Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study

Background and PurposeRestless Legs Syndrome (RLS) is a primary disorder of sensation that affects sleep and has been associated with iron deficiency. The purpose of this study was to determine if symptomatic RLS patients with low-normal serum ferritin levels benefit from oral iron replacement.Patients and MethodsThis was a randomized, placebo-controlled, double-blinded study. Eligible patients were randomized to oral iron therapy vs. appearance-matched placebo and followed over a 12 week period.ResultsBaseline International Restless Leg Scale (IRLS) scores for the treatment (24.8 ± 5.72) and placebo (23.0 ± 5.03) groups were similar. Baseline ferritin levels for the treatment (40.6 ± 15.3 ng/ml) and placebo (36.7 ± 20.8 ng/ml) groups were also similar. After 12 weeks, IRLS scores decreased more in the treatment arm (10.3 ± 7.40) than in the placebo arm (1.14 ± 5.64), (p = 0.01). Ferritin levels increased more in the treatment arm (25.1 ± 20.3 ng/ml) than in the placebo arm (7.5 ± 13.7 ng/ml), (p = 0.04). We observed a nonsignificant trend toward improved quality of life in the treated patients, (p = 0.07).ConclusionsThis is the first double-blinded, placebo-controlled study to demonstrate statistically significant improvement in RLS symptoms using oral iron therapy in patients with low-normal ferritin. The findings from this study suggest that additional larger randomized placebo-controlled trials of iron as treatment for patients with low-normal ferritin are warranted.     

Restless legs syndrome, sleep impairment, and fatigue in chronic obstructive pulmonary disease

ObjectiveTo investigate the frequency of factors associated with restless legs syndrome (RLS) in patients with chronic obstructive pulmonary disease (COPD).MethodsRLS diagnosis was investigated (International RLS Study Group, IRLSSG) and severity was assessed (IRLS rating scale) in 104 consecutive COPD patients (age 69.1 ± 8). Other measures were dyspnea severity (Modified Medical Research Council, MMRC), sleep quality (Pittsburgh Sleep Quality Index, PSQI), daytime somnolence (Epworth Sleepiness Scale, ESS), depressive symptoms (Beck Depression Inventory, BDI-II), and fatigue (Fatigue Severity Scale, FSS). Laboratory values included hemoglobin, ferritin, creatinine, and fibrinogen.ResultsThirty-two patients (30.8%) were diagnosed with RLS (65.6% women), which was moderate/severe (IRLS >11) in 26 (81.3%). RLS symptoms started after age 40 in most patients (93.3%). RLS patients had poorer sleep quality (PSQI >5 = 59.6%; p = 0.002), worse fatigue (FSS >27 = 51%; p = 0.005), and more depressive symptoms (BDI-II >10 = 14.4%; p = 0.005). Patients with RLS also presented more severe dyspnea (p = 0.009) and lower creatinine levels (p = 0.005). Overall, fatigue severity was correlated with older age (p = 0.001); level of dyspnea was positively correlated with PSQI and FSS (p < 0.005) and negatively correlated with ferritin (p = 0.03) and creatinine (p = 0.005), and PSQI scores correlated positively with FSS (p < 0.005) and negatively with ferritin (p = 0.005) and creatinine (p = 0.02). Quality of sleep was independently predicted by dyspnea severity and creatinine and fatigue by age and depression.ConclusionRLS is common in COPD. Patients with RLS have low creatinine, poorer quality of sleep, and more fatigue and depressive symptoms. RLS symptom severity is correlated to lower ferritin and severity of dyspnea.     

Effect of pramipexole on RLS symptoms and sleep: a randomized, double-blind, placebo-controlled trial

BackgroundPatients with Restless Legs Syndrome (RLS) often seek treatment because of sleep problems related to nocturnal symptoms. Our goal was to test the ability of pramipexole to improve sleep in RLS patients and to reconfirm its efficacy for primary RLS symptoms.MethodsAdults with moderate or severe RLS were randomized to receive placebo or pramipexole (flexibly titrated from 0.25 to 0.75 mg), 2–3 h before bedtime for 12 weeks. The co-primary outcome measures were change in Medical Outcomes Study (MOS) sleep disturbance score and International RLS Study Group Rating Scale (IRLS) score at 12 weeks.ResultsThe intent-to-treat population included 357 patients: 178 received pramipexole and 179 received placebo. At 12 weeks, the adjusted mean change from baseline was greater for pramipexole (vs. placebo) for IRLS score (−13.4 ± 0.7 vs. −9.6 ± 0.7) and MOS sleep disturbance score (−25.3 ± 1.5 vs. −16.8 ± 1.5) (p ⩽ 0.0001; ANCOVA). Responder rates (clinical and patient global impression and IRLS) were also significantly higher in the pramipexole group. RLS-QOL score was improved over placebo at Week 12 (p < 0.01) as were MOS sleep adequacy (p = 0.0008) and quantity (p = 0.08) scores. Nine percent of patients in each group withdrew because of adverse events.ConclusionsPramipexole is effective and well-tolerated for RLS and related sleep disturbance.     

