L-Dopa improves Restless Legs Syndrome and periodic limb movements in sleep but not Attention-Deficit-Hyperactivity Disorder in a double-blind trial in children.

BACKGROUND: In a previous open-label study, dopaminergic agents improved Restless Legs Syndrome (RLS) and Periodic Limb Movements in Sleep (PLMS), as well as Attention-Deficit-Hyperactivity Disorder (ADHD) in children with both disorders. We therefore conducted a double-blind placebo-controlled trial of L-DOPA in ADHD children with and without RLS/PLMS. METHODS: Two groups of patients (total n = 29), those with ADHD only or those with ADHD and RLS/PLMS, were randomized to L-DOPA or placebo therapy. At baseline and after therapy patients were assessed with Conners' parent and teacher rating scales; polysomnography; RLS rating scale; and neuropsychometric measures of memory, learning, attention, and vigilance. RESULTS: L-DOPA improved RLS/PLMS symptoms in all patients with those disorders compared with placebo (p = .007). When assessed by the Conners' Scales before therapy, ADHD was more severe in children without RLS/PLMS than in children with RLS/PLMS (p = 0.006). L-DOPA had no effect on Conners' scales, sleep, or neuropsychometric tests when all patients treated with the drug were compared to those on placebo or when patients with ADHD only were compared to those with ADHD and RLS/PLMS. CONCLUSIONS: In this first double-blind study of a dopaminergic therapy in children with RLS/PLMS, L-Dopa significantly improved RLS/PLMS but not ADHD. These results, however, should be interpreted carefully since they may have been influenced by the relatively small sample size and the baseline differences in severity of ADHD symptoms. Further work needs to be done to elucidate the relationship between dopamine, ADHD and RLS/PLMS.

Efficacy and augmentation during 6 months of double-blind pramipexole for restless legs syndrome.

BACKGROUND: Pramipexole is an effective treatment for restless legs syndrome (RLS), but no controlled studies have lasted >12 weeks. METHODS: RLS patients (N=331) with pretreatment serum ferritin >30 ng/mL were randomly assigned to take double-blind optimized pramipexole (0.125-0.75 mg/d) or placebo for 26 weeks. The primary efficacy endpoint was change in International RLS Study Group Rating Scale (IRLS) score. Other endpoints assessed global change, symptoms, and QoL. Patients maintained symptom diaries. Cases meeting predefined criteria for suspected augmentation were reviewed by a blinded expert panel, which used a predefined algorithm. RESULTS: Among 321 patients providing post-baseline data, of whom 234 completed 26 weeks, pramipexole was more effective than placebo by multiple endpoints, including an adjusted mean IRLS score change of -13.7 vs. -11.1 (p=0.0077) and an IRLS responder rate (≥50% score reduction) of 58.6% vs. 42.8% (p=0.0044). Efficacy showed considerable country-to-country variability. Six-month incidence of confirmed augmentation was 9.2% for pramipexole and 6.0% for placebo. The rate increased with treatment duration for pramipexole but not placebo. Treatment-related adverse events (AEs) were more likely for pramipexole than for placebo, but discontinuation due to AEs was less likely. CONCLUSIONS: During a 6-month period, pramipexole was effective, safe, and generally well tolerated. Because risk of augmentation may have increased over 6 months, it should be studied in longer trials. Beginning or mild augmentation is difficult to distinguish from natural RLS fluctuation, at least in a non-iron-deficient population.

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.

Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study.

The European Restless Legs Syndrome (RLS) Study Group performed the first multi-center, long-term study systematically evaluating RLS augmentation under levodopa treatment. This prospective, open-label 6-month study was conducted in six European countries and included 65 patients (85% treatment naive) with idiopathic RLS. Levodopa was flexibly up-titrated to a maximum dose of 600 mg/day. Presence of augmentation was diagnosed independently by two international experts using established criteria. In addition to the augmentation severity rating scale (ASRS), changes in RLS severity (International RLS severity rating scale (IRLS), clinical global impression (CGI)) were analyzed. Sixty patients provided evaluable data, 35 completed the trial and 25 dropped out. Augmentation occurred in 60% (36/60) of patients, causing 11.7% (7/60) to drop out. Median time to occurrence of augmentation was 71 days. The mean maximum dose of levodopa was 311 mg/day (SD: 105). Patients with augmentation compared to those without were significantly more likely to be on higher doses of levodopa (> or =300 mg, 83 vs. 54%, P = 0.03) and to show less improvement of symptom severity (IRLS, P = 0.039). Augmentation was common with levodopa, but could be tolerated by most patients during this 6-month trial. Patients should be followed over longer periods to determine if dropout rates increase with time.

Pregnancy accounts for most of the gender difference in prevalence of familial RLS.

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.

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.

Validation of the self-completed Cambridge-Hopkins questionnaire (CH-RLSq) for ascertainment of restless legs syndrome (RLS) in a population survey.

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.

The four diagnostic criteria for Restless Legs Syndrome are unable to exclude confounding conditions ("mimics").

