Validation of the self-completed Cambridge-Hopkins questionnaire (CH-RLSq) for ascertainment of restless legs syndrome (RLS) in a population survey.

BACKGROUND AND PURPOSE: Epidemiological studies of restless legs syndrome (RLS) have been limited by lack of a well validated patient-completed diagnostic questionnaire that has a high enough specificity to provide a reasonable positive predictive value. Most of the currently used patient completed diagnostic questionnaires have neither been validated nor included items facilitating the differential diagnosis of RLS from conditions producing similar symptoms. The Cambridge-Hopkins diagnostic questionnaire for RLS (CH-RLSq) was developed with several iterations to include items covering the basic diagnostic features of RLS and to provide some basic differential diagnosis. This validation study sought to determine the sensitivity and specificity of the RLS diagnosis based on this questionnaire. PATIENTS AND METHODS: The CH-RLSq was completed by 2005 blood donors who were asked to consent to being contacted for a telephone diagnostic interview. A scoring criterion was established for ascertainment of RLS based on the clinical definition of the disorder and the exclusion of "mimic" conditions. A weighted sample (N=185) of all completed questionnaires was selected for expert clinical diagnosis of RLS using the validated Hopkins Telephone Diagnostic Interview (HDTI). The telephone interviewers were blinded to all questionnaire responses. RESULTS: A telephone diagnosis was obtained on 183 of the sample's 185 questionnaires. The questionnaire's normalized sensitivity and specificity were 87.2% and 94.4%, respectively, for RLS compared to not RLS. The positive predictive values in this sample were 85.5%. CONCLUSIONS: The Cambridge-Hopkins RLS questionnaire provides a reasonable level of sensitivity and specificity for ascertainment of RLS in population-based studies

RLS and blood donation.

BACKGROUND AND PURPOSE: The link between brain iron deficiency and RLS is now well established. In a related observation, several conditions that can deplete iron stores have been linked to increased probability of RLS. Blood donation has been linked to iron deficiency. It has thus been hypothesized that donating blood may be a risk factor for developing RLS. PATIENTS AND METHODS: Two thousand and five UK blood donors, ranging from first-time donors to some who had donated more than 70 times, completed the validated Cambridge-Hopkins RLS questionnaire (CH-RLSq) following their donation session. The questionnaire included a set of questions designed to diagnose RLS. The donors' histories of blood donations were determined both from self-report and from the National Blood Service database. RESULTS: A number of statistical models were constructed to determine whether the probability of RLS diagnosis was related to the history of blood donations. Controlling for age and sex, no evidence was found to suggest that a greater number or frequency of blood donations increased the risk of RLS. Even amongst sub-groups especially vulnerable to iron depletion through blood donation, such as vegetarians or low weight individuals, no evidence for an increased risk of RLS could be found. CONCLUSIONS: We found no evidence that the frequency or number of blood donations up to the UK maximum of three times a year would increase the risk of RLS

Proteomic analysis of the cerebrospinal fluid of patients with restless legs syndrome/Willis-Ekbom disease

BACKGROUND: Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a sensorimotor disorder that causes patients to experience overwhelming and distressing sensations in the legs compelling the patient to move their legs to provide relief. The purpose of this study was to determine if biomarkers in the cerebrospinal fluid can distinguish RLS/WED patients from neurological controls. METHODS: We obtained CSF samples by lumbar puncture from 5 early-onset RLS/WED patients and 5 controls. We performed 2-dimensional difference in-gel electrophoresis (2D-DIGE). Proteins that were significantly altered were identified by Student’s t-test. Protein spots that were differentially expressed (p ≤ 0.05, Av. Ratio ≥ 2.0) between RLS/WED and control CSF samples were identified using MALDI-TOF-MS. Statistical analyses of the validation immunoblot assays were performed using Student’s t-test. RESULTS: In this discovery study we identified 6 candidate CSF protein markers for early-onset RLS/WED. Four proteins (Cystatin C, Lipocalin-type Prostaglandin D2 Synthase, Vitamin D binding Protein, and β-Hemoglobin) were increased and 2 proteins (Apolipoprotein A1 and α-1-acid Glycoprotein) were decreased in RLS/WED patients. CONCLUSIONS: Our results reveal a protein profile in the RLS/WED CSF that is consistent with clinical findings of disruptive sleep, cardiovascular dysfunction and painful symptoms. Moreover, protein profiles are consistent with neuropathological findings of activation of hypoxia inducible factor (HIF) pathways and alterations in dopaminergic systems. These data indicate the CSF of RLS/WED patients may provide information relevant to biological basis for RLS/WED, treatment strategies and potential new treatment targets

