Idiopathic Restless Legs Syndrome Research Articles

A randomized double-blind pilot study to evaluate the efficacy, safety, and tolerability of intravenous iron versus oral iron for the treatment of restless legs syndrome in patients with iron deficiency anemia.

Restless legs syndrome (RLS) is a neurological disorder that can have a profound effect on sleep and quality of life. Idiopathic RLS is associated with brain iron insufficiency despite normal peripheral iron stores. There is, however, a five- to six-fold increase in prevalence of RLS in patients with iron deficiency anemia (IDA). Several open-label trials have demonstrated symptomatic improvement in RLS following treatment of IDA using oral or intravenous iron supplementation. To date, there have been no randomized double-blind controlled trials of intravenous iron compared with oral iron for the treatment of RLS patients with IDA. In the current study, oral ferrous sulfate and ferumoxytol were compared for efficacy and speed of response for treatment of RLS occurring in patients with IDA. The planned recruitment for this study was 70 patients with RLS and IDA, to be randomly assigned 1:1 to oral or intravenous iron, using double-blind, double-dummy procedures. At Week 6, the primary outcomes of Clinical Global Impression-Improvement score and change from baseline in the International Restless Legs Syndrome Study Group rating scale score were assessed. Due to challenges, performing the clinical trial during the COVID-19 pandemic, final-week data were found missing for 30 patients. As a result, in order to maintain the prespecified statistical analysis, an additional 30 patients were recruited. Both IV and oral iron were associated with a marked improvement in RLS symptoms, with no statistically significant difference between treatment groups. No serious adverse events were observed in either treatment group.

White matter microstructure alterations in idiopathic restless legs syndrome: a study combining crossing fiber-based and tensor-based approaches.

Restless legs syndrome (RLS) is a common sensorimotor disorder characterized by an irrepressible urge to move the legs and frequently accompanied by unpleasant sensations in the legs. The pathophysiological mechanisms underlying RLS remain unclear, and RLS is hypothesized to be associated with alterations in white matter tracts. Diffusion MRI is a unique noninvasive method widely used to study white matter tracts in the human brain. Thus, diffusion-weighted images were acquired from 18 idiopathic RLS patients and 31 age- and sex-matched healthy controls (HCs). Whole brain tract-based spatial statistics (TBSS) and atlas-based analyzes combining crossing fiber-based metrics and tensor-based metrics were performed to investigate the white matter patterns in individuals with RLS. TBSS analysis revealed significantly higher fractional anisotropy (FA) and partial volume fraction of primary (F1) fiber populations in multiple tracts associated with the sensorimotor network in patients with RLS than in HCs. In the atlas based analysis, the bilateral anterior thalamus radiation, bilateral corticospinal tract, bilateral inferior fronto-occipital fasciculus, left hippocampal cingulum, left inferior longitudinal fasciculus, and left uncinate fasciculus showed significantl increased F1, but only the left hippocampal cingulum showed significantly higher FA. The results demonstrated that F1 identified extensive alterations in white matter tracts compared with FA and confirmed the hypothesis that crossing fiber-based metrics are more sensitive than tensor-based metrics in detecting white matter abnormalities in RLS. The present findings provide evidence that the increased F1 metric observed in sensorimotor tracts may be a critical neural substrate of RLS, enhancing our understanding of the underlying pathological changes.

Evaluation of the relationship between idiopathic restless legs syndrome and serum hepcidin levels.

The relationship between restless legs syndrome (RLS) and iron deficiency is a well-known topic. However, the etiology of the disease has not been determined. As the central iron deficiency is the most critical biological abnormality for RLS, we planned a study examining the relationship between RLS and hepcidin, which is the only regulatory hormone of iron metabolism known so far. International Restless Legs Syndrome Study Group diagnostic criteria (2014) were taken as a basis. A total of 40 RLS patients and 40 healthy controls were included in the study. To avoid the potential variables that might cause secondary RLS, all the participants were asked to provide hemogram, ferritin, iron, thyroid function tests, and sedimentation analysis. The hepcidin levels were measured with a Human Hepcidin (Hepc 25) ELISA kit (MyBioSource). The statistically significant results of our analysis show that the red blood cell count, the neutrophil count, the percentage of lymphocytes and neutrophils, and, more distinctively, hepcidin levels were higher in RLS patients in comparison with the control group. In this study, no differences were found in iron and ferritin values. High levels of hepcidin, the main regulator of iron metabolism, in those with primary RLS support the possibility that hepcidin may play a role in the pathogenesis of RLS. We think that larger studies on this subject can give clearer ideas.

