Cause Of Restless Legs Syndrome Research Articles

Is Restless Legs Syndrome De Facto Thyroid Disease?

While a primary role in the pathogenesis of restless legs syndrome (RLS) has been attributed to dysfunction of the dopaminergic system and impaired iron metabolism (particularly in the central nervous system), it has been hypothesized that an imbalance between thyroid hormones and dopaminergic activity may be the starting point for all aspects of RLS. Although this hypothesis was proposed more than a decade ago, it has not yet been verified beyond doubt. The main aim of this study is to compare the prevalence of RLS in a population of patients with the most common thyroid gland diseases with a population of individuals with a healthy thyroid gland. The study included 237 participants divided into smaller groups according to the thyroid disease concerning them. Each participant had a laboratory diagnosis, an ultrasound scan and an assessment of the fulfilment of RLS criteria according to the International Restless Legs Syndrome Study Group (IRLSSG) criteria. The results obtained were subjected to statistical analysis. RLS is significantly more common in patients with known thyroid disease; Hashimoto’s disease, among others, manifests a 2.56× higher risk of a positive diagnosis for RLS than the general population. The association of RLS with thyroid disease is notable, although it is difficult to conclude unequivocally that there is a cause-and-effect relationship between the two. Further investigation into a potentially autoimmune cause of restless legs syndrome should be considered.

Association Between CLOCK Gene Variants and Restless Legs Syndrome in Koreans.

ObjectivePrevious studies have suggested various causes of restless legs syndrome (RLS), including iron and dopamine concentrations in the brain. Genetic influences have also been reported in many studies. There is also a possibility that circadian clock genes may be involved because symptoms of RLS worsen at night. We investigated whether CLOCK and NPAS2 gene polymorphisms were associated with RLS. MethodsA total of 227 patients with RLS and 229 non-RLS matched controls were assessed according to the International Restless Legs Syndrome Study Group diagnostic criteria. Genotyping was performed using reverse transcription polymerase chain reaction and high-resolution melting curve analyses. ResultsAlthough the genotype distributions of the CLOCK variants (rs1801260 and rs2412646) were not significantly different between patients with RLS and non-RLS controls, the allele frequencies of CLOCK rs1801260 showed marginally significant differences between the two groups (X2=2.98, p=0.085). Furthermore, there was a significant difference in the distribution of CLOCK haplotypes (rs1801260-rs2412646) between patients with RLS and non-RLS controls (p=0.013). The distributions of allelic, genotypic, and haplotypic variants of NPAS2 (rs2305160 and rs6725296) were not significantly different between the two groups. ConclusionOur results suggest that CLOCK variants may be associated with decreased susceptibility to RLS.

Cerebrovascular Risk in Restless Legs Syndrome: Intima-Media Thickness and Cerebral Vasomotor Reactivity: A Case-Control Study.

PurposeAlthough some studies have suggested an association between cardiovascular disease and restless legs syndrome (RLS), the mechanisms underlying this relationship remain unclear. The intima-media thickness (IMT) and vasomotor reactivity are two simple, non-invasive tools to investigate preclinical atherosclerosis and microangiopathy, respectively. The aims of this study were to evaluate carotid IMT and to explore vasomotor reactivity in idiopathic RLS (iRLS) patients.Patients and MethodsWe enrolled 44 iRLS after exclusion of patients with secondary causes of RLS, history of vascular events, known uncontrolled vascular risk factors and other neurological disorders. Forty-four age and sex matched controls were therefore recruited. No significant differences in demographic data and vascular risk factors were found between the two groups. Carotid IMT was measured with a high-resolution B-mode ultrasound on the far-wall of common carotid artery, 10 mm and 30 mm to the carotid bulb. Vasomotor reactivity to hypo- and hypercapnia was assessed, by right middle cerebral artery transcranial Doppler, accordingly to the changes in peak systolic velocity, peak diastolic velocity and mean blood flow velocity.ResultsMean IMT was significantly increased in patients with iRLS when measured immediately proximally to carotid bifurcation (0.73; sd=0.17), versus controls (0.65; sd=0.13); p=0.035. Patients showed higher cerebrovascular flow velocities (CBFVs) compared to controls. After multivariate analysis, age, hypertension and iRLS proved to be independent IMT predictors.ConclusionIncreased IMT and higher CBFVs in iRLS support the association of iRLS with vascular damage, possibly through enhanced atherogenesis and sympathetic hyperactivity. However, to clarify a causal relationship, further longitudinal assessment of these parameters is needed, trying to control all their physiological modifying factors.

