Search Results (115)

Objective: Restless leg syndrome (RLS) has been associated with an increased risk of vascular disorders, which suggests that endothelial dysfunction plays an important role in the pathogenesis of RLS. In this study, we aimed to evaluate coronary endothelial dysfunction in RLS patients using coronary flow velocity reserve (CFVR) and compared it with healthy controls. Methodology: In this study, the participants were divided into two groups as group RLS (n = 42) and group HC (n = 41). The primary outcome was the CFVR compared between groups. The number of participants with a CFVR value below 2.0 was also evaluated. In addition, a correlation between the international restless legs scale (IRLS) and CFVR, white-blood-cell-count (WBC), and C-reactive protein (CRP) was analyzed. Secondary outcomes were the WBC, hemoglobin, CRP, blood glucose, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and creatinine compared between the two groups. Results: In the group RLS, CFVR was measured lower than healthy controls (p < 0.001). When the groups were compared in terms of the number of participants with a CFVR less than 2.0, the difference between the groups was significant (p < 0.001, 0/41 in group HC and 14/42 in group RLS). Patients with RLS had higher WBC and CRP values. There was a negative correlation between CFVR and IRLS (p < 0.001). The relationship between WBC, CRP, and IRLS was not statistically significant (p = 0.691). Conclusions: In this exploratory study, RLS patients had lower CFVR compared with healthy controls and a negative correlation was observed between RLS severity and CFVR. These findings warrant confirmation in larger, prospectively designed studies with multivariable adjustment. Therefore, we think that it may be beneficial to follow-up patients with RLS in terms of coronary heart disease. Clinical trial number: not applicable. Full article

Background: Restless legs syndrome (RLS) is very common among pregnant women; its prevalence corresponds to parity and occurs more frequently in the later stages of pregnancy. It is associated with numerous adverse pregnancy outcomes such as an increased risk of Caesarean section, preeclampsia, insomnia, and depression. Medical treatment of RLS during pregnancy is challenging considering the risks to both the mother and fetus. Case Description: In this report, we describe the case of a 44-year-old, seventh-time multiparous woman with a positive family history of RLS who presented with severe symptoms in her 24th week of pregnancy. She has had symptoms of RLS in every pregnancy thus far, usually starting in the second trimester, with an ineffective therapeutic response to diazepam and uncomfortable sensations, which usually resolve spontaneously a few weeks after delivery. After replacing diazepam with low-dose clonazepam, the patient reported complete disappearance of unpleasant sensations in her legs, with a significant improvement in her quality of life. Conclusions: A low dose of clonazepam is a good therapeutic option for the treatment of RLS during pregnancy and, if necessary, can also be considered the therapy of choice during lactation. Full article

Objective: Recent research has expanded the understanding of the potential role of sympathetic nervous system activation in the implications of sleep-related movement disorders, particularly in the mechanisms of dopaminergic dysfunction and iron deficiency. This multifactorial perspective aims to provide insights into disease mechanisms and opportunities for targeted interventions that address both neurological and autonomic contributors to sleep-related movements. Methods: To synthesize the current evidence on the role of sympathetic activation in sleep-related movement disorders, we conducted a review of the literature to identify studies exploring the intersection of autonomic nervous system activity and motor phenomena during sleep. Results: Studies indicate that sympathetic activation may contribute directly to the initiation and propagation of motor events during sleep. Evidence from electrophysiological studies and heart rate variability analyses in patients with sleep-related movement disorders shows that sympathetic bursts often precede or coincide with leg movements and arousals, suggesting a causal rather than reactive role. Moreover, iron deficiency appears to exacerbate both dopaminergic and autonomic dysfunction, providing a unifying mechanism that bridges these pathways. Conclusions: These findings support a shift from viewing sympathetic activity as a secondary response to arousal to recognizing it as a possible primary trigger of sleep-related motor events. Full article