Clinical efficacy and safety of intravenous ferric carboxymaltose treatment of pediatric restless legs syndrome and periodic limb movement disorder

BackgroundIron supplementation is the most commonly considered treatment option for children with restless legs syndrome (RLS) or periodic limb movement disorder (PLMD); however, there is a scarcity of evidence on the effectiveness of intravenous preparations. In this study, we evaluated the effectiveness and tolerability of intravenous ferric carboxymaltose (IV FCM) on clinical symptoms and iron indices in children with RLS or PLMD.MethodsThis was a single-center retrospective data analysis. Children with a diagnosis of RLS or PLMD, who underwent a single infusion of IV FCM, were included. Clinical Global Impression (CGI) Scale scores, serum ferritin, and serum iron profile at baseline and after eight weeks post infusion were obtained. Adverse effects were assessed.ResultsThirty-nine children received IV FCM, 29 with RLS and 10 with PLMD. Pre-infusion CGI-Severity revealed moderate illness, with post-infusion CGI-Improvement between “very much improved” and “much improved”. Ferritin increased from 14.6 μg/L ± 7.01 to 112.4 μg/L ± 65.86 (p < 0.00001), together with improvements in iron, total iron binding capacity, and transferrin levels from baseline to post-treatment. When compared to children with RLS, those with PLMD had a similar improvement in clinical symptoms and laboratory parameters. Seven subjects (14.3%) experienced one or two adverse events; all were mild.ConclusionsChildren with RLS and PLMD responded to IV iron supplementation with improvement in both clinical severity and laboratory parameters. Treatment was well tolerated. Although larger, randomized-controlled trials are needed, IV FCM appears to be a promising alternative to oral iron supplementation for the treatment of pediatric RLS or PLMD.     

The severity range of restless legs syndrome (RLS) and augmentation in a prospective patient cohort: Association with ferritin levels

ObjectivesThe aim of the study was to prospectively examine all patients with a diagnosis of RLS consulting a sleep disorders clinic and to assess RLS severity and augmentation and their associations, including ferritin levels.MethodsPatients were stratified into patients with RLS as ancillary diagnosis, RLS sufferers without current augmentation and RLS sufferers with current augmentation. Work-up included RLS severity scales and blood biochemical variables including indices of iron metabolism.ResultsIn an 18-month period, 302 patients with RLS (183 women, 119 men; mean age, 59.1 ± 13.7 years) were recruited. RLS was considered idiopathic in 291 patients (96.4%). Most patients (240, 79.5%) were RLS sufferers, whereas the remaining 62 (20.5%) had RLS as ancillary diagnosis. Nineteen out of 162 patients treated with dopaminergic agents (11.7%) had current augmentation. Almost one-third of all patients (31.1%) had ferritin levels <50 μg/l. Patients with an ancillary diagnosis of RLS had higher ferritin levels than RLS sufferers without current augmentation. The lowest ferritin levels were present in RLS sufferers with current augmentation 132.8 ± 98.0 μg/l vs. 100.6 ± 84.5 μg/l vs. 55.8 ± 43.6 μg/l; p = 0.002). Patients with augmentation did not differ from non-augmented patients regarding age, gender, RLS etiology, presence of previous augmentation, or any other documented comorbidity (p > 0.05).ConclusionThe severity spectrum of RLS in this clinical cohort ranged from the ancillary diagnosis of RLS to augmented RLS. There was an inverse correlation between RLS severity and ferritin levels. Patients with current augmentation had the lowest ferritin levels. Our data further strengthen a putative role of low iron stores as a potential aggravator of idiopathic RLS. Moreover, low ferritin might represent a potential biomarker of RLS augmentation under dopaminergic therapy.     