‘Is RLS a harbinger and consequence of MS?: Striking results of the ‘RELOMS-T’ study’

BackgroundAlthough studies report a high prevalence rate of restless legs syndrome (RLS) among patients with multiple sclerosis (PwMS) ranging from 13.3 to 65.1%, little is known about the causes of this relationship. MethodsTo ascertain the prevalence, features and impact of RLS among PwMS a nation-wide, multicenter, prospective and a cross-sectional survey, designed to reflect all of the PwMS throughout Turkey, was conducted in 13 centers. Exploring the relationship of the two conditions could possibly contribute to the understanding of the causes of the high and wide-ranging prevalence rates and the pathophysiology of both diseases. ResultsOf the 1068 participants 173 (16,2%) found to have RLS [RLS(+)] and 895 (83,8%) did not [RLS(-)]. Among the RLS(+) 173, all but 8 patients (4,6%) were underdiagnosed in terms of RLS. More than half of the patients with RLS had ‘severe’ or ‘very severe’ RLS. The onset of RLS was before or synchronous with the onset of MS in about a half of our patients. ConclusionWe conclude that RLS should be meticulously investigated in PwMS and MS can be a direct cause of RLS at least in part of PwMS. Our data about the timing of the onset of MS and RLS, along with the high prevalence of RLS in PwMS suggest that the pathologic changes in the initial phases of MS can possibly trigger RLS symptoms.

Seeking the Cause of Restless Legs Syndrome in Chronic Kidney Disease.

CITATIONMorse AM, Kothare SV. Seeking the cause of restless legs syndrome in chronic kidney disease. J Clin Sleep Med. 2019;15(11):1559–1560.

MEIS1 and Restless Legs Syndrome: A Comprehensive Review

Restless legs syndrome (RLS) is a common sleep-related disorder for which the underlying biological pathways and genetic determinants are not well understood. The genetic factors so far identified explain less than 10% of the disease heritability. The first successful genome-wide association study (GWAS) of RLS was reported in 2007. This study identified multiple RLS associated risk variants including some within the non-coding regions of MEIS1. The MEIS1 GWAS signals are some of the strongest genetic associations reported for any common disease. MEIS1 belongs to the homeobox containing transcriptional regulatory network (HOX). Work in C. elegans showed a link between the MEIS1 ortholog and iron homeostasis, which is in line with the fact that central nervous system (CNS) iron insufficiency is thought to be a cause of RLS. Zebrafish and mice have been used to study the MEIS1 gene identifying an RLS-associated-SNP dependent enhancer activity from the highly conserved non-coding regions (HCNR) of MEIS1. Furthermore, this gene shows a lower expression of mRNA and protein in blood and thalamus of individuals with the MEIS1 RLS risk haplotype. Simulating this reduced MEIS1 expression in mouse models resulted in circadian hyperactivity, a phenotype compatible with RLS. While MEIS1 shows a strong association with RLS, the protein's function that is directly linked to an RLS biological pathway remains to be discovered. The links to iron and the enhancer activity of the HCNRs of MEIS1 suggest promising links to RLS pathways, however more in-depth studies on this gene's function are required. One important aspect of MEIS1's role in RLS is the fact that it encodes a homeobox containing transcription factor, which is essential during development. Future studies with more focus on the transcriptional regulatory role of MEIS1 may open novel venues for RLS research.

Screening of novel restless legs syndrome-associated genes in French-Canadian families.

