondary to another condition, has been challenged with genetic data providing further insight into the pathophysiology of the condition. Although dopaminergic treatment was formerly the first-line therapy, prolonged use can result in a serious worsening of symptoms known as augmentation. Clinical studies on pregabalin, gabapentin enacarbil, oxycodone-naloxone, and iron preparations have provided new treatment options, but most patients still report inadequate long-term management of symptoms. Studies of the hypoxic pathway activation and iron deficiency have provided valuable information about the pathophysiology of restless legs syndrome that should now be translated into new, more effective treatments for restless legs syndrome.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Schormair B, Zhao C, Bell S, Tilch E, Salminen AV, Pütz B, Dauvilliers Y, Stefani A, Högl B, Poewe W, Kemlink D, Sonka K, Bachmann CG, Paulus W, Trenkwalder C, Oertel WH, Hornyak M, Teder-Laving M, Metspalu A, Hadjigeorgiou GM, Polo O, Fietze I, Ross OA, Wszolek Z, Butterworth AS, Soranzo N, Ouwehand WH, Roberts DJ, Danesh J, Allen RP, Earley CJ, Ondo WG, Xiong L, Montplaisir J, Gan-Or Z, Perola M, Vodicka P, Dina C, Franke A, Tittmann L, Stewart AFR, Shah SH, Gieger C, Peters A, Rouleau GA, Berger K, Oexle K, Di Angelantonio E, Hinds DA, Müller-Myhsok B, Winkelmann J; 23andMe Research Team; DESIR study group.
Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis.
Lancet Neurol. 2017 Nov;16(11):898-907. doi: 10.1016/S1474-4422(17)30327-7.
Abstract/Text
BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets.
METHODS: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10-8) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest.
FINDINGS: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1).
INTERPRETATION: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations.
FUNDING: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.
Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Freeman AA, Rye DB.
The molecular basis of restless legs syndrome.
Curr Opin Neurobiol. 2013 Oct;23(5):895-900. doi: 10.1016/j.conb.2013.07.001. Epub 2013 Jul 26.
Abstract/Text
Restless legs syndrome (RLS) disrupts sleep in a substantial proportion of the population and is associated with higher cross-sectional rates of affective illness and cardiovascular disease. While dopamine and iron availability in the brain modulate emergence of symptoms, and dopamine agonists and iron alleviate the sensory symptoms and motor signs of RLS, the biology of the disorder is incompletely understood. Genetic factors, as opposed to environmental ones, account for most of the disease variance. The at-risk allelic variants exist in non-coding regions of at least six genes rendering it a complex genetic disease. Nonetheless, these provide the first hypothesis independent clues that advance a better understanding of RLS pathophysiology.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG, Earley CJ.
Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome.
Neurology. 2003 Aug 12;61(3):304-9. doi: 10.1212/01.wnl.0000078887.16593.12.
Abstract/Text
OBJECTIVE: To assess neuropathology in individuals with restless legs syndrome (RLS).
METHODS: A standard neuropathologic evaluation was performed on seven brains from individuals who had been diagnosed with RLS. The substantia nigra was examined in greater detail for iron staining and with immunohistochemistry for tyrosine hydroxylase and proteins involved in iron management. Five age-matched individuals with no neurologic history served as controls.
RESULTS: There were no histopathologic abnormalities unique to the RLS brains. Tyrosine hydroxylase staining in the major dopaminergic regions appeared normal in the RLS brains. Iron staining and H-ferritin staining was markedly decreased in the RLS substantia nigra. Although H-ferritin was minimally detected in the RLS brain, L-ferritin staining was strong. However, the cells staining for L-ferritin in RLS brains were morphologically distinct from those in the control brains. Transferrin receptor staining on neuromelanin-containing cells was decreased in the RLS brains compared to normal, whereas transferrin staining in these cells was increased.
CONCLUSIONS: RLS may not be rooted in pathologies associated with traditional neurodegenerative processes but may be a functional disorder resulting from impaired iron acquisition by the neuromelanin cells in RLS. The underlying mechanism may be a defect in regulation of the transferrin receptors.
Schmidauer C, Sojer M, Seppi K, Stockner H, Högl B, Biedermann B, Brandauer E, Peralta CM, Wenning GK, Poewe W.
Transcranial ultrasound shows nigral hypoechogenicity in restless legs syndrome.
Ann Neurol. 2005 Oct;58(4):630-4. doi: 10.1002/ana.20572.
Abstract/Text
In patients with Parkinson's disease, hyperechogenicity of the substantia nigra using transcranial ultrasound has been related to increased tissue concentrations of iron. Recently, deficient iron transport mechanisms in substantia nigra neurons have been described in postmortem tissue of patients with restless legs syndrome (RLS). This study was performed to study substantia nigra echogenicity in RLS patients compared with normal control subjects and Parkinson's disease patients. RLS patients had significantly reduced midbrain areas of hyperechogenicity compared with control subjects, and even more markedly reduced hyperechogenicity compared with Parkinson's disease patients. These findings lend further support to nigral iron deficiency as a pathogenetic factor in RLS.
Clemens S, Rye D, Hochman S.
Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective.
Neurology. 2006 Jul 11;67(1):125-30. doi: 10.1212/01.wnl.0000223316.53428.c9.
Abstract/Text
Restless legs syndrome (RLS) involves abnormal limb sensations that diminish with motor activity, worsen at rest, have a circadian peak in expression in the evening and at night, and can severely disrupt sleep. Primary treatment is directed at CNS dopaminergic systems, particularly activation of D(2)-like (D(2), D(3), and D(4)) receptors. Although RLS affects 2% to 15% of the general population, the neural circuitry contributing to RLS remains speculative, and there is currently no accepted animal model to enable detailed mechanistic analyses. Traditional views suggest that RLS arises from supraspinal sources which favor facilitation of the flexor reflex and emergence of the RLS phenotype. The authors forward the hypothesis that RLS reflects a dysfunction of the little-studied dorsoposterior hypothalamic dopaminergic A11 cell group. They assert that, as the sole source of spinal dopamine, reduced drive in this system can lead to spinal network changes wholly consistent with RLS. The authors summarize their recent investigations on spinal cord dopamine dysfunction that rely on lesions centered on A11, and on studies in D(3) receptor knockout (D(3)KO) mice. Excessive locomotor behavior is evident in both sets of animals, and D(3)KO mice exhibit facilitation rather than the expected depression of spinal reflexes in the presence of dopamine as well as a reversal in their circadian expression of the rate-limiting enzyme for dopamine synthesis, tyrosine hydroxylase. Taken together, these findings are consistent with an involvement of spinal dopamine dysfunction in the etiology of RLS, and they argue that the D(3)KO mouse might serve as a relevant animal model to study the underlying mechanisms of RLS.
Allen RP, Stillman P, Myers AJ.
Physician-diagnosed restless legs syndrome in a large sample of primary medical care patients in western Europe: Prevalence and characteristics.
Sleep Med. 2010 Jan;11(1):31-7. doi: 10.1016/j.sleep.2009.03.007. Epub 2009 May 22.
Abstract/Text
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.
Allen RP, Bharmal M, Calloway M.
Prevalence and disease burden of primary restless legs syndrome: results of a general population survey in the United States.
Mov Disord. 2011 Jan;26(1):114-20. doi: 10.1002/mds.23430. Epub 2010 Nov 10.
Abstract/Text
To assess prevalence, disease burden, and costs of primary Restless Legs Syndrome (RLS) in the US. In 2007, 61,792 (20%) of 313,000 subjects from a representative US panel completed an online "global opinions" survey identifying respondents reporting all four diagnostic features of RLS. 4,484 met all criteria. 1,400 were randomly selected to complete a questionnaire to exclude those with diagnoses indicating possible secondary RLS. Those that did not have diagnoses associated with secondary RLS were asked to complete the Cambridge-Hopkins RLS questionnaire to exclude RLS mimics. Prevalence was estimated for the following groups: (1) RLS symptomatic, (2) primary RLS, and (3) primary RLS sufferers (symptoms ≥2/wk with moderate-to-severe distress). The primary RLS completed a larger online survey including the IRLS, EuroQol, Work Productivity and Activity Impairment questionnaire, and questions about healthcare resource use. The validated diagnostic tools and exclusion of medical conditions likely to cause RLS provide a very conservative estimate of US census-weighted prevalence of 2.4% for primary RLS and 1.5% for primary RLS sufferers. About 33% of respondents had a physician diagnosis of RLS. Primary RLS sufferers had a mean productivity loss of 1 day/wk. All RLS-related costs increased with RLS symptom severity, with increasingly significant decrements in health status, sleep disturbance, and work productivity. Even this very conservative approach finds RLS in this cohort to be common, under-diagnosed, and carried a significant personal and social burden.
Copyright © 2010 Movement Disorder Society.
Nomura T, Inoue Y, Kusumi M, Uemura Y, Nakashima K.
Prevalence of restless legs syndrome in a rural community in Japan.
Mov Disord. 2008 Dec 15;23(16):2363-9. doi: 10.1002/mds.22274.
Abstract/Text
To assess the prevalence and clinical significance of restless legs syndrome (RLS) in a Japanese population, we carried out a community-based survey in a rural area of Japan. We sent questionnaires requesting information on demographics, the Center for Epidemiological Studies Depression scale, the Short Form-8, the Pittsburgh Sleep Quality Index, the National Institutes of Health/International RLS Study Group (IRLSSG) consensus questionnaire, and the IRLSSG severity scale for RLS (IRLS) to 5,528 eligible adult residents in the town of Daisen in the Tottori prefecture of Japan. Next, we performed telephone interviews to identify subjects with probable RLS. Of the 2,812 subjects (51.1%) who gave complete answers on the IRLSSG questionnaire, 50 (1.8%) were judged as RLS positive. The prevalence of RLS was significantly higher in women than in men, and significantly lower in individuals 60 years of age or older. Multiple logistic regression analysis revealed that the existence of RLS was significantly associated with depression, lowered mental quality of life, and sleep disturbances. The prevalence of RLS in adult Japanese populations may be lower than that reported in Caucasian populations. However, in a group of Japanese subjects, RLS had a significant impact on daytime functioning as well as subjective sleep quality.
(c) 2008 Movement Disorder Society.
Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, Ferini-Strambi L.
Restless legs syndrome prevalence and impact: REST general population study.
