Cases Of Restless Legs Syndrome Research Articles

Genomic Analysis Identifies Risk Factors in Restless Legs Syndrome.

Restless legs syndrome (RLS) is a neurological condition that causes uncomfortable sensations in the legs and an irresistible urge to move them, typically during periods of rest. The genetic basis and pathophysiology of RLS are incompletely understood. We sought to identify additional novel genetic risk factors associated with RLS susceptibility. We performed a whole-genome sequencing and genome-wide association meta-analysis of RLS cases (n = 9,851) and controls (n = 38,957) in 3 population-based biobanks (All of Us, Canadian Longitudinal Study on Aging, and CARTaGENE). Genome-wide association analysis identified 9 independent risk loci, of which 8 had been previously reported, and 1 was a novel risk locus (LMX1B, rs35196838, OR 1.14, 95% CI 1.09-1.19, p value = 2.2 × 10-9). Furthermore, a transcriptome-wide association study also identified GLO1 and a previously unreported gene, ELFN1. A genetic correlation analysis revealed significant common variant overlaps between RLS and neuroticism (rg = 0.40, se = 0.08, p value = 5.4 × 10-7), depression (rg = 0.35, se = 0.06, p value = 2.17 × 10-8), and intelligence (rg = -0.20, se = 0.06, p value = 4.0 × 10-4). Our study expands the understanding of the genetic architecture of RLS, and highlights the contributions of common variants to this prevalent neurological disorder. ANN NEUROL 2024.

Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction

Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find new entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 individuals with RLS (cases) and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including three on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (rg = 0.96). Locus annotation prioritized druggable genes such as glutamate receptors 1 and 4, and Mendelian randomization indicated RLS as a causal risk factor for diabetes. Machine learning approaches combining genetic and nongenetic information performed best in risk prediction (area under the curve (AUC) = 0.82–0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up and provided evidence that nonlinear interactions are likely relevant to RLS risk prediction.

Genetic Association Studies in Restless Legs Syndrome: Risk Variants & Ethnic Differences.

Genetic association studies have not produced consistent results in restless legs syndrome (RLS). To conduct a systematic review on genetic association studies in RLS to highlight the common gene variants and ethnic differences. We conducted Pubmed, Embase, and Cochrane search using terms "Genetic association studies" and "restless legs syndrome" for candidate gene-based studies. Out of the initial 43 studies, 18 case control studies (from 2012 to 2022) were included. Thirteen studies including 10794 Caucasian subjects (4984 RLS cases and 5810 controls) and five studies involving 2009 Asian subjects (796 RLS cases and 1213 controls) were tabulated and analyzed. In addition, three Genome-Wide Association Studies (GWAS) in Asians and Europeans/Caucasians were included for comparisons. In the Asian population, gene variants in BST1, SNCA Rep1, IL1B, BTBD9, and MAP2K5/SKOR1 increased the risk of RLS (odds ratio range 1.2-2.8). In Caucasian populations, examples of variants that were associated with an increased risk of RLS (odds ratio range 1.1-1.9) include those in GABRR3 TOX3, ADH1B, HMOX1, GLO1, DCDC2C, BTBD9, SKOR1, and SETBP1. Based on the meta-analysis of GWAS studies, the rs9390170 variant in UTRN gene was identified to be a novel genetic marker for RLS in Asian cohorts, whereas rs113851554 in MEIS1 gene was a strong genetic factor among the >20 identified gene variants for RLS in Caucasian populations. Our systemic review demonstrates that multiple genetic variants modulate risk of RLS in Caucasians (such as MEIS1 BTBD9, MAP2K5) and in Asians (such as BTBD9, MAP2K5, and UTRN).