Restless legs syndrome (RLS) is a common sensorimotor disorder with limited treatment options and incompletely understood pathophysiology. Genome-wide association studies have identified numerous risk loci, but translating these findings into causal genes and therapeutic targets remains challenging. We performed a proteome-wide association study (PWAS) integrating RLS genome-wide association study (GWAS) data from FinnGen with two brain pQTL datasets (ROSMAP and Banner). We validated the identified proteins using TWAS, SMR, and colocalization analyses using brain pQTL and eQTL datasets. To further investigate peripheral protein associations, we performed SMR using plasma pQTL data from the UK Biobank Pharma Proteomics Project (UKB-PPP). We also conducted a phenome-wide association study (PheWAS) to screen for potential off-target effects of the prioritized genes, followed by drug prediction using DSigDB and molecular docking. PWAS identified GLO1, along with GRWD1 and MAP2K5, as significantly associated with RLS. GLO1 was identified by brain-based SMR (p = 0.0001), colocalization (PP.H4 = 0.96), TWAS (p = 0.048), and was confirmed by plasma-based SMR (p = 3.16 × 10⁻⁹) as the only protein associated with RLS. PheWAS analysis, without associations for 783 non-RLS phenotypes, confirmed the specificity of GLO1. Among 27 predicted GLO1-targeting compounds, Gambierol had the strongest binding affinity (−8.3 kcal/mol). This proteogenomic study identifies GLO1 as a prioritized causal gene and promising drug target for RLS, combining brain and plasma data to provide new insights into pathogenesis and candidate drug development. Full article

Restless legs syndrome (RLS) is a common yet underrecognized neurological disorder characterized by uncomfortable sensations and an irresistible urge to move he legs, typically following a circadian pattern. RLS frequently co-occurs with various other neurological diseases, raising questions about shared mechanisms and clinical consequences. This review synthesizes evidence on the prevalence, outcomes, and pathophysiology of RLS in various neurological disorders, including Parkinson’s disease, multiple sclerosis, migraine, dementia, stroke, epilepsy, and peripheral neuropathy. In Parkinson’s disease, RLS is linked to disease progression and dopaminergic therapy. In stroke and multiple sclerosis, RLS is associated with structural lesions at specific locations, such as the pons or spinal cord. In epilepsy, RLS is associated with refractory or nocturnal seizures. In neuropathies, disruption of small sensory fibers may contribute to RLS symptoms. In dementia, RLS adds diagnostic complexity. Overlapping mechanisms between RLS and its neurological comorbidities include altered sensorimotor processing, brainstem and spinal circuitry, and sleep/arousal regulation. RLS in neurological conditions often worsens sleep quality, mood, and fatigue, and contributes to reduced quality of life and worse outcomes. Future research should prioritize longitudinal designs, standardized diagnostic approaches, and mechanistically driven studies to clarify relationships between RLS and these neurological comorbidities. Full article

Restless legs syndrome (RLS) is traditionally conceptualized as a dopamine-responsive sensorimotor disorder; however, new evidence suggests a more complex and heterogeneous neurobiological basis. Findings from neuroimaging, genetic studies, circadian biology, and clinical research indicate that dopaminergic dysfunction occurs within a broader context of neuromodulatory imbalance involving iron metabolism, adenosinergic signalling, glutamatergic excitability, and, potentially, noradrenergic pathways. In parallel, quantitative susceptibility mapping and related approaches have provided indirect evidence of altered brain iron distribution, although results remain variable across studies. Clinically, RLS extends beyond nocturnal discomfort and is associated with sleep fragmentation, impaired quality of life, and neuropsychiatric comorbidity, as well as treatment-related complications such as augmentation. However, current diagnostic frameworks remain predominantly phenomenological, and available biomarkers lack sufficient validation for routine clinical use. In this narrative review, the available clinical, genetic, and neuroimaging evidence is synthesized to propose an integrative, network-based model in which iron-dependent neuromodulatory processes influence excitability across cortico–striatal–thalamo–limbic circuits. This framework is intended as a hypothesis-generating model rather than a definitive explanation of disease mechanisms. Substantial heterogeneity across studies, together with variability in clinical presentation and limited reproducibility of candidate biomarkers, underscores the need for standardized methodologies and longitudinal, multimodal investigations. Future work should aim to test this model empirically, refine biological stratification, and determine whether network-informed approaches can improve diagnosis and therapeutic targeting in RLS. Full article