The utility of implantable loop recorders in patient management: an age- and indication-stratified study in the outpatient-implant era

INTRODUCTION: Implantable loop recorders (ILR) are now routinely implanted for long-term cardiac monitoring in the clinic setting. This study examined the real-world performance of these devices, focusing on the management decision changes made in response to ILR-recorded data. METHODS AND RESULTS: This was a single centre, prospective observational study of consecutive patients undergoing ILR implantation. All patients who underwent implantation of a Medtronic Reveal LINQ device from September 2017 to June 2019 at Barts Heart Centre were included.501 patients were included. 302 (60%) patients underwent ILR implantation for an indication of pre-syncope/syncope, 96 (19%) for palpitations, 72 (14%) for atrial fibrillation (AF) detection with a history of cryptogenic stroke and 31 (6%) for patients deemed to be high risk of serious cardiac arrhythmia.The primary outcome of this study was that an ILR-derived diagnosis altered management in 110 (22%) of patients. Secondary outcomes concerned sub-group analyses by indication: in patients who presented with syncope/presyncope, a change in management resulting from ILR data was positively associated with age (HR: 1.04 [95%CI 1.02-1.06]; p < 0.001) and negatively associated with a normal ECG at baseline (HR 0.54 [0.31-0.93]; p = 0.03). Few patients (1/57, 2%) aged < 40 years in this group underwent device implantation, compared to 19/62 patients (31%) aged 75 years and over (p = 0.0024). 22/183 (12%) of patients in the 40-74 age range had a device implanted.In patients who underwent ILR insertion following cryptogenic stroke, 13/72 patients (18%) had AF detected leading to a decision to commence anticoagulation. CONCLUSION: These results inform the utility of ILR in the clinical setting. Diagnoses provided by ILR that lead to changes in management are rare in patients under age 40, particularly following syncope, presyncope or palpitations. In older patients new diagnoses are frequently made and trigger important changes in treatment

Remote Clinics and Investigations in Arrhythmia Services: What Have We Learnt During Coronavirus Disease 2019?

The coronavirus disease 2019 (COVID-19) pandemic has had a dramatic impact on the way that medical care is delivered. To minimise hospital attendance by both patients and staff, remote clinics, meetings and investigations have been used. Technologies including hand-held ECG monitoring using smartphones, patch ECG monitoring and sending out conventional Holter monitors have aided remote investigations. Platforms such as Google Meet and Zoom have allowed remote multidisciplinary meetings to be delivered effectively. The use of phone consultations has allowed outpatient care to continue despite the pandemic. The COVID-19 pandemic has resulted in a radical, and probably permanent, change in the way that outpatient care is delivered. Previous experience in remote review and the available technologies for monitoring have allowed the majority of outpatient care to be conducted without obviously compromising quality or safety

Brain iron deficiency changes the stoichiometry of adenosine receptor subtypes in cortico-striatal terminals. Implications for restless legs syndrome

Brain iron deficiency (BID) constitutes a primary pathophysiological mechanism in restless legs syndrome (RLS). BID in rodents has been widely used as an animal model of RLS, since it recapitulates key neurochemical changes reported in RLS patients and shows an RLS-like behavioral phenotype. Previous studies with the BID-rodent model of RLS demonstrated increased sensitivity of cortical pyramidal cells to release glutamate from their striatal nerve terminals driving striatal circuits, a correlative finding of the cortical motor hyperexcitability of RLS patients. It was also found that BID in rodents leads to changes in the adenosinergic system, a downregulation of the inhibitory adenosine A1 receptors (A1Rs) and upregulation of the excitatory adenosine A2A receptors (A2ARs). It was then hypothesized, but not proven, that the BID-induced increased sensitivity of cortico-striatal glutamatergic terminals could be induced by a change in A1R/A2AR stoichiometry in favor of A2ARs. Here, we used a newly developed FACS-based synaptometric analysis to compare the relative abundance on A1Rs and A2ARs in cortico-striatal and thalamo-striatal glutamatergic terminals (labeled with vesicular glutamate transporters VGLUT1 and VGLUT2, respectively) of control and BID rats. It could be demonstrated that BID (determined by measuring transferrin receptor density in the brain) is associated with a selective decrease in the A1R/A2AR ratio in VGLUT1 positive-striatal terminals