Efficacy of vitamins C, E, and their combination for treatment of restless legs syndrome in hemodialysis patients: a randomized, double-blind, placebo-controlled trial

BackgroundRestless legs syndrome (RLS) is a common disorder in hemodialysis patients that leads to insomnia and impaired quality of life. Because high oxidative stress has been implicated in the pathogenesis of RLS, we sought to evaluate the efficacy of vitamins C and E and their combination in reducing the severity of RLS symptoms in hemodialysis patients in this randomized, double-blind, placebo-controlled, four-arm parallel trial.MethodsSixty stable hemodialysis patients who had all four diagnostic criteria for RLS developed by the International Restless Legs Syndrome Group with no acute illness or history of renal stone were randomly allocated to four fifteen-patient parallel groups to receive vitamin C (200 mg) and vitamin E (400 mg), vitamin C (200 mg) and placebo, vitamin E (400 mg) and placebo, and double placebo daily for eight weeks. International Restless Legs Scale (IRLS) scores were measured for all patients at baseline and at the end of treatment phase. The primary outcome was absolute change in IRLS sum score from baseline to the end of treatment phase.ResultsMeans of IRLS sum score decreased significantly in the vitamins C and E (10.3 ± 5.3, 95% CI: 7.4–13.3), vitamin C and placebo (10 ± 3.5, 95% CI: 8.1–11.9), and vitamin E and placebo groups (10.1 ± 6, 95% CI: 6.8–13.5) compared with the double placebo group (3.1 ± 3, 95% CI: 1.5–4.8), (P < 0.001); however, no differences were observed between these treatment groups.ConclusionsVitamins C and E and their combination are safe and effective treatments for reducing the severity of RLS in hemodialysis patients over the short-term.     

Increased frequency of restless legs syndrome in chronic obstructive pulmonary disease patients

Background: Despite complaints of poor sleep being very common in people with chronic obstructive pulmonary disease (COPD), restless legs syndrome (RLS) symptoms have not been extensively investigated in these patients.Objective: To assess the prevalence and severity of RLS in patients with COPD and to investigate the factors potentially associated with RLS.Methods: A total of 87 patients with COPD and 110 controls, matched for age and sex, were evaluated regarding the presence and severity of RLS symptoms. A diagnosis of RLS was made according to the criteria of the International RLS Study Group (IRSLSSG), and severity was assessed by the IRLSSG severity scale. Excessive daytime somnolence was assessed using the Epworth sleepiness scale (ESS).Results: RLS was significantly more frequent in COPD patients than in controls (36.8% vs. 11%; p < 0.001). Compared to controls, COPD patients with RLS showed higher disease severity (mean IRLSSG severity scale score: 20.5 ± 2.8 for COPD, and 18 ± 3.5 for controls; p = 0.016) and more pronounced daytime somnolence (mean ESS score: 11.8 ± 1.1 for COPD, and 8.6 ± 3.6 for controls; p = 0.009). Moreover, compared to those without RLS, COPD patients with RLS showed increased daytime sleepiness (mean ESS score: 11.8 ± 1.1 for COPD/RLS, and 7.3 ± 4 for COPD/non-RLS; p < 0.001) and longer disease duration (11.9 ± 7 years for COPD/RLS, and 8.7 ± 6.9 years for COPD/non-RLS; p = 0.045). Multivariate analysis showed that ESS score was the only factor significantly associated with RLS in COPD patients.Conclusions: RLS is a frequent cause of disabling sleep disturbance in patients with COPD and should be specifically investigated in these patients.     

Patient characteristics predicting responses to intravenous ferric carboxymaltose treatment of restless legs syndrome

