Idiopathic Restless Legs Syndrome Patients Research Articles

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.

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.

Changes in Hepcidin Serum Levels Correlate with Clinical Improvement in Idiopathic Restless Legs Syndrome Patients

Background: Restless legs syndrome (RLS) is a common sensory motor neurological disorder that is related to iron–dopamine dysregulation and immune system alteration. We aimed to assess the effects of serum hepcidin, an iron-regulating hormone, in drug-naive RLS patients compared to healthy controls and to evaluate its role in helping to predict clinical improvement after treatment with dopamine agonist. Methods: Nonanemic and drug-naive RLS patients (n = 18) and healthy controls (n = 15) were enrolled. The serum hepcidin and iron-related values in the serum were measured upon the first visit in both groups and 12 weeks later after dopaminergic treatment in 12 patients. Information about sociodemographic characteristics, sleep-related profiles, mood and anxiety was obtained upon the first visit in all participants as well as after treatment in RLS patients. Results: Serum hepcidin levels exhibited no significant differences between patients with drug-naïve RLS and healthy controls at diagnosis (7.1 ± 2.4 vs. 7.0 ± 3.2 ng/mL, p = 0.357). Decreased hepcidin levels were significantly associated with decreased RLS severity (β = 0.002, 95% CI = 0.00−0.00, p = 0.005) and improved quality of life (β = 0.002, 95% CI = 0.00−7.01, p = 0.044) in a dose-dependent manner after 12 weeks of treatment with a dopamine agonist. This association was independent of age, sex, inflammatory markers, sleep quality, insomnia, daytime sleepiness, depression and anxiety. Conclusions: This study demonstrates the role of hepcidin in evaluating the positive therapeutic response in RLS.

Serum vitamin D, vitamin D receptor and binding protein genes polymorphisms in restless legs syndrome.

Several studies showed lower serum 25-hydroxyvitamin D levels in patients with idiopathic restless legs syndrome (RLS) compared with matched controls, and a single study showed an association between the rs731236 single nucleotide polymorphism (SNP) in the vitamin D receptor (VDR) gene and the risk for RLS. We aimed to study the relationship between the serum 25-hydroxyvitamin D levels and to confirm previous findings related to SNPs in the VDR and the GC vitamin D binding protein (GC) gene, with the risk for RLS in the Spanish Caucasian population. We genotyped 285 idiopathic RLS patients and 325 age and sex-matched controls for VDRrs2228750, VDRrs7975232, VDRrs739837, VDRrs78783628, GCrs7041 and GCrs4588 SNPs using TaqMan assays, and determined serum 25-hydroxyvitamin D levels in 111 idiopathic RLS patients and 167 controls using an ELISA commercial kit. Serum 25-hydroxyvitamin D levels were significantly higher in RLS patients than in controls but were unrelated with the 7 SNPs studied. None of the 7 SNPs analyzed was associated with the risk for idiopathic RLS or with a positive family history of RLS. However, RLS patients carrying the rs7975232CC genotype or the rs7975232C allele, had a higher frequency of response to GABAergic drugs. Associations between the age at onset and the severity of RLS with SNPs were inconsistent. This study shows an association between increased serum concentrations of 25-hydroxyvitamin D and a lack of association between 7 SNPs in the VDR and in the GC genes with RLS in the Spanish Caucasian population.

Altered cortical gray matter volume and functional connectivity after transcutaneous spinal cord direct current stimulation in idiopathic restless legs syndrome

