Rotigotine improves restless legs syndrome: a 6-month randomized, double-blind, placebo-controlled trial in the United States.

This randomized, double-blinded, placebo-controlled trial (NCT00135993) assessed efficacy and safety of the dopamine agonist rotigotine in the treatment of idiopathic restless legs syndrome (RLS) over a 6-month maintenance period. A total of 505 eligible participants with moderate to severe RLS (IRLS sum score >or= 15) were randomly assigned to five groups to receive either placebo or rotigotine (0.5, 1, 2, or 3 mg/24 hr) delivered by once-daily transdermal patch (fixed-dose regimen). The two co-primary efficacy parameters decreased from baseline to end of maintenance in IRLS sum score and in clinical global impressions (CGI-1) score. On both primary measures, 2 and 3 mg/24 hr rotigotine was superior to placebo (P < 0.001). Adjusted treatment differences to placebo for the IRLS sum score were -4.5 (95% CI: -6.9, -2.2) for 2 mg/24 hr rotigotine, -5.2 (95% CI: -7.5, -2.9) for 3 mg/24 hr rotigotine, and for CGI item 1 -0.65 (95% CI: -1.0, -0.3) and -0.9 (95% CI: -1.3, -0.5) for the 2 and 3 mg/24 hr doses, respectively. Skin reactions (27%) and known dopaminergic side effects such as nausea (18.1%) and headache (11.6%) were mostly mild or moderate in rotigotine subjects. Rotigotine transdermal patches releasing 2 to 3 mg/24 hr significantly reduced the severity of RLS symptoms. Treatment efficacy was maintained throughout the 6-month double-blind period.

Children show individual night-to-night variability of periodic limb movements in sleep.

STUDY OBJECTIVE: Several studies have documented the occurrence of significant night-to-night variability of periodic limb movements in sleep (PLMS) in adults.The aim of this study was to investigate the night-tonight variability of PLMS in children. DESIGN AND MEASUREMENTS: Two to 4 nights of polysomnography were performed as part of a multisite, placebo-controlled study investigating the effects of carbidopa/levodopa on attention-deficit/hyperactivity disorder in children who were not taking other medications that impacted the central nervous system. Baseline polysomnograms from all children and endpoint polysomnograms from children who were randomly assigned to a placebo group were scored using International Restless Legs Syndrome Study Group criteria for PLMS. PLMS indexes from 101 sleep studies of 36 children, aged 7 to 12 years, were compared. INTERVENTIONS: N/A. RESULTS: For all 36 children as a group, PLMS index on Night 1 was predictive of PLMS index on Night 2 (odds ratio 7.0, 95% confidence interval 1.4-38.4), suggesting that overall diagnostic classification (PLMS index above or below 5/h) was accurate. In addition, for the 15 children with 5 or more PLMS per hour on either night, there was no significant group difference on Night 1 versus Night 2 for mean PLMS index (10.6 vs 8.5/h, P = 0.92) or chance of having 5 or more PLMS per hour, indicating no first-night effect. When looking at individual data, however, 9 of these 15 children (60%) had PLMS indexes over and under the 5 per hour cutoff on these 2 nights. Of these 15, 10 had clinical diagnoses of restless legs syndrome and 5 of periodic limb movement disorder (PLMD). The PLMS indexes of all children who were medication free for a third and fourth night (n = 7) or just a third night (n = 2) and had not shown a PLMS index of 5 or greater on either of the first 2 nights remained under this threshold. CONCLUSIONS: In this sample of children, considerable individual night-to-night variability of PLMS indexes was observed. This finding has important clinical relevance for the diagnosis of restless legs syndrome and PLMD and may have an impact on future studies that correlate individual PLMS severity with frequently associated symptoms, such as negative affect, fatigue, and inattention. Our data, however, also suggest that individual PLMS variability is random and not likely to skew the group-level analysis of treatment outcome studies.

Restless legs syndrome: a common disorder in patients with rheumatologic conditions.