Sleep is tightly regulated by thermoregulatory processes that include core body temperature (CBT) modulation, the distal–proximal temperature gradient (DPG), and melatonin rhythms. In this review, we examine how these factors intersect with sleep physiology and contribute to the pathophysiology of common sleep disorders such as ADHD, insomnia, narcolepsy, Obstructive Sleep Apnea (OSA), depression, and Restless Legs Syndrome (RLS). We discuss evidence showing that delayed or disrupted CBT minima, impaired DPG, and altered melatonin secretion can prolong sleep latency, fragment rest, and lead to daytime symptoms. In addition, we explore temperature-based interventions, including foot baths, passive body heating, whole-body hyperthermia, and adjustments in room temperature, which have demonstrated potential to mitigate symptoms and enhance sleep quality. Collectively, these findings emphasize the need for personalized interventions to address thermoregulatory disruptions, presenting a noninvasive avenue for more effective sleep disorder management. Full article

Restless legs syndrome (RLS) is one of the most prevalent sleep disorders, yet its diagnosis continues to rely almost entirely on subjective symptom descriptions. This persistent dependence on phenomenology reflects the absence of reliable biological markers to aid in the process of diagnosis or monitoring. However, there is accumulating molecular evidence that suggests that RLS is associated with systemic biological alterations. These extend beyond the traditional paradigm of iron deficiency. The present scoping review synthesizes the current research on circulating serum biomarkers investigated in RLS outside classical iron indices. A comprehensive search of PubMed, Scopus, and Web of Science databases identified 1050 records, of which 50 studies met eligibility criteria and were included. In the processing of data, clusters emerged into several recurring biological domains, including dysregulated iron regulatory signaling (hepcidin), low-grade immune activation, oxidative stress, and neuroaxonal injury markers. High-throughput omics studies reveal molecular network perturbations involving inflammatory pathways, complement activation, metabolic signaling, and cellular stress responses. Biomarker associations appear stronger when linked to objective motor burden. These findings suggest that RLS may involve multifarious molecular changes detectable in the serum. Consequently, this can support the transition from symptom-based diagnosis toward biomarker-informed stratification, which may enable more precise disease characterization and improved diagnostic accuracy. Full article

Background: Restless legs syndrome (RLS) is a prevalent neurological sleep disorder that often impairs sleep maintenance. This single-arm, open-label study evaluated the efficacy, safety, and tolerability of extended-duration tonic motor activation (XD-TOMAC) in adults with RLS who experience frequent awakenings with symptoms. Methods: The study comprised three stages: Stage 1 (2 weeks of no intervention), Stage 2 (8 weeks XD-TOMAC), and Stage 3 (2 weeks of no intervention). XD-TOMAC consisted of bilateral high-frequency peroneal nerve stimulation programmed to 180 min duration and administered nightly at bedtime. Nineteen adults with moderate–severe RLS were enrolled, each reporting at least three nights per week of RLS symptoms causing increased awakenings or interfering with returning to sleep after waking. Results: The intent-to-treat analysis population included all patients who began Stage 2 (n = 15). After 8 weeks of XD-TOMAC, the mean change in International RLS Study Group Rating Scale (IRLS) score was −10.6 points (p < 0.001), and the mean change in Medical Outcomes Study Sleep Problems Index II (MOS-II) was −29.5 points (p < 0.001). The mean change in the number of nocturnal awakenings was −1.1 per night (p = 0.009), and the mean change in sleep efficiency was +8.5% (p = 0.001). The mean change in time awake with RLS symptoms after sleep onset was −28.1 min (p = 0.009). Each of these improvements was sustained at the end of Stage 3 (p < 0.01). There were no serious or severe device-related adverse events. Conclusions: Compared with prior 30 min TOMAC studies, XD-TOMAC demonstrated greater efficacy and similar tolerability, supporting its potential as a nonpharmacological therapy for RLS patients whose symptoms frequently disrupt sleep. Full article

Menopause is a natural biological transition marked by the cessation of regular menstrual cycles and is associated with significant endocrine, hormonal, and metabolic changes. Sleep disturbances are among the most common and distressing symptoms during this period, affecting approximately 40–60% of women in the menopausal transition and postmenopause. Vasomotor symptoms, including hot flushes and night sweats, often occur alongside fatigue, anxiety, and mood disturbances. These symptoms frequently coexist with sleep disorders such as insomnia, early morning awakenings, fragmented sleep, obstructive sleep apnea, restless legs syndrome, and circadian rhythm disruptions. Evidence from animal models, translational research, and clinical studies highlights the complex interaction between hormonal fluctuations, neuroendocrine dysregulation, metabolic changes, and circadian rhythm disruption. These factors contribute to altered sleep regulation, appetite control, and weight gain during the menopausal transition. This review summarizes current evidence on the mechanisms of underlying sleep disturbances in menopause, their clinical manifestations, diagnostic approaches, and available therapeutic strategies. Improving the management of sleep disorders during this stage may substantially enhance overall health and quality of life in menopausal women. We discuss presentation of different sleep disorders in menopause, their current management and future direction of research for development of precision-based algorithm of treatment considering the endocrine and hormonal profile of the women. Full article