The long-term treatment of restless legs syndrome/Willis–Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group

AbstractA Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) to develop evidence-based and consensus-based recommendations for the long-term pharmacologic treatment of restless legs syndrome/Willis–Ekbom disease (RLS/WED). The Task Force reviewed the results of all studies of RLS/WED treatments with durations of 6months or longer presented at meetings over the past 2years, posted on Web sites of pharmaceutical companies, or published in peer-reviewed journals, asking the questions, “What is the efficacy of this treatment in patients with RLS/WED?” and “What is the safety of this treatment in patients with RLS/WED?”The Task Force developed guidelines based on their review of 61 papers meeting inclusion criteria, and using a modified evidence-grading scheme. Pregabalin has been established as effective for up to 1year in treating RLS/WED (Level A evidence). Pramipexole, ropinirole, and rotigotine have been established as effective for up to 6months in treating RLS/WED (Level A). The following drugs have been established as probably effective (Level B) in treating RLS/WED for durations ranging from 1 to 5years: gabapentin enacarbil, pramipexole, and ropinirole (1year); levodopa (2years); and rotigotine (5years). Because of associated safety concerns, pergolide and cabergoline should not be used in the treatment of RLS/WED unless the benefits clearly outweigh the risks. Other pharmacologic therapies have insufficient evidence to support their long-term use in treating RLS/WED.The IRLSSG Task Force also developed consensus-based strategies for the prevention and treatment of complications (such as augmentation, loss of efficacy, excessive daytime sleepiness, and impulse control disorders) that may develop with the long-term pharmacologic treatment of RLS/WED. The use of either a dopamine-receptor agonist or α2δ calcium-channel ligand is recommended as the first-line treatment of RLS/WED for most patients, with the choice of agent dependent on the patient’s severity of RLS/WED symptoms, cognitive status, history, and comorbid conditions

A direct interaction between two Restless Legs Syndrome predisposing genes : MEIS1 and SKOR1

Restless Legs syndrome (RLS) is a common sleep disorder for which the genetic contribution remains poorly explained. In 2007, the frst large scale genome wide association study (GWAS) identifed three genomic regions associated with RLS. MEIS1, BTBD9 and MAP2K5/SKOR1 are the only known genes located within these loci and their association with RLS was subsequently confrmed in a number of follow up GWAS. Following this fnding, our group reported the MEIS1 risk haplotype to be associated with its decreased expression at the mRNA and protein levels. Here we report the efect of the risk variants of the three other genes strongly associated with RLS. While these variants had no efect on the mRNA levels of the genes harboring them, we fnd that the homeobox transcription factor MEIS1 positively regulates the expression of the transcription co-repressor SKOR1. This regulation appears mediated through the binding of MEIS1 at two specifc sites located in the SKOR1 promoter region and is modifed by an RLS associated SNP in the promoter region of the gene. Our fndings directly link MEIS1 and SKOR1, two signifcantly associated genes with RLS and also prioritize SKOR1 over MAP2K5 in the RLS associated intergenic region of MAP2K5/SKOR1 found by GWAS

Epidemiology of Insomnia in Korean Adults: Prevalence and Associated Factors

Background and Purpose Insomnia is a common complaint in adults. However, large epidemiologic studies of insomnia involving Asian populations are rarely reported. We performed an epidemiologic study of insomnia in a large Korean adult population. Methods A total of 5,000 subjects (2,470 men and 2,530 women) were interviewed by telephone. A representative sample of subjects aged 20 to 69 years was constituted according to a stratified, multistage random sampling method. Insomnia was defined as either any difficulty getting to sleep or getting back to sleep after waking in the night. Results More than one fifth (n=1,141, 22.8%) of the 5,000 subjects complained of insomnia, with the prevalence being significantly higher in women (25.3%) than in men (20.2%, P<0.001). Logistic regression revealed that the prevalence of insomnia increased significantly with age (p<0.001), being higher in those aged 60-69 years than in those aged 20-29 years (OR=2.368, 95% CI=1.762-3.182, p<0.001), and was lower in those with a monthly income of >4.5 million Korean won than in those with an income of <1.5 million Korean won (OR=0.689, 95% CI= 0.523-0.906,p<0.01). Conclusions Insomnia is a common complaint in Korean adults, and its prevalence is similar to that in adults in Western countries. J Clin Neurol 2009;5:20-23This work was supported by the research promoting grant from the Keimyung University Dongsan Medical Center in 2006