Arch Intern Med. 2005 Jun 13;165(11):1286-92. doi: 10.1001/archinte.165.11.1286.
Abstract/Text
BACKGROUND: Restless legs syndrome (RLS), a common sensorimotor disorder, has a wide range of severity from merely annoying to affecting sleep and quality of life severely enough to warrant medical treatment. Previous epidemiological studies, however, have failed to determine the prevalence of those with clinically significant RLS symptoms and to examine the life effects and medical experiences of this group.
METHODS: A total of 16 202 adults (aged >/=18 years) were interviewed using validated diagnostic questions to determine the presence, frequency, and severity of RLS symptoms; respondents reporting RLS symptoms were asked about medical diagnoses and the impact of the disorder and completed the Short Form-36 Health Survey (SF-36). Criteria determined by RLS experts for medically significant RLS (frequency at least twice a week, distress at least moderate) defined "RLS sufferers" as a group most likely to warrant medical treatment.
RESULTS: In all, 15 391 fully completed questionnaires were obtained; in the past year, RLS symptoms of any frequency were reported by 1114 (7.2%). Symptoms occurred at least weekly for 773 respondents (5.0%); they occurred at least 2 times per week and were reported as moderately or severely distressing by 416 (2.7%). Of those 416 (termed RLS sufferers), 337 (81.0%) reported discussing their symptoms with a primary care physician, and only 21 (6.2%) were given a diagnosis of RLS. The SF-36 scores for RLS sufferers were significantly below population norms, matching those of patients with other chronic medical conditions.
CONCLUSION: Clinically significant RLS is common (prevalence, 2.7%), is underdiagnosed, and significantly affects sleep and quality of life.
Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J; Restless Legs Syndrome Diagnosis and Epidemiology workshop at the National Institutes of Health; International Restless Legs Syndrome Study Group.
Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health.
Sleep Med. 2003 Mar;4(2):101-19. doi: 10.1016/s1389-9457(03)00010-8.
Abstract/Text
BACKGROUND: Restless legs syndrome is a common yet frequently undiagnosed sensorimotor disorder. In 1995, the International Restless Legs Syndrome Study Group developed standardized criteria for the diagnosis of restless legs syndrome. Since that time, additional scientific scrutiny and clinical experience have led to a better understanding of the condition. Modification of the criteria is now necessary to better reflect that increased body of knowledge, as well as to clarify slight confusion with the wording of the original criteria.
SETTING: The restless legs syndrome diagnostic criteria and epidemiology workshop at the National Institutes of Health.
PARTICIPANTS: Members of the International Restless Legs Syndrome Study Group and authorities on epidemiology and the design of questionnaires and scales.
OBJECTIVE: To modify the current criteria for the diagnosis of restless legs syndrome, to develop new criteria for the diagnosis of restless legs syndrome in the cognitively impaired elderly and in children, to create standardized criteria for the identification of augmentation, and to establish consistent questions for use in epidemiology studies.
RESULTS: The essential diagnostic criteria for restless legs syndrome were developed and approved by workshop participants and the executive committee of the International Restless Legs Syndrome Study Group. Criteria were also developed and approved for the additional aforementioned groups.
Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW, Zucconi M, Ferri R, Trenkwalder C, Lee HB; International Restless Legs Syndrome Study Group.
Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria--history, rationale, description, and significance.
Sleep Med. 2014 Aug;15(8):860-73. doi: 10.1016/j.sleep.2014.03.025. Epub 2014 May 17.
Abstract/Text
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.
Sun ER, Chen CA, Ho G, Earley CJ, Allen RP.
Iron and the restless legs syndrome.
Sleep. 1998 Jun 15;21(4):371-7.
Abstract/Text
STUDY OBJECTIVES: Using blinded procedures, determine the relation between serum ferritin levels and severity of subjective and objective symptoms of the restless legs syndrome (RLS) for a representative patient sample covering the entire adult age range.
DESIGN: All patient records from the past 4 years were retrospectively reviewed to obtain data from all cases with RLS. All patients were included who had ferritin levels obtained at about the same time as a polysomnogram (PSG), met diagnostic criteria for RLS, and were not on iron or medications that would reduce the RLS symptoms at the time of the PSG.
SETTING: Sleep Disorders Center.
PATIENTS: 27 (18 females, 9 males), aged 29-81 years.
INTERVENTIONS: None.
MEASUREMENTS AND RESULTS: Measurements included clinical ratings of RLS severity and PSG measures of sleep efficiency and periodic limb movements (PLMS) in sleep with and without arousal. Lower ferritin correlated significantly to greater RLS severity and decreased sleep efficiency. All but one patient with severe RLS had ferritin levels < or = 50 mcg/l. Patients with lower ferritin (< or = 50 mcg/l) also showed significantly more PLMS with arousal than did those with higher ferritin, but the PLMS/hour was not significantly related to ferritin. This last finding may be due to inclusion of two 'outliers' or because of severely disturbed sleep of the more severe RLS patients.
CONCLUSIONS: These data are consistent with those from a prior unblinded study and suggest that RLS patients will have fewer symptoms if they have ferritin levels greater than 50 mcg/l.
Earley CJ, Connor JR, Beard JL, Malecki EA, Epstein DK, Allen RP.
Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome.
Neurology. 2000 Apr 25;54(8):1698-700. doi: 10.1212/wnl.54.8.1698.
Abstract/Text
CSF and serum were obtained from 16 patients with idiopathic restless legs syndrome (RLS) and 8 age-matched healthy control subjects. Patients with RLS had lower CSF ferritin levels (1. 11 +/- 0.25 ng/mL versus 3.50 +/- 0.55 ng/mL; p = 0.0002) and higher CSF transferrin levels (26.4 +/- 5.1 mg/L versus 6.71 +/- 1.6 mg/L; p = 0.018) compared with control subjects. There was no difference in serum ferritin and transferrin levels between groups. The presence of reduced ferritin and elevated transferrin levels in CSF is indicative of low brain iron in patients with idiopathic RLS.
Summary of Recommendations for the Long-Term Treatment of RLS/WED from an IRLSSG Task Force [Internet]. [cited 2016 Feb 10]. Available from: http://irlssg.org/summary/
Allen RP, Picchietti DL, Auerbach M, Cho YW, Connor JR, Earley CJ, Garcia-Borreguero D, Kotagal S, Manconi M, Ondo W, Ulfberg J, Winkelman JW; International Restless Legs Syndrome Study Group (IRLSSG).
Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report.
Sleep Med. 2018 Jan;41:27-44. doi: 10.1016/j.sleep.2017.11.1126. Epub 2017 Nov 24.
Abstract/Text
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.
Picchietti DL, Bruni O, de Weerd A, Durmer JS, Kotagal S, Owens JA, Simakajornboon N; International Restless Legs Syndrome Study Group (IRLSSG).
Pediatric restless legs syndrome diagnostic criteria: an update by the International Restless Legs Syndrome Study Group.
Sleep Med. 2013 Dec;14(12):1253-9. doi: 10.1016/j.sleep.2013.08.778. Epub 2013 Sep 4.
Abstract/Text
BACKGROUND: Specific diagnostic criteria for pediatric restless legs syndrome (RLS) were published in 2003 following a workshop at the National Institutes of Health. Due to substantial new research and revision of the adult RLS diagnostic criteria, a task force was chosen by the International Restless Legs Syndrome Study Group (IRLSSG) to consider updates to the pediatric diagnostic criteria.
METHODS: A committee of seven pediatric RLS experts developed a set of 15 consensus questions to review, conducted a comprehensive literature search, and extensively discussed potential revisions. The committee recommendations were approved by the IRLSSG executive committee and reviewed by the IRLSSG membership.
RESULTS: The pediatric RLS diagnostic criteria were simplified and integrated with the newly revised adult RLS criteria. Specific recommendations were developed for pediatric application of the criteria, including consideration of typical words used by children to describe their symptoms. Pediatric aspects of differential diagnosis, comorbidity, and clinical significance were then defined. In addition, the research criteria for probable and possible pediatric RLS were updated and criteria for a related condition, periodic limb movement disorder (PLMD), were clarified.
CONCLUSIONS: Revised diagnostic criteria for pediatric RLS have been developed, which are intended to improve clinical practice and promote further research.
Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.
Hening WA, Allen RP, Washburn M, Lesage SR, Earley CJ.
The four diagnostic criteria for Restless Legs Syndrome are unable to exclude confounding conditions ("mimics").
Sleep Med. 2009 Oct;10(9):976-81. doi: 10.1016/j.sleep.2008.09.015. Epub 2009 Jan 29.
Abstract/Text
BACKGROUND: Epidemiological survey studies have suggested that a large fraction of the adult population, from five to more than 10%, have symptoms of Restless Legs Syndrome (RLS). Recently, however, it has become clear that the positive predictive value of many questionnaire screens for RLS may be fairly low and that many individuals who are identified by these screens have other conditions that can "mimic" the features of RLS by satisfying the four diagnostic criteria. We noted the presence of such confounders in a case-control family study and sought to develop methods to differentiate them from true RLS.
METHODS: Family members from the case-control study were interviewed blindly by an RLS expert using the validated Hopkins telephone diagnostic interview (HTDI). Besides questions on the four key diagnostic features of RLS, the HTDI contains open-ended questions on symptom quality and relief strategies and other questions to probe the character of provocative situations and modes of relief. Based on the entire HDTI, a diagnosis of definite, probable or possible RLS or Not-RLS was made.
RESULTS: Out of 1255 family members contacted, we diagnosed 1232: 402 (32.0%) had definite or probable RLS, 42 (3.3%) possible RLS, and 788 (62.8%) Not-RLS. Of the 788 family members who were determined not to have RLS, 126 could satisfy all four diagnostic criteria (16%). This finding indicates that the specificity of the four criteria was only 84%. Those with mimic conditions were found to have atypical presentations whose features could be used to assist in final diagnosis.
CONCLUSION: A variety of conditions, including cramps, positional discomfort, and local leg pathology can satisfy all four diagnostic criteria for RLS and thereby "mimic" RLS by satisfying the four diagnostic criteria. Definitive diagnosis of RLS, therefore, requires exclusion of these other conditions, which may be more common in the population than true RLS. Short of an extended clinical interview and workup, certain features of presentation help differentiate mimics from true RLS.
Ferini-Strambi L, Walters AS, Sica D.