Resistant case of restless leg syndrome due to hyperinsulinemia

Resistant case of restless leg syndrome due to hyperinsulinemia

0987 Asking the Right Questions: A Case of Restless Legs Syndrome and Spinal Muscular Atrophy

Abstract Introduction The association between iron deficiency and restless legs syndrome (RLS) is well established. However, there is limited data on the association between motor neuron diseases such as spinal muscular atrophy (SMA) and RLS. A forty-three-year-old with Type 2 SMA presented to clinic for management of chronic respiratory failure. She had recently undergone surgery and chemotherapy for newly diagnosed anal cancer. However, she reported persistent abdominal pain, anorexia, weight loss, and rectal bleeding. She reported “muscle twitching” and bilateral lower extremity pain and tingling that was worse at night. Her husband would awaken every 2 hours to massage her legs. She assumed these symptoms had emerged as a result of an increase in motor function due to risdiplam, a survival motor neuron 2 splicing modifier drug. Further questioning led to the diagnosis of RLS. Bloodwork revealed severe iron deficiency anemia (hemoglobin of 6.0 g/dL, iron 13 mcg/dL, and ferritin 3 ng/ml). She received a blood transfusion and underwent sigmoidoscopy for evaluation of cancer recurrence given the report of bleeding. Fortunately, her cancer remained in remission. Her symptoms of RLS significantly improved after blood transfusions and iron supplementation. Report of case(s) n/a Conclusion RLS is a complex sensorimotor syndrome. The diagnosis of RLS is clinical, relying on diagnostic criteria that requires lower extremity movement. The case is a reminder of the variable presentation of RLS in individuals with neuromuscular disorders, including SMA. How are symptoms of restless legs disclosed in patients with the inability to move and with potentially altered sensorium? The focus of the patient encounter could have anchored on the common and expected sequalae of SMA, chronic respiratory failure. Unfortunately, anchoring bias would have delayed the diagnosis and treatment of what could have been a potentially fatal disease – metastatic cancer. Ironically, the patient’s longing for motor function repressed her ability to lament. To the patient, symptoms of frequent nighttime awakenings and limb discomfort were perceived as a desired side effect of a medication that would increase movement. This case emphasizes the importance of the patient interview and its value of uncovering subtle complaints that may broaden the differential diagnosis and guide further work-up. Support (if any)

The prevalence of restless legs syndrome (RLS) in patients with multiple sclerosis (MS): a systematic review and meta-analysis-an update.

The prevalence of restless legs syndrome (RLS) is reported to vary in patients with multiple sclerosis (MS) in studies which are conducted in different populations. The goal of this systematic review and meta-analysis is to update the prevalence of RLS in MS cases. We searched PubMed, Scopus, EMBASE, CINAHL, Web of Science, Google Scholar, and gray literature including references from identified studies and conference abstracts which were published up to June 2021. Data on the total number of participants, first author, country, disease duration, number of controls, mean patient age, male and female numbers, mean EDSS, and number of cases and/or controls with RLS were extracted from the included studies. The literature search revealed 855 articles; after deleting duplicates, 530 remained. For the meta-analysis, 75 studies were included (Fig.1). In six articles, the authors did not differentiate between CIS and MS cases when reporting RLS cases. In total, 15,411 MS/CIS patients were evaluated and 4309 had RLS. The pooled prevalence of RLS was 28% (95% CI: 24-33%). The pooled prevalence of RLS in men was 22% (95% CI: 17-26%), and the pooled prevalence of RLS in women was 30% (95% CI: 25-35%). The pooled prevalence of RLS in controls was 8% (95% CI: 6-10%). The results of this systematic review and meta-analysis show that the pooled prevalence of RLS is 28% in MS cases and 8%. The pooled prevalence is higher in women than men (30% vs 22%).

The Prevalence and Predictors of Restless Legs Syndrome in Patients with Liver Cirrhosis.

