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Restless legs syndrome (RLS) has been associated with anxiety, depression, insomnia, lifestyle factors and infections. We aimed to study the prevalence of symptoms of RLS during the COVID-19 pandemic versus pre-pandemic. We hypothesized that pre-existing RLS symptoms worsened and pandemic-related factors may have triggered new symptoms of RLS. Adults (≥18 years) from fifteen countries across four continents participated in an online survey between May and August 2020. The harmonized questionnaire included a validated single question on RLS with response alternatives from 1 to 5 on a scale from never to every/almost every evening or night. Other measures were the Insomnia Severity Index (ISI), measures of symptoms of anxiety (GAD-2) and depression (PHQ-2), and questions on different pandemic-related factors. Altogether, 17 846 subjects (63.8 % women) were included in the final analyses. The mean age was 41.4 years (SD 16.1). During the pandemic, symptoms of RLS (≥3 evenings/nights per week) were more common 9.1 % (95 % CI 8.7–10.1) compared to 5.4 % (95 % CI 4.9–6.0) before the pandemic (P < 0.0001). Alltogether 1.3 % (95 % CI 1.1–1.6) respondents had new-onset symptoms (≥3 evenings/nights per week). Moderate-severe insomnia was strongly associated with RLS symptoms. The occurrences of new-onset RLS symptoms were 5.6 % (95 % CI 0.9–13.0) for participants reporting COVID-19 and 1.1 % (95 % CI 0.7–1.5) for non-COVID-19 participants. In the fully adjusted logistic regression model, the occurrence of new-onset RLS symptoms was associated with younger age, social restrictions and insomnia severity. In a similar analysis, RLS symptoms (≥3 evenings/nights per week) were associated with lower education, financial hardship, sleep apnea symptoms, use of hypnotics, insomnia severity, symptoms of depression and possible post-traumatic stress disorder. Our findings indicate that RLS symptoms were more common during the pandemic than before. Usually, the prevalence of RLS increases with age. However, during the pandemic, new-onset symptoms of RLS were more common in younger age groups. This may be due to the pandemic-related factors being more pronounced in the younger compared to the older. The association between insomnia, psychiatric symptoms and RLS warrants clinical attention. • Restless legs symptoms were more prevalent during the COVID-19 pandemic than before. • Insomnia and psychiatric symptoms were associated with RLS symptoms. • New-onset RLS symptoms were more common among younger subjects. [ABSTRACT FROM AUTHOR]

Patients having COPD share some factors, e.g., chronic hypoxemia, anemia of chronic disease and nicotine use, which are also the risk factors for RLS hence predispose them to experience RLS in higher then general population. There are limited studies with methodological constraints evaluating the prevalence and/or correlates of RLS among patients with COPD. Consecutive adult patients of either gender, having stable COPD as per GOLD guidelines 2021, were assessed for RLS using IRLSSG (2014) criteria (excluding RLS mimics) and the severity of RLS was determined in participants having RLS. Phenomenology of RLS, past medical history and laboratory parameters were gathered. Insomnia and depression were assessed using the insomnia severity index and PHQ-9, respectively. Participants' (N = 210) mean age was 63.02 ± 8.19 years, and 83.8% of subjects were men. 12.9% of participants were found to have RLS. Among those having RLS, nearly half (51.9%) had moderate symptoms, and 18.5% experienced severe symptoms. RLS was more prevalent among younger, females, those having severe COPD, participants having exacerbation of COPD in the previous year, lower post-bronchodilator FEV1, higher dyspnea and COPD assessment test score. Multivariate analysis showed that younger age, female gender, lower post-bronchodilator FEV1, lower FEV1/FVC ratio and higher serum creatinine increased the odds of having RLS. Depressive symptoms were more frequent in participants having RLS. The present study found that the prevalence of RLS among patients with stable COPD was higher than the general population. Female gender, younger age, higher airflow limitation and higher serum creatinine (though in the physiological range) increase the odds of having RLS. Stable patients with COPD having these characteristics must be screened for RLS. • 210 stable COPD patients were evaluated using IRLSSG (2014) criteria and the IRLS severity rating scale. • 12.9% of patients were found to have RLS, which is six times higher than the general population. • 51.9% of patients had moderate RLS, while 18.5% experienced severe symptoms. • Younger age, female gender, higher airflow obstruction and higher serum creatinine increased the odds of having RLS. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) is a common sleep-related movement disorder in populations of European descent and disease risk is strongly influenced by genetic factors. Common variants have been assessed extensively in several genome-wide association studies, but the contribution of rarer genetic variation has not been investigated at this scale. We therefore genotyped a case-control set of 9246 individuals for mainly rare and low frequency exonic variants using the Illumina ExomeChip. However, standard single variant and gene-level association tests were negative. This does not preclude a role of rare variants in RLS, but is likely due to the small sample size and the limited selection of rare genetic variation captured on the array. Therefore, exome or whole genome sequencing should be performed rather than increasing the sample size of ExomeChip studies in order to identify rare risk variants for RLS. [ABSTRACT FROM AUTHOR]

Objective/background: X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease that causes progressive gait and balance problems. Leg discomfort, sleep disturbances, and pain contribute to daily disability. We sought to investigate the prevalence and severity of Restless Legs Syndrome (RLS) in patients with ALD.Patients/methods: We administered questionnaires and conducted diagnostic telephone interviews to assess RLS severity. We retrospectively extracted data from neurological examinations, functional gait measures, and laboratory assessments.Results and Conclusions: Thirty-two adults with ALD (21 female, 11 male) were recruited to participate. Thirteen patients (40.6%) had RLS (10/21 females and 3/11 males). The median age of RLS onset was 35 years [IQR = 22-54]. Patients with RLS had more signs and symptoms related to myelopathy, but not the brain demyelination seen in ALD. This pilot study suggests a high prevalence of RLS in adults with ALD, which may contribute to sleep problems and impair quality of life. [ABSTRACT FROM AUTHOR]