BackgroundSignificant benefit of intravenous ferric carboxymaltose (FCM) treatment for restless legs syndrome (RLS) has been well-established. However, no clinical indicators predicting treatment response of RLS have been established. This study aimed to determine factors predicting outcome of clinical FCM treatment of RLS patients.MethodsData were retrospectively reviewed from all patients who received FCM treatment for RLS from April 2016 to April 2019. These data included: detailed history, international RLS scale score (IRLS), questionnaires, comorbidity, and previous RLS medication use. Morning fasting serum iron, ferritin, and total iron-binding capacity were measured before and at four weeks after treatment. RLS patients with possible secondary RLS were identified by reviewing the medical histories. This included patients with iron deficiency anemia, lumbosacral radiculopathy, and gastrectomy. Primary RLS included those with no indication of secondary medical factors contributing to RLS. Treatment response was assessed using the IRLS and clinical ratings at four weeks after FCM administration. Patients with a greater than 40% decrease in IRLS were classified as responders.ResultsThe study comprised 164 patients with IRLS and clinical ratings obtained before and at four weeks after intravenous (IV) iron. Treatment responses differed considerably between diagnostic groups of RLS. Percentage responding was: 64.7% (66 of 102) for patients with primary RLS, 90.9% (10 of 11) with gastrectomy, 91.3% (21 of 23) with iron deficiency anemia and 39.3% (11 of 28) with lumbosacral radiculopathy. When responders were compared to non-responders in primary RLS patients, responders had significantly lower serum iron (80.5 ± 26.7 vs. 95.8 ± 30.5 μg/dL, p = 0.022) and percentage transferrin saturation (%TSAT) (25.4 ± 9.6 vs. 30.5 ± 10.5%, p = 0.026) in females, but not males. Logistic regression controlling for major subject variables showed that %TSAT significantly predicted response. (odds ratio [OR]: 0.955, confidence interval: 0.913–0.998, p = 0.040).ConclusionIntravenous FCM in moderate to severe RLS patients is beneficial as a first-line or add-on treatment, particularly for patients with compromised peripheral iron state. Overall, lower %TSAT predicted better chance of responding to the IV iron treatment especially for females.     

Evaluation of oral iron treatment in pediatric restless legs syndrome (RLS)

ObjectiveWe conducted a retrospective chart review of children with restless legs syndrome (RLS) to evaluate the efficacy of oral iron treatment, which was administered open-label during the course of clinical care. In addition, we provided detailed clinical information about RLS in this pediatric cohort.Patients and methodsThe study included 30 consecutive Japanese children with RLS who visited the Pediatric Sleep Clinic at Osaka University Hospital, and consisted of 17 boys and 13 girls, aged 2–14 years (mean ± SD, 6.5 ± 2.8). All-night polysomnography was performed in 18 patients and serum ferritin levels were measured in all the patients. After the diagnosis of RLS, iron was administered at doses between 1.6 and 7.8 mg/kg/day (3.2 ± 1.3). Serum ferritin was re-evaluated 3–6 months after iron treatment, or when RLS symptoms had disappeared.ResultsThe patient age at onset of RLS symptoms ranged from six months to 13 years (4.3 ± 3.6). A positive family history was recognized in 19 children (63.3%). Serum ferritin levels before therapy were 9–62 ng/ml (26.6 ± 12.8) and oral iron supplementation was reported to be highly effective in 17 children, effective in 10, and ineffective in three. The serum ferritin level at follow-up was 23–182 ng/ml (83.5 ± 49.8). The onset of treatment effect was within approximately three months.ConclusionsIron treatment could be effective in Japanese pediatric RLS.     

Clinical efficacy of ropinirole for restless legs syndrome is not affected by age at symptom onset

ObjectiveTo determine whether clinical response to the dopamine agonist, ropinirole, in the treatment of primary restless legs syndrome (RLS), depends upon the age-at-onset of RLS symptoms.MethodsPooled data from four 12-week, randomized, double-blind, placebo-controlled studies of ropinirole in patients with moderate-to-severe primary RLS were analyzed post hoc. The relationship between age-at-onset and response to treatment, based on change from the baseline International Restless Legs Syndrome Study Group (IRLSSG) rating scale (the International Restless Legs Scale [IRLS]) total score and the proportion of responders (rated ‘much’/‘very much’ improved) on the Clinical Global Impression–Improvement (CGI-I) scale, was explored.ResultsThe range of age-at-onset of RLS symptoms was 2–75 years. No relationship was observed between the age-at-onset of RLS symptoms and baseline IRLS total score (correlation r = −0.06), and between dose administered at Week 12 last observation carried forward (LOCF) and age-at-onset (r = −0.04). The age-at-onset by treatment interaction was non-significant (P = 0.952 for the IRLS and P = 0.716 for the CGI-I scale), indicating there was no significant relationship between age-at-onset and the magnitude of ropinirole treatment effect.ConclusionsThese data suggest that ropinirole provides effective relief of symptoms, regardless of age at RLS symptom onset.     