Incident mental health episodes after initiation of gabapentinoids vs. dopamine agonists for early-onset idiopathic restless legs syndrome

Limited long-term safety information exists for gabapentinoid treatment of idiopathic restless legs syndrome (RLS). We estimated incident mental health-related emergency department visits and hospitalizations with a primary mental health diagnosis (primary outcome) among early-onset idiopathic RLS patients following first-line treatment initiation and examined outcome risk with gabapentinoids compared with dopamine agonists (DAs). A retrospective cohort study was conducted using administrative claims data from 2012 to 2019. Adults with early-onset (18–44 years) idiopathic RLS initiating either gabapentinoids or DAs within 60 days of new diagnosis were followed up to two years. Incidence rates were calculated and a log-binomial regression model with propensity score weighting estimated relative risk of the outcome and of substance use disorders (SUDs) as a secondary analysis with gabapentinoids. Among a cohort of 6,672 patients, 4,986 (74.7%) initiated DAs and 1,686 (25.3%) gabapentinoids. Incidence of the primary outcome (49.8 [95% CI 40.8–69.3] per 1,000 person-years) and SUDs (49.5 [95% CI 40.6–59.9] per 1,000 person-years) were higher in the gabapentinoid group compared with the DA group. A statistically significant risk of mental health diagnoses with gabapentinoids was not detected, but SUD risk was significant after covariate adjustment. High-risk mental health comorbidities (i.e., SUDs) should be considered when initiating RLS treatments.

Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome.

Restless legs syndrome (RLS) is responsive to opioid, dopaminergic and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, β-endorphin and perhaps Met-enkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anaemia and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic hormone and α-melanocyte stimulating hormone are derived from pro-opiomelanocortin as is β-endorphin. However, they cause RLS-like symptoms and periodic limb movements when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.

Defect of the Endogenous Inhibitory Pain System in Idiopathic Restless Legs Syndrome: A Laser Evoked Potentials Study.

Restless legs syndrome (RLS) is a complex sensorimotor disorder. Symptoms worsen toward evening and at rest and are temporarily relieved by movement. Symptoms are perceived as painful in up to 45% of cases, and nociception system may be involved. To assess the descending diffuse noxious inhibitory control in RLS patients. Twenty-one RLS patients and twenty age and sex-matched healthy controls (HC) underwent a conditioned pain modulation protocol. Cutaneous heat stimuli were delivered via laser evoked potentials (LEPs) on the dorsum of the right hand (UL) and foot (LL). N2 and P2 latencies, N2/P2 amplitude and pain ratings (NRS) were recorded before (baseline), during, and after a heterotopic noxious conditioning stimulation (HNCS) application. The baseline/HNCS ratio was calculated for both UL and LL. N2 and P2 latencies did not vary between groups at each condition and limbs. Both groups showed a physiological N2/P2 amplitude and NRS reduction during the HNCS condition in UL and LL in comparison to baseline and post conditions (all, P < 0.003). Between-groups comparisons revealed a significant lower amplitude reduction in RLS at the N2/P2 amplitude during the HNCS condition only for LL (RLS, 13.6 μV; HC, 10.1 μV; P = 0.004). Such result was confirmed by the significant difference at the ratio (RLS, 69%, HC, 52.5%; P = 0.038). The lower physiological reduction during the HNCS condition at LL in RLS patients suggests a defect in the endogenous inhibitory pain system. Further studies should clarify the causal link of this finding, also investigating the circadian modulation of this paradigm. © 2023 International Parkinson and Movement Disorder Society.

Investigation of the relationship between serum irisin level in the idiopathic restless legs syndrome: Could be a marker independent of physical activity?