Background: Restless Legs Syndrome (RLS) is a neurological sensorimotor disorder that occurs in the evening and night, thereby often impacting quality of sleep in sufferers. The aetiology of RLS is not completely understood although iron dysregulation has been suggested as a likely pathway. The relationship between RLS and the iron regulatory protein hepcidin has not been studied in large cohorts. We aimed to assess whether an association between plasma hepcidin variation and RLS exists in a large cohort of healthy individuals.Methods: Plasma hepcidin levels were measured in 9708 Danish blood donors from the Danish Blood Donor Study all of whom correctly completed the validated Cambridge-Hopkins RLS-questionnaire for RLS assessment.Results: A total of 466 blood donors were determined as current RLS cases in the sample (4.8%). RLS cases had a significantly higher proportion of females (56.7% vs 46.7%; P < 0.001) and were older (median age [IQR] 40.6 years vs 38.0 years; P = 0.010) than controls. RLS cases were also more frequent smokers (P = 0.004). No significant differences were found in body mass index (BMI), alcohol consumption, time of donation and donation history between cases and controls. No difference in plasma hepcidin levels was observed between RLS cases and controls (median concentration [IQR]: 10.5 ng/ml [6.3-16.4] in RLS cases vs 10.5 ng/ml [6.0-16.5] in controls). Using a logistic regression model, we found that hepcidin levels were not associated with RLS after adjusting for age, sex, alcohol consumption, smoking status, donation time and donation history (OR = 1.00 [0.99-1.02] per 1 ng/ml increase of hepcidin; P = 0.429).Conclusion: Our study in Danish blood donors did not find an association between RLS and plasma hepcidin levels. Our findings suggest that plasma hepcidin's role as a potential diagnostic biomarker of RLS is inadequate. [ABSTRACT FROM AUTHOR]

Background: Significant 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.Methods: Data 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.Results: The 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).Conclusion: Intravenous 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. [ABSTRACT FROM AUTHOR]

Background: Brain iron deficiency (BID), especially for the substantia nigra (SN), without peripheral iron deficiency (ID) has been well documented as a ubiquitous finding for restless legs syndrome (RLS) patients. This close association suggests the biology of RLS BID can produce RLS symptoms. Association, however, cannot establish such a direct relationship. Instead, the BID of RLS could be experimentally produced to determine if it then produces significant RLS-like biological or behavioral features. Forward genetics approach led to identification from the BXD strains the BXD40 females (BXD40f) as a putative animal model for the RLS BID. The BXD40f on an iron-sufficient diet have a lower iron in the VMB (containing the SN) during the active but not inactive period. This was not found for the other BXD strains evaluated. The BXD40f on an ID diet uniquely have even greater reduced VMB but not peripheral iron, matching the RLS BID pathophysiology. A prior report found that the BXD40f on an iron-sufficient diet had an RLS-like behavior of increased activity occurring only in the last part of the active period that was not present in the other strains without the low VMB iron. This increased activity matches the circadian pattern of symptoms in RLS patients with increased urge or drive to move in the last part of the day. This study asks first: if you decrease the VMB iron by an iron deficient diet do the RLS-like behaviors worsen; and second will the dopaminergic treatments effective for RLS also reduce the worsened RLSlike behaviors.Methods: In sum, 13 BXD40f mice post weaning were randomly assigned for 100 days to either a iron-sufficient diet (n = 6) or an ID diet (N = 7). They were then evaluated for 24-h activity in their home cage using implanted G2 EMitter telemetry device. At 3 h before the end of the active period IP doses were given every other day of either: saline (vehicle only), 12.5 mg levodopa, 25 mg levodopa, 0.5 mg quinpirole, or 1 0.0 mg quinpirole.Results: The ID compared to irons-sufficient diet produced earlier onset of the RLS-like behavior matching the earlier onset of symptoms with increasing severity of RLS. The dopaminergic treatments significantly reduced the RLS-like behavior. Added analyses of the RLS-like behaviors as decreased resting times showed similar results to activity increases.Conclusions: These data demonstrate both that The BXD40f provide a useful animal model of RLS and also strongly support the hypothesis that the biology of RLS BID can produce RLS symptoms. [ABSTRACT FROM AUTHOR]

We assessed corticomotor excitability in the primary motor cortex (M1) of participants with moderate-to-severe restless legs syndrome (RLS) symptoms using transcranial magnetic stimulation (TMS) in relation to the clinical and sleep aspects of the disease. Thirty-five participants (20 F; mean age: 59.23 ± 1.66 years; range: 42-78 years) affected by primary RLS (off medications) and 31 age-matched controls (19 F; mean age: 57.90 ± 1.50 years; range: 43-79 years) underwent TMS following two nights of polysomnography (PSG). Paired-pulse TMS measures [short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI), and intracortical facilitation (ICF)] of the dominant M1hand and M1leg muscles were collected and analyzed in relation to clinical features of RLS and PSG. We found decreased corticomotor excitability in M1hand, whereas it was increased in M1leg, which was greater in patients with more severe RLS. Participants with RLS with a history of dopamine-agonist-induced symptom augmentation showed decreased LICI (reduced inhibition) compared to nonaugmented participants with RLS for M1leg. None of the TMS measures (M1hand or M1leg) correlated with the PSG parameters. This study shows hyperexcitability in M1leg, and this appears related to RLS disease severity and decreased excitability in M1hand. The results provide new insight into the complex neurobiology of RLS, particularly in more advanced stages of the disease. [ABSTRACT FROM AUTHOR]

Objective: The 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.Methods: First, 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.Results: The 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.Conclusions: These findings may provide novel insight into the pathophysiology of RLS. [ABSTRACT FROM AUTHOR]

Objectives: Perampanel is a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) antagonist that has been approved for the treatment of partial seizures. Here we report on the first open study evaluating its efficacy in idiopathic restless legs syndrome (RLS).Methods: The study was designed as a prospective two-month open trial. Twenty-two previously untreated patients diagnosed with idiopathic RLS began treatment with 2 mg perampanel, which was increased to 4 mg at week four if clinically necessary. Multiple Suggested Immobilization Tests (mSITs) followed by polysomnography were performed at baseline and at week eight. Severity ratings were performed every two weeks by means of the IRLS scale, and Clinical Global Index (CGI) subscale. The main endpoint was therapeutic response, defined as a 50% improvement in IRLS total score.Results: Twenty patients completed the study. During the 8-week treatment period, the IRLS score improved from a mean (±standard deviation (SD)) 23.7 ± 4.2 to 11.5 ± 5.3. Twelve of 20 patients were full responders (improvement 50% in IRLS total score), and four responded partially. The mean effective dose of perampanel at the end of treatment was 3.8 mg/day. Treatment with perampanel also resulted in an improvement in the mean (±SD) periodic leg movement index from 27.8 ± 6.9 to 4.36 ± 2.0. Perampanel was well tolerated. The main side effects were dizziness, somnolence, headache, and irritability.Conclusion: These preliminary results suggest that perampanel has significant therapeutic effects on both sensory and motor symptoms. If confirmed by future controlled studies, perampanel might become a promising alternative to existing dopaminergic treatments due to its glutamatergic mechanism of action. The study provides class IV evidence supporting the therapeutic effects of perampanel in RLS/WED. [ABSTRACT FROM AUTHOR]