OBJECTIVES: To review the symptoms, differential diagnosis, and treatment of the restless legs syndrome (RLS), and its relevance within rheumatologic practice. METHODS: Review of the scientific literature on RLS to summarize symptom presentation, burden, diagnosis, treatment, and association with rheumatologic conditions. RESULTS: RLS is a sensorimotor neurological disorder characterized by an irresistible urge to move the legs, usually accompanied or caused by unpleasant sensations within the legs. These sensations are sometimes described as achy or painful. They may cause sleep disruption and impair quality of life. RLS may be primary, of unknown etiology, with a likely genetic basis, or secondary, provoked by other conditions. Secondary RLS often improves when the underlying condition is treated or resolves. Since RLS is common in rheumatologic disorders such as rheumatoid arthritis or Sjögren's syndrome, rheumatologists need to be familiar with the condition. Primary care physicians may misattribute RLS symptoms to other conditions and refer patients to specialists for treatment. Since RLS symptoms can be similar to, and mistaken for, symptoms in rheumatologic diseases, patients may be referred to rheumatologists. Therefore, it is important that rheumatologists be able to recognize, differentiate, diagnose, and treat RLS. CONCLUSIONS: The clinical diagnosis of RLS is based on 4 essential diagnostic criteria related to the urge to move that characterizes this disorder. Beyond good sleep hygiene and behavioral measures, dopaminergic agents are first-line treatments for primary RLS. Anticonvulsants, opioids, and sedative/hypnotics may also have a role in management.

Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice.

Only in the last three decades, the restless legs syndrome (RLS) has been examined in randomized controlled trials. The Movement Disorder Society (MDS) commissioned a task force to perform an evidence-based review of the medical literature on treatment modalities used to manage patients with RLS. The task force performed a search of the published literature using electronic databases. The therapeutic efficacy of each drug was classified as being either efficacious, likely efficacious, investigational, nonefficacious, or lacking sufficient evidence to classify. Implications for clinical practice were generated based on the levels of evidence and particular features of each modality, such as adverse events. All studies were classed according to three levels of evidence. All Level-I trials were included in the efficacy tables; if no Level-I trials were available then Level-II trials were included or, in the absence of Level-II trials, Level-III studies or case series were included. Only studies published in print or online before December 31, 2006 were included. All studies published after 1996, which attempted to assess RLS augmentation, were reviewed in a separate section. The following drugs are considered efficacious for the treatment of RLS: levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin. Drugs considered likely efficacious are rotigotine, bromocriptine, oxycodone, carbamazepine, valproic acid, and clonidine. Drugs that are considered investigational are dihydroergocriptine, lisuride, methadone, tramadol, clonazepam, zolpidem, amantadine, and topiramate. Magnesium, folic acid, and exercise are also considered to be investigational. Sumanirole is nonefficacious. Intravenous iron dextran is likely efficacious for the treatment of RLS secondary to end-stage renal disease and investigational in RLS subjects with normal renal function. The efficacy of oral iron is considered investigational; however, its efficacy appears to depend on the iron status of subjects. Cabergoline and pergolide (and possibly lisuride) require special monitoring due to fibrotic complications including cardiac valvulopathy. Special monitoring is required for several other medications based on clinical concerns: opioids (including, but not limited to, oxycodone, methadone and tramadol), due to possible addiction and respiratory depression, and some anticonvulsants (particularly, carbamazepine and valproic acid), due to systemic toxicities.

Validation of the Hopkins telephone diagnostic interview for restless legs syndrome.

BACKGROUND: Because the diagnosis of restless legs syndrome (RLS) depends on clinical features ascertained by interview, it is important to have structured diagnostic instruments that can guide a diagnostician to an accurate diagnosis. With this aim in mind, the RLS Center at Johns Hopkins has been developing the Hopkins telephone diagnostic interview (HTDI). A previous validation was performed on a patient group. In the current report, we have extended that validation to a non-patient group drawn from on ongoing family study. METHODS: Family members from a case-control RLS study were diagnosed by telephone. Once all available family members in a given family had been interviewed, those who lived locally and had responded were asked to come to Johns Hopkins-Bayview Medical center and had dual clinical interviews to ascertain RLS diagnosis. We then compared the results between the two clinical interviews and between the HTDI and the clinical interviews. RESULTS: Diagnostic agreement between two expert clinicians was 93-96% (kappa 0.87-0.92). Compared to those subjects on whom the clinicians agreed, the HTDI agreed at least 90% of the time; sensitivity was at least 0.90, specificity 0.91, positive predictive value 0.86, and negative predictive value 0.94. CONCLUSION: The HTDI managed a high level of diagnostic accuracy, showing only slightly less agreement than the two clinical interviewers. Because of a mean 12-month period between HTDI and clinical interview, this result also indicates that the subjects' reports of symptoms are consistent and stable. The HTDI should be useful for confirming questionnaire diagnoses or screening subjects to enter basic or therapeutic trials.