ObjectiveTo explore the neurophysiological mechanism of clinically effective transcutaneous spinal cord direct current stimulation (tsDCS) on idiopathic restless legs syndrome (RLS), structural magnetic resonance imaging (sMRI), and resting-state functional MRI (rs-fMRI) were applied to reveal the structural and functional changes in idiopathic RLS patients after tsDCS. MethodsThirty idiopathic RLS patients and 20 gender- and age-matched healthy controls (HC) were enrolled. All patients were randomly divided into anodal treatment group and sham treatment group and were treated with tsDCS for 2 weeks. The international RLS Rating Scale (IRLS-RS) and Pittsburgh Sleep Quality Index (PSQI) were used to evaluate the severity of RLS and sleep quality respectively. The sMRI and rs-fMRI data of anodal treatment group and HC were collected. Voxel-based morphology (VBM) and resting-state functional connectivity analysis were used to assess the change of cortical gray matter volume (GMV) and corresponding functional connectivity (FC) respectively in anodal treatment group after tsDCS treatment. ResultsSham treatment group showed no significant change in IRLS-RS and PSQI scores after tsDCS, while significant decrease scores were observed in anodal treatment group, and the improvement sustained up to 2 weeks. Anodal treatment group showed significant regional decrease of GMV in bilateral cuneus compared to the HC. After tsDCS treatment, the GMV in the bilateral cuneus and left ventral post central gyrus (PoCG_L) decreased significantly. The FC between bilateral cuneus and left primary visual cortex (V1_L), and between right cuneus (Cune_R) and right lingual gyrus (LG_R) increased significantly after tsDCS, whereas the FC between PoCG_L and supplementary motor area (SMA) decreased significantly. The changed FC between PoCG_L and SMA, between Cune_R and V1_L were correlated with the changed IRLS-RS. ConclusionDisturbance of sensorimotor network and visual processing network may be involved in the pathogenesis of RLS. tsDCS probably can regulate FC in the sensorimotor cortex and visual processing cortex to relieve the symptom of RLS. Continuous tsDCS may improve the symptoms of RLS patients for a long time. tsDCS probably could provide a potential non-pharmacologic treatment for idiopathic RLS patients.

0796 Dipyridamole for the Treatment of RLS: Preliminary Results of a Cross-Over, Placebo-Controlled, Double-Blind Trial

Abstract Introduction Recent animal models of restless legs syndrome (RLS) suggest that brain iron deficiency is associated with a hypoadenosinergic state, with downregulation of adenosine A1 receptors (A1R) in the striatum. Dipyridamole is a non-selective inhibitor of ENT1/ENT2 (the main reuptake mechanism of adenosine) and increases thereby extracellular adenosine. We hypothesized that treatment with dipyridamole would improve RLS symptoms more than placebo. Methods We performed a randomized, double-blind, placebo-controlled clinical trial on 15 previously untreated idiopathic RLS patients that underwent a two week treatment with either 300 mg dipyridamol or placebo (randomized for the order of treatments), following a cross-over design. Treatment started with a dose of 100 mg/day, followed by a forced up-titration to 200 mg on day 4, and to 300 mg on day 7. Severity was assessed at baseline, day 7 and day 14 of each treatment condition by means of the IRLS and CGI scales. The primary endpoint was therapeutic response (50% improvement in IRLS total score). Results Fifteen patients (nine women), never before treated with dopaminergic agents, completed both arms of the study. Mean age was 60,2 (±7,1), and the mean duration of illness was 6,03 (±3,1) yrs. IRLS score improved during treatment with dipyridamole from a mean (±S.D.) of 24,36 (±3,3) to 9,78 (±3,4), in contrast to a change from 23,9 (±3,8) to 16,6 (±3,7) under placebo (p< 0.05). Corresponding improvements on the CGI were 61,3% and 11,8% for dipyridamole and placebo, respectively. 7/ 15 patients improved by more than 50% during treatment with dipyridamole vs. 4/15 under placebo. Main side effects were abdominal cramps, diarrhea, dizziness, and flushing. Conclusion These preliminary results suggest that dipyridamole is an effective agent on RLS symptoms. It also provides evidence of hypoadenosinergic mechanisms playing a central role in RLS. Support No funding was provided for this investigation.

Increased Gray Matter Density and Functional Connectivity of the Pons in Restless Legs Syndrome.