At the outset of genetic studies in restless legs syndrome (RLS), the disorder was assumed to be a classical monogenic disorder that runs in families. However, years of family studies did not reveal any causally-related genes or genetic variants. The advent of high-throughput genotyping technology led to a change; genome-wide association studies in large case-control samples became feasible, which led to the identification of first genetic risk variants for RLS. Variants detected by this approach are common ones, which that individually confer only a minor increase in risk of disease. Overall, the currently known risk variants in six genomic loci account for only a small proportion of the genetically determined susceptibility to RLS. Additional risk loci and individual variants remain to be discovered. First studies indicate that rare genetic variants are also important contributors in RLS. These are expected to have a larger impact on the phenotype and may thus prove to be excellent candidates for functional studies and, in the long-term, targets for developing therapeutics or preventive measures. To enable their discovery, large-scale studies including tens of thousands of affected individuals may be needed. Next-generation sequencing technologies such as whole exome or whole genome sequencing will be essential for this endeavor. Even though the number of known risk variants is still limited, they have been indispensable in terms of deciphering the underlying pathophysiology of RLS, providing the molecular starting points for animal models and in vitro studies to understand disease mechanisms. In addition, genetic risk variants can be valuable tools for disentangling the phenotypic complexity observed in RLS. Testing RLS risk variants for associations with periodic limb movements (PLMs) identified a significant role of some of the variants and suggested PLMs as an endophenotype in RLS. Further advances in genetics research in RLS will be driven by large-scale sequencing projects and the identification of additional common, but also rarer risk variants with larger effects on disease risk. Another uncharted territory in RLS research epigenetic effect on gene activity. Overall, genetic studies continue to hold great potential for understanding biology of the disease. [ABSTRACT FROM AUTHOR]

In this article, we review the original findings from MRI and autopsy studies that demonstrated brain iron status is insufficient in individuals with restless legs syndrome (RLS). The concept of deficient brain iron status is supported by proteomic studies from cerebrospinal fluid (CSF) and from the clinical findings where intervention with iron, either dietary or intravenous, can improve RLS symptoms. Therefore, we include a section on peripheral iron status and how peripheral status may influence both the RLS symptoms and treatment strategy. Given the impact of iron in RLS, we have evaluated genetic data to determine if genes are directly involved in iron regulatory pathways. The result was negative. In fact, even the HFE mutation C282Y could not be shown to have a protective effect. Lastly, a consistent finding in conditions of low iron is increased expression of proteins in the hypoxia pathway. Although there is lack of clinical data that RLS patients are hypoxic, there are intriguing observations that environmental hypoxic conditions worsen RLS symptoms; in this chapter we review very compelling data for activation of hypoxic pathways in the brain in RLS patients. In general, the data in RLS point to a pathophysiology that involves decreased acquisition of iron by cells in the brain. Whether the decreased ability is genetically driven, activation of pathways (eg, hypoxia) that are designed to limit cellular uptake is unknown at this time; however, the data strongly support a functional rather than structural defect in RLS, suggesting that an effective treatment is possible. [ABSTRACT FROM AUTHOR]

Conventional pharmacologic treatment of restless legs syndrome (RLS) may be limited in some people. Up to 65% of patients with RLS regularly use alternative practices for symptom relief. We reviewed the current clinical evidence, and we proposed physiologic basis for various alternative practices for RLS including mind-body interventions (conventional exercise, yoga, and acupuncture), non-pharmacologic lifestyle interventions (pneumatic compression devices [PCDs], light therapy, and cognitive-behavioral therapy [CBT]), and neutraceuticals (vitamins, valerian, and Chinese herbs). Based on the available evidence, regular physical activity should be recommended for the treatment of RLS symptoms. Oral iron supplementation should be considered for people with RLS who have low ferritin levels, although criteria to identify probable responders, and optimal formulations and durations of treatment are needed. Supplementation for low levels of vitamins E, C, and D could be considered, although evidence specifically in RLS is limited, and it is unclear if levels should routinely be checked in patients with RLS. Insufficient evidence exists for yoga, acupuncture, PCDs, near-infrared light therapy, CBT, valerian, or Chinese herbs, but preliminary studies on each of these suggest that high-quality randomized controlled trials may be warranted to support and verify the data presented. [ABSTRACT FROM AUTHOR]

Background Restless legs syndrome (RLS) is a common disorder, with several known genetic risk factors, yet the actual genetic causes are unclear. Methods Whole-exome sequencing (WES) was performed in seven RLS families, focusing on six known genetic loci: MEIS1 , BTBD9 , PTPRD , MAP2K5 / SKOR1 , TOX3 , and rs6747972 . Genotyping using specific TaqMan assays was performed in two case–control cohorts (627 patients and 410 controls), and in a familial cohort (n = 718). Results WES identified two candidate GLO1 variants (within the BTBD9 locus), p.E111A and the promoter variant c.-7C>T, both co-segregated with the disease in four families. The GLO1 p.E111A variant was associated with RLS in the French-Canadian cohort (odds ratio, OR = 1.38, p = 0.02), and demonstrated a similar trend in the US cohort (OR = 1.26, p = 0.09, combined analysis OR = 1.28, p = 0.009). However, the original genome-wide association study (GWAS) marker, BTBD9 rs9357271, had stronger association with RLS (OR = 1.84, p = 0.0003). Conditional haplotype analysis, controlling for the effect of the BTBD9 variant rs9357271, demonstrated that the association of GLO1 p.E111A turned insignificant ( p = 0.54). In the familial cohort, the two GLO1 variants were not associated with RLS. Other variants in the SKOR1 (p.W200R and p.A672V) and PTPRD (p.R995C, p.Q447E, p.T781A, p.Q447E, and c.551-4C > G) genes, did not co-segregate with the disease. Conclusions The GLO1 variations studied here are not the source of association of the BTBD9 locus with RLS. It is likely that the genetic variants affecting RLS susceptibility are located in regulatory regions. [ABSTRACT FROM AUTHOR]