BACKGROUND: Epidemiological survey studies have suggested that a large fraction of the adult population, from five to more than 10%, have symptoms of Restless Legs Syndrome (RLS). Recently, however, it has become clear that the positive predictive value of many questionnaire screens for RLS may be fairly low and that many individuals who are identified by these screens have other conditions that can "mimic" the features of RLS by satisfying the four diagnostic criteria. We noted the presence of such confounders in a case-control family study and sought to develop methods to differentiate them from true RLS. METHODS: Family members from the case-control study were interviewed blindly by an RLS expert using the validated Hopkins telephone diagnostic interview (HTDI). Besides questions on the four key diagnostic features of RLS, the HTDI contains open-ended questions on symptom quality and relief strategies and other questions to probe the character of provocative situations and modes of relief. Based on the entire HDTI, a diagnosis of definite, probable or possible RLS or Not-RLS was made. RESULTS: Out of 1255 family members contacted, we diagnosed 1232: 402 (32.0%) had definite or probable RLS, 42 (3.3%) possible RLS, and 788 (62.8%) Not-RLS. Of the 788 family members who were determined not to have RLS, 126 could satisfy all four diagnostic criteria (16%). This finding indicates that the specificity of the four criteria was only 84%. Those with mimic conditions were found to have atypical presentations whose features could be used to assist in final diagnosis. CONCLUSION: A variety of conditions, including cramps, positional discomfort, and local leg pathology can satisfy all four diagnostic criteria for RLS and thereby "mimic" RLS by satisfying the four diagnostic criteria. Definitive diagnosis of RLS, therefore, requires exclusion of these other conditions, which may be more common in the population than true RLS. Short of an extended clinical interview and workup, certain features of presentation help differentiate mimics from true RLS.

RLS and blood donation.

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.

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.

Restless legs syndrome is associated with DSM-IV major depressive disorder and panic disorder in the community.

The authors examined the association between restless legs syndrome (RLS) and DSM-IV major depressive disorder and panic disorder based on Wave III and IV of the Baltimore ECA follow-up study. Of 1071 participants, 1024 completed the RLS Questionnaire and Diagnostic Interview Schedule. Adjusted odds ratio for diagnosis of major depressive disorder (4.7, 95% confidence interval [1.6, 14.5]) and panic disorder (12.9 [3.6, 46.0]) and comorbidity of major depressive disorder and panic disorder (9.7 [1.4, 69.0]) in the past 12 months suggested a strong association between restless legs syndrome and major depressive disorder and/or panic disorder.

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.

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.

Clinical significance of RLS.

While the restless legs syndrome (RLS) may have been known in antiquity, it has only recently come to medical attention. Individuals with RLS fall along a spectrum from mild, infrequent symptoms to those with severe daily life-impairing discomforts and sleep disruption. These problems can cause impaired mood, daytime fatigue, cognitive difficulties, and inability to participate in a variety of quiet activities. This leads to a general reduction in quality of life similar to other significant psychiatric and medical disorders. Recent studies suggest that RLS may be a risk factor for developing both psychiatric disorders (such as major depression and anxiety) and somatic diseases (such as hypertension and cardiovascular disease). In dialysis patients, RLS has been found to be a risk factor for mortality. Therefore, those with RLS who have clinically significant symptoms suffer increased morbidity and are at risk for impaired long-term medical outcomes.

Restless legs syndrome: nonpharmacologic and pharmacologic treatments.

Treatment of restless legs syndrome (RLS) has as its goals alleviation of the primary symptoms of the disorder and establishment of normal sleep. Dopamine agonists are considered first-line treatment when daily treatment for primary RLS is indicated. Gabapentin and opioids may be of value for refractory cases. Initial treatment of secondary RLS should address the underlying cause.

Restless legs syndrome: demographics, presentation, and differential diagnosis.

Restless legs syndrome (RLS) is a sensorimotor disorder characterized by a distressing urge to move the legs and sometimes other parts of the body. Diagnosis is based on clinical features that may be easily remembered with the mnemonic URGE: Urge to move, Rest induced, Gets better with activity, and Evening and night accentuation. RLS is common, its prevalence increases with age, and women are more frequently affected. The course is chronic with often severe sleep disruption, including periodic leg movements. Differential diagnosis includes disorders of restlessness and leg discomfort. Primary RLS is familial and likely to be genetic. Important causes of secondary RLS are end-stage renal disease, pregnancy, and iron deficiency. Every patient should be checked for iron status with a serum ferritin measurement.

Definition of restless legs syndrome, how to diagnose it, and how to differentiate it from RLS mimics.

Restless legs syndrome (RLS) is a clinical diagnosis based primarily on self-reports of individuals. The International RLS Study Group has published diagnostic criteria that are essential for an operational diagnosis of RLS; further clinical features are considered by the group supportive for or associated with RLS. However, sensitivity and specificity are not perfect and "mimics" of RLS have been reported, i.e., other conditions like nocturnal cramps sometimes can appear to fulfill the essential diagnostic criteria indicating the need for more thorough understanding of the diagnostic criteria and better differential diagnoses. To contribute to the accuracy of diagnostic processes in RLS, we recapitulate the definition of RLS as an urge to move focused on the legs (and arms in some patients). This urge to move often but not always occurs together with dysesthesia, i.e. unpleasant abnormal sensations appearing without any apparent sensory stimulation. The urge to move and any accompanying dysesthesia must be engendered by rest, relieved by movement and worse in the evening or night. Succinctly, RLS can be summarized in medical terminology as a "movement-responsive quiescegenic nocturnal focal akathisia usually with dysesthesias." Empirical approaches to investigate the independence of the essential criteria "worsening at night" and "worsening at rest" are reported. Possible differential diagnoses of RLS are discussed under the perspective of the NIH diagnostic criteria of RLS. Standardized methods to assess a RLS diagnosis are presented which might improve differential diagnosis and in general the reliability and validity of RLS diagnosis.

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.