The relationship among restless legs syndrome (Willis-Ekbom Disease), hypertension, cardiovascular disease, and cerebrovascular disease.
J Neurol. 2014 Jun;261(6):1051-68. doi: 10.1007/s00415-013-7065-1. Epub 2013 Aug 21.
Abstract/Text
Untreated sleep disorders may contribute to secondary causes of uncontrolled hypertension, cardiovascular disease (CVD), and stroke. Restless legs syndrome, or Willis-Ekbom Disease (RLS/WED), is a common sensorimotor disorder with a circadian rhythmicity defined by an uncontrollable urge to move the legs that worsens during periods of inactivity or at rest in the evening, often resulting in sleep disruptions. Sleep disorders such as insomnia and obstructive sleep apnea (OSA) are established risk factors for increased risk of hypertension and vascular diseases. This literature review outlines the lessons learned from studies demonstrating insomnia and OSA as risk factors for hypertension and vascular diseases to support the epidemiologic and physiologic evidence suggesting a similar increase in hypertension and vascular disease risk due to RLS. Understanding the relationships between RLS and hypertension, CVD, and stroke has important implications for reducing the risks associated with these diseases.
García-Borreguero D, Allen RP, Kohnen R, Högl B, Trenkwalder C, Oertel W, Hening WA, Paulus W, Rye D, Walters A, Winkelmann J, Earley CJ; International Restless Legs Syndrome Study Group.
Diagnostic standards for dopaminergic augmentation of restless legs syndrome: report from a World Association of Sleep Medicine-International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute.
Sleep Med. 2007 Aug;8(5):520-30. doi: 10.1016/j.sleep.2007.03.022. Epub 2007 Jun 1.
Abstract/Text
OBJECTIVES: Augmentation of symptom severity is the main complication of dopaminergic treatment of restless legs syndrome (RLS). The current article reports on the considerations of augmentation that were made during a European Restless Legs Syndrome Study Group (EURLSSG)-sponsored Consensus Conference in April 2006 at the Max Planck Institute (MPI) in Munich, Germany, the conclusions of which were endorsed by the International RLS Study Group (IRLSSG) and the World Association of Sleep Medicine (WASM). The Consensus Conference sought to develop a better understanding of augmentation and generate a better operational definition for its clinical identification.
DESIGN AND METHODS: Current concepts of the pathophysiology, clinical features, and therapy of RLS augmentation were evaluated by subgroups who presented a summary of their findings for general consideration and discussion. Recent data indicating sensitivity and specificity of augmentation features for identification of augmentation were also evaluated. The diagnostic criteria of augmentation developed at the National Institutes of Health (NIH) conference in 2002 were reviewed in light of current data and theoretical understanding of augmentation. The diagnostic value and criteria for each of the accepted features of augmentation were considered by the group. A consensus was then developed for a revised statement of the diagnostic criteria for augmentation.
RESULTS: Five major diagnostic features of augmentation were identified: usual time of RLS symptom onset each day, number of body parts with RLS symptoms, latency to symptoms at rest, severity of the symptoms when they occur, and effects of dopaminergic medication on symptoms. The quantitative data available relating the time of RLS onset and the presence of other features indicated optimal augmentation criteria of either a 4-h advance in usual starting time for RLS symptoms or a combination of the occurrence of other features. A paradoxical response to changes in medication dose also indicates augmentation. Clinical significance of augmentation is defined.
CONCLUSION: The Consensus Conference agreed upon new operational criteria for the clinical diagnosis of RLS augmentation: the MPI diagnostic criteria for augmentation. Areas needing further consideration for validating these criteria and for understanding the underlying biology of RLS augmentation are indicated.
Garcia-Borreguero D, Silber MH, Winkelman JW, Högl B, Bainbridge J, Buchfuhrer M, Hadjigeorgiou G, Inoue Y, Manconi M, Oertel W, Ondo W, Winkelmann J, Allen RP.
Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation.
Sleep Med. 2016 May;21:1-11. doi: 10.1016/j.sleep.2016.01.017. Epub 2016 Feb 23.
Abstract/Text
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.
Guilleminault C, Cetel M, Philip P.
Dopaminergic treatment of restless legs and rebound phenomenon.
Neurology. 1993 Feb;43(2):445. doi: 10.1212/wnl.43.2.445.
Abstract/Text
Comella CL.
Restless legs syndrome: treatment with dopaminergic agents.
Neurology. 2002 Feb 26;58(4 Suppl 1):S87-92. doi: 10.1212/wnl.58.suppl_1.s87.
Abstract/Text
Restless legs syndrome (RLS) is a common neurologic disorder that affects 5 to 10% of the population and increases in prevalence with aging. The clinical hallmarks of RLS include dysesthesias or paresthesias in the legs and sometimes the arms, occurring primarily at rest, which are usually worse in the evening and are alleviated by movement. RLS can be a disabling disorder, causing sleep disturbance at night and excessive sleepiness during the day. Although treatment with levodopa alleviates symptoms, many RLS patients develop rebound (occurrence of symptoms during the night) or augmentation (occurrence of symptoms before levodopa dosing in the evening). Augmentation occurs in up to 82% of patients treated with levodopa, limiting the long-term usefulness of this agent. The direct dopamine receptor agonists are long-acting drugs often administered as a single dose at bedtime. Among these agents, pergolide, pramipexole, ropinirole, and cabergoline have all been shown to alleviate RLS symptoms in 70 to 100% of patients. The most common adverse effect is nausea. Augmentation, although it may be associated with chronic agonist use, is usually mild and responsive to additional dosing. The direct dopamine receptor agonists have largely replaced levodopa as the most effective treatment for RLS.
Winkelmann J, Allen RP, Högl B, Inoue Y, Oertel W, Salminen AV, Winkelman JW, Trenkwalder C, Sampaio C.
Treatment of restless legs syndrome: Evidence-based review and implications for clinical practice (Revised 2017)§.
Mov Disord. 2018 Jul;33(7):1077-1091. doi: 10.1002/mds.27260. Epub 2018 May 14.
Abstract/Text
The objective of the current review was to update the previous evidence-based medicine review of treatments for restless legs syndrome published in 2008. All randomized, controlled trials (level I) with a high quality score published between January 2007 and January 2017 were reviewed. Forty new studies qualified for efficacy review. Pregabalin, gabapentin enacarbil, and oxycodone/naloxone, which did not appear in the previous review, have accrued data to be considered efficacious. Likewise, new data enable the modification of the level of efficacy for rotigotine from likely efficacious to efficacious. Intravenous ferric carboxymaltose and pneumatic compression devices are considered likely efficacious in idiopathic restless legs syndrome. Bupropion and clonidine were reviewed, but the lack of data determined a rating of insufficient evidence for efficacy. The following interventions continue to be considered efficacious as in 2008: levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin. Bromocriptine, oxycodone, carbamazepine, and valproic acid are considered likely efficacious. Oral iron is nonefficacious in iron-sufficient subjects, but its benefit for patients with low peripheral iron status has not been adequately evaluated. Restless legs syndrome augmentation has been identified as a significant long-term treatment complication for pramipexole more than pregabalin and possibly for all dopaminergic agents more than α2δ ligands. Therefore, special monitoring for augmentation is required for all dopaminergic medications as well as tramadol. Other drugs also require special safety monitoring: cabergoline, pergolide, oxycodone, methadone, tramadol, carbamazepine, and valproic acid. Finally, we also highlighted gaps and needs for future clinical research and studies of restless legs syndrome. © 2018 International Parkinson and Movement Disorder Society.
© 2018 International Parkinson and Movement Disorder Society.
Winkelman JW, Armstrong MJ, Allen RP, Chaudhuri KR, Ondo W, Trenkwalder C, Zee PC, Gronseth GS, Gloss D, Zesiewicz T.
Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.
Neurology. 2016 Dec 13;87(24):2585-2593. doi: 10.1212/WNL.0000000000003388. Epub 2016 Nov 16.
Abstract/Text
OBJECTIVE: To make evidence-based recommendations regarding restless legs syndrome (RLS) management in adults.
METHODS: Articles were classified per the 2004 American Academy of Neurology evidence rating scheme. Recommendations were tied to evidence strength.
RESULTS AND RECOMMENDATIONS: In moderate to severe primary RLS, clinicians should consider prescribing medication to reduce RLS symptoms. Strong evidence supports pramipexole, rotigotine, cabergoline, and gabapentin enacarbil use (Level A); moderate evidence supports ropinirole, pregabalin, and IV ferric carboxymaltose use (Level B). Clinicians may consider prescribing levodopa (Level C). Few head-to-head comparisons exist to suggest agents preferentially. Cabergoline is rarely used (cardiac valvulopathy risks). Augmentation risks with dopaminergic agents should be considered. When treating periodic limb movements of sleep, clinicians should consider prescribing ropinirole (Level A) or pramipexole, rotigotine, cabergoline, or pregabalin (Level B). For subjective sleep measures, clinicians should consider prescribing cabergoline or gabapentin enacarbil (Level A), or ropinirole, pramipexole, rotigotine, or pregabalin (Level B). For patients failing other treatments for RLS symptoms, clinicians may consider prescribing prolonged-release oxycodone/naloxone where available (Level C). In patients with RLS with ferritin ≤75 μg/L, clinicians should consider prescribing ferrous sulfate with vitamin C (Level B). When nonpharmacologic approaches are desired, clinicians should consider prescribing pneumatic compression (Level B) and may consider prescribing near-infrared spectroscopy or transcranial magnetic stimulation (Level C). Clinicians may consider prescribing vibrating pads to improve subjective sleep (Level C). In patients on hemodialysis with secondary RLS, clinicians should consider prescribing vitamin C and E supplementation (Level B) and may consider prescribing ropinirole, levodopa, or exercise (Level C).
© 2016 American Academy of Neurology.
Allen RP, Adler CH, Du W, Butcher A, Bregman DB, Earley CJ.
Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multi-centred, placebo-controlled preliminary clinical trial.
Sleep Med. 2011 Oct;12(9):906-13. doi: 10.1016/j.sleep.2011.06.009. Epub 2011 Oct 5.
Abstract/Text
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.
Manconi M, Garcia-Borreguero D, Schormair B, Videnovic A, Berger K, Ferri R, Dauvilliers Y.
Restless legs syndrome.
Nat Rev Dis Primers. 2021 Nov 3;7(1):80. doi: 10.1038/s41572-021-00311-z. Epub 2021 Nov 3.