Restless legs syndrome (RLS) is a common but underdiagnosed neurological syndrome. It is characterized by the feeling of discomfort and desire to move, especially in the lower extremities, which often occurs at night, and the cure or relief of symptoms with movement. Irisin is a hormonelike polypeptide that was first identified in 2012, weighs 22kDa, consists of 163 amino acids, and is mainly synthesized in muscle. Its synthesis increases with exercise. Here in this study, we planned to investigate the relationship among serum irisin level, physical activity, lipid profile, and RLS. A total of 35 patients with idiopathic RLS and 35 volunteers were included in the study. Then, venous blood was taken from the participants in the morning after 12h of night fasting. The mean value of serum irisin level was 16.9±14.1ng/mL in the case group and 5.1±5.9ng/mL in the control group, which was statistically quite significant (p<.001). A significant efficiency (under the curve area 0.886 [0.804-0.967]) of irisin value was observed in the differentiation of patients in the case and control groups. Serum irisin level was significantly higher in the case group than in the control group. In conclusion, we suggest that irisin may play a role in the pathophysiology of RLS independently of the intensity and duration of physical activity and anthropometric data, such as body weight, body mass index, and waist/hip ratio.

Epigenetic Association Analyses and Risk Prediction of RLS.

As opposed to other neurobehavioral disorders, epigenetic analyses and biomarkers are largely missing in the case of idiopathic restless legs syndrome (RLS). Our aims were to develop a biomarker for RLS based on DNA methylation in blood and to examine DNA methylation in brain tissues for dissecting RLS pathophysiology. Methylation of blood DNA from three independent cohorts (n = 2283) and post-mortem brain DNA from two cohorts (n = 61) was assessed by Infinium EPIC 850 K BeadChip. Epigenome-wide association study (EWAS) results of individual cohorts were combined by random-effect meta-analysis. A three-stage selection procedure (discovery, n = 884; testing, n = 520; validation, n = 879) established an epigenetic risk score including 30 CpG sites. Epigenetic age was assessed by Horvath's multi-tissue clock and Shireby's cortical clock. EWAS meta-analysis revealed 149 CpG sites linked to 136 genes (P < 0.05 after Bonferroni correction) in blood and 23 CpG linked to 18 genes in brain (false discovery rate [FDR] < 5%). Gene-set analyses of blood EWAS results suggested enrichments in brain tissue types and in subunits of the kainate-selective glutamate receptor complex. Individual candidate genes of the brain EWAS could be assigned to neurodevelopmental or metabolic traits. The blood epigenetic risk score achieved an area under the curve (AUC) of 0.70 (0.67-0.73) in the validation set, comparable to analogous scores in other neurobehavioral disorders. A significant difference in biological age in blood or brain of RLS patients was not detectable. DNA methylation supports the notion of altered neurodevelopment in RLS. Epigenetic risk scores are reliably associated with RLS but require even higher accuracy to be useful as biomarkers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Restless legs syndrome in DNAJC12 deficiency.

Restless legs syndrome (RLS) is characterized by an unpleasant or painful sensation generally localized to lower limbs and relieved by movement. Its pathogenesis is hypothesized to involve the dopaminergic system, also in the light of the response of RLS to ex adiuvantibus treatment with dopamine agonists. DNAJC12 deficiency is a recently identified inherited metabolic disease coupling hyperphenylalaninemia to deficient dopaminergic and serotoninergic neurotransmission, due to the combined impairment of the three aromatic amino acids' (i.e., phenylalanine, tyrosine, and tryptophan) hydroxylases. DNAJC12 deficiency was reported in 43 patients so far, presenting with wide spectrum of clinical symptoms. Here, we report RLS as a novel clinical manifestation of DNAJC12 deficiency, occurring in two adults while on treatment with L-dopa at longitudinal follow-up. The adjunct of low-dose pramipexole was effective in both patients to treat RLS. Besides, this treatment also allowed an improvement of dopaminergic homeostasis, as evidenced by clinical amelioration and stabilization of a peripheral short prolactin profile (a tool to indirectly evaluate dopaminergic homeostasis). Besides including RLS as a new treatable clinical manifestation of DNAJC12, these observations may suggest the opportunity of a selective screening for DNAJC12 deficiency in patients with idiopathic RLS.

Opioids and restless legs syndrome: a double-edged sword.