BackgroundNeurophysiological and radiological studies provide accumulating evidence for the involvement of the brainstem in the pathogenesis of restless legs syndrome (RLS). The analysis of the various subregions of the brainstem may help us better understand the pathophysiological mechanisms underlying the disorder. In this study, we investigated the structural and functional changes in the various subregions of the brainstem in RLS patients.MethodsThe subregional changes in gray matter density and functional connectivity in the brainstem were analyzed in 20 drug-naive idiopathic RLS patients, as well as 18 normal control (NC) subjects for comparison. Correlation analyses and multivariate pattern analyses using linear support vector machine (SVM) were conducted.ResultsWe found significantly increased gray matter density in two clusters in the pons (designated pons_1 and pons_2) and in one cluster in the midbrain in RLS patients compared with NC subjects. Further functional connectivity analyses revealed significantly decreased functional connectivity between the midbrain and the right middle occipital gyrus, between pons_1 and the right orbital part of the superior frontal gyrus, and between pons_2 and the right parahippocampus in RLS compared with NC. Moreover, the functional connectivity between pons_2 and the right supplementary motor area (SMA) was significantly increased in RLS compared with NC. This change in RLS was marginally correlated with RS_RLS scores in the RLS patients. SVM-based classification showed an AUC of 0.955 using gray matter density of pons_2, and functional connectivity between pons_2 and SMA as features.ConclusionCollectively, our findings suggest that changes in gray matter density and functional connectivity in the pons may play a pathologic role in RLS. Furthermore, these abnormal changes in the pons might help to discriminate RLS from healthy subjects.

Resting-state connectivity and the effects of treatment in restless legs syndrome

ObjectivesResting-state brain connectivity has been shown to differ for Restless Legs Syndrome (RLS) compared to healthy control (CON) groups. This study evaluates the degree these RLS-CON differences are changed by concurrent treatment. MethodsResting-state functional MRIs were obtained from 32 idiopathic RLS patients during the morning asymptomatic period and 16 age and gender-matched CON subjects. Of the 32 RLS patients, 16 were drug-naïve (DN-RLS), and 16 were regularly drug-treated using a dopamine agonist (DT-RLS). Various assessments of disease characteristics were also performed. The primary purpose was to assess the replicability of prior results and the effects of treatment on these differences between controls and untreated RLS patients. Resting-state connectivity was analyzed by a seed-based method using the bilateral ventral-posterolateral nuclei (VPLN) in the thalamus. ResultsIn the DN-RLS group, compared to the CON group, three areas (the bilateral lingual gyri and right middle temporal gyrus) were replicated. The three replicated areas did not significantly differ for DT-RLS compared to DN-RLS. DT-RLS compared to DN-RLS had significantly higher thalamic connectivity for the left uvula, right tuber, left anterior insula, and right declive. ConclusionsThalamic connectivity to the bilateral lingual gyri and right middle temporal gyrus is a replicable finding in DN-RLS that was not affected by dopamine agonist treatments. Other changes in thalamic connectivity were altered by dopamine agonist treatment. These treatment effects may be pertinent to the known treatment benefits of a dopamine agonist on RLS symptoms.

Abnormal Circadian Modification of Aδ-Fiber Pathway Excitability in Idiopathic Restless Legs Syndrome.

Restless legs syndrome (RLS) is characterized by unpleasant sensations generally localized to legs, associated with an urge to move. A likely pathogenetic mechanism is a central dopaminergic dysfunction. The exact role of pain system is unclear. The purpose of the study was to investigate the nociceptive pathways in idiopathic RLS patients. We enrolled 11 patients (mean age 53.2 ± 19.7 years; 7 men) suffering from severe, primary RLS. We recorded scalp laser-evoked potentials (LEPs) to stimulation of different sites (hands and feet) and during two different time conditions (daytime and nighttime). Finally, we compared the results with a matched control group of healthy subjects. The Aδ responses obtained from patients did not differ from those recorded from control subjects. However, the N1 and the N2-P2 amplitudes' night/day ratios after foot stimulation were increased in patients, as compared to controls (N1: patients: 133.91 ± 50.42%; controls: 83.74 ± 34.45%; p = 0.016; Aδ-N2-P2: patients: 119.15 ± 15.56%; controls: 88.42 ± 23.41%; p = 0.003). These results suggest that RLS patients present circadian modifications in the pain system, which are not present in healthy controls. Both sensory-discriminative and affective-emotional components of pain experience show parallel changes. This study confirms the structural integrity of Aδ nociceptive system in idiopathic RLS, but it also suggests that RLS patients present circadian modifications in the pain system. These findings could potentially help clinicians and contribute to identify new therapeutic approaches.