Abstract/Text
Restless legs syndrome (RLS) is a common sensorimotor disorder characterized by an urge to move that appears during rest or is exacerbated by rest, that occurs in the evening or night and that disappears during movement or is improved by movement. Symptoms vary considerably in age at onset, frequency and severity, with severe forms affecting sleep, quality of life and mood. Patients with RLS often display periodic leg movements during sleep or resting wakefulness. RLS is considered to be a complex condition in which predisposing genetic factors, environmental factors and comorbidities contribute to the expression of the disorder. RLS occurs alone or with comorbidities, for example, iron deficiency and kidney disease, but also with cardiovascular diseases, diabetes mellitus and neurological, rheumatological and respiratory disorders. The pathophysiology is still unclear, with the involvement of brain iron deficiency, dysfunction in the dopaminergic and nociceptive systems and altered adenosine and glutamatergic pathways as hypotheses being investigated. RLS is poorly recognized by physicians and it is accordingly often incorrectly diagnosed and managed. Treatment guidelines recommend initiation of therapy with low doses of dopamine agonists or α2δ ligands in severe forms. Although dopaminergic treatment is initially highly effective, its long-term use can result in a serious worsening of symptoms known as augmentation. Other treatments include opioids and iron preparations.
© 2021. Springer Nature Limited.
Silber MH, Buchfuhrer MJ, Earley CJ, Koo BB, Manconi M, Winkelman JW; Scientific and Medical Advisory Board of the Restless Legs Syndrome Foundation.
The Management of Restless Legs Syndrome: An Updated Algorithm.
Mayo Clin Proc. 2021 Jul;96(7):1921-1937. doi: 10.1016/j.mayocp.2020.12.026.
Abstract/Text
Restless legs syndrome (RLS) is a common disorder. The population prevalence is 1.5% to 2.7% in a subgroup of patients having more severe RLS with symptoms occurring 2 or more times a week and causing at least moderate distress. It is important for primary care physicians to be familiar with the disorder and its management. Much has changed in the management of RLS since our previous revised algorithm was published in 2013. This updated algorithm was written by members of the Scientific and Medical Advisory Board of the RLS Foundation based on scientific evidence and expert opinion. A literature search was performed using PubMed identifying all articles on RLS from 2012 to 2020. The management of RLS is considered under the following headings: General Considerations; Intermittent RLS; Chronic Persistent RLS; Refractory RLS; Special Circumstances; and Alternative, Investigative, and Potential Future Therapies. Nonpharmacologic approaches, including mental alerting activities, avoidance of substances or medications that may exacerbate RLS, and oral and intravenous iron supplementation, are outlined. The choice of an alpha2-delta ligand as first-line therapy for chronic persistent RLS with dopamine agonists as a second-line option is explained. We discuss the available drugs, the factors determining which to use, and their adverse effects. We define refractory RLS and describe management approaches, including combination therapy and the use of high-potency opioids. Treatment of RLS in pregnancy and childhood is discussed.
Copyright © 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
Garcia-Borreguero D, Ferini-Strambi L, Kohnen R, O'Keeffe S, Trenkwalder C, Högl B, Benes H, Jennum P, Partinen M, Fer D, Montagna P, Bassetti CL, Iranzo A, Sonka K, Williams AM; European Federation of Neurological Societies; European Neurological Society; European Sleep Research Society.
European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society.
Eur J Neurol. 2012 Nov;19(11):1385-96. doi: 10.1111/j.1468-1331.2012.03853.x. Epub 2012 Sep 3.
Abstract/Text
BACKGROUND: Since the publication of the first European Federation of Neurological Societies (EFNS) guidelines in 2005 on the management of restless legs syndrome (RLS; also known as Willis-Ekbom disease), there have been major therapeutic advances in the field. Furthermore, the management of RLS is now a part of routine neurological practice in Europe. New drugs have also become available, and further randomized controlled trials have been undertaken. These guidelines were undertaken by the EFNS in collaboration with the European Neurological Society and the European Sleep Research Society.
OBJECTIVES: To provide an evidence-based update of new treatments published since 2005 for the management of RLS.
METHODS: First, we determined what the objectives of management of primary and secondary RLS should be. We developed the search strategy and conducted a review of the scientific literature up to 31 December 2011 (print and electronic publications) for the drug classes and interventions employed in RLS treatment. Previous guidelines were consulted. All trials were analysed according to class of evidence, and recommendations made according to the 2004 EFNS criteria for rating.
RECOMMENDATIONS: Level A recommendations can be made for rotigotine, ropinirole, pramipexole, gabapentin enacarbil, gabapentin and pregabalin, which are all considered effective for the short-term treatment for RLS. However, for the long-term treatment for RLS, rotigotine is considered effective, gabapentin enacarbil is probably effective, and ropinirole, pramipexole and gabapentin are considered possibly effective. Cabergoline has according to our criteria a level A recommendation, but the taskforce cannot recommend this drug because of its serious adverse events.
© 2012 The Author(s) European Journal of Neurology © 2012 EFNS.
Allen RP, Earley CJ.
Augmentation of the restless legs syndrome with carbidopa/levodopa.
Sleep. 1996 Apr;19(3):205-13. doi: 10.1093/sleep/19.3.205.
Abstract/Text
Dopaminergic agents and carbidopa/levodopa have become the preferred treatment for both the restless legs (RL) syndrome and for periodic limb movements in sleep (PLMS). For once-nightly treatments with carbidopa/ levodopa, a problem with morning end-of-dose rebound increases in leg movements has been reported to occur in the about one-fourth of the patients. In our clinical studies a previously unreported but far more significant problem of markedly augmented RL symptoms occurred in the afternoon and the evening prior to taking the next nightly dose. A systematic prospective evaluation of this augmentation in 46 consecutive patients treated with carbidopa/ levodopa for RL syndrome or PLMS disorder found this augmentation to be the major adverse effect of treatment. Augmentation occurred for 31% of PLMS patients and 82% of all RL patients. It was greater for subjects with more severe RL symptoms and for patients on higher doses (> or = 50/200 mg carbidopa/levodopa) but was unrelated to gender, age or baseline severity of PLMS. This augmentation was severe enough to require medication change for 50% of the RL patients and 13% of PLMS patients. Augmentation resolved with cessation of the medication and could be minimized by keeping the dose low.
Winkelman JW, Johnston L.
Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome (RLS).
Sleep Med. 2004 Jan;5(1):9-14. doi: 10.1016/j.sleep.2003.07.005.
Abstract/Text
BACKGROUND: Dopaminergic agents have become first-line treatments for restless legs syndrome (RLS). The most common serious complications of L-Dopa treatment of RLS are "augmentation", in which RLS symptoms appear earlier during the day, and tolerance, in which medication effectiveness wanes over time. The aims of this study were to assess rates of augmentation and tolerance, and their interrelationship, with pramipexole treatment of RLS.
PATIENTS AND METHODS: Retrospective assessment of all patients (N=59) treated for RLS with pramipexole for at least 6 months (mean duration=21.2+/-11.4 months) by the senior author. Pramipexole dosing and clinical follow-up were performed in a standardized fashion. L-Dopa was discontinued and other medications for RLS were tapered as tolerated. Rates of augmentation (need for earlier administration of the same dose of pramipexole) and tolerance (need for an increase in pramipexole dose) were determined.
RESULTS: Augmentation developed in 32% (19/59), and tolerance occurred in 46% (27/59), of patients. These two complications were statistically related (P<0.05). The only clinical predictors of these complications were previous augmentation or tolerance to L-Dopa.
CONCLUSIONS: Augmentation and tolerance are more common with extended pramipexole treatment of RLS than has been previously reported in preliminary studies. However, these complications are generally manageable by earlier dosing or small dose increases of this agent, and only rarely require medication discontinuation.
Silver N, Allen RP, Senerth J, Earley CJ.
A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome.
Sleep Med. 2011 May;12(5):440-4. doi: 10.1016/j.sleep.2010.11.002. Epub 2011 Jan 15.
Abstract/Text
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.
Inoue Y, Hirata K, Hayashida K, Hattori N, Tomida T, Garcia-Borreguero D; Rotigotine Study Group.
Efficacy, safety and risk of augmentation of rotigotine for treating restless legs syndrome.
Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jan 10;40:326-33. doi: 10.1016/j.pnpbp.2012.10.012. Epub 2012 Oct 25.
Abstract/Text
The present study aimed to examine the long-term efficacy and safety of rotigotine treatment for restless legs syndrome (RLS), as well as the rate of clinically significant augmentation, in a 1-year open-label study of Japanese subjects. Japanese patients with RLS who had been treated with rotigotine or placebo in a double-blind trial were enrolled in a 1-year, open-label, uncontrolled extension study and treated with rotigotine at a dose of up to 3 mg/24 h after an 8-week titration phase. Outcomes included International Restless Legs Syndrome Study Group rating scale (IRLS scale), Pittsburgh Sleep Quality Index (PSQI), safety, and investigator-/expert panel-assessed augmentation (including Augmentation Severity Rating Scale). Overall, 185 patients entered the open-label study and 133 completed the study. IRLS and PSQI total scores improved throughout the 52-week treatment period (IRLS, from 23.2±5.1 to 7.8±7.6 and PSQI, from 8.0±3.1 to 5.0±2.9). Treatment-emergent adverse events were mild to moderate in severity, and included application site reactions (52.4%) and nausea (28.6%). Clinically significant augmentation occurred in five patients (2.7%). These results indicate a good long-term efficacy of rotigotine for treating RLS, with a relatively low risk of clinically significant augmentation.
Copyright © 2012 Elsevier Inc. All rights reserved.
Beneš H, García-Borreguero D, Ferini-Strambi L, Schollmayer E, Fichtner A, Kohnen R.
Augmentation in the treatment of restless legs syndrome with transdermal rotigotine.
Sleep Med. 2012 Jun;13(6):589-97. doi: 10.1016/j.sleep.2011.09.016. Epub 2012 Apr 13.
Abstract/Text
OBJECTIVE: To assess the risk of augmentation under treatment with the transdermally delivered dopamine agonist rotigotine for restless legs syndrome (RLS).