ObjectiveTo examine whether any rare, protein-altering variants could be identified across 13 recently identified restless legs syndrome (RLS) loci in familial French-Canadian cases.MethodsWhole-exome sequences from 7 large French-Canadian families (4–8 affected per family for a total of 38 cases) were examined for variants in any genes located within 1 Mb on either side of each locus.ResultsAmong the 43 rare protein-altering variants identified, none segregated with RLS in the families.ConclusionsOur study does not support a role for causative protein-altering variants in the genes that are located either in the previously or newly identified RLS loci. It is therefore possible that noncoding regulatory variants within these loci or yet unidentified loci could be the cause of RLS in our families.

Restless legs syndrome in a bipolar disorder patient treated with low dose olanzapine: is there an association?

Objective: To report a case of restless legs syndrome (RLS) in a patient with bipolar disorder (BD) caused by olanzapine. Case: A female patient was diagnosed with mixed episode of BD. Olanzapine 10 mg/d was added to the extended release valproic acid 1000 mg/d treatment that the patient was using. In the next day after the beginning of olanzapine, itching, aching and tingling sensations begun in her legs at rest. She was diagnosed as RLS caused by olanzapine. Then the dose of olanzapine gradually reduced. But the symptoms were continuing at the dose of 2,5 mg/d. RLS symptoms disappeared in the next day after discontinuation of olanzapine. Discussion: One of the causes of RLS is antipsychotic drugs. It is not clear, how often antipsychotic drugs caused RLS. Again it is not clear that antipsychotic drugs are caused dose-dependent RLS. Mostly case reports on this topic are available. Further systematic studies on this topic will help us to diagnose the RLS correctly and apply appropriate treatment. Conclusion: Further studies are needed about antipsychotic drugs induced RLS.

Restless legs syndrome in patients with type 2 diabetes: effectiveness of pramipexole therapy

ObjectiveWe investigated the prevalence of restless legs syndrome (RLS) in Japanese patients with type 2 diabetes and assessed the efficacy of pramipexole therapy.DesignOne hundred patients with type 2 diabetes without...

Diseases in Patients Coming to a Sleep Center with Symptoms Related to Restless Legs Syndrome

Study ObjectiveTo explore the profile of patients who visit a sleep center with symptoms that fulfill the four essential criteria for restless legs syndrome (RLS).DesignA prospective study.SettingOutpatients from one sleep disorders clinic in Taiwan.Participants1,200 consecutive patients visit sleep disorders clinic with any sleep complaints.InterventionsAfter completing a history and physical examination, all participants answered the RLS questionnaire. Subjects who fulfilled the four essential criteria for RLS were referred to a special clinic. A work-up including blood tests, polysomnography, and specialized neurological tests etc. was performed to make the final diagnosis.Measurements and ResultsA total of 1,185 participants were enrolled, and, of these, 131(11.1%) fulfilled the four essential criteria for RLS, and 121 completed the supplemental work-up. Their mean age was 47.6±13.3 and 52.9% were male. Insomnia and snoring were the most common chief complaints. Obstructive sleep apnea syndrome and other diseases were found in 103 patients. Only 18 (14.9%) patients had no comorbid condition and were diagnosed with primary RLS.ConclusionsSymptoms of RLS are common in patients with sleep complaints. Even in a sleep clinic, using a questionnaire approach for identification of RLS has a low positive predictive value. Clinicians should pay attention to the limitations of the 4-item questionnaire in diagnosis of RLS and also the importance of a careful differential diagnosis to identify possible secondary causes of RLS.

Restless Legs Syndrome as the Initial Presentation of Multiple Sclerosis

The restless legs syndrome (RLS) is a common central nervous system disorder. It is characterized by complaints of unpleasant sensation in the legs occurring during periods of leg inactivity which worsen or only occur in the evening or at night and relieved partially or totally by movement. The RLS may be idiopathic or due to secondary causes. It is associated with several pathological or physiological conditions. Iron metabolism and dysfunctions of the dopaminergic system are the most important factors in the pathophysiology. There are several studies suggesting multiple sclerosis as one of the causes of symptomatic RLS. Here, we report a case of RLS as the initial presentation of MS. The sudden onset of RLS symptoms in our patient suggested the possibility of an underlying cause. His diagnostic evaluation excluded other causes of RLS and his clinical course suggested that RLS was due to MS. MS with the spinal cord involvement is mostly associated with RLS, but any lesion in the hypothalamic-spinal connection may cause disinhibition of lower spinal levels, resulting in RLS. RLS as the initial presentation of MS reflects that the pathophysiology of RLS in MS is related to inflammatory demyelination rather than axonal degeneration.