Introduction and aim. Sleep disorders are highly prevalent in patients with liver cirrhosis. The aim of this study was to investigate the prevalence of restless legs syndrome (RLS), as well as its risk factors and possible predictors, in a cohort of patients with liver cirrhosis. Material and methods. We performed a cross-sectional prospective study over a period of 14 months and enrolled 69 patients with liver cirrhosis, after applying the inclusion and exclusion criteria. The cases of RLS were assessed according to the International Restless Legs Syndrome Study Group (IRLSSG) criteria and severity scale. Results. Out of the total number of patients, 55% fulfilled the criteria for RLS. Age, diabetes, severity of cirrhosis, serum creatinine, glomerular filtration rate (GFR), and mean hemoglobin were associated with the presence of RLS. Moreover, there was a significantly higher prevalence of RLS among patients with decompensated cirrhosis. From all the risk factors introduced into the multivariate analysis, only the GFR could predict the presence of RLS. Conclusions. This research shows that patients with liver cirrhosis have a high risk of RLS. Even though there are multiple risk factors associated with RLS, only the GFR could predict its occurrence in our cohort.

Does Repeated Dosing of Intravenous Ferric Carboxymaltose Alleviate Symptoms of Restless Legs Syndrome?

Background: Several studies have reported the efficacy of intravenous (IV) iron for patients with restless legs syndrome (RLS), but little is known about the efficacy or safety of repeated IV iron treatment. The aim of this study was to evaluate the effectiveness of repeated doses of IV ferric carboxymaltose (FCM) in treating RLS symptoms. Methods: Patients who received FCM more than twice for RLS from April 2016 to January 2020 were retrospectively reviewed. Patients who had shown positive response to initial IV FCM re-visited the clinic when their symptoms returned, and received repeated IV FCM (1000 mg). Blood iron panels were measured before initial and repeated IV FCM. We defined ‘responders’ as patients with a greater than 40% decrease in International Restless Legs Study Group Severity Scale (IRLS) compared with pre-treatment levels. Results: A total of 42 patients, including 26 with primary RLS, 5 with gastrectomy, and 11 with anemia, completed the evaluation. Patients received IV FCM infusion 2–4 times. A total of 21 of 26 (80.8%) primary cases of RLS, 4 of 5 (80.0%) patients with a history of gastrectomy, and 9 of 11 (81.8%) patients with anemia responded to repeated FCM treatment. Serum ferritin levels of patients with primary RLS were higher before the second treatment than the baseline levels. There were no serious adverse events observed in the study. Conclusions: Repeated IV FCM for recurring symptoms is an effective treatment for primary RLS and RLS associated with iron deficiency. Serum ferritin might not be a reliable factor to monitor the sustained effects of IV iron for RLS.

A case of restless legs Syndrome - Ill-ness or ill-spirit?

A case of restless legs Syndrome - Ill-ness or ill-spirit?

Investigating the inflammation marker neutrophil-to-lymphocyte ratio in Danish blood donors with restless legs syndrome.

Restless Legs Syndrome (RLS) is a neurological sensorimotor disorder that occurs in the evening and night, thereby impacting quality of sleep in sufferers. The pathophysiology of RLS is poorly understood but inflammation has been proposed as possibly being involved. The neutrophil-to-lymphocyte ratio (NLR) can be used as an inflammation marker but results from small studies have been inconclusive in determining whether NLR is associated with RLS. We aimed to assess whether an association between NLR and RLS exists in a large cohort of healthy individuals. Neutrophils and lymphocytes were measured in blood samples of 13,055 individuals from the Danish Blood Donor Study, all of whom completed the validated Cambridge-Hopkins RLS-questionnaire for RLS assessment. In the sample, 661 individuals were determined as current RLS cases (5.1%). A higher proportion of individuals with RLS were females (62.5% vs 47.5%; P<0.001) and RLS cases were older than controls (P<0.001), but no differences in body mass index (BMI), smoking or alcohol consumption were found between the two groups. An increased NLR was observed in RLS cases compared to controls (median NLR: 1.80 vs 1.72; P = 0.033). In an unadjusted logistic regression model, increased NLR was associated with RLS (OR = 1.10 per NLR unit increase [95%CI:1.01-1.20]; P = 0.032); however, the association was not significant in multivariate models adjusting for sex and age (P = 0.094) or sex, age, alcohol consumption, smoking status and BMI (P = 0.107). We found no association between RLS and NLR among Danish blood donors after adjusting for sex, age, alcohol consumption, smoking status and BMI. Further studies are needed to determine whether inflammation is a risk factor for RLS.