METHODS: Experts in RLS augmentation retrospectively reviewed data from two double-blind, placebo-controlled 6-month trials (745 rotigotine and 214 placebo subjects, NCT00136045 and NCT00135993) and from two open-label 1-year trials (620 rotigotine subjects, NCT00498108 and NCT00263068). All study visits were systematically evaluated applying the Max Planck Institute (MPI) criteria for the diagnosis of both augmentation and clinically relevant augmentation.
RESULTS: MPI criteria for augmentation were met on at least one visit by 8.2% of all subjects in the double-blind trials with 12 subjects meeting the criteria for clinically relevant augmentation: 11 under rotigotine (1.5%) and one under placebo treatment. In the open-label trials, 9.7% of all subjects met the MPI criteria for augmentation and 2.9% met the criteria for clinically relevant augmentation. None of the patients treated with rotigotine for up to 1.5 years (double-blind plus open-label trial) discontinued prematurely owing to augmentation. Neither could dose-dependency or a time pattern for clinically relevant augmentation episodes be detected.
CONCLUSIONS: Our analyses suggest that the risk for clinically relevant augmentation for the duration of up to 18 months of rotigotine treatment is low.
Copyright © 2012 Elsevier B.V. All rights reserved.
Oertel W, Trenkwalder C, Beneš H, Ferini-Strambi L, Högl B, Poewe W, Stiasny-Kolster K, Fichtner A, Schollmayer E, Kohnen R, García-Borreguero D; SP710 study group.
Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label extension study.
Lancet Neurol. 2011 Aug;10(8):710-20. doi: 10.1016/S1474-4422(11)70127-2. Epub 2011 Jun 24.
Abstract/Text
BACKGROUND: Safety and efficacy of non-ergot dopamine agonists for the treatment of idiopathic restless legs syndrome have been shown in short-term trials. We did a prospective open-label extension of a 6-week, double-blind randomised trial to assess the safety, tolerability, and efficacy of rotigotine transdermal patch for up to 5 years in patients with restless legs syndrome.
METHODS: Patients (aged 18-75 years) with moderate-to-severe idiopathic restless legs syndrome were treated with once-daily rotigotine transdermal patch in 33 centres in Austria, Germany, and Spain between July 31, 2003, and April 15, 2009. The dose was titrated in weekly increments (up to 4 weeks) from 0·5 mg/24 h to a maximum of 4 mg/24 h, and was followed by up to 5 years of maintenance at the optimum dose. Primary safety outcomes included occurrence of adverse events and dropouts. Efficacy assessments were secondary and included the International Restless Legs Syndrome study group severity rating scale (IRLS). Augmentation of symptoms was assessed by means of standard diagnostic criteria and was confirmed by an international expert panel. All patients who received at least one dose of study drug were included in assessments. This study is registered with ClinicalTrials.gov, number NCT00498186.
FINDINGS: 295 patients entered the open-label study, of whom 126 (43%) completed 5 years of follow-up. 169 (57%) patients discontinued treatment, 89 (30%) because of adverse events and 31 (11%) because of lack of efficacy. 70 patients (24%) discontinued during year 1 of maintenance. The most common adverse events were application site reactions, which occurred in 37% (106/290) of patients in year 1, 17% (38/220) of patients in year 2, 14% (27/191) of patients in year 3, and in less than 6% of patients during year 4 (8/159) and year 5 (8/147). 56 patients (19%) discontinued because of application site reactions. Mean rotigotine dose was 2·43 mg/24 h (SD 1·21) after initial titration and 3·09 mg/24 h (1·07) at the end of maintenance. Of 89 patients who discontinued because of adverse events, 28 (31%) were on 4 mg/24 h rotigotine. Mean IRLS score of patients entering the open-label study was 27·8 (SD 5·9) at baseline of the double-blind trial. In patients who completed the maintenance period, mean IRLS score was reduced from a baseline score of 27·7 (SD 6·0) by a mean of 18·7 points (SD 9·5) to a score of 9·0 (SD 9·2) at the end of maintenance. 39% (48/123) of patients who completed the trial were classified as symptom free according to the IRLS. Clinically significant augmentation was recorded in 39 patients (13%), of whom 15 (5%) were receiving a dose of rotigotine within the range approved by the European Medicines Agency (EMA; 1-3 mg/24 h) and 24 (8%) were receiving 4 mg/24 h rotigotine.
INTERPRETATION: Rotigotine transdermal patch is generally well tolerated after 1 year and provides sustained efficacy for patients with moderate-to-severe restless legs syndrome at a stable dose for up to 5 years. Thus, rotigotine transdermal patch is an appropriate long-term treatment option for moderate-to-severe restless legs syndrome, a disorder that often requires lifelong treatment.
FUNDING: UCB BioSciences, on behalf of Schwarz Pharma, Ireland.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Oertel WH, Stiasny-Kolster K, Bergtholdt B, Hallström Y, Albo J, Leissner L, Schindler T, Koester J, Reess J; Pramipexole RLS Study Group.
Efficacy of pramipexole in restless legs syndrome: a six-week, multicenter, randomized, double-blind study (effect-RLS study).
Mov Disord. 2007 Jan 15;22(2):213-9. doi: 10.1002/mds.21261.
Abstract/Text
We evaluated the efficacy of pramipexole versus placebo in restless legs syndrome (RLS) for 6 weeks. Overall, 345 patients were randomly assigned in a 1:2 ratio to receive either placebo (n = 115) or pramipexole (n = 230) with a starting dose of 0.125 mg/day. The dose was individually optimized according to the Patient Global Impression (PGI) assessment, up to a maximum of 0.75 mg/day. The primary endpoint consisted of two assessments: the change from baseline in the International RLS Study Group Rating Scale (IRLS) and the proportion of patients with Clinical Global Impressions-Improvement (CGI-I) assessments of "much/very much improved" (CGI-I responders) at week 6. Secondary endpoints included PGI and IRLS responder rates. Patient demographics and baseline characteristics were comparable between treatment groups. At baseline, mean IRLS scores were 24.9 (placebo) and 24.7 (pramipexole), representing severely affected patients. After 6 weeks, adjusted mean reductions (+/-SE) in IRLS score were 5.7 (+/-0.9) for placebo (median dose 0.47 mg/day) and 12.3 (+/-0.6) for pramipexole (median dose 0.35 mg/day; P < 0.0001). CGI-I responder rates were 32.5% (placebo) and 62.9% (pramipexole) (P < 0.0001). For all secondary endpoints, pramipexole showed superior results. Pramipexole was well tolerated throughout the study.
(c) 2006 Movement Disorder Society.
Winkelman JW, Sethi KD, Kushida CA, Becker PM, Koester J, Cappola JJ, Reess J.
Efficacy and safety of pramipexole in restless legs syndrome.
Neurology. 2006 Sep 26;67(6):1034-9. doi: 10.1212/01.wnl.0000231513.23919.a1. Epub 2006 Aug 23.
Abstract/Text
OBJECTIVE: To evaluate the efficacy and safety of pramipexole in patients with moderate to severe restless legs syndrome (RLS) METHODS: The authors conducted a 12-week, double-blind, randomized, placebo-controlled trial of fixed doses of pramipexole (0.25, 0.50, and 0.75 mg/day). Patients (N = 344) were up-titrated to their randomized dose over 3 weeks. The primary efficacy endpoints were patient ratings of symptom severity on the International RLS Study Group Rating Scale (IRLS) and clinician ratings of improvement on the Clinical Global Impressions-Improvement (CGI-I) scale. Secondary efficacy endpoints included visual analogue ratings of sleep and quality of life (QOL) RESULTS: By both primary measures, pramipexole was superior to placebo. For IRLS, the adjusted mean (SE) change from baseline to week 12 was -9.3 (1.0) for placebo, -12.8 (1.0) for 0.25 mg/day, -13.8 (1.0) for 0.50 mg/day, and -14.0 (1.0) for 0.75 mg/day (all p < 0.01). Similarly, pramipexole increased the percentage of patients with a CGI-I rating of "very much improved" or "much improved" at the end of the trial (51.2% for placebo and 74.7%, 67.9%, and 72.9% for pramipexole; all p < 0.05). Pramipexole significantly improved ratings of symptom severity, day and night, and also ratings of sleep satisfaction and QOL. Pramipexole was well tolerated: The most frequent adverse events with higher occurrence in the pramipexole group were nausea (19.0% vs 4.7%) and somnolence (10.1% vs 4.7%)
CONCLUSION: As rated by patients and by clinicians, pramipexole was efficacious and safe in reducing the symptoms of restless legs syndrome.
Inoue Y, Hirata K, Kuroda K, Fujita M, Shimizu T, Emura N, Uchimura N, Kagimura T, Sha K, Nozawa T.
Efficacy and safety of pramipexole in Japanese patients with primary restless legs syndrome: A polysomnographic randomized, double-blind, placebo-controlled study.
Sleep Med. 2010 Jan;11(1):11-6. doi: 10.1016/j.sleep.2009.03.009. Epub 2009 Dec 4.
Abstract/Text
OBJECTIVE: To evaluate the efficacy of pramipexole on polysomnographic measures, patient ratings and a clinical rating in Japanese patients with primary restless legs syndrome (RLS).
METHODS: Patients with moderate to severe RLS having periodic limb movements in bed index (PLMI)>or=5 were randomly assigned to receive pramipexole or placebo in a 6-week, double-blind, placebo-controlled study with forced titration from 0.125 to 0.75mg/day. Both polysomnography (PSG) and the suggested immobilization test (SIT) were performed at baseline and 6weeks after starting treatment.
RESULTS: The analysis of covariance of log-transformed PLMI showed that the adjusted means at the end of study were significantly smaller in the pramipexole group than in the placebo group (p=0.0019). In all patients, variables on SIT did not show any differences between the two groups, whereas a significant improvement was shown in the pramipexole group compared with the placebo group for patients with a SIT-PLM index at baseline >or=15. Pramipexole group showed a significant reduction in the International Restless Legs Syndrome Study Group rating scale (IRLS; p=0.0005), a significant improvement in both Patient Global Impression (PGI; p<0.0001) and Clinical Global Impressions (CGI-I; p=0.0488), and a significantly greater mean reduction in the Pittsburgh Sleep Quality Index (PSQI; p=0.0016), when compared with those of placebo group at week 6.
CONCLUSIONS: Pramipexole is highly efficacious in the reduction of PLMI and in the improvement of subjective severity of RLS and subjective sleep disturbance caused by the disorder.
Copyright 2009 Elsevier B.V. All rights reserved.