Objective The 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. Methods Fifteen 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. Results Compared 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. Conclusions High-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. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Few studies have examined the long-term use of dopamine agonists for restless legs syndrome (RLS). We report a cohort study of 50 patients initially prescribed pramipexole between 1998 and 2002. The objective was to determine duration of treatment, long-term efficacy, development of side effects and augmentation over an extended period. Methods: We performed a long-term analysis on a previously reported group of patients initially followed for a mean of 27.2months. Data were collected using retrospective chart reviews, written surveys and systematic telephone interviews. Results: Pramipexole was used for a mean of 8years (range 0.6–12years). Nine (18%) discontinued pramipexole because of poor efficacy (four), impulse control disorders (ICD) (two), augmentation (one) and resolved symptoms (two). Pramipexole was reported completely effective in 40% (compared to 67% at the end of the initial study), partially effective in 58% and ineffective in 2%. The median daily dose increased from 0.38mg after initial stabilization to 1.0mg at the end of the study. As many as 74% of patients experienced side effects. A total of 56% reported daytime sleepiness including 10% reporting sleep attacks while driving and 10% developed ICDs. Augmentation developed in 42% of patients, after a mean of 16.5months, and no later than 4.1years after commencing treatment. A total of 28% needed additional non-dopaminergic medications. Conclusion: The efficacy of pramipexole dropped with time, with increase in dose and addition of other agents, although the majority of patients remained on the drug. Problems included the development of augmentation within the first 4years of therapy and side effects such as sleepiness increasing with time and the development of ICDs. The study highlights the need for further research into alternative non-dopaminergic treatments for RLS. [Copyright &y& Elsevier]

Abstract: Background: Restless legs syndrome (RLS) is an under-diagnosed and under-treated disorder in the community. Little is known regarding the factors associated with treatment seeking for RLS. Based on Andersen’s behavioral model for health service utilization, we compared predisposing factors, enabling or impeding factors and need for care factors among participants without RLS (NRs), participants with untreated RLS (URs) and participants with treated RLS (TRs). Methods: The study sample consisted of 105 participants (NRs: n =41; URs: n =29; TRs: n =35) who were evaluated face-to-face based on the Hopkins Telephone Diagnostic Interview. We compared the groups with respect to sociodemographic variables, insurance status, attitudes and beliefs toward RLS and RLS treatment, symptom severity, impact on quality of life and subjective description of RLS symptoms. Results: URs were older (72.6years versus 61.1years) and had a higher proportion of African Americans (44.8% versus 8.6%) (p <0.01 for both). Compared to NRs and URs, TRs endorsed a stronger belief that RLS is a serious medical condition and causes marked psychosocial impairment (p <0.01 for both). TRs reported greater RLS symptom severity than URs (p <0.01), but the impact of RLS on quality on life was similar in both groups. TRs were more likely to use specific descriptors to describe symptoms of RLS than URs. Conclusions: Based on Andersen’s model, predisposing and need for care factors including Caucasian race, greater concern about the impact of RLS on daily activity and more frequent endorsement of RLS symptom descriptors were associated with receiving treatment for RLS. Further study is needed to identify barriers to treatment in individuals with undiagnosed and untreated RLS in the community. [Copyright &y& Elsevier]

Abstract: Objective: There has been recent interest in characterizing potential abnormalities of pain processing in patients with sleep disorders such as Restless Legs Syndrome (RLS). The aim of this study was to evaluate psychophysical responses to noxious heat and pressure stimuli in both treated and untreated RLS patients, compared to matched controls. Methods: This study is a cross-sectional group comparison of RLS patients with matched controls. A total of 31 patients (15 treated, 16 untreated) with a confirmed diagnosis of RLS were compared to 18 controls with no history of RLS or related sleep disorders. Results: RLS patients (both treated and untreated) demonstrated reduced pain thresholds and reported greater clinical pain relative to controls. Moreover, RLS patients demonstrated enhanced temporal summation of heat pain (p <.05), which may reflect aberrant central nervous system facilitation of pain transmission. Both treated and untreated RLS patients reported disrupted sleep relative to controls, and mediation analyses suggested that the reduced pain thresholds in RLS were attributable to sleep disturbance. However, the effect of RLS on the magnitude of temporal summation of heat pain was independent of sleep disturbance. Conclusions: These findings suggest that central nervous system pain processing may be amplified in RLS, perhaps partially as a consequence of sleep disruption. RLS patients, even those whose symptoms are managed pharmacologically, may be at elevated long-term risk for the development or maintenance of persistent pain conditions. Further studies in larger samples could help to improve the prospects for pain management in RLS patients. [Copyright &y& Elsevier]

Abstract: Objective: Assess the rate of augmentation as it occurs during standard long-term dopaminergic treatment of RLS, potential risk factors or predictors of augmentation, the relationship between treatment duration and augmentation, and the clinical impact of augmentation on subjects’ health outcomes. Methods: Two hundred sixty-six patients with dopamine-treated RLS completed a one-time online survey. All subjects were recruited by their PCP/neurologist and were 18 or older. Augmentation was assessed using NIH guidelines and an augmentation classification system was developed through this research. Results: Overall, 20% of the patients were classified as having definitive or highly suggestive clinical indications of augmentation. Five factors were considered likely to reflect increased risk of developing augmentation, including more frequent RLS symptoms pre-treatment, greater discomfort with RLS symptoms before treatment, and longer treatment duration. RLS augmentation occurred at a rate of about 8% each year for at least the first 8years of dopamine treatment. Subjects reporting definite or highly suggestive clinical indicators of augmentation had an average IRLS score of 23.6, indicating generally inadequate treatment with generally poor clinical outcomes. Only 25% of the patients reported no indications of augmentation and they were the only group to show on average a low (<15) IRLS score and good clinical outcomes. Conclusions: As currently used, long term dopaminergic treatment for an average±SD of 2.7±2.4years produced significant augmentation problems in at least 20% of the patients and only 25% of the patients were totally free of this problem. It is important for physicians to carefully screen patients for changes in RLS symptoms for as long as they are on dopamine agents, with particular attention paid to those patients who present with the most severe RLS symptoms prior to treatment initiation. Given the marked increase in suffering with augmentation, a method for early detection and intervention would be an important contribution to the effective management and treatment of RLS. [Copyright &y& Elsevier]

Abstract: Objective: Periodic limb movements in sleep (PLMS) show a time-of-night pattern, with most movements at the beginning of the night. Our study aimed to determine whether this pattern is due to an endogenous circadian rhythm, like that in the related movement disorder Restless Legs Syndrome (RLS). Methods: Four healthy older adults with a screening PLMI>20 were studied in an inpatient forced desynchrony protocol with an imposed sleep–wake cycle of 20h for 12 “nights,” allowing separation of circadian and sleep homeostatic influences on leg movements. We recorded sleep polysomnographically throughout each scheduled episode, including left and right anterior tibialis EMG. Results: PLMS in Stage 2 showed both a significant time-within-sleep pattern and a significant circadian rhythm. The circadian rhythm in PLMS peaked at the circadian phases when usual sleep onset occurs, preceding the evening rise in melatonin secretion. Conclusions: In our subjects, the circadian pattern of PLMs expression was very similar to that previously reported in patients with RLS. This evidence for a circadian rhythm in PLMS has implications for treatment and provides direction for future studies of the pathophysiology of this movement disorder. [Copyright &y& Elsevier]