Impaired slow oscillation, sleep spindle, and slow oscillation−spindle coordination in patients with idiopathic restless legs syndrome

ObjectivesThalamocortical abnormalities have been implicated in the pathophysiology of restless legs syndrome (RLS). We hypothesized that sleep spindle and slow oscillation (SO) activity is impaired in RLS, and that this dysfunction may contribute to sleep disturbance in these patients. To address this issue, we characterized sleep spindle and SO activity in RLS. MethodsFifteen drug-naive, idiopathic RLS patients (13 female and 2 male) and 15 female healthy controls participated in this study. Nineteen-channel electroencephalograms were obtained during polysomnographic (PSG) recordings. An automated sleep spindle and SO detection algorithm was used to detect sleep spindle (12–16 Hz) and SO (<1 Hz) activity. The quantitative characteristics of sleep spindle and SO activity were investigated. ResultsCompared with the healthy controls, in RLS patients, we observed density and power reduction in sleep spindles. In SOs, density reduction and duration increment were shown in RLS patients. In addition, SO−spindle coordination was deficient in RLS as revealed by reduced SO locked spindle power, dispersed and delayed spindle phase, and decreased SO−spindle coupling. Although sleep spindle power was negatively correlated with wake after sleep onset (WASO) time, SO duration was positively correlated with the arousal index in RLS. ConclusionsOur study suggests that sleep disturbances may be mediated by a combined deficit in spindle and SO activity and SO−spindle coordination. The abnormal SO and spindle activity observed in RLS support the notion that thalamocortical abnormalities underlie this condition and may promote disturbed sleep integrity.

Clinical and Polysomnographic Characteristics of Patients with Restless Legs Syndrome

Background and Objective Although restless legs syndrome (RLS) symptoms are relatively clear, many people are suffering from RLS without proper care because RLS is often underdiagnosed and misdiagnosed. Purpose of this study was to examine clinical and polysomnographic aspects of RLS to better understand the disorder for future diagnosis. Methods This study enrolled 113 idiopathic untreated RLS patients, including 74 (65.5%) women and 39 (34.5%) men. Restless legs syndrome rating scale (RLSRS) and RLS checklist were examined. All patients underwent suggested immobilization test (SIT) and polysomnogram (PSG). Results RLS occurred in all age groups. It was the most prevalent in age groups of 50s and 60s. On average, RLS was diagnosed 12.5 years after the first occurrence of RLS symptoms. RLS occurred twice as often among women than that among men. Based on average RLSRS, 57.5% and 26.5% of patients belonged to severe and very severe categories, respectively. While symptoms were the most prominent between 8 PM and 4 AM, patients reported that calves were the main site of discomfort. Of all participants, 54.9% reported family history of RLS. RLS patients’ PSGs showed lower sleep efficiency (SE), total sleep time, and slow wave percentage with higher leg movement arousal index (LMAI), arousal index, and sleep latency (SL). RLSRS was positively correlated with LMAI (r = 0.221, p < 0.05), periodic leg movement during wake index-PSG (PLMWI-PSG) (r = 0.214, p < 0.05), and SL (r = 0.207, p < 0.05). RLSRS was also negatively correlated with SE (r = -0.222, p < 0.05). RLSRS was not correlated with PLMWI-SIT or PLMI. Conclusions The results suggest that the severity of RLS patients is related to SL, LMAI, PLMWI-PSG, and SE. In order to effectively diagnose RLS, not only clinical characteristics, but also polygraphic characteristics such as SL, LMAI, PLMWI-PSG, and SE should be taken into account. Key words: Restless legs syndrome, Characteristics, Correlates, Polysomnography

Mapping the changed hubs and corresponding functional connectivity in idiopathic restless legs syndrome