Diagnostic standards for dopaminergic augmentation of restless legs syndrome: report from a World Association of Sleep Medicine-International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute.

OBJECTIVES: Augmentation of symptom severity is the main complication of dopaminergic treatment of restless legs syndrome (RLS). The current article reports on the considerations of augmentation that were made during a European Restless Legs Syndrome Study Group (EURLSSG)-sponsored Consensus Conference in April 2006 at the Max Planck Institute (MPI) in Munich, Germany, the conclusions of which were endorsed by the International RLS Study Group (IRLSSG) and the World Association of Sleep Medicine (WASM). The Consensus Conference sought to develop a better understanding of augmentation and generate a better operational definition for its clinical identification. DESIGN AND METHODS: Current concepts of the pathophysiology, clinical features, and therapy of RLS augmentation were evaluated by subgroups who presented a summary of their findings for general consideration and discussion. Recent data indicating sensitivity and specificity of augmentation features for identification of augmentation were also evaluated. The diagnostic criteria of augmentation developed at the National Institutes of Health (NIH) conference in 2002 were reviewed in light of current data and theoretical understanding of augmentation. The diagnostic value and criteria for each of the accepted features of augmentation were considered by the group. A consensus was then developed for a revised statement of the diagnostic criteria for augmentation. RESULTS: Five major diagnostic features of augmentation were identified: usual time of RLS symptom onset each day, number of body parts with RLS symptoms, latency to symptoms at rest, severity of the symptoms when they occur, and effects of dopaminergic medication on symptoms. The quantitative data available relating the time of RLS onset and the presence of other features indicated optimal augmentation criteria of either a 4-h advance in usual starting time for RLS symptoms or a combination of the occurrence of other features. A paradoxical response to changes in medication dose also indicates augmentation. Clinical significance of augmentation is defined. CONCLUSION: The Consensus Conference agreed upon new operational criteria for the clinical diagnosis of RLS augmentation: the MPI diagnostic criteria for augmentation. Areas needing further consideration for validating these criteria and for understanding the underlying biology of RLS augmentation are indicated.

Validation of the Augmentation Severity Rating Scale (ASRS): a multicentric, prospective study with levodopa on restless legs syndrome.

BACKGROUND: Augmentation is the main complication during long-term dopaminergic treatment of restless legs syndrome (RLS) and reflects an overall increase in RLS severity. Its severity varies considerably from a minor problem to a devastating exacerbation of disease. Despite its clinical relevance, systematic evaluations have rarely been undertaken and there has been no development of methods to assess the severity of augmentation. To fill this gap, the European RLS Study Group (EURLSSG) has developed the Augmentation Severity Rating Scale (ASRS), using three items that assess the degree of change in three specific dimensions of augmentation. The changes in each dimension are summed to give an ASRS total score. METHODS: The ASRS was developed to cover the basic dimensions defining RLS augmentation. The items were developed by an interactive process involving professional and patient input. The ASRS that was evaluated included four major items and two alternative forms of one item. The validation was conducted using 63 (85%) mostly untreated RLS patients from six centers, who were treated for six months with levodopa (L-Dopa) (up to 500 mg/day, as clinically needed). Two consecutive assessments before and at baseline measured test-retest reliability. Consecutive ASRS ratings by two independent raters on a subsample of patients evaluated inter-rater reliability. Comparison with clinical severity ratings of two independent experts provided external validation of the ASRS. Comparison of patients with and without augmentation with regard to the items and the total score of the ASRS added discriminant validity. RESULTS: Sixty patients (63% females, mean age: 53 years, baseline International RLS Severity Rating (IRLS) score 24.7+/-5.2) were treated with a median daily dose of 300 mg L-Dopa (range: 50-500 mg). Thirty-six patients (60%) experienced augmentation. Item analyses indicated that one item could be removed as it did not contribute significantly to the test score and only one form of the duplicated item needed to be used. The final ASRS then included three items. Test-retest reliability for the total score was rho=0.72, and inter-rater reliability was rcc=0.94. Cronbach's alpha was 0.62. Validity as assessed by the correlation between the worst ASRS total score during the trial and the expert rating was rho=0.72. ASRS total score differed between patients without versus with augmentation (mean: 7.4 (standard deviation (SD)=4.0) vs. 2.0 (2.7) (P<0.0001). CONCLUSIONS: The ASRS is a reliable and valid scale to measure the severity of augmentation. Due to the need to systematically quantify augmentation for both long-term efficacy and tolerability, the ASRS may become a useful tool to monitor augmentation in future clinical trials.