One year open-label safety and efficacy trial with rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome

BackgroundLong-term efficacy and tolerability data are not yet available for patch formulations of dopamine agonists in restless legs syndrome.MethodsEfficacy and safety of rotigotine (0.5–4 mg/24 h), formulated as a once-daily transdermal system (patch), were investigated in an open extension (SP710) of a preceding 6-week placebo-controlled trial (SP709, 341 randomized patients) in patients with idiopathic restless legs syndrome. For efficacy assessment the international RLS severity scale (IRLS), the RLS-6 scales, the clinical global impressions (CGI) and the QoL-RLS questionnaire were administered. In addition, long-term tolerability and safety were assessed.ResultsOf 310 patients who finished the controlled trial, 295 (mean age 58 ± 10 years, 66% females) with a mean IRLS score of 27.8 ± 5.9 at baseline of SP709 were included. We report results after one year of this ongoing long-term trial. Two hundred twenty patients (retention rate = 74.6%) completed the 12-month follow-up period. The mean daily dose was 2.8 ± 1.2 mg/24 h with 4 mg/24 h (40.6%) being the most frequently applied dose; 14.8% were sufficiently treated with 0.5 or 1.0 mg/24 h. The IRLS total score improved by −17.4 ± 9.9 points between baseline and end of Year 1 (p < 0.001). The other measures of severity, sleep satisfaction and quality of life supported the efficacy of rotigotine (p < 0.001 for pre-post-comparisons of all efficacy variables). The tolerability was described as “good” or “very good” by 80.3% of all patients. The most common adverse events were application site reactions (40.0%), which led to withdrawal in 13.2%. Further relatively frequent adverse events were nausea (9.5%) and fatigue (6.4%). Two drug-related serious adverse events, nausea and syncope, required hospitalization. Symptoms of augmentation were not reported by the patients.ConclusionRotigotine provided a stable, clinically relevant improvement in all efficacy measures throughout one year of maintenance therapy. The transdermal patch was safe and generally well tolerated by the majority of patients. Comparable to any transdermal therapy, application site reactions were the main treatment complication.     

Assessing health-related quality of life in patients with restless legs syndrome in Korea: Comparison with other chronic medical diseases

BackgroundThere have been few quality of life (QoL) studies of patients with restless legs syndrome (RLS) in Asian countries. We studied the QoL of patients with RLS and compared it to normal controls and patients with hypertension, type 2 diabetes, or osteoarthritis in Korea.MethodsA total of 215 RLS patients (141 female; mean age 51.7 ± 13.5) were enrolled. All patients completed the questionnaires, including all the Korean versions of SF-36, RLS QoL, the International RLS Severity scale (IRLS), the Pittsburgh Sleep Quality Index (PSQI), and the Beck Depression Inventory-2 (BDI-2). These results were compared with the scores from normal controls (N = 214) and from patients with hypertension (196), uncomplicated type 2 diabetes (185), or osteoarthritis of the knee (177).ResultsThe SF-36 QoL in patients with RLS was lower than that of the normal controls, and even lower than patients with hypertension or diabetes, but higher than those with osteoarthritis. The SF-36 Qol of RLS patients showed a significantly negative correlation with the severity of RLS symptoms (r = ?0.430, p < 0.001) and the severity of depression (r = ?0.565, p < 0.001), but was not significantly related to gender, age, or age-of-symptom onset (early or late-onset). Step-wise multiple regression identified three factors related to SF-36 QoL: depression (46.5% of RLS had responses on BDI-2 indicating depression) (β = ?.899, p < 0.001), RLS symptom severity (K-IRLS) (β = ?.718, p < 0.001), and gender (female) (β = ?6.128, p = 0.007).ConclusionsThese findings show that RLS has a considerable impact on the QoL of Koreans, which is comparable with studies of western countries. The QoL impairment relates to the degree of depression with RLS for Koreans.     