Stiasny-Kolster K, Kohnen R, Schollmayer E, Möller JC, Oertel WH; Rotigotine Sp 666 Study Group.
Patch application of the dopamine agonist rotigotine to patients with moderate to advanced stages of restless legs syndrome: a double-blind, placebo-controlled pilot study.
Mov Disord. 2004 Dec;19(12):1432-8. doi: 10.1002/mds.20251.
Abstract/Text
Efficacy and safety of the dopamine agonist rotigotine (RTG) was investigated in patients with moderate to severe idiopathic restless legs syndrome (RLS), including daytime symptoms. Three fixed doses of rotigotine (1.125 mg, 2.25 mg, and 4.5 mg) and placebo were applied by patches (size, 2.5 cm2 per 1.125 mg) in a double-blind, randomized, parallel-group, multicenter, 1-week, proof-of-principle trial. The primary efficacy measure was the total score on the International Restless Legs Syndrome Scale (IRLS). Additionally, the RLS-6 scale, the Clinical Global Impressions (CGI), and a sleep diary were used. Of 68 enrolled patients, 63 (mean age, 58+/-; 9 years; 64% women) were randomly assigned. RLS severity improved related to dose by 10.5 (1.125 mg RTG/die; P = 0.41), 12.3 (2.25 mg RTG/die; P = 0.18), and 15.7 points (4.5 mg RTG/die; P < 0.01) on the IRLS compared to placebo (8 points). According to the RLS-6 scales, daytime symptoms significantly improved with all rotigotine doses. The CGI items supported the favorable efficacy of the 4.5-mg dose. Skin tolerability of the patches and systemic side effects were similar between rotigotine and placebo. This pilot study suggests that continuous delivery of rotigotine by means of a patch may provide an effective and well-tolerated treatment of RLS symptoms both during night and day.
2004 Movement Disorder Society.
Hening WA, Allen RP, Ondo WG, Walters AS, Winkelman JW, Becker P, Bogan R, Fry JM, Kudrow DB, Lesh KW, Fichtner A, Schollmayer E; SP792 Study Group.
Rotigotine improves restless legs syndrome: a 6-month randomized, double-blind, placebo-controlled trial in the United States.
Mov Disord. 2010 Aug 15;25(11):1675-83. doi: 10.1002/mds.23157.
Abstract/Text
This randomized, double-blinded, placebo-controlled trial (NCT00135993) assessed efficacy and safety of the dopamine agonist rotigotine in the treatment of idiopathic restless legs syndrome (RLS) over a 6-month maintenance period. A total of 505 eligible participants with moderate to severe RLS (IRLS sum score >or= 15) were randomly assigned to five groups to receive either placebo or rotigotine (0.5, 1, 2, or 3 mg/24 hr) delivered by once-daily transdermal patch (fixed-dose regimen). The two co-primary efficacy parameters decreased from baseline to end of maintenance in IRLS sum score and in clinical global impressions (CGI-1) score. On both primary measures, 2 and 3 mg/24 hr rotigotine was superior to placebo (P < 0.001). Adjusted treatment differences to placebo for the IRLS sum score were -4.5 (95% CI: -6.9, -2.2) for 2 mg/24 hr rotigotine, -5.2 (95% CI: -7.5, -2.9) for 3 mg/24 hr rotigotine, and for CGI item 1 -0.65 (95% CI: -1.0, -0.3) and -0.9 (95% CI: -1.3, -0.5) for the 2 and 3 mg/24 hr doses, respectively. Skin reactions (27%) and known dopaminergic side effects such as nausea (18.1%) and headache (11.6%) were mostly mild or moderate in rotigotine subjects. Rotigotine transdermal patches releasing 2 to 3 mg/24 hr significantly reduced the severity of RLS symptoms. Treatment efficacy was maintained throughout the 6-month double-blind period.
Trenkwalder C, Benes H, Poewe W, Oertel WH, Garcia-Borreguero D, de Weerd AW, Ferini-Strambi L, Montagna P, Odin P, Stiasny-Kolster K, Högl B, Chaudhuri KR, Partinen M, Schollmayer E, Kohnen R; SP790 Study Group.
Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial.
Lancet Neurol. 2008 Jul;7(7):595-604. doi: 10.1016/S1474-4422(08)70112-1.
Abstract/Text
BACKGROUND: Continuous administration of a dopamine agonist could be used to treat patients with restless legs syndrome. Our aim was to investigate the efficacy of transdermal rotigotine in the treatment of idiopathic restless legs syndrome.
METHODS: In this randomised, double-blind, placebo-controlled trial, 458 patients with moderate-to-severe idiopathic restless legs syndrome (average baseline International Restless Legs Syndrome Study Group severity rating scale [IRLS] sum score of 28.1) were randomly assigned to receive transdermal rotigotine 1 mg over 24 h (n=115), 2 mg over 24 h (n=112), or 3 mg over 24 h (n=114), or to receive placebo (n=117). Study medication was delivered via patches, applied once a day for 6 months. Randomisation was done with a computer-generated randomisation list, stratified by centre. Primary efficacy outcomes were absolute change from baseline to end of maintenance in IRLS sum score and in the clinical global impressions (CGI) item 1 score, assessed by analysis of covariance in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00136045.
FINDINGS: Efficacy analyses were done on 112 patients in the 1 mg group, 109 in the 2 mg group, 112 in the 3 mg group, and 114 in the placebo group. Mean change in IRLS sum score from baseline at the end of the maintenance phase was -13.7 (SE 0.9) in the 1 mg group, -16.2 (0.9) in the 2 mg group, -16.8 (0.9) in the 3 mg group, and -8.6 (0.9) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Mean change in CGI item 1 score from baseline at the end of the maintenance phase was -2.09 (0.14) in the 1 mg group, -2.41 (0.14) in the 2 mg group, -2.55 (0.14) in the 3 mg group, and -1.34 (0.14) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Skin reactions, mostly mild or moderate, were seen in 145 (43%) of 341 patients who received rotigotine and in two (2%) of 117 who received placebo. Ten patients had serious adverse event that were deemed to be related to rotigotine: elevation of liver enzymes (one patient), worsening of tinnitus (one patient), non-response to anticoagulation (one patient), electrocardiogram changes (one patient), and application-site reactions (six patients). No admissions to hospital were needed for the application-site reactions, and they all resolved within a short time of patch removal without any other therapeutic intervention. The rate of typical dopaminergic side-effects in patients who received rotigotine was low; no signs of augmentation were noted.
INTERPRETATION: 24 h transdermal delivery of low-dose rotigotine could be used to relieve the night-time and daytime symptoms of restless legs syndrome.
FUNDING: Schwarz Biosciences.
Inoue Y, Shimizu T, Hirata K, Uchimura N, Ishigooka J, Oka Y, Ikeda J, Tomida T, Hattori N; Rotigotine Trial Group.
Efficacy and safety of rotigotine in Japanese patients with restless legs syndrome: a phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group study.
Sleep Med. 2013 Nov;14(11):1085-91. doi: 10.1016/j.sleep.2013.07.007. Epub 2013 Aug 21.
Abstract/Text
OBJECTIVE: We aimed to ascertain the efficacy and safety of transdermal rotigotine (2 and 3mg/24h) in Japanese patients with restless legs syndrome (RLS).
METHODS: In our double-blind placebo-controlled study, 284 Japanese patients with idiopathic RLS were randomly assigned to receive rotigotine 2mg/24h or 3mg/24h, or placebo, for 13 weeks. The primary endpoint was the change in International Restless Legs Syndrome Study Group rating scale (IRLS) total score.
RESULTS: The placebo-subtracted decreases in IRLS total score for rotigotine 2 mg/24 h and 3 mg/24 h were -2.8±1.3 and -3.1±1.3, respectively, which were significant (P<0.05). The interaction between baseline Pittsburgh Sleep Quality Index (PSQI) and treatment group for the change in IRLS total score was significant, indicating greater improvements in IRLS total score in patients with severe insomnia. Overall, 80.0%, 86.2%, and 51.6% of patients in the rotigotine 2 mg/24 h, 3 mg/24 h, and placebo groups, respectively, experienced adverse events (AEs) including application site reactions in 42.1%, 50.0%, and 7.4% of patients, respectively. None of the AEs were severe.
CONCLUSIONS: Our results showed that rotigotine was effective without major safety concerns at doses of up to 3 mg/24 h in Japanese patients with RLS.
Copyright © 2013 Elsevier B.V. All rights reserved.
Kushida CA, Becker PM, Ellenbogen AL, Canafax DM, Barrett RW; XP052 Study Group.
Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS.
Neurology. 2009 Feb 3;72(5):439-46. doi: 10.1212/01.wnl.0000341770.91926.cc.
Abstract/Text
OBJECTIVE: To assess the efficacy and tolerability of the nondopaminergic agent XP13512/GSK1838262 in adults with moderate to severe primary restless legs syndrome (RLS).
METHODS: Patient Improvements in Vital Outcomes following Treatment in Restless Legs Syndrome I was a 12-week, multicenter, randomized, double-blind, placebo-controlled trial of XP13512 1,200 mg or placebo taken once daily at 5:00 pm with food. Coprimary endpoints were mean change from baseline International Restless Legs Scale (IRLS) total score and proportion of investigator-rated responders (very much improved or much improved on the Clinical Global Impression-Improvement scale) at week 12 (last observation carried forward). Tolerability was assessed using adverse events, vital signs, and clinical laboratory parameters.
RESULTS: A total of 222 patients were randomized (XP13512 = 114, placebo = 108) and 192 patients (XP13512 = 100, placebo = 92) completed the study. At week 12, the mean change from baseline IRLS total score was greater with XP13512 (-13.2) compared with placebo (-8.8). Analysis of covariance, adjusted for baseline score and pooled site, demonstrated a mean treatment difference of -4.0 (95% confidence interval [CI], -6.2 to -1.9; p = 0.0003). More patients treated with XP13512 (76.1%) were responders compared with placebo (38.9%; adjusted OR 5.1; 95% CI, 2.8 to 9.2; p < 0.0001). Significant treatment effects for both coprimary measures were identified at week 1, the earliest time point measured. The most commonly reported adverse events were somnolence (XP13512 27%, placebo 7%) and dizziness (XP13512 20%, placebo 5%), which were mild to moderate in intensity and generally remitted.