Abstract: Background: A close temporal relationship was shown between the onset of melatonin secretion at night and the worsening of restless legs syndrome (RLS) symptoms, suggesting that melatonin may play a role in the genesis of this phenomenon. To test this hypothesis we studied the effects of the administration of exogenous melatonin and, conversely, the suppression of endogenous melatonin secretion by bright light exposure on the severity of RLS symptoms. Methods: Eight RLS subjects were studied in three conditions: at baseline, after administration of melatonin and during bright light exposure. The severity of RLS symptoms was assessed by the suggested immobilization test (SIT), which allows quantification of both sensory and motor manifestations (SIT-PLM) of RLS. Results: Analyses showed a significant increase of SIT-PLM index when subjects received exogenous melatonin compared to both baseline and bright light conditions, but bright light exposure had no effect on leg movements compared to the baseline condition. Analyses also revealed a small but significant decrease in sensory symptoms with bright light exposure compared to baseline. Conclusion: Exogenous melatonin may have a detrimental effect on motor symptoms, and bright light exposure produced small but significant improvement of leg discomfort. The study shows the interest of using the SIT to measure outcome of intervention in RLS. Further studies will be needed to assess the therapeutic value of bright light in RLS. [Copyright &y& Elsevier]

Abstract: Background: Restless legs syndrome (RLS) is characterized by abnormal leg sensations and an uncontrollable urge to move the lower extremities during rest periods. Evidence suggests that reflex tasks that involve sensory–motor integration may be altered in RLS patients. This led us to determine if RLS patients show alterations in a sensory–motor reflex conditioning task called differential eyeblink conditioning. Methods: RLS subjects were washed out of treatment medication for 7days prior to testing. Subjects (20 RLS and 19 Control) received 120 discrimination conditioning trials consisting of 60 CS+ trials (i.e., an auditory stimulus paired with the airpuff-US separated by a silent 900ms trace interval) and 60 CS− trials (i.e., a different auditory stimulus that was NOT paired with the US). Results: Control subjects showed normal differential responding to the CS+ and CS−, but the RLS patients showed little or no differential responding. A post-test questionnaire provides evidence that symptomatic interference was not responsible for the eyeblink conditioning deficits in the RLS subjects, and further suggests that neurophysiological factors were responsible for these deficits. Conclusions: Together these results suggest that deficits in eyeblink conditioning are related to the pathophysiology of RLS. The eyeblink conditioning test may also be useful for supporting a clinical diagnosis or treatment strategy for RLS. [Copyright &y& Elsevier]

Abstract: Objective: This study was designed to evaluate the associated risk of RLS with pregnancy in relation to the family history and the age of symptom onset of RLS. Methods and subjects: Data from a prior RLS family history study in which 1019 subjects (527 males, 492 females) were interviewed, provided a diagnosis and characterization of RLS and determination of pregnancy status on which the current study analysis was undertaken. Results: In the family members of RLS probands, the prevalence of RLS was significantly higher for parous women than for nulliparous women (49.5% vs. 33.7%, OR=1.92, 95% CI=1.16–3.19) or for men (49.5% vs. 30.0%, OR 2.29, 1.69–3.10), but no different for nulliparous women compared to men (33.7% vs. 30.0%, OR 1.19, 0.72–1.96). When only those whose RLS started at or after age 30 were considered, similar differences occurred. These differences were not observed among family members of control probands. Conclusions: These data indicate pregnancy has a major impact on the risk of developing RLS for those with a family history of RLS. This pregnancy effect appears to account for most of the gender differences often reported in overall RLS prevalence data. [Copyright &y& Elsevier]

Abstract: Background: Restless legs syndrome (RLS) is a medical condition with established neuropathology and genetic associations. Significant questions have, however, recently been raised about its true prevalence, medical significance and the degree to which it is under or over-diagnosed. This study therefore aimed to determine its prevalence, morbidity and adequacy of diagnosis based on physician evaluations of their own patients in primary care practice. Methods: Screening questionnaires were completed by adult patients attending 62 primary care practices across six western European countries within a one-week period. Patients screening positive for significant RLS symptoms were clinically evaluated for RLS by their physician. Physicians also classified the degree RLS affected the patient’s health and well-being. Patients independently completed the SF-36 Quality of Life and Medical Outcomes Study (MOS) sleep questionnaires. Results: Ten thousand five hundred and sixty-four patients completed the screening questionnaire; 804 responded positively to RLS symptoms and 630 of these were subsequently evaluated by their physician. The physicians diagnosed RLS in 365 patients. Ninety-one percent of these had not been previously diagnosed with RLS. In this cohort of adult primary care patients (without or with prorating for missed interviews) the estimated prevalence for diagnosed RLS was 3.5% or 4.4% and for medically-significant RLS 2.1% or 2.7%. A moderate to high degree of RLS negative impact on health related strongly to a lower vitality subscale on the SF-36 and short sleep times (5.2–5.4h) with more sleep disturbance on the MOS sleep scale. Conclusion: RLS in these western European countries is a common, clinically-significant medical condition that, despite all the publicity, remains largely undiagnosed. RLS evaluation is particularly recommended for patients complaining of insomnia. [Copyright &y& Elsevier]

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

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

Abstract: Boissier de Sauvages de La Croix and Gilles de la Tourette, French neurologists, noticed that patients with “anxiety in the lower limbs, shooting pain, tingling legs” may have an insomnia “at the time of wake–sleep transition [and] experience sudden jerks in the lower limbs.” Their descriptions confirm that the clinical features of RLS were previously described in French literature in the 18th century. [Copyright &y& Elsevier]

Abstract: Objective: To characterize periodic leg movements (PLM) and their association with sleep disturbances in drug-free patients with restless legs syndrome (RLS) and healthy subjects without sleep complaints. Methods: Polysomnographic recordings of 95 patients with idiopathic RLS and 31 age-matched controls were compared, and correlation analysis between sleep efficiency and PLM variables was performed. All patients and controls were free of medication for 10 days prior to polysomnography. Results: PLM measures revealed a significantly longer mean duration of single PLM during wakefulness and non rapid eye movement (NREM) sleep in RLS patients as compared to controls. PLM indices were higher in RLS patients than in controls during all sleep stages, but not during wakefulness and slow wave sleep. A significantly higher number of PLM sequences was found in RLS patients than in controls. In RLS patients decreased sleep efficiency was associated with a higher number and a shorter duration of PLM sequences. Conclusions: The mean duration of single PLM might be an appropriate parameter to discriminate between healthy subjects with PLM and patients with RLS. High numbers of PLM sequences of short duration might be an indicator for the decreased sleep quality in RLS patients. [Copyright &y& Elsevier]