Prevalence of restless legs syndrome among adults in Iceland and Sweden: Lung function, comorbidity, ferritin, biomarkers and quality of life

ObjectiveThis study investigates the prevalence and the association between restless legs syndrome (RLS) and a large variety of health variables in two well-characterized random samples from the general population in Reykjavik, Iceland, and Uppsala, Sweden.MethodsUsing the national registries of inhabitants, a random sample from adults aged 40 and over living in Reykjavík, Iceland (n = 939), and Uppsala, Sweden (n = 998), were invited to participate in a study on the prevalence of COPD (response rate 81.1% and 62.2%). In addition, the participants were asked to answer the following questionnaires: International RLS Rating Scale, Short Form-12, the Epworth Sleepiness Scale, and questions about sleep, gastroeosophageal reflux, diabetes and hypertension, as well as pharmacological treatment. Interleukin-6 (IL-6), C-reactive protein (CRP) and ferritin were measured in serum.ResultsRLS was more commonly reported in Reykjavik (18.3%) than in Uppsala (11.5%). Icelandic women reported RLS almost twice as often as Swedish women (24.4 vs. 13.9% p = 0.001), but there was no difference in prevalence of RLS between Icelandic and Swedish men. RLS was strongly associated with sleep disturbances and excessive daytime sleepiness. Subjects with RLS were more likely to be ex- and current smokers than subjects without RLS (p < 0.001). Respiratory symptoms and airway obstruction were more prevalent among those reporting RLS and they also estimated their physical quality of life lower than those without RLS (p < 0.001). RLS was not associated with symptoms of the metabolic syndrome like hypertension, obesity, markers of systemic inflammation (IL-6 and CRP) or cardiovascular diseases. Ferritin levels were significantly lower in RLS participants (p = 0.0002), but not (p = 0.07) after adjustment for center, age, sex and smoking history.ConclusionRestless legs syndrome was twice as common among Icelandic women compared to Swedish women. No such difference was seen for men. RLS was strongly associated with smoking and respiratory symptoms, decreased lung function, sleep disturbances, excessive daytime sleepiness, and physical aspects of life quality. RLS was not associated with markers of the metabolic syndrome like hypertension, obesity, cardiovascular diseases or biomarkers of systemic inflammation.     

Assessment of nitric oxide, advanced oxidation protein products, malondialdehyde, and thiol levels in patients with restless legs syndrome

ObjectivesWe aimed to determine the importance of oxidative stress in the pathogenesis of restless legs syndrome (RLS) by quantification of advanced oxidation protein products and total thiol levels (as markers of oxidative protein damage), nitric oxide levels (as an antioxidant and endothelial function), and malondialdehyde levels (as a marker of lipid peroxidation) in patients with RLS.Design and methodsA total of 22 patients with primary RLS were enrolled in the study and 20 age-and-gender-matched healthy subjects were enrolled as a control group. Serum nitric oxide, malondialdehyde, thiol levels, and plasma advanced oxidation protein products levels were determined by spectrophotometric methods.ResultsSerum nitric oxide and thiol levels were lower in the patient group than in controls (p = 0.007 and p = 0.017, respectively). Plasma advanced oxidation protein products levels and serum malondialdehyde levels were found to be higher in patients with RLS than in controls (p = 0.017 and p = 0.008, respectively). Serum malondialdehyde level was found to be positively correlated with plasma advanced oxidation protein products levels (p = 0.039). Serum thiol level was found to be negatively correlated with plasma advanced oxidation protein products levels (p = 0.030).ConclusionsIncreased advanced oxidation protein products, malondialdehyde levels, and decreased thiol and nitric oxide levels, may suggest that patients with RLS are under oxidative stress. Although both lipid peroxidation and protein oxidation may have a role in atherosclerosis in RLS, those factors may be related to the pathogenesis of RLS.     

Is preeclampsia associated with restless legs syndrome?

ObjectiveRestless legs syndrome (RLS) is a common neurologic disorder. Secondary RLS includes pregnancy and iron deficiency. Prevalence of RLS in pregnancy ranges from 11% to 27%. We aimed to assess the frequency and characteristics of RLS in pregnancy in a Peruvian population and to evaluate the possible pregnancy or delivery complications due to RLS.MethodsWe assessed 218 consecutive expectant mothers at the inpatient clinic of the Hospital San Bartolome in Lima, Peru. Assessment was performed by using the standard diagnostic criteria for RLS and by using a clinical and diagnostic interview. Questionnaires for RLS severity, idiopathic RLS (IRLS), and excessive daytime sleepiness (EDS) according to the Epworth sleepiness scale (ESS) were used. Blood examination was performed for hemoglobin and hematocrit. For comparison, RLS patients were matched for age and body mass index (BMI) with pregnant women without RLS.ResultsOut of 218 patients, 40 (18.4%) fulfilled diagnostic criteria for RLS. In RLS patients, prophylactic iron supplementation therapy during pregnancy was less frequently taken (P = .02). Pregnant women with RLS had a higher ESS score than pregnant controls (10.6 +/− 3.1 vs 7.6. +/− 3.6; P < .001). Preeclampsia was more frequent in RLS (7/40 vs 1/39; P = .03).ConclusionsIn our study, RLS was frequent in pregnant Peruvian women, especially in those without prophylactic iron supplementation. RLS patients described more EDS. Preeclampsia was more common in RLS. Our study is the first study to indicate a possible association between RLS and preeclampsia.     