Sleep disorders and primary headache syndromes frequently coexist, and accumulating evidence suggests that this relationship is bidirectional and biologically mediated rather than coincidental. Patients with migraine, tension-type headache, and cluster headache commonly report poor sleep quality, insomnia symptoms, and irregular sleep patterns, while individuals with sleep disorders such as insomnia, obstructive sleep apnea, restless legs syndrome, and narcolepsy experience a higher prevalence, severity, and chronification of headache disorders. This narrative review synthesizes current clinical, epidemiologic, and translational evidence supporting shared neurobiological mechanisms linking sleep and headache disorders. We focus on five major overlapping pathways: dopaminergic dysfunction, iron deficiency, hypothalamic and circadian dysregulation, central sensitization, and neuroinflammation. Evidence from population-based studies, clinical cohorts, neuroimaging, genetic research, and experimental models demonstrates that these mechanisms converge within hypothalamic, brainstem, and trigeminovascular circuits that regulate arousal, pain processing, and homeostasis. Conditions such as insomnia, obstructive sleep apnea, restless legs syndrome, and circadian disruption not only exacerbate headache burden but may act as modifiable risk factors that promote headache onset and progression. Recognizing sleep disorders as integral components of headache pathophysiology has important clinical implications, emphasizing the need for systematic sleep assessment and targeted sleep interventions as part of comprehensive headache management strategies. Full article

Background: Patients undergoing hemodialysis commonly exhibit deficiencies in water-soluble vitamins, primarily as a result of inadequate dietary intake and loss into the dialysate. Given the essential role of vitamin C in numerous metabolic pathways, routine supplementation has been proposed as a potentially beneficial intervention in this population. Aim: We aimed to evaluate the current evidence on vitamin C supplementation in patients undergoing hemodialysis, with particular attention to clinical conditions associated with renal replacement therapy, including anemia, chronic inflammation, restless legs syndrome (RLS), and secondary hyperparathyroidism. Methods: This systematic review was conducted in accordance with PRISMA guidelines. The MEDLINE (via PubMed) and EMBASE databases were searched. The initial search yielded 844 articles, of which 37 studies met the inclusion criteria for this review. Results: Evidence indicates that hemodialysis patients exhibit vitamin C deficiency, both in dietary intake and in plasma or serum concentrations. Despite its intrinsic antioxidant properties and proposed anti-inflammatory effects, vitamin C supplementation has demonstrated inconsistent effects on inflammatory markers. Most clinical studies support a beneficial role of vitamin C supplementation in functional iron deficiency and in alleviating symptoms of RLS within this population. Conclusions: Evidence on vitamin C supplementation for functional iron deficiency and RLS suggests that it might be an effective therapeutic approach. However, despite low serum vitamin C level in hemodialysis patients, current data does not justify the routine use of vitamin C in the hemodialyzed population for other comorbidities, including chronic inflammation and secondary hyperparathyroidism. Further high-quality studies are required to establish the broader clinical utility of targeted vitamin C supplementation. Full article