Prevalence and correlates of restless legs syndrome: results from the 2005 National Sleep Foundation Poll.

PURPOSES: The purpose of this analysis was to investigate the prevalence and correlates of restless legs syndrome (RLS) symptoms in the 2005 National Sleep Foundation (NSF) Sleep in America 2005 Poll. The NSF poll is an annual telephone interview of a random, representative sample of US adults. METHODS: The NSF 2005 poll included 1,506 adults. Their mean age was 49 years, and 775 were women. RESULTS: Symptoms of RLS that included unpleasant feelings in the legs for at least a few nights a week, which were worse at night, were reported by 9.7% of individuals in this poll, including 8% of men and 11% of women. Those from the northeast United States were much less likely to be at risk than those from other regions of the country (p < 0.05). Those who were unemployed (p < 0.05) or smoked daily (p < 0.5) were more likely to be at risk for RLS, as were those with hypertension, arthritis, gastroesophageal reflux disease, depression, anxiety, and diabetes (p < 0.05 for all). Adults who were at risk for RLS appeared to also be at increased risk for sleep apnea and insomnia (p < 0.05), and were more likely to stay up longer than they planned, to take longer than 30 min to fall asleep, to drive when drowsy, and to report daytime fatigue than those who were not at risk (p < 0.05 for all). They were also more likely to report being late to work, missing work, making errors at work, and missing social events because of sleepiness than other respondents in the poll (p < 0.05 for all). CONCLUSIONS: RLS is significantly associated with medical and psychiatric conditions, other sleep disorders, unfavorable lifestyle behaviors, and adverse effects on daytime function. Chest physicians who practice sleep medicine need to be able to identify and manage RLS, which is prevalent and is associated with considerable morbidity.

Undiagnosed individuals with first-degree relatives with restless legs syndrome have increased periodic limb movements.

BACKGROUND AND PURPOSE: To evaluate periodic limb movements during sleep (PLMS) in first-degree relatives of both restless legs syndrome (RLS) patients and matched controls without RLS in order to analyze patterns of this motor sign of RLS. PATIENTS AND METHODS: First-degree relatives of a consecutive case series of RLS patients and matched community controls without RLS were evaluated for diagnosis of primary RLS and for PLMS as determined by a leg activity meter. The data were analyzed to determine whether or not PLMS rates are higher than expected for RLS subjects in these families, who have mostly milder disease, and family members of early-onset RLS patients not themselves diagnosed with RLS. RESULTS: PLMS activity in family members was significantly higher for those diagnosed as RLS compared to those diagnosed as not-RLS. This difference was greater for older than younger subjects. In family members older than the median study age (52 years old) who were diagnosed as not-RLS, PLMS were significantly more frequent in those related to an early-onset RLS proband than in those related to either a control or late-onset RLS proband. CONCLUSIONS: PLMS are elevated even in those with mild RLS and reveal an age-related worsening of the motor component of RLS. PLMS may represent an incomplete expression of RLS tendencies in families of patients with early-onset RLS, but this needs to be confirmed in future longitudinal studies. The increase in PLMS with age, reported in healthy controls, may in fact occur in part as a partial expression of familial or genetic factors associated with RLS.

Race and restless legs syndrome symptoms in an adult community sample in east Baltimore.