Abstract: Background: In accordance with the diagnostic criteria of the International Restless Legs Syndrome (RLS) Study Group, the diagnosis of RLS is exclusively based on subjective information. Patients must report an urge to move the legs (and arms) with or without unpleasant sensations which is engendered by rest, relieved by movement, and worse in the evening or at night than during the day (essential criteria). Objective information such as excessive periodic leg movements, positive response to dopaminergic medication, family history of RLS or findings of a neurological examination cannot substitute any of the essential criteria but are considered both supportive for the RLS diagnosis and important for decisions on differential diagnoses. In this article, we report a systematic empirical analysis of the accuracy of diagnostic decisions based on all diagnostic criteria being either “essential” or “non-essential.” Methods: We re-analyzed data from a validation study for the RLS Diagnostic Index, in which ten items related to diagnostic criteria were compared with an expert diagnosis of RLS (n =86) and other sleep-related diagnoses (n =93). The value of individual diagnostic criteria and features of RLS predictive of the expert diagnoses were analyzed with logistic regression models by increasing the set of diagnostic criteria stepwise based on delta–χ 2 tests. Results: The essential diagnostic criteria share a large amount of variance in the prediction of the expert diagnosis. Three of the four essential criteria (urge to move the legs, which is engendered by rest and worse in the evening) almost completely determine the expert diagnosis. However, adding response to dopaminergic medication to the set of the essential criteria increased the effect size in the logistic regression model from 69.4% to 88.4%, indicating a relevant improvement of the accuracy in supporting or excluding the diagnosis of RLS. Conclusion: On the basis of our exploratory empirical analysis we conclude that the accuracy of diagnostic decision making in patients suspicious for RLS can be improved by inclusion of objective information. Response to dopaminergics is the most important criterion which both supports the “true” diagnosis of RLS, if present, and is also relevant to exclude mimics of RLS. [Copyright &y& Elsevier]

Abstract: Background: There is a need for structured methods to improve sensitivity and specificity of diagnostic decision making in Restless Legs Syndrome (RLS). We present the RLS-Diagnostic Index (RLS-DI), a diagnostic algorithm which combines essential and supportive diagnostic criteria from patient interviews, polysomnography and neurological examination in an adaptive procedure. Method: The RLS-DI consists of 10 items which are related to the essential diagnostic criteria established by the International RLS Study Group (five items) as well as their supportive criteria (3 items) and features associated with RLS (2 items). Items have to be completed using three categories per item that address frequency of occurrence of symptoms or certainty of presence or absence of other diagnostic information. Negative weights were given when the clinically most relevant items were not present. The RLS-DI was administered in a telephone interview to 179 patients (86 with RLS, 93 with other sleep disorders) of the 21 month cohort of one sleep center in Germany. Results: With receiver-operating characteristics, a cut-off of ⩾11 points on a scale ranging from −22 (no RLS) to 20 (definite RLS) was identified by comparing the RLS-DI total score to the diagnosis of two independent sleep experts. Sensitivity was 93.0%, specificity was 98.9%, and 96.1% of the patients could be correctly diagnosed. Specificity was higher in items related to supportive or associated diagnostic information (95.7%) than in those related to the essential diagnostic criteria (81.7%). Patients with RLS scored a higher RLS-DI than those with primary insomnia or other neurological or psychiatric disorders (p <.001). Conclusion: The RLS-DI demonstrated the ability to validly diagnose an actual and persistently present Restless Legs Syndrome in patients of a sleep lab population and to exclude those patients whose sleep disturbances have other causes. [Copyright &y& Elsevier]

Abstract: The symptoms of restless legs syndrome (RLS) have a circadian pattern and central nervous system dopamine has been implicated in the pathogenesis of the condition. We sought to characterize circadian variation in dopamine and related compounds in human cerebro-spinal fluid (CSF). CSF was continuously withdrawn for 22h from an implanted lumbar intradural catheter and sampled from three patients with RLS, three patients with Parkinson’s disease (PD) and three healthy volunteers. Patients had moderate disease severity and took no medications. We assayed CSF dopamine (DA), homovanillic acid (HVA), dihydroxy-phenylacetic acid (DOPAC) and 5-hydroxyindole acetic acid (5-HIAA) from samples every 30min by reversed-phase HPLC coupled with electrochemical detection. We also measured CSF levels of hypocretin-1 every hour by RIA. The procedure was well-tolerated. One patient ended the study early due to lumbar radicular pain and was not included in the analysis. There were no changes in CSF cell counts or protein levels from the first to the last samples. There was no difference in any of the compounds between groups, so we fit 24-h cosines to examine if the entire group had significant phase consistency. There was a peak for dopamine at 10 a.m. (p <0.025) and for HVA at 2 p.m. (p <0.01), but no evidence of a significant 24-h rhythm for DOPAC, 5-HIAA, the HVA/5-HIAA ratio, or hypocretin-1. These results demonstrate a circadian rhythm for CSF dopamine and HVA concentrations in humans, with higher levels in the daytime than at nighttime. This circadian variation could underlie the symptoms of RLS and sleep-related variation in motor function in PD. [Copyright &y& Elsevier]

Abstract: Objective: To 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. Methods: Pooled 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. Results: The 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. Conclusions: These data suggest that ropinirole provides effective relief of symptoms, regardless of age at RLS symptom onset. [Copyright &y& Elsevier]

Abstract: Background and purpose: Using transcranial B-mode sonography (TCS), the first morphological marker for restless legs syndrome (RLS), hypoechogenicity of the substantia nigra (SN) has been found. The aim of this study was to validate SN hypoechogenicity as a morphological marker for RLS in a large patient cohort and to investigate further RLS-associated brain abnormalities using TCS. Methods: One hundred forty-three RLS patients (37 with symptomatic RLS) and 45 controls, matched for age and gender, underwent TCS by an experienced and independent rater who was blinded to clinical data. Results: The basal ganglia, ventricular system and cerebral lobes showed no RLS-specific abnormalities. SN hypoechogenicity correlated with a family history of RLS (p <0.001) and showed good sensitivity (82%), specificity (83%) and positive predictive value (94%). Red nucleus hyperechogenicity and brainstem raphe (BR) hypoechogenicity were more prevalent in RLS than in controls (both p <0.001) and correlated with reported periodic limb movements and depression, respectively (both p <0.001). Seventy-six percent of the patients (7% of controls) showed a co-occurrence of two or more sonographical abnormalities; 60% of symptomatic RLS patients showed the same sonographic features as the majority of RLS patients. Conclusions: TCS is a useful additional tool for diagnosing RLS and RLS-related disorders that demonstrate various brainstem abnormalities. [Copyright &y& Elsevier]

