Course Of Restless Legs Syndrome Research Articles

Consensus guidelines on the construct validity of rodent models of restless legs syndrome.

ABSTRACTOur understanding of the causes and natural course of restless legs syndrome (RLS) is incomplete. The lack of objective diagnostic biomarkers remains a challenge for clinical research and for the development of valid animal models. As a task force of preclinical and clinical scientists, we have previously defined face validity parameters for rodent models of RLS. In this article, we establish new guidelines for the construct validity of RLS rodent models. To do so, we first determined and agreed on the risk, and triggering factors and pathophysiological mechanisms that influence RLS expressivity. We then selected 20 items considered to have sufficient support in the literature, which we grouped by sex and genetic factors, iron-related mechanisms, electrophysiological mechanisms, dopaminergic mechanisms, exposure to medications active in the central nervous system, and others. These factors and biological mechanisms were then translated into rodent bioequivalents deemed to be most appropriate for a rodent model of RLS. We also identified parameters by which to assess and quantify these bioequivalents. Investigating these factors, both individually and in combination, will help to identify their specific roles in the expression of rodent RLS-like phenotypes, which should provide significant translational implications for the diagnosis and treatment of RLS.

Restless arms syndrome: prevalence, impact, and management strategies.

This literature review focuses on restless arms syndrome (RAS), an upper limb variant of restless legs syndrome (RLS). RLS, also known as Willis-Ekbom disease, is a frequently occurring neurological disorder characterized by an irresistible urge to move the lower limbs often accompanied by unpleasant sensations in the legs, worsened at rest and in the evening, improved by movement. Extension of leg restlessness to the upper limbs is frequently reported in typical patients who had RLS only in the legs and usually occurs later in the course of RLS, restlessness remaining most invalidating in the lower limbs. In RAS, the arms are predominantly affected with little or no involvement of the legs. Cases of restless shoulders syndrome or periodic arm movements without arm restlessness were not considered. A total of 9 articles with 10 cases were included and analyzed for the adherence to the five essential diagnostic criteria of the International RLS Study Group (IRLSSG) classification, as well as for the additional supportive features. All of the reported cases were classified as having definite RAS. The clinical history and disease evolution of two previously reported patients were completed and updated. Overall, the clinical picture of RAS does not differ from that of RLS, except for the symptoms localization on the upper limbs. Underlying mechanisms of the spread of RLS to upper limb restlessness and of RAS remain unknown. Whether RAS is a phenotypic variant of RLS or a separate entity needs further investigations. RAS likely remains underdiagnosed and according to IRLSSG diagnostic criteria RAS should be considered when RLS-like symptoms are present in one or both arms, especially when they have a circadian pattern and are improved by movement and dopaminergic therapy. Clinicians should be aware of this rare condition, especially as treatment using dopaminergic agonists proves to be very efficient.

Symptom Persistence after Iron Normalization in Women with Restless Legs Syndrome.

ObjectiveThe aim of this study was to determine the clinical course of restless legs syndrome (RLS) and potential risk factors for the persistence of RLS symptoms after iron normalization in women with RLS and low serum ferritin (<50 μg/L). MethodsWe reviewed 39 women with RLS and iron deficiency, who achieved iron normalization after oral iron replacement for three months. Risk factors contributing to symptom persistence were estimated by logistic regression analyses. Remission was defined as no RLS symptoms for at least 6 months after the iron normalization. ResultsOver the observation period of 2.5±1.4 years, 15 patients reported no RLS symptom whereas 24 patients still complained of RLS symptoms. The remission rate of RLS with iron replacement was 38.5%. The relative risk of symptom persistence was increased by the duration of RLS symptoms (OR: 1.88, 95% CI: 1.01–3.49) or by the age at RLS diagnosis (OR: 1.25, 95% CI: 1.01–1.56). ConclusionAlmost two-third of RLS patients with iron deficiency showed persistence of the symptom even after iron normalization. Considering that longer duration of RLS symptoms and older age at RLS diagnosis were risk factors for symptom persistence, early intervention of iron deficiency in RLS is warranted.