CONCLUSIONS: XP13512 1,200 mg, taken once daily, significantly improved restless legs syndrome (RLS) symptoms compared with placebo and was generally well tolerated in adults with moderate to severe primary RLS.
Bogan RK, Bornemann MA, Kushida CA, Trân PV, Barrett RW; XP060 Study Group.
Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study.
Mayo Clin Proc. 2010 Jun;85(6):512-21. doi: 10.4065/mcp.2009.0700.
Abstract/Text
OBJECTIVE: To assess maintenance of efficacy and tolerability of gabapentin enacarbil in patients with moderate to severe primary restless legs syndrome (RLS).
PATIENTS AND METHODS: This study (conducted April 18, 2006, to November 14, 2007) comprised a 24-week, single-blind (SB) treatment phase (gabapentin enacarbil, 1200 mg) followed by a 12-week randomized, double-blind (DB) phase. Responders from the SB phase (patients with improvements on the International Restless Legs Scale [IRLS] and investigator-rated Clinical Global Impression-Improvement scale at week 24 and stable while taking a gabapentin enacarbil dose of 1200 mg for at least 1 month before randomization) were randomized to gabapentin enacarbil, 1200 mg, or placebo once daily at 5 pm with food. The primary end point was the proportion of patients experiencing relapse (worse scores on the IRLS and investigator-rated Clinical Global Impression of Change scale on 2 consecutive visits at least 1 week apart or withdrawal because of lack of efficacy) during the DB phase.
RESULTS: A total of 221 of 327 patients completed the SB phase, 194 (96 in the gabapentin enacarbil group and 98 in the placebo group) were randomized to DB treatment, and 168 (84 in the gabapentin enacarbil group and 84 in the placebo group) completed the DB phase. A significantly smaller proportion of patients treated with gabapentin enacarbil (9/96 [9%]) experienced relapse compared with the placebo-treated patients (22/97 [23%]) (odds ratio, 0.353; 95% confidence interval, 0.2-0.8; P=.02). Somnolence and dizziness were the most common adverse events. One death occurred (unintentional choking during the SB phase) and was judged as being unrelated to the study drug. No clinically relevant changes were observed in laboratory values, in vital signs, or on electrocardiograms.
CONCLUSION: Gabapentin enacarbil, 1200 mg, maintained improvements in RLS symptoms compared with placebo and showed long-term tolerability in adults with moderate to severe primary RLS for up to 9 months of treatment.
Lee DO, Ziman RB, Perkins AT, Poceta JS, Walters AS, Barrett RW; XP053 Study Group.
A randomized, double-blind, placebo-controlled study to assess the efficacy and tolerability of gabapentin enacarbil in subjects with restless legs syndrome.
J Clin Sleep Med. 2011 Jun 15;7(3):282-92. doi: 10.5664/JCSM.1074.
Abstract/Text
STUDY OBJECTIVE: To evaluate the efficacy and tolerability of gabapentin enacarbil (GEn) 1200 mg or 600 mg compared with placebo in subjects with moderate-to-severe primary restless legs syndrome (RLS).
METHODS: This 12-week, multicenter, double-blind, placebo-controlled study randomized subjects (1:1:1) to GEn 1200 mg, 600 mg, or placebo. Co-primary endpoints: mean change from baseline in International Restless Legs Scale (IRLS) total score and proportion of responders (rated as "very much" or "much" improved) on the investigator-rated Clinical Global Impression-Improvement scale (CGI-I) at Week 12 LOCF for GEn 1200 mg compared with placebo. Secondary endpoints included GEn 600 mg compared with placebo on the IRLS and CGI-I at Week 12 LOCF and subjective measures for sleep. Safety and tolerability assessments included adverse events.
RESULTS: 325 subjects were randomized (GEn 1200 mg = 113; 600 mg = 115; placebo = 97). GEn 1200 mg significantly improved mean [SD] IRLS total score at Week 12 LOCF (baseline: 23.2 [5.32]; Week 12: 10.2 [8.03]) compared with placebo (baseline: 23.8 [4.58]; Week 12: 14.0 [7.87]; adjusted mean treatment difference [AMTD]: -3.5; p = 0.0015), and significantly more GEn 1200 mg-treated (77.5%) than placebo-treated (44.8%) subjects were CGI-I responders (p < 0.0001). Similar significant results were observed with GEn 600 mg for IRLS (AMTD: -4.3; p < 0.0001) and CGI-I (72.8% compared with 44.8%; p < 0.0001). GEn also significantly improved sleep outcomes (Post-Sleep Questionnaire, Pittsburgh Sleep Diary and Medical Outcomes Sleep Scale) compared with placebo. The most commonly reported adverse events were somnolence (GEn 1200 mg = 18.0%; 600 mg = 21.7%; placebo = 2.1%) and dizziness (GEn 1200 mg = 24.3%; 600 mg = 10.4%; placebo = 5.2%). Dizziness increased with increased dose and led to discontinuation in 2 subjects (GEn 1200 mg, n = 1; GEn 600 mg, n = 1). Somnolence led to discontinuation in 3 subjects (GEn 600 mg).
CONCLUSIONS: GEn 1200 mg and 600 mg significantly improve RLS symptoms and sleep disturbance compared with placebo and are generally well tolerated.
Inoue Y, Uchimura N, Kuroda K, Hirata K, Hattori N.
Long-term efficacy and safety of gabapentin enacarbil in Japanese restless legs syndrome patients.
Prog Neuropsychopharmacol Biol Psychiatry. 2012 Mar 30;36(2):251-7. doi: 10.1016/j.pnpbp.2011.10.009. Epub 2011 Oct 19.
Abstract/Text
Several short- and long-term studies conducted in Europe/North America have demonstrated good efficacy and tolerability of 600-1800 mg gabapentin enacarbil (GEn). However, no studies have evaluated the efficacy of long-term treatment with GEn in Asian patients. Therefore, the objective of this study was to evaluate the efficacy and safety of long-term treatment with GEn in Japanese patients with restless legs syndrome (RLS) in a multicenter open-label study. RLS patients aged 20-80 years were allocated to receive oral GEn 1200 mg/day for a treatment period of 52 weeks. International Restless Legs Syndrome Scale (IRLS) score, investigator- and patient-rated Clinical Global Impression (CGI) scores, Pittsburgh Sleep Quality Index (PSQI) total scores and subscores, and short form (SF)-36 subscores were assessed, and adverse events (AEs) were monitored. In 181 patients (mean age, 54.9±12.2 years; BMI, 23.0±2.6 kg/m²) IRLS score decreased from 24.4±0.4 at baseline to 6.3±0.6 at week 52, with a reduction of -18.0±0.6. The IRLS responder rate was 80.3% at week 52. ICGI and PCGI responder rates were 87.1% and 87.1%, respectively. PSQI and SF-36 also showed significant improvements. AEs were reported in 96.2% of patients but remained mild-to-moderate in nearly all the cases. Serious AEs occurred in 1.6%. Dizziness and somnolence were noted in 46.2% and 41.2% of patients, respectively, and mostly occurred during the first 4 weeks. No episodes of augmentation were reported. In conclusion, long-term treatment with GEn improved RLS symptoms as well as investigator- and patient-reported outcomes in Japanese patients with moderate-to-severe RLS, with an acceptable safety profile. Randomized, double-blind, placebo/active-controlled trials are desirable to confirm these preliminary results.
Copyright © 2011 Elsevier Inc. All rights reserved.
Trenkwalder C, Winkelmann J, Inoue Y, Paulus W.
Restless legs syndrome-current therapies and management of augmentation.
Nat Rev Neurol. 2015 Aug;11(8):434-45. doi: 10.1038/nrneurol.2015.122. Epub 2015 Jul 28.
Abstract/Text
Idiopathic restless legs syndrome (RLS) can severely affect quality of life and disturb sleep, so that pharmacological treatment is necessary, especially for elderly patients. Treatment guidelines recommend initiation of therapy with dopamine agonists (pramipexole, ropinirole or the rotigotine transdermal patch, all approved in most countries) or α-2-δ ligands (gabapentin enacarbil, approved in the USA and Japan), depending on the country and availability. Where approved, opioids (prolonged release oxycodone-naloxone, approved in Europe) are also recommended as a second-line therapy for severe RLS. Several iron formulations can be effective but are not yet approved for RLS therapy, whereas benzodiazepines and other anticonvulsants are not recommended or approved. Less is known about effective management of RLS that is associated with other conditions, such as uraemia or pregnancy. Furthermore, very little data are available on the management of RLS when first-line treatment fails or patients experience augmentation. In this Review, we summarize state-of-the-art therapies for RLS in the context of the diagnostic criteria and available guidelines, based on knowledge ranging from Class I evidence for the treatment of idiopathic RLS to Class IV evidence for the treatment of complications such as augmentation. We consider therapies, including combination therapies, that are used in clinical practice for long-term management of RLS, despite a lack of trials and approval, and highlight the need for practical long-term evaluation of current trials.
Allen RP, Chen C, Garcia-Borreguero D, Polo O, DuBrava S, Miceli J, Knapp L, Winkelman JW.
Comparison of pregabalin with pramipexole for restless legs syndrome.
N Engl J Med. 2014 Feb 13;370(7):621-31. doi: 10.1056/NEJMoa1303646.
Abstract/Text
BACKGROUND: Dopaminergic medications relieve symptoms of the restless legs syndrome (RLS) but have the potential to cause iatrogenic worsening (augmentation) of RLS with long-term treatment. Pregabalin may be an effective alternative.
METHODS: In this 52-week, randomized, double-blind trial, we assessed efficacy and augmentation in patients with RLS who were treated with pregabalin as compared with placebo and pramipexole. Patients were randomly assigned to receive 52 weeks of treatment with pregabalin at a dose of 300 mg per day or pramipexole at a dose of 0.25 mg or 0.5 mg per day or 12 weeks of placebo followed by 40 weeks of randomly assigned active treatment. The primary analyses involved a comparison of pregabalin and placebo over a period of 12 weeks with use of the International RLS (IRLS) Study Group Rating Scale (on which the score ranges from 0 to 40, with a higher score indicating more severe symptoms), the Clinical Global Impression of Improvement scale (which was used to assess the proportion of patients with symptoms that were "very much improved" or "much improved"), and a comparison of rates of augmentation with pregabalin and pramipexole over a period of 40 or 52 weeks of treatment.