A Polysomnographic and Cluster Analysis of Periodic Limb Movements in Sleep of Restless Legs Syndrome Patients with Psychiatric Conditions

Only survey studies have linked specific individual psychiatric disorders such as anxiety, depression and schizophrenia to Restless Legs Syndrome (RLS), Periodic Limb Movements in Sleep (PLMS) or both. We therefore aim to polysomnographically characterize sleep in a sample of physician-based, newly diagnosed cases of RLS with various ICD-10 psychiatric diagnoses. Retrospective analysis of data from a convenience sample of psychiatric patients (n = 43) per standard clinical sleep disorder cut-offs was conducted. Next, a cluster analysis was performed on the sleep data, taking into account the psychiatric diagnosis, comorbid non-psychiatric somatic problems and medication. We found that 37.2% of our sample showed clinically significant PLMS ≥ 15 and 76.5% exhibited an apnea hypopnea index (AHI) ≥ 5. Sleep structure was unaltered apart from the PLMS-related parameters. Two clusters were statistically identified: Cluster 1 primarily representing recurrent major depressive issues and Cluster 2 representing present but not predominant mood symptomatology as well as mixed disorders with personality problems. The known confounders were controlled. A PLMS index ≥ 15 was differentially distributed among the two clusters with Cluster 1: 10 out of 17 with PLMS index ≥ 15; Cluster 2: 1 out of 16 with PLMS index ≥15; whilst AHI was not different. Patients in Cluster 1 have a higher rate of periodic leg movements than patients in Cluster 2. This suggests that the high association with PLMS is primarily driven by affective disorders. Our findings warrant questioning of RLS symptomatology in patients with psychiatric conditions.

Restless legs syndrome in systemic lupus erythematosus: A case-control study.

Sleep disturbances in systemic lupus erythematosus (SLE) are not well understood. The restless legs syndrome (RLS) is one of the frequent occurring sleep disturbances in SLE. The aim of this study was to evaluate the prevalence of RLS and its characteristics in SLE. We evaluated, in a prospective case-control study, 26 patients with SLE and 26 patients without SLE in an age- and sex-matched control group. An RLS-positive diagnosis met International RLS Study Group (IRLSSG) criteria. We used standardized questionnaires, which included demographic data, medical history and sleep assessment. We used validated questionnaires and scales to assess sleep. There were 23/26 females (88.46%) in each group; the mean patient age in the SLE subgroup was 51.65 years, while in the control subgroup, 52.07 years (range 30-74). Nine (34.2%) patients had RLS-positive criteria in the SLE group and 2 (7.69%) of 26 in the control group. Eight out of 9 patients described RLS onset after SLE was diagnosed. In the SLE group, 8 cases were of moderate severity and 1 was considered mild. The control group had one mild and one moderate case of RLS. RLS prevalence in SLE is higher and the quality of sleep is poorer compared with the control group.

Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes

Restless legs syndrome (RLS) is a common neurological condition, with a prevalence of 5–15% in Central Europe and North America. Although genome-wide association studies (GWAS) have identified some common risk regions for RLS, the causal genes have yet to be fully elucidated. We conducted a transcriptome-wide association study involving 15,126 RLS cases and 95,725 controls, from the most recent meta-analysis of GWAS, and gene expression weights of GTEx v7 and the CMC dorsolateral prefrontal cortex tissue panels. We identified 13 associations (in 8 independent loci) at the transcriptome-wide significant level, of which 6 were not implicated in the previous GWAS: SKAP1, SLC36A1, CCDC57, FN3KRP, NCOA6/TRPC4AP. A fine-mapping approach prioritized CMTR1, RP1-153P14.5, PRPF6, and PPP3R1 – to our knowledge, the latter of which is the first RLS-associated gene directly implicated in dopaminergic pathways. Overall, our findings highlight the power of integrating gene expression data with GWAS to prioritize putative causal genes for functional follow-up studies.