ObjectiveThe hubs of the brain network play a key role in integrating and transferring information between different functional modules. However, whether the changed pattern in functional network hubs contributes to the onset of leg discomfort symptoms in restless legs syndrome (RLS) patients remains unclear. Using resting-state functional magnetic resonance imaging (rs-fMRI) and graph theory methods, we investigated whether alterations of hubs can be detected in RLS. MethodsFirst, we constructed the whole-brain voxelwise functional connectivity and calculated a functional connectivity strength (FCS) map in each of 16 drug-naive idiopathic RLS patients and 26 gender- and age-matched healthy control (HC) subjects. Next, a two-sample t test was applied to compare the FCS maps between HC and RLS patients, and to identify significant changes in FCS in RLS patients. To further elucidate the corresponding changes in the functional connectivity patterns of the aberrant hubs in RLS patients, whole-brain resting-state functional connectivity analyses for the hub areas were performed. ResultsThe hub analysis revealed decreased FCS in the cuneus, fusiform gyrus, paracentral lobe, and precuneus, and increased FCS in the superior frontal gyrus and thalamus in idiopathic drug-naive RLS patients. Subsequent functional connectivity analyses revealed decreased functional connectivity in sensorimotor and visual processing networks and increased functional connectivity in the affective cognitive network and cerebellar–thalamic circuit. Furthermore, the mean FCS value in the superior frontal gyrus was significantly correlated with Hamilton Anxiety Rating Scale scores in RLS patients, and the mean FCS value in the fusiform gyrus was significantly correlated with Hamilton Depression Rating Scale scores. ConclusionsThese findings may provide novel insight into the pathophysiology of RLS.

Treatment of restless legs syndrome/Willis-Ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis

ObjectivesRecent animal models of restless legs syndrome (RLS) suggest that brain iron deficiency is associated with a hypoadenosinergic state, with downregulation of adenosine A1 receptors (A1R) in the striatum and cortex. We hypothesized that an increase in extracellular adenosine induced by inhibitors of adenosine transporters, such as the non-selective ENT1/ENT2 inhibitor dipyridamole, would result in an improvement in RLS symptoms. MethodsIn a prospective two-month open-label, non-placebo controlled clinical trial, 15 untreated idiopathic RLS patients began treatment with 100 mg dipyridamole (with uptitration to 400 mg if necessary). Multiple Suggested Immobilization Tests and polysomnography were performed at baseline and at eight weeks. Severity was assessed at four and eight weeks using the IRLS, and the CGI scales. The primary endpoint was therapeutic response (50% improvement in IRLS total score). ResultsThirteen patients completed the study. IRLS score improved from a mean (±S.D.) of 23.4 ± 4.6 at baseline to 10.7 ± 4.5 at eight weeks. Six out of 13 patients were full responders and four were partial responders. The mean (±S.D.) effective dose of dipyridamole at eight weeks was 281.8 ± 57.5 mg/day. Sleep variables also improved, and the mean (±S.D.) periodic leg movement index decreased from 26.7 ± 7.2 to 4.3 ± 1.9. Dipyridamole was generally well tolerated. Main side effects were abdominal cramps, diarrhea, dizziness, and flushing. ConclusionsThese preliminary results suggest that dipyridamole has significant therapeutic effects on both sensory and motor symptoms, as well as sleep. In addition, it provides evidence that hypoadenosinergic mechanisms play a central role in RLS. Classification of evidenceThe study provides class III evidence supporting the therapeutic effects of dipyridamole in RLS.

Clinical efficacy of ferric carboxymaltose treatment in patients with restless legs syndrome

ObjectiveThere have been three randomized, placebo-controlled, double-blind studies of intravenous iron in restless legs syndrome (RLS), with differing outcomes. The one positive study used ferric carboxymaltose (FCM) at a total dose of 1000 mg. The purpose of this study was to replicate and extend the findings from the prior FCM study. MethodsNon-anemic, idiopathic RLS patients were enrolled in a randomized, double-blinded, placebo-controlled study and received either 1000 mg FCM or placebo as a single infusion (phase I). Subjects were off any RLS medications for at least two weeks prior to baseline assessment. The primary outcome variable was change from baseline at week 6 on the International Restless Legs Syndrome Severity (IRLSS) scale and a subject-completed, visual analog scale (VAS) of severity. Phase II of the study involved long-term (30 weeks) follow-up after completion of the six-week efficacy phase. ResultsAt week 6 postinfusion, FCM compared to placebo recipients showed significantly greater change from baseline for both primary outcome measures (IRLSS scale, −11.9 ± 8.04 vs −7.88 ± 5.89, p = 0.03; VAS, −40.6 ± 22.7 vs −21.3 ± 20.0, p = 0.001). None of the secondary outcome variables showed a significant difference at week 6. After six weeks of treatment, the FCM group had 19 (59.4%) responders, of which 12 had IRLSS scores <10 (“remitters”). Twelve (37.5%) of the 32 subjects treated with iron in phase I remained free of further RLS medications at 30 weeks. There were no serious adverse events observed in this study. ConclusionTwo studies now support the value of FCM treatment both in the short term (six weeks) and long term (30 weeks) for improving RLS symptoms.