Relation of the International Restless Legs Syndrome Study Group rating scale with the Clinical Global Impression severity scale,the restless legs syndrome 6-item questionnaire,and the restless legs syndrome-quality of life questionnaire

BackgroundThe SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life questionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To provide clinical context for the IRLS and to guide the choice of assessment scales for RLS studies, our post hoc analysis of SP790 data evaluated associations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and RLS-QoL.MethodsScale associations were analyzed at baseline and at the end of maintenance (EoM) using data from the safety set (rotigotine and placebo groups combined [n = 458]). Changes from baseline to EoM in IRLS score vs comparator scale scores also were analyzed.ResultsThere was a trend towards increasing IRLS severity category with increasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation coefficients showed correlations between IRLS and comparator scale scores at baseline and EoM as well as correlations for change from baseline to EoM.ConclusionCorrelations between the IRLS and comparator scales were substantial. These data indicate that the IRLS is clinically meaningful. The IRLS and CGI-1 are generally sufficient to evaluate the overall severity and impact of RLS symptoms in clinical trials.     

Lower molecular weight intravenous iron dextran for restless legs syndrome

BackgroundVarious techniques used to assess brain iron concentrations have demonstrated the presence of low iron stores in patients with restless legs syndrome (RLS). Previous open-label and randomized studies generally support the value of iron treatment for RLS symptoms. Only one of these studies assessed iron therapy response to changes in brain iron status. The current study was designed to assess the effect of iron therapy on RLS symptoms and on CSF measures of brain iron status.MethodsIdiopathic RLS patients drawn from the Korean population received four weekly intravenous (IV) doses of 250 mg low-molecular weight iron dextran for a total dose of 1 g. One week after the last dose, any subject on RLS medication tapered off the RLS medications. Blood and CSF samples were taken to measure iron parameters at baseline and again, three weeks after the last dose. We have been following their response to the drug for two years after treatment.ResultsTwenty-five patients (age 55.2 ± 9.3, 18 female) enrolled in this study without serious adverse reactions. Seventeen of the 25 patients (68%) showed moderate or complete improvement of all RLS symptoms after treatment based on the Korean-translated versions of the International RLS Severity scale (K-IRLS). Changes in the K-IRLS did not correlate significantly with changes in CSF ferritin. The response to IV iron could not be predicted by patients’ demographics, or by blood or CSF iron baseline characteristics. RLS symptom improvement started between one and six weeks after treatment and the treatment benefits lasted from one month to 22 months. Fourteen patients, (56%) completely stopped all medications, for a mean duration of 31.3 ± 33.1 weeks. These results are comparable to those from a prior study with high molecular weight dextran.ConclusionsIntravenous low-molecular weight iron dextran produced significant improvement of RLS symptoms in a majority of patients without any significant adverse effects. Serious anaphylaxis occurs with high molecular weight, but rarely, if ever, with this low molecular weight dextran. Given apparent comparable efficacy the low molecular weight and not the high molecular weight iron dextran, should be considered for RLS treatment. Although changes in CSF ferritin were seen following therapy, these changes were not related to clinical improvements.     

Restless legs syndrome in end-stage renal disease: Clinical characteristics and associated comorbidities