Free AccessCommentaryOpioids and restless legs syndrome: a double-edged sword John W. Winkelman, MD, PhD John W. Winkelman, MD, PhD Address correspondence to: John Winkelman, MD, PhD, 1 Bowdoin Square, 6th Floor, Boston, MA 02114; Email: E-mail Address: [email protected] Massachusetts General Hospital, Boston, Massachusetts Harvard Medical School, Boston, Massachusetts Search for more papers by this author Published Online:April 1, 2023https://doi.org/10.5664/jcsm.10524SectionsPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutINTRODUCTIONOpioids have been used to treat restless legs syndrome (RLS) for hundreds of years.1 More recently, 2 randomized controlled trials have demonstrated the efficacy of this class of medications for RLS.2,3 The larger study enrolled refractory patients, who, even though they were resistant to other treatments, had a beneficial therapeutic response to oxycodone/naloxone at low–moderate doses. Further, large-scale, open-label observational studies demonstrate the continued efficacy of these medications (predominantly methadone) over 2–10 years for RLS, although a minority require small dose increases over time.4–8In general medical practice, opioids are primarily used for the treatment of both acute and chronic pain. They are also administered outside of medical practice by those with opioid use disorder (OUD). Discontinuation of chronic opioids is often unsuccessful for a variety of reasons, including the aversive symptoms of opioid withdrawal. Opioid withdrawal symptoms are monitored in medical detoxification settings with the use of clinical scales employing both behavioral and physiological indicators; chief among these are the COWS (Clinical Opioid Withdrawal Scale9) and the SOWS (Subjective Opioid Withdrawal Scale10).“Restlessness” has long been recognized as one of the cardinal features of opioid withdrawal and is 1 of the 10 items in the COWS assessment. Only recently has it been recognized that this restlessness is in fact RLS, directly as a consequence of opioid withdrawal (“secondary RLS,” like that due to pregnancy, iron deficiency, or end-stage renal disease). Two recent studies have documented an incidence of RLS of approximately 50% in patients undergoing inpatient detoxification for OUD.11,12 Although RLS as an opioid withdrawal symptom is widely recognized among those with OUD, the medical community, even those working in detoxification programs, is mostly unaware of this. Unfortunately, for many of those with substantial RLS symptoms during opioid withdrawal, a return to opioids is perceived as the only recourse for their relief.In this issue of the Journal of Clinical Sleep Medicine McCarter et al13 report a 36% incidence of RLS, with maximum appearance 2 weeks after discharge, for patients with chronic pain attending a 15-day outpatient program supporting withdrawal from long-term use (mean = 87 months) of opioids. Symptoms were moderate–severe. Those with withdrawal-related RLS had nearly double the opioid doses at admission to the program than those without such emergent symptoms, and morphine milligram equivalents > 20 at admission was a strong predictor of such symptoms. The majority of those with withdrawal-related RLS symptoms had remission of symptoms by 3 months after discharge from the program. They did not present data on longer-term outcomes of opioid use.RLS diagnosis in clinical practice, where symptoms can be precisely assessed, is often straightforward. However, RLS ascertainment by brief self-administered surveys is much more difficult. This is particularly true where patients have conditions with symptoms that overlap with the core features of RLS (eg, Parkinson’s disease,14,15 multiple sclerosis,16 adrenoleukodystrophy,17 akathisia,18 peripheral neuropathy19). For this reason, a recent International Restless Legs Syndrome Study Group task force strongly recommended that, where feasible, prevalence studies should always employ confirmatory follow-up clinical interviews20 following such self-administered surveys.It should be noted that the studies cited above examining incidence of opioid withdrawal–related RLS, including that by McCarter et al, used the Cambridge-Hopkins brief questionnaire, a self-completed survey that asks about the core diagnostic features of RLS and the presence of common mimics.21 However, none of the studies cited above, including our own, used follow-up clinical interviews. Given that opioid withdrawal includes multiple symptoms that mimic RLS22 (ie, generalized restlessness, anxiety, neuropathy, muscle cramps), both RLS prevalence and incidence figures in these studies must be considered tentative. In particular, the 27% RLS prevalence in patients entering the detoxification program in the McCarter et al study, while taking opioids, and with 52% of their patients taking alpha-2-delta ligands at therapeutic RLS doses, raises eyebrows.Regardless of the precise incidence of RLS in the context of opioid withdrawal, the important issue is that it is not uncommon. RLS is not only distressing and produces substantial sleep disturbance but it may in fact interfere with opioid abstinence. Both opioid withdrawal symptoms,23 as well as sleep disturbance, independently24 contribute to relapse to opioid use. Anecdotally, patients with OUD describe a return to opioid use directly related to seeking relief from RLS. RLS also has other relevant substantial morbidity, including suicide and self-harm events.25 On the other hand, case reports suggest26,27 that, like most cases of both “primary” and “secondary” RLS, opioid withdrawal–related RLS is treatable with dopaminergic agonists. To examine this issue more carefully, a National Institute of Drug Abuse-funded trial of28 short-term pramipexole treatment of opioid withdrawal–related RLS is underway, examining the hypothesis that not only RLS symptoms and sleep disturbance are effectively treated with this dopaminergic agonist in a detoxification setting but that opioid craving and detoxification treatment adherence