Prevalence of Restless Legs Syndrome in Patients Treated with Peritoneal Dialysis: Clinical and Biochemical Characteristics among Patients with and without Restless Legs Syndrome

Introduction and Aims:This is a prospective study identifying prevalence of Restless Legs Syndrome (RLS) in patients ongoing peritoneal dialysis (PD) due to end stage renal disease (ESRD) and comparing clinical and biochemical characteristics among patients with and without RLS. Methods: Two hundred ESRD patients who received PD at least six months assessed by neurologist and nephrologist with regards to presence of RLS. Also, clinical and biochemical features of these patients are determined. One hundred and forty four patients were excluded from study because they had other secondary causes of RLS except for ESRD. Results: Thirteen of 56 patients (23.2%) had RLS. The use of vitamin B + folic acid supplements was significantly lower in patients with RLS than in those without RLS (69.2% vs 97.7%; p = 0.008). There was no significant difference between patient groups with and without RLS in terms of age, gender, body mass index, cause of ESRD, peritoneal membrane transport characteristic, smoking, consuming alcohol, use of erythropoietin, duration of PD, hemoglobin, serum calcium, serum phosphorus, serum albumin, levels of serum iron, total iron binding capacity, ferritin, folic acid and vitamin B12, transferrin saturation, weekly Kt/V urea value, and amount of residual urine volume (p > 0.05). Conclusion: RLS is more common among PD patients than general population. Although essential cause is not exactly known, use of folic acid and vitamin B complex decrease the RLS prevalence in this particular patient group.

The neurobiology and treatment of restless legs syndrome.

Background: Restless legs syndrome (RLS) is a relatively common neurological disorder affecting sleep and health-related quality of life. Neuroimaging studies, autopsy investigations and experimental studies using animal models have been conducted to investigate the potential causes of RLS, resulting in the generation of multiple pathophysiological hypotheses. Methods: This paper reviews the neurobiology and pharmacotherapy of RLS, with a critical analysis of the heterogeneity and methodological limitations of the existing scientific literature. Results: Although several neurotransmitter systems dysfunction and neuroanatomical abnormalities have been implicated in RLS pathogenesis, dopamine dysfunction within basal ganglia pathways, iron deficiency and opioid system abnormalities have consistently been found to be involved. Their involvement is further strengthened by the therapeutic effectiveness of dopaminergic agents, iron supplementation and opioid medications. Discussion: Converging evidence from neuroimaging, autoptic and animal studies points towards dopamine dysregulation and iron metabolism alterations as the main contributors to RLS pathophysiology. The possible interactions between different neurotransmitter systems should guide further neuropharmacological research in order to improve therapeutic efficacy for this disabling condition.

Clozapine-Induced Restless Legs Syndrome Treated With Aripiprazole

Clozapine-Induced Restless Legs Syndrome Treated With Aripiprazole

Remission of severe restless legs syndrome and periodic limb movements in sleep after bilateral excision of multiple foot neuromas: a case report