Motor disorders are increasingly recognized as a significant complication of chronic kidney disease (CKD), yet they remain underdiagnosed, undertreated, and often overlooked in clinical practice. Patients with CKD experience a broad spectrum of motor disturbances, including restless legs syndrome, myoclonus, flapping tremor, periodic limb movements in sleep, Parkinsonism, and peripheral neuropathy. These disorders arise from complex and often overlapping mechanisms such as uremic neurotoxicity, vascular injury, electrolyte and hormonal imbalances, or inflammatory processes, reflecting the systemic impact of impaired renal function on the central and peripheral nervous systems. The presence of motor disorders in CKD is associated with substantial clinical consequences for quality of life, contributing to impaired mobility, persistent insomnia, daytime fatigue, higher fall risk, and diminished independence. Moreover, these disturbances have been linked to increased cardiovascular morbidity and mortality, further exacerbating the already high burden of disease in this population. Current management approaches focus on optimizing kidney function through dialysis or transplantation, pharmacological therapies such as dopaminergic agents, gabapentinoids, and iron supplementation, as well as non-pharmacological interventions including structured exercise programs and sleep hygiene measures. Despite these strategies, robust evidence on long-term outcomes, comparative effectiveness, and optimal treatment algorithms remains limited. Greater recognition of the clinical impact of motor disorders in CKD, combined with targeted research efforts, is urgently needed to improve patient-centered outcomes and guide evidence-based care. Full article

Objective: Restless legs syndrome (RLS) is a highly prevalent neurological complication in end-stage renal disease (ESRD) patients. This study aimed to explore the transcranial sonography (TCS) characteristics of the substantia nigra (SN) and brainstem raphe (BR) in ESRD patients with and without RLS and to evaluate the diagnostic value of SN echogenicity for ESRD-related RLS. Methods: A total of 65 ESRD patients (45 with RLS [ESRD + RLS] and 20 without RLS [ESRD − RLS]) from the dialysis center and 30 age- and gender-matched healthy controls (NC) from the health management center were enrolled between January 2017 and December 2022. All participants underwent TCS to measure the bilateral SN echogenic area, and the total SN echogenic area (SNsA) was calculated. BR echogenicity was assessed using a semiquantitative scale. Receiver operating characteristic (ROC) curves were plotted to determine the optimal SNsA cutoff for diagnosing ESRD + RLS. Results: The SNsA in the ESRD + RLS group [0.15 (0.13–0.22) cm²] was significantly smaller than that in the ESRD − RLS group [0.27 (0.23–0.31) cm²] and the NC group [0.27 (0.22–0.30) cm²] (both p < 0.001). ROC curve analysis showed that SNsA had the highest diagnostic efficacy for ESRD + RLS, with an area under the curve (AUROC) of 0.823 (95% confidence interval [CI]: 0.722–0.924). At a cutoff of 0.22 cm², SNsA yielded a sensitivity of 85.0%, specificity of 73.3%, accuracy of 76.92%, positive predictive value (PPV) of 58.6%, and negative predictive value (NPV) of 91.7%. The prevalence of BR hypoechogenicity was significantly higher in ESRD + RLS (33.33%) and ESRD − RLS (35.00%) groups than in the NC group (10.00%) (both p < 0.05), but no difference was observed between the two ESRD subgroups (p > 0.05). No significant differences in third ventricle (TV) width or bilateral middle cerebral artery peak systolic velocity (MCA-PSV) were found among the three groups (all p > 0.05). Conclusions: ESRD + RLS patients exhibit significant SN hypoechogenicity compared with ESRD − RLS patients and healthy controls. SNsA with a cutoff of 0.22 cm² serves as a reliable imaging biomarker for diagnosing ESRD + RLS, and TCS is a valuable noninvasive tool to assist clinical decision-making in this population. Full article

Background: Although multiple sclerosis (MS)-associated tremor and ataxia are well described in the neurological literature, other extrapyramidal movement disorders (MDs), including Holmes tremor, dystonia, chorea, myoclonus, parkinsonism, and restless legs syndrome, have received far less attention and are generally regarded as rare manifestations of MS. Rationale: Although MS is traditionally considered a white matter disease, increasing evidence has demonstrated clinically relevant grey matter involvement, particularly within the basal ganglia, thalamus, and cerebellar–brainstem pathways. Understanding extrapyramidal MDs in MS may therefore provide important insights into the functional networks disrupted by demyelination and inflammation. Aim: This review aims to highlight the available literature on extrapyramidal MDs in MS, outlining their clinical presentations, lesion correlates, and proposed mechanisms. We examined reported cases, reviews, and findings in the literature explaining these disorders and their occurrence in association with acute relapses, as well as their development during the progressive phase of MS. Conclusions: By integrating clinical and pathophysiological evidence, this review highlights how rare extrapyramidal MDs may reflect underlying grey matter pathology and network-level disruption, with potential implications for diagnosis, monitoring, and treatment. Full article