are improved.As was the case 30 years ago for primary RLS prior to the success of randomized controlled trials and educational initiatives, the first steps in advancing treatment of opioid withdrawal–related RLS are recognition of the problem and appropriate diagnosis. The McCarter et al paper in the current issue of the Journal is a valuable addition to this process. If short-term dopamine agonists prove successful in the treatment of RLS in the acute period of opioid withdrawal, their use in this context may be an important advance in reducing the morbidity of opioid withdrawal, maintaining participation in detoxification programs, and thus improving outcomes in OUD.DISCLOSURE STATEMENTJohn Winkelman receives consultation fees from Emalex, Noctrix, and Disc Medicine, and research support from National Institute of Drug Abuse, the RLS Foundation, and the Baszucki Brain Research Fund.REFERENCES1. Miranda M, Williams AM, Garcia-Borreguero D. Thomas de Quincey and his restless legs symptoms as depicted in “Confessions of an English Opium-Eater”. Mov Disord. 2010;25(13):2006–2009 . CrossrefGoogle Scholar2. Walters AS, Wagner ML, Hening WA, et al.. Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo. Sleep. 1993;16(4):327–332 . CrossrefGoogle Scholar3. 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Walters AS, Winkelmann J, Trenkwalder C, et al.. Long-term follow-up on restless legs syndrome patients treated with opioids. Mov Disord. 2001;16(6):1105–1109 . CrossrefGoogle Scholar8. Ondo WG. Methadone for refractory restless legs syndrome. Mov Disord. 2005;20(3):345–348 . CrossrefGoogle Scholar9. Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 2003;35(2):253–259 . CrossrefGoogle Scholar10. Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD. Two new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse. 1987;13(3):293–308 . CrossrefGoogle Scholar11. Gupta R, Ali R, Ray R. Willis-Ekbom disease/restless legs syndrome in patients with opioid withdrawal. Sleep Med. 2018;45:39–43 . CrossrefGoogle Scholar12. Mackie SE, McHugh RK, McDermott K, Griffin ML, Winkelman JW, Weiss RD. Prevalence of restless legs syndrome during detoxification from alcohol and opioids. J Subst Abuse Treat. 2017;73:35–39 . CrossrefGoogle Scholar13. McCarter SJ, Labott JR, Mazumder MK, et al.. Emergence of restless legs syndrome during opioid discontinuation. J Clin Sleep Med. 2023;19(4): 741–748 . LinkGoogle Scholar14. Gjerstad MD, Tysnes OB, Larsen JP. Increased risk of leg motor restlessness but not RLS in early Parkinson disease. Neurology. 2011;77(22):1941–1946 . CrossrefGoogle Scholar15. Suzuki K, Okuma Y, Uchiyama T, et al. Kanto NMPD investigators. Characterizing restless legs syndrome and leg motor restlessness in patients with Parkinson’s disease: a multicenter case-controlled study. Parkinsonism Relat Disord. 2017;44:18–22 . CrossrefGoogle Scholar16. Mery V, Kimoff RJ, Suarez I, et al.. High false-positive rate of questionnaire-based restless legs syndrome diagnosis in multiple sclerosis. Sleep Med. 2015;16(7):877–882 . CrossrefGoogle Scholar17. Winkelman JW, Grant NR, Molay F, Stephen CD, Sadjadi R, Eichler FS. Restless legs syndrome in X-linked adrenoleukodystrophy. Sleep Med. 2022;91:31–34 . CrossrefGoogle Scholar18. Chokroverty S. Differential diagnoses of restless legs syndrome/Willis-Ekbom disease: mimics and comorbidities. Sleep Med Clin. 2015;10(3):249–262 . CrossrefGoogle Scholar19. Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JAG. Association between restless legs syndrome and peripheral neuropathy: a systematic review and meta-analysis. Eur J Neurol. 2021;28(7):2423–2442 . CrossrefGoogle Scholar20. Fulda S, Allen RP, Earley CJ, et al.. We need to do better: a systematic review and meta-analysis of diagnostic test accuracy of restless legs syndrome screening instruments. Sleep Med Rev. 2021;58:101461 . CrossrefGoogle Scholar21. Allen RP, Burchell BJ, MacDonald B, Hening WA, Earley CJ. Validation of the self-completed Cambridge-Hopkins questionnaire (CH-RLSq) for ascertainment of restless legs syndrome (RLS) in a population survey. Sleep Med. 2009;10(10):1097–1100 . CrossrefGoogle Scholar22. Bruneau A, Frimerman L, Verner M, et al.. Day-to-day opioid withdrawal symptoms, psychological distress, and opioid craving in patients with chronic pain prescribed opioid therapy. Drug Alcohol Depend. 2021;225:108787 . CrossrefGoogle Scholar23. Davis JP, Eddie D, Prindle J, et al.. Sex differences in factors predicting post-treatment opioid use. Addiction. 2021;116(8):2116–2126 . CrossrefGoogle Scholar24. Beswick T, Best D, Rees S, Bearn J, Gossop M, Strang J. Major disruptions of sleep during treatment of the opiate withdrawal syndrome: differences between methadone and lofexidine detoxification treatments. Addict Biol. 2003; 8(1):49–57 . CrossrefGoogle Scholar25. Zhuang S, Na M, Winkelman JW, et al.. Association of restless legs syndrome with risk of suicide and self-harm. JAMA Netw Open. 2019;2(8):e199966 . CrossrefGoogle Scholar26. Sakurai A, Wakuda T, Yoshida R, Katoh SY, Yamasue H. Successful discontinuation of oxycodone under pramipexole treatment for restless legs syndrome due to withdrawal. Psychiatry Clin Neurosci. 2021;75(3):112–113 . CrossrefGoogle Scholar27. Ghosh A, Basu D. Restless legs syndrome in opioid dependent patients. Indian J Psychol Med. 2014;36(1):85–87 . CrossrefGoogle Scholar28. Clinicaltrials.gov. Treatment of Restless Legs Symptoms with Pramipexole to Improve the Outcomes of Protracted Opioid Withdrawal in OUD: A Pilot Double-Blind, Randomized Clinical Trial. PI: JW Winkelman. 2021. https://clinicaltrials.gov/ct2/show/NCT04759703. Accessed February 12, 2023. Google Scholar Previous article Next article FiguresReferencesRelatedDetails Volume 19 • Issue 4 • April 1, 2023ISSN (print): 1550-9389ISSN (online): 1550-9397Frequency: Monthly Metrics History Submitted for publicationFebruary 15, 2023Accepted for publicationFebruary 15, 2023Published onlineApril 1, 2023 Information© 2023 American Academy of Sleep MedicinePDF download