Reduced afferent-induced facilitation of primary motor cortex excitability in restless legs syndrome

Restless legs syndrome (RLS) is characterized by the association of an urge to move, and vesperal or nocturnal sensory symptoms; it is frequently associated with periodic limb movements. Evidence from imaging and electrophysiological studies suggests that RLS is linked to changes in sensorimotor integration. Nevertheless, the underlying mechanisms have not been characterized, and the cortical origin has yet to be confirmed.The objective of the present study was to establish whether or not sensorimotor integration in RLS patients is impaired in the evening. The time-dependent modulation of motor cortex excitability following peripheral electric nerve stimulation was studied in 14 idiopathic RLS patients, and 14 paired healthy controls. Different inter-stimulus intervals were used to measure short-latency and long-latency afferent inhibition (SAI and LAI) and afferent-induced facilitation (AIF). Motor evoked potentials were recorded from the first dorsal interosseous muscle in two experimental sessions (one in the morning and one in the evening).With the exception of LAI (which was present in the morning but absent in the evening in both healthy controls and RLS patients), no circadian variations were observed in sensorimotor integration. Although SAI was present in patients with RLS, AIF was disrupted (relative to controls) – suggesting the presence of an indirect sensorimotor integration disorder affecting the long corticocortical pathways in patients with RLS. The lack of circadian modulation in sensorimotor integration suggests that clinical circadian variations have other causes.

Mapping intrinsic functional brain changes and repetitive transcranial magnetic stimulation neuromodulation in idiopathic restless legs syndrome: a resting-state functional magnetic resonance imaging study

ObjectiveThe objectives of this study were, first, to explore differences in brain activity between normal people and idiopathic restless legs syndrome (RLS) patients during asymptomatic periods; and, second, to determine whether administering repetitive transcranial magnetic stimulation (rTMS) to specific cortical regions would reverse any observed differences in brain activity and alleviate patient symptoms. MethodsFifteen idiopathic RLS patients (nine drug-naive patients) and 14 gender- and age-matched healthy controls were enrolled. Resting-state functional magnetic resonance imaging was used to measure the amplitude of low-frequency fluctuations (ALFF) in spontaneous brain activity during asymptomatic periods. Seven patients received high-frequency (5 Hz) rTMS directed toward the leg area of the primary motor cortex. Scores on the International Restless Legs Syndrome Study Group (IRLSSG) Rating Scale and ALFF values were measured before and after treatment. ResultsCompared with healthy controls, RLS patients showed lower ALFF in the sensorimotor and visual processing regions, and higher ALFF in the insula, parahippocampal and hippocampal gyri, left posterior parietal areas, and brainstem. These results were largely conserved when only drug-naive patients were considered. After rTMS treatment, ALFF in several sensorimotor and visual regions were significantly elevated and IRLSSG Rating Scale scores decreased, indicating improved RLS symptoms. ConclusionsHigh-frequency rTMS delivered to the leg area of the primary motor cortex may raise functional activity in the sensorimotor and occipital regions, leading to improve symptoms in RLS patients. These results provide novel insight into RLS pathophysiology and suggest a potential mechanism for rTMS therapy in idiopathic RLS patients.

Augmentation in restless legs syndrome patients in Korea.

Augmentation has been known as the major complication of long-term dopaminergic treatment of restless legs syndrome (RLS). However, there have been no reports on the prevalence of augmentation in Korea. Thus, we aimed to assess the rate of augmentation and evaluate related factors in Korean RLS patients. Ninety-four idiopathic RLS patients who have been treated over a period of at least 6 months were enrolled. Thirty subjects were treated with a dopamine agonist only, and 64 were treated with a dopamine agonist and alpha two delta ligands. We assessed the clinical characteristics of those RLS subjects and evaluated the rate of augmentation. Augmentation was assessed using the NIH criteria for augmentation by two RLS experts independently. Eleven subjects (11.7%) were classified as having definitive or highly suggestive clinical indication of augmentation. In comparing the augmentation group with the non-augmentation group, there were no significant differences of baseline clinical characteristics. Four (13.3%) of the dopamine agonists monotherapy group and seven (10.9%) of the combination therapy group were categorized as augmentation. There was no significant difference in the augmentation rate between these two groups. We found an 11.7% augmentation rate in Korean RLS subjects. There was no difference in the rate of RLS augmentation between the dopaminergic monotherapy group and the combined treatment group. It may be related with using a similar dosage of dopaminergic drugs.