BACKGROUND & PURPOSE: Due to the relative absence of African-Americans seeking treatment for restless legs syndrome (RLS) in specialty clinics, a lower prevalence of RLS among African-Americans than Caucasians has been suggested. We compared the prevalence of RLS in African-Americans and Caucasians in a biracial community sample as part of Wave IV of the Baltimore Health and Mental Health Study. METHODS: Subjects included 1071 adults [358 African-Americans (35.0%), and 633 Caucasians (61.8%), and 33 others]. Diagnosis of RLS was based on endorsement of RLS symptoms on a seven-item RLS questionnaire during a household interview. Adjusted odds and 95% confidence intervals were calculated based on logistic regression models with diagnosis of RLS as the main outcome variables and African-American race as the main predictor while adjusting for other relevant sociodemographic and/or health-related variables. RESULTS: The prevalence of RLS in this population was 4.1%. The rates were similar for African-Americans (4.7%) and Caucasians (3.8%). After adjustment for age, gender, medical comorbidities, and socioeconomic status, no difference in the prevalence of RLS was found between African-Americans and Caucasians. CONCLUSION: RLS is comparably prevalent among African-American and Caucasian adults in the general population. Barriers affecting access to care settings for African-American RLS patients should be investigated in the future.

The reliability, validity and responsiveness of the International Restless Legs Syndrome Study Group rating scale and subscales in a clinical-trial setting.

PATIENTS AND METHODS: To assess the reliability, validity, and responsiveness of the International Restless Legs Syndrome Study Group's rating scale (the International Restless Legs Scale (IRLS)) (V2.0), using pooled data from two matching, placebo-controlled studies of ropinirole for treating Restless Legs Syndrome (RLS). RESULTS: Pooled patient samples comprised 550 patients in the baseline (validation) sample and 439 patients in the week 12 longitudinal (responsiveness) sample. Factor analysis revealed acceptability of the IRLS total score (accounting for 40% of the variance) and that nine of the 10 IRLS items could also be assigned to two distinct subscales, the symptoms or symptoms impact subscales. The IRLS total score, symptoms and symptoms impact subscales had acceptable construct validity, internal consistency reliability (alpha=0.81, 0.80, and 0.76, respectively), and concurrent validity (r=-0.68, -0.52, -0.70, respectively, with the Restless Legs Syndrome Quality of Life questionnaire (RLSQoL) overall life impact score). IRLS scores differed significantly between different levels of sleep problems and Clinical Global Impression (CGI) of health status (P<0.0001), indicating known groups and clinical validity, respectively. Changes in scores differed significantly among CGI 'global improvement' levels (P<0.0001), providing evidence of responsiveness. CONCLUSIONS: The IRLS total score, symptoms, and symptoms impact subscales are reliable, valid, and responsive in a clinical trial setting.

Restless legs syndrome prevalence and impact: REST general population study.

BACKGROUND: Restless legs syndrome (RLS), a common sensorimotor disorder, has a wide range of severity from merely annoying to affecting sleep and quality of life severely enough to warrant medical treatment. Previous epidemiological studies, however, have failed to determine the prevalence of those with clinically significant RLS symptoms and to examine the life effects and medical experiences of this group. METHODS: A total of 16 202 adults (aged >/=18 years) were interviewed using validated diagnostic questions to determine the presence, frequency, and severity of RLS symptoms; respondents reporting RLS symptoms were asked about medical diagnoses and the impact of the disorder and completed the Short Form-36 Health Survey (SF-36). Criteria determined by RLS experts for medically significant RLS (frequency at least twice a week, distress at least moderate) defined "RLS sufferers" as a group most likely to warrant medical treatment. RESULTS: In all, 15 391 fully completed questionnaires were obtained; in the past year, RLS symptoms of any frequency were reported by 1114 (7.2%). Symptoms occurred at least weekly for 773 respondents (5.0%); they occurred at least 2 times per week and were reported as moderately or severely distressing by 416 (2.7%). Of those 416 (termed RLS sufferers), 337 (81.0%) reported discussing their symptoms with a primary care physician, and only 21 (6.2%) were given a diagnosis of RLS. The SF-36 scores for RLS sufferers were significantly below population norms, matching those of patients with other chronic medical conditions. CONCLUSION: Clinically significant RLS is common (prevalence, 2.7%), is underdiagnosed, and significantly affects sleep and quality of life.

Investigation of altering single-nucleotide polymorphism density on the power to detect trait loci and frequency of false positive in nonparametric linkage analyses of qualitative traits.