Abstract: Objectives: The autosomal recessive disorder PARK6 manifests as early-onset Parkinson’s disease (PD) with a particularly mild progression. PARK6 is of particular scientific interest, since it is caused by loss-of-function mutations in the mitochondrial protein kinase PINK1 and may thus serve as a model for oxidative damage in PD and in other basal ganglia disorders. Sleep disturbances are very common in PD but have not yet been reported for PARK6 patients. The present study reports on sleep of a Spanish family with PARK6. Of the 5 siblings, 3 were homozygous and severely affected, and 2 were heterozygous and clinically asymptomatic. Research questions concerned possible differences in sleep recordings between homozygote and heterozygote siblings and similarities between PARK6 and sporadic PD sleep profiles. Method: The data from detailed clinical interviews of the patients and their bedpartners are reported and compared with polysomnographic data from second-night recordings. Conclusions: All siblings had good subjective and objective sleep quality. Restless legs syndrome and rapid eye movement (REM) sleep behaviour disorder (RBD) were not observed, suggesting that sleep disturbances are not commonly found in PARK6 patients. Good sleep quality and the absence of RBD might be a useful diagnostic guide in the differential diagnosis of sporadic PD versus PARK6. [Copyright &y& Elsevier]

Abstract: Background and objective: To demonstrate the long-term efficacy and safety of pramipexole for Restless Legs Syndrome (RLS) using physician and patient RLS ratings, along with subjective assays of sleep parameters, in a 26-week, open-label trial. Patients and methods: Among 107 Finnish adults with moderate to severe RLS, pramipexole initiated at 0.125mg/day was titrated to a maximum 0.75mg/day. Efficacy evaluations included the International RLS Study Group Rating Scale (IRLS), Patient Global Impression (PGI) scale, Clinical Global Impressions-Improvement (CGI-I) scale, Epworth Sleepiness Scale (ESS), and Short Form-36 (SF-36) Health Survey. Subjective Sleep Quality was assessed by patient ratings of sleep and morning tiredness. Safety was documented by Adverse Events reported in >5% of patients. Results: The mean reduction in IRLS score was 73.5% (P <0.05). The IRLS responder rate, defined by score reduction of ⩾50%, was 81.3%. On the PGI scale, 89.7% of patients rated themselves as “very much” or “much” better. By CGI-I assessment, 94.8% of patients were considered either “very much” or “much” improved. Mean ESS score showed a modest but statistically significant reduction (P <0.05) within the normal range, indicating that long-term pramipexole did not increase daytime sleepiness. On the SF-36 all 8 domains showed improvement, 5 of them statistically significant (P <0.05) and 4 of these 5 (role-physical, bodily pain, vitality, and role-emotional) by >10 points on a 100-point scale. Subjective Sleep Quality also improved. The most frequent Adverse Events were influenza (17.8%), headache (15.0%), and fatigue (10.3%). Conclusion: Pramipexole is well tolerated and effective for long-term treatment of RLS. [Copyright &y& Elsevier]

Abstract: Objective: To determine the distribution of age-at-onset in a large cohort of patients with restless legs syndrome (RLS) and to compare clinical and polysomnographic characteristics of patients with early and late age-at-onset of RLS. Methods: Two hundred and fifty patients with RLS were studied. Information on age-at-onset, etiology, familial history and symptoms severity of RLS was obtained. Age-at-onset density functions were determined from bootstrap methods and kernel density estimators. Results: Age-at-onset showed a significant bimodal distribution with a large peak occurring at 20years of age and a smaller peak in the mid-40s. Early- and late-onset RLS could be separated with a cut-off at 36years of age. Distributions of age-at-onset differed as a function of presence/absence of a familial history and etiology of RLS. Age-at-onset clearly differentiated patients with a primary RLS (early onset) from those with secondary RLS. Finally, early-onset RLS was associated with increased RLS severity with higher indices of periodic leg movements in sleep (PLMS) associated with microarousals and periodic leg movements during wakefulness (PLMW). Conclusions: Early- and late-onset RLS could be distinguished depending on familial history and etiology of RLS. Our data suggest that different pathological processes are involved in these two groups, the early-onset group being highly genetically determined. [Copyright &y& Elsevier]

Abstract: Restless legs syndrome (RLS) is a clinical disorder that currently is not characterized by a uniform pathophysiologiocal definition. The diagnosis of RLS requires circadian variation in symptoms, although no pathophysiological basis has been verified. Clinical observations and research studies confirm the variation in symptoms, of both sensory and motor components, over the course of the day. This contribution reviews the current literature on circadian variation in RLS and discusses potential intrinsic and extrinsic causes. [Copyright &y& Elsevier]

Abstract: Objectives: Iron deficiency is considered a putative cause for restless legs syndrome (RLS), a human sensorimotor disorder characterized by a circadian presentation of symptoms during the evening hours that disrupts one’s ability to sleep. We sought to evaluate the sleep–wake effects of diet-induced iron deficiency in mice as an animal model of RLS. To this end, we hypothesized that the iron-deprived mice would exhibit a sleep–wake circadian pattern characteristic of the human syndrome: increased wakefulness during the hours immediately preceding the sleep-predominant period. Methods: Following weaning at post-natal day (PND) 21, C57BL/6J mice were assigned to one of two dietary treatments: iron-deficient (ID, n =7) or iron-adequate (i.e., control, CTL, n =6). At PND 44, the mice were surgically instrumented for polysomnographic (PSG) recording, and data were collected at young adulthood: PNDs 59 and 60. Sleep–wake architecture was characterized for the 12-h light and dark periods and also for six consecutive 4-h blocks comprising a 24-h day. Results: The ID mice showed marked increases in wake time in the 4-h period prior to lights-on; both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep were reduced. In contrast, sleep–wake activity did not differ across the 12-h light period. Conclusions: Dietary iron deficiency in mice elicited increases in wakefulness during a particular circadian time point that corresponds to the period during which RLS symptoms would maximally disturb sleep onset and progression in humans. These data indicate that iron-deficient mice may provide a potentially useful animal model for RLS. [Copyright &y& Elsevier]