RESULTS: A total of 719 participants received daily treatment, 182 with 300 mg of pregabalin, 178 with 0.25 mg of pramipexole, 180 with 0.5 mg of pramipexole, and 179 with placebo. Over a period of 12 weeks, the improvement (reduction) in mean scores on the IRLS scale was greater, by 4.5 points, among participants receiving pregabalin than among those receiving placebo (P<0.001), and the proportion of patients with symptoms that were very much improved or much improved was also greater with pregabalin than with placebo (71.4% vs. 46.8%, P<0.001). The rate of augmentation over a period of 40 or 52 weeks was significantly lower with pregabalin than with pramipexole at a dose of 0.5 mg (2.1% vs. 7.7%, P=0.001) but not at a dose of 0.25 mg (2.1% vs. 5.3%, P=0.08). There were six cases of suicidal ideation in the group receiving pregabalin, three in the group receiving 0.25 mg of pramipexole, and two in the group receiving 0.5 mg of pramipexole.
CONCLUSIONS: Pregabalin provided significantly improved treatment outcomes as compared with placebo, and augmentation rates were significantly lower with pregabalin than with 0.5 mg of pramipexole. (Funded by Pfizer; ClinicalTrials.gov number, NCT00806026.).
Inoue Y, Hirata K, Hoshino Y, Yamaguchi Y.
Difference in background factors between responders to gabapentin enacarbil treatment and responders to placebo: pooled analyses of two randomized, double-blind, placebo-controlled studies in Japanese patients with restless legs syndrome.
Sleep Med. 2021 Sep;85:138-146. doi: 10.1016/j.sleep.2021.07.004. Epub 2021 Jul 7.
Abstract/Text
OBJECTIVE: Restless legs syndrome (RLS) is a sensorimotor disorder that is characterized by uncomfortable and unpleasant sensations mainly in the legs. Two placebo-controlled studies (Phase II/III and post-marketing) in Japanese patients with RLS failed to demonstrate the efficacy of gabapentin enacarbil (GE) 600 mg in the change from baseline in International Restless Legs Syndrome Rating Scale (IRLS) score at the end of the treatment period. The high response to placebo is thought to be a possible reason why the post-marketing study failed. The objectives of these post hoc analyses were to determine potential predictive factors associated with improvement in IRLS score with GE treatment and to identify subgroups with higher placebo responses.
METHODS: We combined data from the two Japanese studies and analyzed change from baseline in IRLS score in the pooled population and subgroups defined by several patient characteristics. Moreover, we calculated the variable importance of each factor and performed predictive enrichment analysis to identify an enrichable subpopulation with greater improvement by GE treatment.
RESULTS: The post hoc analyses suggested that higher baseline IRLS score (≥21) and higher body mass index (≥25 kg/m2) were associated with higher placebo responses. On the other hand, positive family history of RLS, prior use of dopaminergic receptor agonists, and higher baseline ferritin level (≥50 ng/mL) were associated with higher responses to GE.
CONCLUSIONS: Our results suggest that patients with typical idiopathic RLS characteristics, including positive family history and no low ferritin level, would be expected to derive the greatest benefits from GE treatment.
Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.
Picchietti DL, Hensley JG, Bainbridge JL, Lee KA, Manconi M, McGregor JA, Silver RM, Trenkwalder C, Walters AS; International Restless Legs Syndrome Study Group (IRLSSG).
Consensus clinical practice guidelines for the diagnosis and treatment of restless legs syndrome/Willis-Ekbom disease during pregnancy and lactation.
Sleep Med Rev. 2015 Aug;22:64-77. doi: 10.1016/j.smrv.2014.10.009. Epub 2014 Nov 4.
Abstract/Text
Restless legs syndrome (RLS)/Willis-Ekbom disease (WED) is common during pregnancy, affecting approximately one in five pregnant women in Western countries. Many report moderate or severe symptoms and negative impact on sleep. There is very little information in the medical literature for practitioners on the management of this condition during pregnancy. Accordingly, a task force was chosen by the International RLS Study Group (IRLSSG) to develop guidelines for the diagnosis and treatment of RLS/WED during pregnancy and lactation. A committee of nine experts in RLS/WED and/or obstetrics developed a set of 12 consensus questions, conducted a literature search, and extensively discussed potential guidelines. Recommendations were approved by the IRLSSG executive committee, reviewed by IRLSSG membership, and approved by the WED Foundation Medical Advisory Board. These guidelines address diagnosis, differential diagnosis, clinical course, and severity assessment of RLS/WED during pregnancy and lactation. Nonpharmacologic approaches, including reassurance, exercise and avoidance of exacerbating factors, are outlined. A rationale for iron supplementation is presented. Medications for RLS/WED are risk/benefit rated for use during pregnancy and lactation. A few are rated "may be considered" when RLS/WED is refractory to more conservative approaches. An algorithm summarizes the recommendations. These guidelines are intended to improve clinical practice and promote further research.
Copyright © 2014. Published by Elsevier Ltd.
Karadeniz D, Ondze B, Besset A, Billiard M.
Are periodic leg movements during sleep (PLMS) responsible for sleep disruption in insomnia patients?
Eur J Neurol. 2000 May;7(3):331-6. doi: 10.1046/j.1468-1331.2000.00070.x.
Abstract/Text
On the basis of polygraphic findings, it has been suggested that periodic leg movements during sleep are not responsible for sleep impairment (Lugaresi et al., 1972). However, for some authors it is an important cause of insomnia (Guilleminault et al., 1975; Coleman, 1982). Thus, the relationship between periodic leg movements during sleep, sleep disruption and the complaint of patients is particularly complex. We investigated the macro- and micro-structure of sleep with and without leg movements in 10 PLMS patients complaining of insomnia to clarify whether periodic leg movements are responsible for sleep disruption. The total sleep time without periodic leg movements was significantly longer than sleep time with leg movements. Sleep time without leg movements was longer than sleep time with leg movements in stage 2, slow wave sleep (SWS) and rapid eye movement (REM) sleep. Short lasting awakenings were significantly more frequent during periodic leg movements associated sleep whilst long lasting awakenings were equally frequent during sleep with and without periodic leg movements. The percentage of the four electroencephalogram (EEG) activities (delta, theta, alpha and spindles) did not show any significant difference between periodic leg movements associated and not associated with sleep stages and total sleep time. The lack of significant differences in both the macro- and micro-structure of sleep and EEG activity content regarding the association with movements confirm the hypothesis that periodic leg movements did not primarily cause sleep disturbance.
Ancoli-Israel S, Kripke DF, Klauber MR, Mason WJ, Fell R, Kaplan O.
Periodic limb movements in sleep in community-dwelling elderly.
Sleep. 1991 Dec;14(6):496-500. doi: 10.1093/sleep/14.6.496.
Abstract/Text
The prevalence of periodic limb movements in sleep (PLMS) in a randomly selected elderly sample is reported. In San Diego, 427 elderly volunteers aged 65 yr and over were recorded in their homes. Forty-five percent had a myoclonus index, MI greater than or equal to 5. Correlates of PLMS included dissatisfaction with sleep, sleeping alone and reported kicking at night. Although statistically significant, the strengths of the associations between interview variables and myoclonus indices were all small. No combination of demographic variables and symptoms allowed highly reliable prediction of PLMS.
Ancoli-Israel S, Kripke DF, Mason W, Kaplan OJ.
Sleep apnea and periodic movements in an aging sample.
J Gerontol. 1985 Jul;40(4):419-25. doi: 10.1093/geronj/40.4.419.
Abstract/Text
Individuals 65 years of age and older were randomly selected, from a primarily white upper-class population, to participate in a study of sleep disorders in elderly adults. One hundred forty-five volunteers had a brief telephone interview, a home interview, and a portable sleep recording using the Medilog and Respitrace systems. By research classifications, we found that 18% of the elderly participants had sleep apnea (apnea index greater than 5), 34% had periodic movements in sleep (myoclonus index greater than 5) (PMS), and 10% had both sleep apnea and PMS. These were not clinical diagnoses. The home recording indicated that the individuals with PMS slept significantly less than other older adults.
Guilleminault C, Billiard M, Montplaisir J, Dement WC.
Altered states of consciousness in disorders of daytime sleepiness.
J Neurol Sci. 1975 Nov;26(3):377-93. doi: 10.1016/0022-510x(75)90209-9.
Abstract/Text
Patients with daytime sleepiness present altered states of consciousness. The occurrence of these states impairs their professional, social and familial activities and may threaten life itself. The automatic behavior syndrome is characterized by continuation of mechanical activity and complete amnesia. Episodes lasting from a few seconds to several hours are correlated with repetitive micro-sleep periods. During cataplectic attacks, patients may have a meshing of reality with hallucinatory dream contents. Sleep-induced apnea may lead to abnormal movement and abnormal ambulation during sleep as well as hallucinations in the early morning. These altered states of consciousness must be considered as diagnostic indexes in differentiating epileptic syndromes from syndromes of daytime sleepiness.
Montplaisir J, Boucher S, Poirier G, Lavigne G, Lapierre O, Lespérance P.
Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria.
Mov Disord. 1997 Jan;12(1):61-5. doi: 10.1002/mds.870120111.
Abstract/Text
One hundred thirty-three cases of restless legs syndrome (RLS), diagnosed with criteria recently formulated by an international study group, were studied by questionnaire and with all-night polysomnographic recordings. Results show that RLS starts at a mean age of 27.2 years and before age 20 in 38.3% of patients. Symptoms often appear in one leg only and also involve upper limbs in about half of all cases. Most patients (94%) report sleep-onset insomnia or numerous nocturnal awakenings due to RLS symptoms. A strong relationship was found between these complaints and polysomnographic findings; increasing sleep latency and number of awakenings and decreasing sleep efficiency were associated with worsening symptoms. Periodic leg movements in sleep (index > 5 movements/h sleep) were found in 80.2% of patients. This study shows that this percentage is increased when 2 recording nights are considered (most severe score). Eighty patients of 127 (63%) reported the presence of RLS in at least one of their first-degree relatives. In these families, 221 of 568 first-degree relatives (39%) were reported by the patients to be affected with RLS.
American Academy of Sleep Medicine.International Classification of Sleep Disorders.3rd ed. Darien,IL:American Academy of Sleep Medicine;2014.
Berry RB, Brooks R, Gamaldo CE, et al. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications, version 2.0, American Academy of Sleep Medicine, Darien, IL 2012.