LAG3/CD4 Genes Variants and the Risk for Restless Legs Syndrome.

According to several studies, inflammatory factors could be related to the pathogenesis of idiopathic restless legs syndrome (RLS). In addition, RLS and Parkinson's disease (PD) have shown a possible relationship, and recent studies have shown an association between CD4 rs1922452 and CD4 rs951818 single nucleotide variants (SNVs) and the risk for PD. For these reasons, we investigated the possible association between common variants in the LAG3/CD4 genes (which encoded proteins involved in inflammatory and autoimmune responses) and the risk for RLS in a Caucasian Spanish population. We assessed the frequencies of CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 genotypes and allelic variants in 285 patients with idiopathic RLS and 350 healthy controls using a specific TaqMan-based qPCR assay. We also analyzed the possible influence of the genotypes' frequencies on several variables, including age at onset of RLS, gender, family history of RLS, and response to drugs commonly used in the treatment of RLS. We found a lack of association between the frequencies of genotypes and allelic variants of the 3 SNVs studied and the risk of RLS, and a weak though significant association between the CD4 rs1922452 GG genotype and an older age at onset of RLS. With the exception of this association, our findings suggest that common SNVs in the CD4/LAG3 genes are not associated with the risk of developing idiopathic RLS in Caucasian Spanish people.