IntroductionRestless legs syndrome is a sensorimotor neurological disorder characterized by an urge to move the legs in response to uncomfortable leg sensations. While asleep, 70 to 90 percent of patients with restless legs syndrome have periodic limb movements in sleep. Frequent periodic limb movements in sleep and related brain arousals as documented by polysomnography are associated with poorer quality of sleep and daytime fatigue. Restless legs syndrome in middle age is sometimes associated with neuropathic foot dysesthesias. The causes of restless legs syndrome and periodic limb movements in sleep are unknown, but the sensorimotor symptoms are hypothesized to originate in the central nervous system. We have previously determined that bilateral forefoot digital nerve impingement masses (neuromas) may be a cause of both neuropathic foot dysesthesias and the leg restlessness of restless legs syndrome. To the best of our knowledge, this case is the first report of bilateral foot neuromas as a cause of periodic limb movements in sleep.Case presentationA 42-year-old Caucasian woman with severe restless legs syndrome and periodic limb movements in sleep and bilateral neuropathic foot dysesthesias was diagnosed as having neuromas in the second, third, and fourth metatarsal head interspaces of both feet. The third interspace neuromas represented regrowth (or 'stump') neuromas that had developed since bilateral third interspace neuroma excision five years earlier. Because intensive conservative treatments including repeated neuroma injections and various restless legs syndrome medications had failed, radical surgery was recommended. All six neuromas were excised. Leg restlessness, foot dysesthesias and subjective sleep quality improved immediately. Assessment after 18 days showed an 84 to 100 percent reduction of visual analog scale scores for specific dysesthesias and marked reductions of pre-operative scores of the Pittsburgh sleep quality index, fatigue severity scale, and the international restless legs syndrome rating scale (36 to 4). Polysomnography six weeks post-operatively showed improved sleep efficiency, a marked increase in rapid eye movement sleep, and marked reductions in hourly rates of both periodic limb movements in sleep with arousal (135.3 to 3.3) and spontaneous arousals (17.3 to 0).ConclusionThe immediate and near complete remission of symptoms, the histopathology of the excised tissues, and the marked improvement in polysomnographic parameters documented six weeks after surgery together indicate that this patient's severe restless legs syndrome and periodic limb movements in sleep was of peripheral nerve (foot neuroma) origin. Further study of foot neuromas as a source of periodic limb movements in sleep and as a cause of sleep dysfunction in patients with or without concomitant restless legs syndrome, is warranted.

Advances in the Science of Genomics in Restless Legs Syndrome

Restless legs syndrome (RLS) is a sleep and movement disorder that affects up to 15% of the population across the lifespan. Many health care providers have doubted its validity as an illness and are uncertain as to the implications of health care outcomes. The cause of RLS is unknown. Common treatment options include dopaminergics, benzodiazepines, and opioids; however, the pharmacogenetic mechanisms of treatment are unknown. One of the greatest genetic discoveries in 2007 was the identification of genetic variance associated with RLS. There is, however, a lack of knowledge related to RLS and its genetic basis. Therefore, the purposes of this article are to (a) provide information about the science of clinical care related to RLS; (b) present a systematic review of the literature on the status of genetics/genomics of RLS, including the discovery of associated genetic variance; and (c) identify implications of the current state of the science for health care providers and biobehavioral researchers. With the continuing genetic discoveries in RLS, health care providers, specifically nurses who play a major role in research, genetic counseling, and education, need to understand the implications of this sleep and movement disorder for patients across the lifespan.

Pharmacologically Induced/Exacerbated Restless Legs Syndrome, Periodic Limb Movements of Sleep, and REM Behavior Disorder/REM Sleep Without Atonia: Literature Review, Qualitative Scoring, and Comparative Analysis

Pharmacologically induced/exacerbated restless legs syndrome (RLS), periodic limb movements in sleep (PLMS), and REM behavior disorder/REM sleep without atonia (RSWA) are increasingly recognized in clinical sleep medicine. A scoring system to evaluate the literature was created and implemented. The aim was to identify the evidence with the least amount of confound, allowing for more reliable determinations of iatrogenic etiology. Points were provided for the following criteria: manuscript type (abstract, peer-reviewed paper); population size studied (large retrospective study, small case series, case report); explicitly stated dosage timing; identification of peak symptoms related to time of medication administration (i.e., medication was ingested in the evening or at bedtime); initiation of a treatment plan; symptoms subsided or ceased with decreased dosage or drug discontinuation (for RLS articles only); negative personal history for RLS prior to use of the medication; exclusion of tobacco/alcohol/excessive caffeine use; exclusion of sleep disordered breathing by polysomnography (PSG); and PSG documentation of presence or absence of PLMS. For RLS and PLMS articles were also given points for the following criteria: each 2003 National Institutes of Health (NIH) RLS criteria met; exclusion of low serum ferritin; and exclusion of peripheral neuropathy by neurological examination. Thirty-two articles on drug-induced RLS, 6 articles on drug-induced PLMS, and 15 articles on drug-induced RBD/ RSWA were analyzed. Based on scores < or = 10 and trials of medication reduction/cessation, the strongest evidence available for drug induced RLS are for the following drugs: escitalopram; fluoxetine; L-dopa/carbidopa and pergolide; L-thyroxine; mianserin; mirtazapine; olanzapine; and tramadol. Since none of the PLMS articles assessed PLMI in trials of medication reduction/cessation, the strongest evidence based on scores > or = 10 are for the following drugs: bupropion, citalopram, fluoxetine, paroxetine, sertraline, and venlafaxine. Based on scores > or = 10 and/or trials of medication cessation, the strongest evidence for drug induced RBD/ RSWA is for the following drugs: clomipramine, selegiline, and phenelzine.