Genome-wide linkage analysis using microsatellite markers has been successful in the identification of numerous Mendelian and complex disease loci. The recent availability of high-density single-nucleotide polymorphism (SNP) maps provides a potentially more powerful option. Using the simulated and Collaborative Study on the Genetics of Alcoholism (COGA) datasets from the Genetics Analysis Workshop 14 (GAW14), we examined how altering the density of SNP marker sets impacted the overall information content, the power to detect trait loci, and the number of false positive results. For the simulated data we used SNP maps with density of 0.3 cM, 1 cM, 2 cM, and 3 cM. For the COGA data we combined the marker sets from Illumina and Affymetrix to create a map with average density of 0.25 cM and then, using a sub-sample of these markers, created maps with density of 0.3 cM, 0.6 cM, 1 cM, 2 cM, and 3 cM. For each marker set, multipoint linkage analysis using MERLIN was performed for both dominant and recessive traits derived from marker loci. Our results showed that information content increased with increased map density. For the homogeneous, completely penetrant traits we created, there was only a modest difference in ability to detect trait loci. Additionally, as map density increased there was only a slight increase in the number of false positive results when there was linkage disequilibrium (LD) between markers. The presence of LD between markers may have led to an increased number of false positive regions but no clear relationship between regions of high LD and locations of false positive linkage signals was observed.

An item response analysis of the international restless legs syndrome study group rating scale for restless legs syndrome.

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.

Circadian variation in neuroendocrine response to L-dopa in patients with restless legs syndrome.

STUDY OBJECTIVE: To investigate circadian changes in dopaminergic function by means of a neuroendocrine challenge (growth hormone and prolactin responses to an acute oral administration of L-dopa) in patients with idiopathic restless legs syndrome (RLS) and controls. DESIGN: Randomized administration of the L-dopa neuroendocrine challenge. SETTING: Sleep disorders laboratory at a 500-bed academic hospital. PATIENTS OR PARTICIPANTS: Twelve patients diagnosed with idiopathic RLS and 12 age- and sex-matched healthy controls. INTERVENTIONS: Following a comprehensive evaluation that included nocturnal polysomnographic study, all participants underwent the L-dopa neuroendocrine challenge on 2 occasions (11 am and 11 pm). Subjects were previously randomly assigned to the time of first challenge (11 am or 11 pm). On each occasion, subjects took 200 mg of L-dopa (plus 50 mg carbidopa) by mouth. Blood was drawn 20 minutes and 5 minutes before administration of the drug, as well as 15, 30, 45, 60, 75, 90, 102, and 120 minutes after administration. RESULTS: Prechallenge levels of plasma values of growth hormone or prolactin did not differ in the 2 subject groups. Following only the nighttime administration of L-dopa, RLS patients manifested a more pronounced inhibition of prolactin release and an increase in growth hormone secretion. Prolactin plasma levels were significantly correlated to the periodic limb movement index on the polysomnogram. CONCLUSIONS: These findings may reflect enhanced circadian variations in dopaminergic function and support an increased sensitivity at night of dopamine receptors in patients with RLS.

An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder.

This paper reviews evidence from April, 1998 through April 2002 for the dopaminergic treatment of the restless legs syndrome (RLS) and periodic limb movement disorder (PLMD). There has been increased study of dopaminergic agents for the treatment of these conditions since publication of a review paper and practice parameters that covered all types of medical treatment of RLS and PLMD in 1999. For this reason, the Restless Legs Syndrome Task Force and the Standards of Practice Committee decided to update the evidence on dopaminergic treatment of these conditions. This paper reviews the literature on levodopa, dopaminergic agonists (pergolide, pramipexole, ropinirole, talipexole, cabergoline, piribidel, DHEC), and other dopaminergic agents (amantadine, selegiline).

An algorithm for the management of restless legs syndrome.

Restless legs syndrome (RLS) is a common disorder with a prevalence of 5% to 15%. Primary care physicians must become familiar with management of this disorder. This algorithm for the management of RLS was written by members of the Medical Advisory Board of the Restless Legs Syndrome Foundation and is based on scientific evidence and expert opinion. Restless legs syndrome is divided into intermittent, daily, and refractory types. Nonpharmacological approaches, including mental alerting activities, avoiding substances or medications that may exacerbate RLS, and addressing the possibility of iron deficiency, are discussed. The role of carbidopa/levodopa, dopamine agonists, opioids, benzodiazepines, and anticonvulsants for the different types of the disorder is delineated.

Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study.

OBJECTIVES: To assess the frequency, impact, and medical response to the restless legs syndrome (RLS) in a large multi-national primary care population. METHOD: Questionnaire surveys of matched patients and primary care physicians (PCPs) in five modern industrialized western countries. RESULTS: An RLS screening questionnaire was completed by 23,052 patients: 2223 (9.6%) reported weekly RLS symptoms; 1557 of these patients had medical follow-up questionnaires completed both by themselves and by their physician. An RLS sufferer subgroup (n=551) likely warranting treatment was defined as reporting at least twice weekly symptoms with appreciable negative impact on quality of life. A total of 88.4% of RLS sufferers reported at least one sleep-related symptom. Most reported impaired sleep consistent with a diagnosis of insomnia. Out of 551 sufferers, 357 (64.8%) reported consulting a physician about their RLS symptoms, but only 46 of these 357 (12.9%) reported having been given a diagnosis. PCPs reported that 209 (37.9%) RLS sufferers consulted them about RLS symptoms, but only 52 (24.9%) were given an RLS diagnosis. In most countries, sufferers, regardless of diagnosis, were prescribed therapies not known to be effective in RLS. CONCLUSIONS: RLS significantly impairs patients' lives, often by severely disrupting sleep. The marked under-diagnosis and inappropriate treatment of RLS indicates that PCPs need better education about this condition. Recognizing how often disrupted sleep results from RLS should improve diagnosis.

Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health.

BACKGROUND: Restless legs syndrome is a common yet frequently undiagnosed sensorimotor disorder. In 1995, the International Restless Legs Syndrome Study Group developed standardized criteria for the diagnosis of restless legs syndrome. Since that time, additional scientific scrutiny and clinical experience have led to a better understanding of the condition. Modification of the criteria is now necessary to better reflect that increased body of knowledge, as well as to clarify slight confusion with the wording of the original criteria. SETTING: The restless legs syndrome diagnostic criteria and epidemiology workshop at the National Institutes of Health. PARTICIPANTS: Members of the International Restless Legs Syndrome Study Group and authorities on epidemiology and the design of questionnaires and scales. OBJECTIVE: To modify the current criteria for the diagnosis of restless legs syndrome, to develop new criteria for the diagnosis of restless legs syndrome in the cognitively impaired elderly and in children, to create standardized criteria for the identification of augmentation, and to establish consistent questions for use in epidemiology studies. RESULTS: The essential diagnostic criteria for restless legs syndrome were developed and approved by workshop participants and the executive committee of the International Restless Legs Syndrome Study Group. Criteria were also developed and approved for the additional aforementioned groups.

Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome.

BACKGROUND: There is a need for an easily administered instrument which can be applied to all patients with restless legs syndrome (RLS) to measure disease severity for clinical assessment, research, or therapeutic trials. The pathophysiology of RLS is not clear and no objective measure so far devised can apply to all patients or accurately reflect severity. Moreover, RLS is primarily a subjective disorder. Therefore, a subjective scale is at present the optimal instrument to meet this need. METHODS: Twenty centers from six countries participated in an initial reliability and validation study of a rating scale for the severity of RLS designed by the International RLS study group (IRLSSG). A ten-question scale was developed on the basis of repeated expert evaluation of potential items. This scale, the IRLSSG rating scale (IRLS), was administered to 196 RLS patients, most on some medication, and 209 control subjects. RESULTS: The IRLS was found to have high levels of internal consistency, inter-examiner reliability, test-retest reliability over a 2-4 week period, and convergent validity. It also demonstrated criterion validity when tested against the current criterion of a clinical global impression and readily discriminated patient from control groups. The scale was dominated by a single severity factor that explained at least 59% of the pooled item variance. CONCLUSIONS: This scale meets performance criteria for a brief, patient completed instrument that can be used to assess RLS severity for purposes of clinical assessment, research, or therapeutic trials. It supports a finding that RLS is a relatively uniform disorder in which the severity of the basic symptoms is strongly related to their impact on the patient's life. In future studies, the IRLS should be tested against objective measures of RLS severity and its sensitivity should be studied as RLS severity is systematically manipulated by therapeutic interventions.