Polysomnographic features of idiopathic restless legs syndrome: a systematic review and meta-analysis of 13 sleep parameters and 23 leg movement parameters.

This study aims to explore the polysomnographically measured sleep and leg movement differences between idiopathic restless legs syndrome (RLS) patients and healthy controls. An electronic literature search was conducted in EMBASE, MEDLINE, all EBM databases, CINAHL, and PsycINFO. Only observational case-control studies were included in the meta-analysis. The differences in 13 sleep parameters and 23 leg movement parameters between RLS patients and healthy controls were explored. Thirty-eight studies were identified for systematic review, 31 of which were used for meta-analysis. Meta-analyses revealed significant reductions in total sleep time, sleep efficiency, stage N2 and rapid eye movement (REM) sleep percentages, and increases in wake time after sleep onset, stage shifts per hour, stage N1 percentage, REM latency, arousal index, and apnea-hypopnea index. Some leg movement parameters, such as periodic limb movement during sleep (PLMS) index, PLMS sequence duration, number of PLMS sequence, and periodicity index, were higher in RLS patients compared with healthy controls. Further, our meta-analysis revealed a higher PLMS index during non-REM sleep compared with that during REM sleep. RLS patients manifest a lightening of sleep, increased sleep fragmentation, and greater sleep-related breathing disruption and limb movements during sleep relative to healthy normal individuals. The distributions of PLMS during a night's sleep may provide more information to clarify the specific characteristics of leg movements in RLS. PLMS in RLS are concentrated in non-REM sleep. The periodicity index may be a more sensitive and specific marker of RLS than the PLMS index. Zhang H, Zhang Y, Ren R, etal. Polysomnographic features of idiopathic restless legs syndrome: a systematic review and meta-analysis of 13 sleep parameters and 23 leg movement parameters. J Clin Sleep Med. 2022;18(11):2561-2575.

Association of BST1 polymorphism with idiopathic restless legs syndrome in Chinese population

Association of BST1 polymorphism with idiopathic restless legs syndrome in Chinese population

CO133 Initiation of Pharmacotherapies for Newly Diagnosed Early-Onset Idiopathic Restless Legs Syndrome from 2012-2019

CO133 Initiation of Pharmacotherapies for Newly Diagnosed Early-Onset Idiopathic Restless Legs Syndrome from 2012-2019

Treatment initiation and utilization patterns of pharmacotherapies for early-onset idiopathic restless legs syndrome

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

Reassessment of candidate gene studies for idiopathic restless legs syndrome in a large genome-wide association study dataset of European ancestry.

Several candidate gene studies have been published for idiopathic restless legs syndrome (RLS) in populations of European ancestry, but the reported associations have not been confirmed in independent samples. Our aim was to reassess these findings in a large case-control dataset in order to evaluate their validity. We screened PubMed for RLS candidate gene studies. We used the genome-wide association study (GWAS) dataset of the International EU-RLS-GENE Consortium as our replication sample, which provided genome-wide single-variant association data based on at most 17 220 individuals of European ancestry. We performed additional gene-based tests using the software MAGMA and assessed the power of our study using the genpwr R package. We identified 14 studies conducted in European samples which assessed 45 variants in 27 genes of which 5 variants had been reported as significantly associated. None of these individual variants were replicated in our GWAS-based reassessment (nominal p > 0.05) and gene-based tests for the respective five genes ADH1B, GABRR3, HMOX1, MAOA, and VDR, were also nonsignificant (nominal p > 0.05). Our replication dataset was well powered to detect the reported effects, even when adjusting for effect size overestimation due to winner's curse. Power estimates were close to 100% for all variants. In summary, none of the significant single-variant associations from candidate gene studies were confirmed in our GWAS dataset. Therefore, these associations were likely false positive. Our observations emphasize the need for large sample sizes and stringent significance thresholds in future association studies for RLS.