日本人特発性レストレスレッグス症候群の臨床的特徴

Little is known about the diagnosis and management of restless legs syndrome (RLS) in Japanese neurology clinics. To validate the diagnostic criteria of the International RLS Study Group (IRLSSG) and the treatment algorithm of the Mayo Clinic in a Japanese neurology clinic setting and to clarify the features of Japanese patients with idiopathic RLS. Patients with RLS symptoms were examined by a neurologist and the assessment included neurological examination, tests for periodic limb movements (PLM) and dopaminergic response, and the clinical diagnosis was made according to IRLSSG diagnostic criteria. Patients diagnosed with idiopathic RLS were treated with dopaminergic agents and the efficacy was evaluated. The study subjects were 151 Japanese patients who presented with RLS symptoms. Idiopathic RLS was diagnosed in 113 patients, secondary RLS in 16 and RLS mimics in 22. The cause of RLS mimics was either myelopathy, radiculopathy or neuropathy in 11 patients. The mean age of patients with idiopathic RLS was 50.1 (SD 20.0) years, 63% were woman, 97% had daily RLS, 31% had family history (40% of the early-onset subgroup), 86% reported unpleasant sensations in the lower legs, 43% had PLM in the daytime suggested immobilization test, 81% suffered from insomnia, 49% had limitations of work and activities, 71% reported impaired mood, 27% had consulted physicians about their symptoms, 4% had been diagnosed with RLS, 73% improved after dopaminergic treatments, and 33% experienced complete remission. The clinical features of Japanese patients with idiopathic RLS were identical to those reported in western countries, which suggests that IRLSSG diagnostic criteria and Mayo Clinic treatment algorism are valid in Japanese neurology clinics. Both patients and physicians were not fully aware of RLS in this country. Neurological examination was important in excluding RLS mimics and making a diagnosis of RLS.

The numb and the restless

Restless legs syndrome (RLS) is characterized by diurnal restless discomfort, usually affecting the lower extremities, often associated with periodic limb movements in sleep. It is among the most prevalent neurologic syndromes and yet remains a puzzle in many respects; even its prevalence has been a matter of debate, with estimates ranging from 1 to 20%.1,2 RLS may be classified as primary or secondary with secondary causes including myelopathy, uremia, iron deficiency, and Parkinson disease. Peripheral neuropathy has been cited as a potential cause of RLS, though this association has been controversial, with prevalence estimates of RLS in patients with peripheral neuropathy ranging from 5 to 54%. In the current issue of Neurology® , Hattan et al.3 report the results of a prospective, case-control study examining the prevalence of RLS …

Autosomal‐dominant locus for restless legs syndrome in French‐Canadians on chromosome 16p12.1

We describe an autosomal-dominant locus for Restless Legs Syndrome (RLS) in a French-Canadian (FC) pedigree. Genome-wide microsatellite scan and linkage analysis were used in this study. The locus maps to chromosome 16p12.1 and spans 1.18 Mega bases. The maximum multipoint LOD scores are of 3.5 over the total of 10 markers. Evidence for the same locus was also found in a smaller FC pedigree sime095. The analysis of the sequence of 8 annotated genes within the region did not reveal any pathogenic mutations. Copy number variation and karyotype analyses did not reveal any chromosomal abnormality in the region. Further analyses of the region are necessary to find the genetic cause of RLS in this family.