Restless legs syndrome in ischemic stroke patients: clinical features and significance

To investigate the clinical features and implication of restless legs syndrome (RLS) in ischemic stroke patients. A total of 199 ischemic stroke patients were enrolled and assessed by polysomnography (PSG). RLS was identified according to criteria of International Restless Legs Syndrome Study Group. Epworth Sleepiness Scale (ESS), Mini-mental State Examination (MMSE) and Patient Health Questionnaire (PHQ-9) were used to evaluate the sleep quality, cognitive function and post-stroke depression, respectively. The National Institute of Health Stroke Scale (NIHSS) was used to evaluate the neurological function 3 months after stroke onset. Gender-and age-matched non-ischemic stroke patients with RLS (primary PLS) were selected as controls. Twenty-two cases of RLS were identified among 199 ischemic stroke patients (11.1%). Generalized linear model and logistic regression showed that low serum ferritin level (β=-133.3 mg/L, 95%CI:-200.4--0.1, P<0.01), subcortical infarction (OR=4.05, 95%CI:1.15-14.18, P<0.05) and female (OR=2.54, 95%CI:1.04-6.23, P<0.05) were identified as the risk factors of RLS in ischemic stroke patients. Compared with ischemic stroke patients without RLS, ESS increased by 4.37 (95%CI:2.33-6.41, P<0.01), PHQ-9 increased by 2.17 (95%CI:0.39--3.94, P<0.05), and reduced NIHSS from the baseline deceased by 0.97 (95%CI:-1.79--0.15, P<0.05) in ischemic stroke patients with RLS. In addition, the incidence of moderate-severe depression increased (OR=4.27, 95%CI:1.40-13.10, P<0.05) in ischemic stroke patients with RLS. The index of periodic leg movements of sleep (PLMS) with arousal in ischemic stroke patients with RLS was significantly higher than that in patients with primary RLS (β=12.85, 95%CI:2.04-23.67, P<0.05). RLS is common in ischemic stroke patients and has adverse influences on patients.

A case of restless legs syndrome with cold sensation successfully treated with acupuncture and moxibustion treatment

A case of restless legs syndrome with cold sensation successfully treated with acupuncture and moxibustion treatment

Evaluation of restless legs syndrome and sleep disorders in patients with psoriatic arthritis.

Restless legs syndrome (RLS) is aneurological disease with achronic course that is characterised by sleep disorders and sensorimotor impairment. The aim of this study was to evaluate the prevalence and severity of RLS in psoriatic arthritis (PSA) patients and those with psoriasis(P). The study included 50patients with psoriasis (28females, 22males), 50PSA patients (33females, 17males) and 50 healthy control subjects (34females, 16males), and all 3groups were matched with respect to age, gender and body mass index (BMI). Evaluations were made using the International RLS Rating Scale, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, Insomnia Severity Index, Fatigue Severity Scale (FSS), Beck Depression Index (BDI) and the SF-36 quality of life scores. RLS was determined at ahigher rate in the PSA patients (64.0%), compared to the Pgroup (20.0%, p < 0.001) and the control group (14.0%, p < 0.001). The number of moderate and severe RLS cases was significantly higher in the PSA group (68.7%) compared to the Pgroup (30%, p < 0.001) and the control group (0%, p < 0.001). In regression analysis, an independent correlation was found between the RLS score and PSQI (beta [β] = 0.269, p = 0.002), FSS (β = 0.243, p = 0.003), SF-36 physical score (β = 0.242, p = 0.004) and BDI (β = 0.177, p = 0.036). RLS was determined in PSA patients at ahigher rate than in psoriasis patients. The presence of RLS in PSA and psoriasis patients is related to impairments in sleep and quality of life, fatigue and depression.

Reassessing GWAS findings for the shared genetic basis of insomnia and restless legs syndrome.