Attention-deficit/hyperactivity and obsessive-compulsive symptoms in adult patients with primary restless legs syndrome

Comorbidity between Restless Legs Syndrome and Attention-Deficit/Hyperactivity Disorder remains a matter of debate. This putative association, possibly reflecting a shared brain iron homeostasis and dopaminergic dysfunction, supports the hypothesis of a neurodevelopmental component in Restless Legs Syndrome pathogenesis. The aim of this study was to investigate Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder symptoms prevalence in adult patients with primary Restless Legs Syndrome compared to another ill group of patients with obstructive sleep apnea syndrome to control for the disease specific effects on psychiatric symptoms and a healthy individuals control group. Clinical data were obtained through standardized and validated self-administrated questionnaires evaluating Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder symptoms frequencies in 139 outpatients with idiopathic Restless Legs Syndrome, 111 patients with treated obstructive sleep apnea syndrome and 136 healthy subjects. Our findings demonstrate a higher prevalence of Attention-Deficit/Hyperactivity Disorder symptoms among both male and female patients with Restless Legs Syndrome, compared to obstructive sleep apnea syndrome patients and healthy subjects (33.3 and 43.5%, respectively, p < 0.001). Only women presented a strong relationship between Attention-Deficit/Hyperactivity Disorder and Restless Legs Syndrome severity (p < 0.001). Male and female in the three groups showed similar Obsessive-Compulsive Disorder symptom prevalence. These findings indicate that Attention-Deficit/Hyperactivity Disorder symptoms among adult patients with Restless Legs Syndrome populations are a robust phenomenon. These data provide arguments in favor of an enlargement of the clinical neuropsychological presentation of Restless Legs Syndrome and question the role of decreased brain iron of these psychiatric symptoms.

Serum Trace Elements Concentrations in Patients with Restless Legs Syndrome.

Increased brain and serum zinc levels in patients with idiopathic restless legs syndrome (idiopathic RLS or iRLS) were described when compared with controls, suggesting a possible role of zinc in the pathogenesis of this disease. However, serum magnesium, calcium, manganese, iron, and copper levels of RLS patients were similar to controls, suggesting a specific impairment of zinc-dependent metabolism in RLS. The aim of this study is to assess the serum concentrations of trace elements involved in oxidative stress or causing peripheral nerve toxicity in a large series of patients with iRLS and controls. We determined serum levels of iron, copper, manganese, zinc, magnesium, selenium, calcium, aluminium, lead, cadmium, arsenic and mercury in 100 patients diagnosed with iRLS and in 110 age- and sex-matched controls using Inductively Coupled Plasma Mass Spectrometry. Serum copper, magnesium, selenium, and calcium concentrations were significantly higher in RLS patients than in controls. These differences were observed both in men and women. There were no major correlations between serum trace metal concentrations and age at onset of RLS or RLS severity, nor was there any association with a family history of RLS or drug response. This study shows an association between increased serum concentrations of copper, magnesium, selenium, and calcium with RLS in a Spanish Caucasian population and does not confirm the previously reported increase in serum zinc concentrations in patients suffering from this disease, suggesting that the different accuracy of the analytical methods used could have influenced the inconsistent results found in the literature.

Stroke-related restless legs syndrome: Clinical and anatomo-functional characterization of an emerging entity.

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

The Safety and Efficacy of Pregabalin Add-on Therapy in Restless Legs Syndrome Patients.

Pregabalin is increasingly being used as a first-line treatment for symptomatic control of restless legs syndrome (RLS). This study aimed to evaluate the efficacy and safety of pregabalin as add-on therapy in RLS patients already taking dopamine agonists (DA) but still in need of further management. Patients with idiopathic RLS were enrolled, and all had already been prescribed DA for at least 3 months but still had either persistent symptoms, side effects, or comorbid insomnia. An initial dose of 75 mg pregabalin was begun, adjusted as needed, and maintained at a stable dose for 4 weeks, followed by observation for a total of 8 weeks. RLS symptoms and insomnia scores were evaluated before and after add-on pregabalin treatment. Patients were monitored for side effects that could be attributed to pregabalin. A total of 32 RLS patients were enrolled, and 20 subjects remained until the endpoint. After the pregabalin add-on, the mean IRLS score showed significant improvement compared to the baseline (p < 0.001). The insomnia severity index score also improved (p = 0.036), and no serious adverse effects were observed. Our preliminary data suggests the potential for pregabalin as an add-on therapy to DA with regards to both efficacy and safety in patients who have inadequate RLS improvement.