Symptom Severity of Restless Legs Syndrome Predicts Its Clinical Course

ObjectiveThis study examines the clinical course of restless legs syndrome according to its severity and factors associated with the remission of restless legs syndrome symptoms. MethodsThe remission or persistence of restless legs syndrome symptoms was investigated by considering patients with restless legs syndrome at the sleep clinic of Seoul National University Bundang Hospital. All subjects were observed for at least 18 months, and an incidence of remission was defined as having no restless legs syndrome symptoms for at least 1 year. Restless legs syndrome severity was evaluated by the International Restless Legs Syndrome Study Group Rating Scale. ResultsA total of 306 patients participated in this study. Over the observation periods of 4.1 ± 1.6 years, the cumulative incidence of remission is 32.5% (95% confidence interval [CI], 27.0-38.0) and decreased with baseline restless legs syndrome severity (P < .001): 60% (95% CI, 44.9-75.1), 44% (95% CI, 34.4-53.6), and 16.7% (95% CI, 10.6-22.8) in mild, moderate, and severe to very severe restless legs syndrome cases, respectively. Most cases of remission (82/96) were observed within 1 year, and the remission occurred sooner for mild restless legs syndrome. The hazard ratios of remission by Cox proportional hazards model were lower for moderate (0.556; 95% CI, 0.340-0.909) and severe to very severe (0.193; 95% CI, 0.108-0.343) restless legs syndrome than for mild restless legs syndrome. The remission incidence was lower for those patients who had a family history of restless legs syndrome and were older at restless legs syndrome diagnosis. ConclusionsMild restless legs syndrome severity, no family history, and young age at restless legs syndrome diagnosis were significant predictors of restless legs syndrome remission. More than 80% of patients with severe restless legs syndrome showed a chronic clinical course.

A prospective study of cumulative incidence and course of RLS in de novo PD patients during chronic dopaminergic therapy

Objectives: We performed a prospective long-term follow-up study aimed at the assessment of the cumulative incidence and clinical course of restless legs syndrome (RLS) in de novo previously untreated Parkinson's disease (PD) patients.

A prospective study of the cumulative incidence and course of restless legs syndrome in de novo patients with Parkinson’s disease during chronic dopaminergic therapy

The authors report the cumulative incidence of Restless Legs Syndrome (RLS) over a 3 years follow-up period in 92 de novo Parkinson's disease patients under chronic dopaminergic therapy and the clinical course of the sensory-motor disorder over 12 months as from its onset. The overall cumulative incidence of RLS was found by 15.3%, i.e. 14 incident cases, and by 11.9%, i.e. 11 incident cases, after the exclusion of possible "secondary" forms of the disorder. These figures are higher than those reported in general population in Germany (Study of Health in Pomerania), confirming our previous findings of incidence rate of the disorder. At the end of the 3 years follow-up period the prevalence of "current" RLS was significantly higher than that previously found in drug naïve Parkinson's disease patients and in controls, supporting the view that RLS emerging in the course of chronic dopaminergic therapy is the main determinant of the co-morbid association with Parkinson's disease. During the 12 months period of observation the RLS showed a frequency of occurrence of 6.08 episodes per month on average and a remittent clinical course was prevailing in the 11 incident cases, with a significant frequency decrease in the second as compared to the first 6 months, i.e. 3.26 versus 8.9 episodes per month, and none of the patients developed augmentation in the same period. It is hypothesized that the remittent course could be due to long-term adaptation (downregulation) of the hypersensitive post-synaptic dopamine receptors in the spinal cord to a continuous dopaminergic stimulation, possibly coupled with compensatory up-regulation of pre-synaptic dopamine re-uptake mechanism, in the patients in which the hypothalamic A11 area, site of origin of the dopamine-mediated diencephalo-spinal pathway, is involved in the neurodegenerative process.

Increased prevalence of restless legs syndrome in patients with Crohn’s disease

To determine (a) the incidence of restless legs syndrome (RLS) in patients with Crohn's disease (CD), (b) whether and how the occurrence and severity of RLS is related to severity of CD, and (c) how RLS influences the quality of life of CD patients. We carried out a cross-sectional questionnaire study in a random selection of 144 CD patients and 80 controls. Differences were calculated using a χ-test (categorical data), an independent T-test (continuous data, normal distribution), or a Mann-Whitney U-test (continuous data, non-normal distribution). Logistic regression analysis was carried out to establish the relation between CD and RLS after adjusting for risk factors. The prevalence of RLS was 25.7% (37/144) in CD patients compared with 12.5% (10/80) in the control group (P=0.02). CD patients using caffeine and patients with arthralgias had a higher risk for RLS. A higher score on the modified Harvey Bradshaw Index and CD-related surgery were also associated with a higher risk for RLS. CD-related surgery was also associated with a more severe course of RLS. Patients and controls with RLS had a lower score on 'physical functioning', one of the subcategories of the RAND-36 quality-of-life questionnaire. RLS occurs more frequently in patients with CD compared with healthy individuals. A more severe course of CD seems to be associated with a higher risk for RLS. The presence of RLS has a negative influence on quality of life, mainly interfering with physical activities of daily life.