Gray matter anomalies in anterior cingulate cortex as a correlate of depressive symptoms in drug-naïve idiopathic restless legs syndrome

BackgroundDepressive symptoms are frequent in idiopathic restless legs syndrome (RLS). However, little is known, so far, about the neurological basis. The present study aimed to explore the neuroanatomical anomalies in depressed drug-naïve RLS patients using voxel-based morphometry (VBM) analysis. MethodsWe recruited 16 drug-naïve idiopathic RLS patients with depressive symptoms (RLS-D), 18 drug-naïve idiopathic RLS patients without depressive symptoms (RLS-ND), and 18 normal controls. All participants underwent structural MRI scans on a 3-T MR system. The differences in regional gray matter (GM) density were determined across groups by VBM8. Additional regression analysis was used to identify any associations between regional GM density and clinical symptoms. ResultsGM density of the bilateral anterior cingulate cortex (ACC) was significantly reduced in RLS-D patients when compared to RLS-ND patients or to the healthy controls. However, there were no significant differences of GM density either when the whole RLS group or the RLS-ND group was compared to healthy controls, respectively. Particularly, we found GM density of right ACC was negatively correlated with the severity and duration of depressive symptoms in RLS-D patients. ConclusionsDepressive symptoms are associated with GM anomalies in ACC in patients with RLS. We propose that ACC is perhaps an important neuroimaging marker for facilitating treatment strategies in patients with RLS when assessing depressive symptoms.

Low brain iron content in idiopathic restless legs syndrome patients detected by phase imaging

The objective of this study was to use phase imaging to evaluate brain iron content in patients with idiopathic restless legs syndrome (RLS). Fifteen RLS patients and 15 healthy controls were studied using gradient-echo imaging. Phase analysis was performed on localized brain regions of interest selected on phase maps, sensitive to paramagnetic tissue. Differences between the 2 subject groups were evaluated using ANCOVA including age as a covariate. Significantly higher phase values were present in the RLS patients compared with healthy controls at the level of the substantia nigra, thalamus, putamen, and pallidum, indicating reduced iron content in several regions of the brain of the patients. We have used MRI phase analysis to study brain iron content in idiopathic RLS in vivo for the first time. Our results support the hypothesis of reduced brain iron content in RLS patients, which may have an important role in the pathophysiology of the disorder.

Periodic Limb Movements in Sleep and Cardiovascular Disease: Time to Act

Periodic limb movements in sleep (PLMS) is a common sleep disorder in both the general population and in patients with chronic diseases such as patients receiving hemodialysis therapy. PLMS can be assessed during an overnight polysomnographic examination and are described as repetitive, stereotypical, and unconscious leg movements that occur during sleep. It is noteworthy, that PLMS are present in up to 80% of patients with a condition occurring during wakefulness, called restless legs syndrome (RLS). Indeed, the presence of PLMS is considered to be one of the supportive criteria for the diagnosis of the later condition (1). PLMS may also occur in patients with sleep apnea, narcolepsy, and rapid eye movement behavior disorder or even can be present in patients without any sleep or medical-related pathological condition, and especially in the elderly (2). PLMS could cause significant sleep disturbance and result in non-restorative sleep via its associated arousals and motor restlessness. It is logical then to assume that as PLMS interferes with the expected sleep associated dipping of blood pressure (3), it may constitute a risk factor for cardiac disease and mortality. Notably, a role of PLMS as a predictor of mortality has been proposed in small survival study by Benz et al. (4) in which PLMS was strongly and independently associated with mortality in renal patients. Recently direct observations on cardiac structure added strong support on the association between the severity of PLMS and cardiovascular (CV) mortality and morbidity first in secondary RLS by us (5) and then verified in idiopathic RLS patients (6) as well.