BackgroundDespite being frequently described in patients with end-stage renal disease (ESRD), clinical characteristics and comorbidities in association with restless legs syndrome (RLS) are still to be confirmed.ObjectivesThe aim of this study was to investigate clinical factors associated with RLS in ESRD patients in hemodialysis.MethodsThis is a cross-sectional study of 400 patients on hemodialysis, evaluating RLS, clinical features and other sleep abnormalities.ResultsOut of 400, 86 patients presented RLS (21.5%; mean age 48.8 ± 13.8 y), being more frequent in females (p < 0.005). Forty-eight individuals (12% mean age 50.7 ± 13.1 y) had moderate/severe RLS, 14 reported symptoms prior to hemodialysis, 13 described family history of RLS, and eight described symptoms as disturbing during dialysis. RLS cases showed lower hemoglobin (p < 0.005), poorer quality of sleep (Pittsburgh Sleep Quality Index >5, p = 0.002), higher scores on the Beck Depression Inventory Scale (p < 0.005), greater scores on the Charlson Comorbidity Index (p = 0.01) and the Epworth Sleepiness Scale (p = 0.001) and higher risk of obstructive sleep apnea (OSA; Berlin questionnaire, p = 0.01). Hypertension was more frequent in cases with moderate/severe RLS (p = 0.01) and remained after controlling for the risk of OSA (p = 0.02).ConclusionIn ESRD patients in hemodialysis, RLS is present in 21.5%; 16% report symptoms prior to hemodialysis and a family history of RLS. Symptoms are disturbing during hemodialysis in 9% of cases. RLS is associated with lower hemoglobin, worse sleep quality, excessive daytime sleepiness, depressive symptoms and higher risk of OSA. Hypertension is associated with moderate/severe RLS.     

Efficacy and safety of pramipexole in Japanese patients with primary restless legs syndrome: A polysomnographic randomized,double-blind,placebo-controlled study

ObjectiveTo evaluate the efficacy of pramipexole on polysomnographic measures, patient ratings and a clinical rating in Japanese patients with primary restless legs syndrome (RLS).MethodsPatients with moderate to severe RLS having periodic limb movements in bed index (PLMI) ? 5 were randomly assigned to receive pramipexole or placebo in a 6-week, double-blind, placebo-controlled study with forced titration from 0.125 to 0.75 mg/day. Both polysomnography (PSG) and the suggested immobilization test (SIT) were performed at baseline and 6 weeks after starting treatment.ResultsThe analysis of covariance of log-transformed PLMI showed that the adjusted means at the end of study were significantly smaller in the pramipexole group than in the placebo group (p = 0.0019). In all patients, variables on SIT did not show any differences between the two groups, whereas a significant improvement was shown in the pramipexole group compared with the placebo group for patients with a SIT-PLM index at baseline ? 15. Pramipexole group showed a significant reduction in the International Restless Legs Syndrome Study Group rating scale (IRLS; p = 0.0005), a significant improvement in both Patient Global Impression (PGI; p < 0.0001) and Clinical Global Impressions (CGI-I; p = 0.0488), and a significantly greater mean reduction in the Pittsburgh Sleep Quality Index (PSQI; p = 0.0016), when compared with those of placebo group at week 6.ConclusionsPramipexole is highly efficacious in the reduction of PLMI and in the improvement of subjective severity of RLS and subjective sleep disturbance caused by the disorder.     

Relationship between blood harmane and harmine concentrations in familial essential tremor, sporadic essential tremor and controls

IntroductionHarmane, a potent tremor-producing β-carboline alkaloid, may play a role in the etiology of essential tremor (ET). Blood harmane concentrations are elevated in ET cases compared with controls yet the basis for this elevation remains unknown. Decreased metabolic conversion (harmane to harmine) is one possible explanation. Using a sample of >500 individuals, we hypothesized that defective metabolic conversion of harmane to harmine might underlie the observed elevated harmane concentration in ET, and therefore expected to find a higher harmane to harmine ratio in familial ET than in sporadic ET or controls.MethodsBlood harmane and harmine concentrations were quantified by high performance liquid chromatography.ResultsThere were 78 familial ET cases, 187 sporadic ET cases, and 276 controls. Blood harmane and harmine concentrations were correlated with one another (Spearman's r = 0.24, p < 0.001). The mean (±SD) harmane/harmine ratio = 23.4 ± 90.9 (range = 0.1–987.5). The harmane/harmine ratio was highest in familial ET (46.7 ± 140.4), intermediate in sporadic ET (28.3 ± 108.1), and lowest in controls (13.5 ± 50.3) (p = 0.03). In familial ET cases, there was no association between this ratio and tremor severity (Spearman's r = 0.08, p = 0.48) or tremor duration (Spearman's r = 0.14, p = 0.24).ConclusionThe basis for the elevated blood harmane concentration, particularly in familial ET, is not known, although the current findings (highest harmane/harmine ratio in familial ET cases) lends support to the possibility that it could be the result of a genetically-driven reduction in harmane metabolism.