Prospective survey on the natural course of restless legs syndrome over two years in a closed cohort

This study was set out to identify the population with restless legs syndrome (RLS) developing a chronic course and the impact of long-term morbidity of RLS on disorder related dysfunctions. Two population-based epidemiological surveys were performed in 2005 and 2007 on the same cohort in Japan. Questionnaires including demographics, measurement scales for depression, quality of life, subjective sleep disturbances, and the NIH/IRLSSG consensus questionnaire for RLS diagnosis, were distributed to participants, and then telephone interviews were performed to determine the diagnosis and severity of RLS. Among 1592 valid respondents, only 20 (40%) of 50 RLS-positive subjects at the first survey were repeatedly RLS-positive at the second survey. The frequency of RLS symptoms at the first survey was associated with the repeated appearance of RLS symptoms (odds ratio 8.70, p=0.0302). The chronic morbidity of RLS seemed to be associated with the existence of depression and subjective sleep disturbance. RLS may not be persistent in more than 50% of the affected population. The frequency of RLS symptoms, but not the severity, may predict the persistence of this disorder.

Evolution of non-treated restless legs syndrome

The primary concern of this study is to evaluate the clinical course of restless legs syndrome (RLS) in a group of patients who refused treatment. This study compares the outcome of a group of RLS patients after one year without any specific treatment. The International Restless Legs Syndrome Scale (IRLS) was applied at baseline (irls_1) and after one year (irls_2). The patients answered a simple questionnaire for the evaluation of possible environmental or life habit changes after one-year evolution. Serum ferritin was determined at baseline. An improvement index (%improvement) was established through the formula: irls_1- irls_2/irls_1 x 100. Results were compared and a correlation analysis performed. A negative significant correlation was found between the patients' age and irls_2 (r= -0.9 p=0.0018) and between %improvement and irls_2 (r= -0.88 p=0.0039). A positive and significant correlation was determined between %improvement and age. There was only a marginally significant correlation between serum ferritin and ilrs_2 (r= -0.7 p=0.052). No significant changes were found in the other elements analyzed. A favorable outcome was found in this group of RLS patients after one year evolution without treatment. The outcome was positively influenced by the patients' age.

Evaluation of Effect of Renal Transplantation in Treatment of Restless Legs Syndrome

Background Restless legs syndrome (RLS) is a common cause of sleep disturbance frequently experienced by hemodialysis patients. It is a neurological movement disorder. Patients with RLS suffer an irresistible urge to move the legs during inactivity with relief by motion and various activities. Materials and Methods We investigated the clinical course of RLS in 30 (12 female and 18 male) hemodialysis patients with mean dialysis duration of 16.8 ± 14.13 months who underwent kidney transplantation. Patients were given a standardized questionnaire evaluating details of RLS at baseline and twice after kidney transplantation. They were diagnosed to have RLS by International RLS Study Group criteria. Biochemical (serum calcium, phosphate, Na, and K and blood urea and creatinine) and hematological indices (serum iron, hemoglobin) were measured at each time. Results RLS in hemodialysis patients was significantly reduced by renal transplantation (43.3%; P < .0001). There was a significant association between RLS and lower serum iron ( P < .01) and phosphorus ( P < .02) after renal transplantation: We did not observe any association between hemoglobin levels, age, sex, dialysis duration, and time after transplantation with RLS. Conclusion Kidney transplantation showed a strong, positive influence on RLS symptoms in hemodialysis patients. Correction of serum phosphate and serum iron (by mechanisms different than its effect on hemoglobin) can affect RLS in kidney transplant patients.

Long-term course of restless legs syndrome in dialysis patients after kidney transplantation.

Restless legs syndrome (RLS) is a common cause of sleep disturbance and is frequently experienced by hemodialysis patients. Factors triggering the disease in uremia have not yet been identified. To our knowledge, the course of RLS symptoms after kidney transplantation has not been investigated systematically. We investigated the clinical long-term course of RLS in hemodialysis patients who underwent kidney transplantation. Patients were given a standardized questionnaire three times: at baseline, and twice after their kidney transplants. The severity of RLS was rated by the patients (0 =no symptoms, 10 = very severe symptoms). The description of the final outcome was based on the last follow-up visit. Eleven of 64 hemodialysis patients with RLS received a transplant (5 men, 6 women; severity of RLS at baseline, 7.8 +/- 0.7 [mean +/- SEM]). In all patients, RLS symptoms disappeared within 1 to 21 days after transplantation. At follow-up visits, 4 patients whose transplanted kidneys still functioned well were still free of RLS symptoms up to the longest follow-up period of 9 years. In 3 other patients, RLS symptoms gradually reappeared (severity, 1 +/- 0). In 3 of 11 patients, the transplant failed and RLS symptoms reoccurred within 10 days to 2 months (severity, 7.3 +/- 2.6). RLS symptoms reoccurred in 1 patient with failure of the transplant but disappeared again after a second, successful transplant. Kidney transplantation has a strong and positive influence on RLS symptoms in hemodialysis patients. Hemodialysis patients can expect a substantial improvement of RLS symptoms after a successful kidney transplant.