Abstract: Background and purpose: To evaluate the effects of pramipexole (0.125–0.75mg/d) on polysomnographic (PSG) measures and patient and clinician ratings of restless legs syndrome (RLS). Patients and methods: Patients (n=109) with moderate to severe RLS were randomized to placebo or fixed doses of pramipexole during a 3-week, double-blind, placebo-controlled, dose-finding study. Results: In each pramipexole dose group, the periodic limb movements during time in bed index (PLMI) decreased significantly, compared with placebo (adjusted mean difference in log-transformed data: 0.125mg, −1.54; 0.25mg, −1.93; 0.50mg, −1.89; and 0.75mg, −1.52; P<0.0001). At all doses, International RLS Study Group Rating Scale (IRLS) scores were also significantly reduced, with the greatest adjusted mean reduction in the 0.50mg group (−17.01). At all but the lowest pramipexole dose, the percentage of responders (≥50% reduction of IRLS score) was substantially higher than for placebo (61.9–77.3, vs 33.3%). In the pramipexole groups, 50.0–77.3% of patients rated their condition as ‘much better’ or ‘very much better’, compared with 38.1% of patients in the placebo group (P=0.0139 for the 0.50mg dose). Clinical global impressions (CGI) scale ratings of ‘much improved’ or ‘very much improved’ were given to 61.9–86.4% of patients in the pramipexole groups, compared with 42.9% in the placebo group (P<0.05 for the 0.25, 0.50, and 0.75mg groups). Pramipexole was well tolerated and did not produce somnolence at any dose. Conclusion: Pramipexole is effective and safe in the treatment of both objective and subjective facets of RLS. [Copyright &y& Elsevier]

Abstract: Background and purpose: The association of obstructive sleep apnea syndrome (OSAS) and restless legs syndrome (RLS) has been reported in the literature for many years. Nevertheless, this pathological association has not yet been extensively studied and many questions remain unanswered. The primary concern of this study is to evaluate the influence of nasal continuous positive airway pressure (n-CPAP) therapy on daytime sleepiness and fatigue as well as the presence of a possible long-term beneficial effect on RLS severity and, secondarily, to ascertain the clinical, neurophysiological and polysomnographic characteristics of a group of patients with both OSAS and RLS. Patients and methods: All patients had a diagnostic polysomnography (PSG) and a second polysomnography for titration of n-CPAP. Laboratory tests (blood glucose, serum ferritin), body mass index (BMI) calculation and a neurophysiological evaluation (auditory P300 and electroneuromyography) were done. The Epworth Sleepiness Scale (ESS) and the Pichot''s questionnaire of fatigue/depression (PIC) were applied to all patients before and after three months of n-CPAP treatment. The International Restless Legs Syndrome Study Group rating scale (IRLS) was applied before and after n-CPAP. Results were compared. Results: The ESS scores decreased from 10.64±4.83 at baseline to 7.41±3.5 (P<0.05). PIC scores decreased from 16.65±7.27 to 10.12±6.40 (P<0.01). IRLS scores decreased from 17.60±7.11 before to 12.52±9.25 after n-CPAP (P<0.05). Conclusions: Our findings suggest that not only fatigue and sleepiness but also the severity of RLS show a favorable response to n-CPAP in the group of patients with OSAS and RLS. [Copyright &y& Elsevier]

Background and Purpose: Restless legs syndrome (RLS) is a common central nervous system disorder; however, there is currently a lack of well-validated and easily-administered measures of RLS severity available. The International Restless Legs Syndrome Study Group has recently developed a 10-item scale to meet this need. The International Restless Legs Severity Scale (IRLS) has been shown to have a high degree of reliability, validity, and internal consistency. In order to further demonstrate the validity of the IRLS, the present study examined the relationship between scores on individual IRLS items and overall RLS severity.Patients and Methods: The 10-item IRLS was administered to 196 RLS patients. Option characteristic curves (the probability of scoring different options for a given item as a function of overall IRLS score) were generated in order to illustrate the scoring patterns for each item across the range of total RLS severity. Item characteristic curves (the expected score on an item as a function of overall IRLS score) were also generated to illustrate the relationship between scores on the individual items and total RLS severity.Results: The IRLS items demonstrated excellent item response properties, with option and item characteristic curves closely approximating those of an ideal item. Item 3 (relief of arm or leg discomfort from moving around) was the most problematic item in that a 'floor' effect was evident; however, the item response characteristics for this item were still acceptable.Conclusions: Each IRLS item showed a good relationship between responses on that item and overall RLS severity, providing further evidence for the validity of the IRLS as a measure of RLS severity in RLS patients. [ABSTRACT FROM AUTHOR]

Abstract: The objective of this study is to examine the causal relationships between the symptoms of restless legs syndrome (RLS) and specific clinical and subjective health-related, quality of life consequences. Structural equation modeling was applied to data from a questionnaire-based observational study. The RLS morbidities of decreased functional alertness and emotional distress in our sample of patients appear to be mostly secondary to the sleep disturbance associated with RLS. There was no clear indication of any other feature of RLS affecting these two aspects of RLS morbidity. A primary treatment goal should be the reduction of the sleep disturbance of RLS, both to decrease the RLS-related nocturnal distress and to improve daytime functioning. [Copyright &y& Elsevier]

Abstract: An 11-year-old girl was referred for an irresistible urge to move her legs associated with uncomfortable sensations. She was diagnosed with definite Restless Legs Syndrome (RLS) according to 2003 NIH criteria. The IRLSSG severity scale score was 31 (very severe). The girl also presented with dysthymic disorder according to DSM-IV criteria, as confirmed by the semi-structured interview Kiddie-SADS-PL. The score on the Children Depression Inventory (CDI) was in the clinical range (21). The total score on the Sleep Disturbance Scale for Children (SDSC) was 100. A standard PSG revealed a periodic limb movement index of 16.5, indicating that the child also presented with Periodic Limb Movements Disorder. The girl was treated with ropinirole (a D2/D3 dopamine agonist). After 3 months of treatment (0.50mg/day at 8.00 PM), RLS, as well as depressive symptoms, remarkably improved, as suggested by the improvement in the IRLSSG severity and CDI scores (14 and 4, respectively). No side effects were reported. The total score on the SDSC also improved (73). The PLM index did not remarkably change. We strongly recommend double blind, randomized, controlled studies to gain insight into the effective treatment strategies for RLS and depression when they coexist in children. [Copyright &y& Elsevier]