Two genome-wide association studies (GWAS) suggest that insomnia and restless legs syndrome (RLS) share a common genetic basis. While the identified genetic variation in the MEIS1 gene was previously associated with RLS, the two GWAS suggest a novel and independent association with insomnia symptoms. To test the potential pleiotropic effect of MEIS1, we genotyped three MEIS1 variants in 646 chronic insomnia disorder (CID) patients with and without RLS. To confirm our results, we compared the allelic and genotypic distributions of the CID cohort with ethnically matched controls and RLS cases in the French Canadian cohort. The CID cohort was diagnosed by sleep medicine specialists and 26% of the sample received the combined diagnosis of CID+RLS. We find significant differences in allele and genotype distributions between CID-only and CID+RLS groups, suggesting that MEIS1 is only associated with RLS. Genotype distributions and minor allele frequencies of the three MEIS1 SNPs of the CID-only and control groups were similar (rs113851554: 5.3% vs. 5.6%; rs2300478: 25.3% vs. 26.5%; rs12469063: 23.6% vs. 24.4%; all p > 0.05). Likewise, there were no differences between CID+RLS and RLS-only groups (all p > 0.05). In conclusion, our data confirms that MEIS1 is a genetic risk factor for the development of RLS, but it does not support the pleiotropic effect of MEIS1 in CID. While a lack of power precluded us from refuting small pleiotropic effects, our findings emphasize the critical importance of isolating CID from other disorders that can cause sleep difficulties, particularly RLS, for future genetic studies.

Lack of Association Between Shape and Volume of Subcortical Brain Structures and Restless Legs Syndrome.

Previous studies on patients with restless legs syndrome (RLS) yielded inconclusive results in the magnetic resonance imaging (MRI)-based analyses of alterations of subcortical structures in the brain. The aim of this study was to compare volumes as well as shapes of subcortical structures and the hippocampus between RLS cases and controls. Additionally, the associations between the genetic risks for RLS and subcortical volumes were investigated. We compared volumetric as well as shape differences assessed by 3 T MRI in the caudate nucleus, hippocampus, globus pallidus, putamen, and thalamus in 39 RLS cases versus 117 controls, nested within a population-based sample. In a subsample, we explored associations between known genetic risk markers for RLS and the volumes of the subcortical structures and the hippocampus. No significant differences between RLS cases and controls in subcortical and hippocampal shapes and volumes were observed. Furthermore, the genetic risk for RLS was unrelated to any alterations of subcortical and hippocampal gray matter volume. We conclude that neither RLS nor the genetic risk for the disease give rise to changes in hippocampal and subcortical shapes and gray matter volumes.

A curious case of restless legs syndrome masquerading as akathisia

A curious case of restless legs syndrome masquerading as akathisia

Risk factors of primary and secondary restless legs syndrome among a middle-aged population in Saudi Arabia: A community-based study.

INTRODUCTION:Restless legs syndrome (RLS) is etiologically divided into primary and secondary syndromes. However, a comparative description of both types is lacking in the literature. We compared primary and secondary RLS with respect to demographic determinants, associated risk factors, and comorbidities.METHODS:Following a cross-sectional survey on the prevalence of RLS in a Saudi population, RLS cases were identified using the International RLS Study Group (IRLSSG) criteria. Cases were assessed with an interview-based questionnaire regarding baseline characteristics, risk factors, and comorbidities and with lower limb examinations and laboratory measurements. RLS severity was assessed using the IRLSSG Severity Rating Scale.RESULTS:In total, 78 patients with RLS, including 50 (64.1%) primary and 28 (35.9%) secondary cases, were examined. Of the primary cases, 35 (70%) were male; of the secondary cases, 25 (89.3%) were female (P < 0.001). Multivariate regression confirmed the association of male gender with primary RLS (odds ratio = 14.53, 95% confidence interval [2.9–75], P = 0.001). There were more dark- and black-skinned participants in the primary RLS group (38, 72%) than in the secondary group (15, 28%) (P = 0.042). Iron deficiency was observed in most (26, 92%) of the secondary cases. More severe symptoms were reported in secondary than in primary RLS cases (P < 0.05).CONCLUSIONS:Primary RLS is more common but less severe than secondary RLS. Male gender and ethnicity play significant roles in primary RLS, whereas female gender and iron deficiency may be the main risk factors associated with secondary RLS.