Rethinking clinical trials in restless legs syndrome: A roadmap.

The number of large clinical trials of restless legs syndrome (RLS) have decreased in recent years, this coincides with reduced interest in developing and testing novel pharmaceuticals. Therefore, the International Restless Legs Syndrome Study Group (IRLSSG) formed a task force of global experts to examine the causes of these trends and make recommendations to facilitate new clinical trials. In our article, we delve into potential complications linked to the diagnostic definition of RLS, identify subpopulations necessitating more attention, and highlight issues pertaining to endpoints and study frameworks. In particular, we recommend developing alternative scoring methods for more accurate RLS diagnosis, thereby improving clinical trial specificity. Furthermore, enhancing the precision of endpoints will increase study effect sizes and mitigate study costs. Suggestions to achieve this include developing online, real-time sleep diaries with high-frequency sampling of nightly sleep latency and the use of PLMs as surrogate markers. Furthermore, to reduce the placebo response, strategies should be adopted that include placebo run-in periods. As RLS is frequently a chronic condition, priority should be given to long-term studies, using a randomized, placebo-controlled, withdrawal design. Lastly, new populations should be investigated to develop targeted treatments such as mild RLS, pregnancy, hemodialysis, or iron-deficient anemia.

Generative Models for Periodicity Detection in Noisy Signals.

We present the Gaussian Mixture Periodicity Detection Algorithm (GMPDA), a novel method for detecting periodicity in the binary time series of event onsets. The GMPDA addresses the periodicity detection problem by inferring parameters of a generative model. We introduce two models, the Clock Model and the Random Walk Model, which describe distinct periodic phenomena and provide a comprehensive generative framework. The GMPDA demonstrates robust performance in test cases involving single and multiple periodicities, as well as varying noise levels. Additionally, we evaluate the GMPDA on real-world data from recorded leg movements during sleep, where it successfully identifies expected periodicities despite high noise levels. The primary contributions of this paper include the development of two new models for generating periodic event behavior and the GMPDA, which exhibits high accuracy in detecting multiple periodicities even in noisy environments.

Time to rest a hypothesis? Accumulating evidence that periodic leg movements during sleep are not increased in children with attention-deficit hyperactivity disorder (ADHD): results of a case-control study and a meta-analysis.

STUDY OBJECTIVES: To address the hypothesis that periodic leg movements during sleep (PLMS) are more frequent in children with attention-deficit hyperactivity disorder (ADHD) when compared with typically developing (TD) children. To that end, we analyzed PLMS in a recent case-control study and conducted a systematic review and meta-analysis of PLMS frequency in children with ADHD and TD children. METHODS: In our case-control study, we compared the PLMS frequency of 24 children with ADHD (mean age 11 years, 17 males) to that of 22 age-matched typically developing (TD) children (mean age 10 years, 12 males). A subsequent meta-analysis included 33 studies that described PLMS frequency in groups of children with ADHD and/or groups of TD children. RESULTS: The case-control study did not show any differences in the frequency of PLMS between children with ADHD and TD children, a result that was consistent across a range of different definitions of PLMS, which in turn had a significant and systematic effect on PLMS frequency. The meta-analysis compared the average PLMS indices and the proportion of children with elevated PLMS indices between children with ADHD and TD children and across a number of analyses did not find any meta-analytic results that supported the hypothesis that PLMS are more frequent in children with ADHD. CONCLUSIONS: Our results suggest that PLMS are not more frequent in children with ADHD compared with TD children. A finding of frequent PLMS in a child with ADHD should therefore be considered a separate disorder and prompt specific diagnostic and therapeutic strategies.

Weight-gain independent effect of mirtazapine on fasting plasma lipids in healthy men.

Treatment with mirtazapine, a widely prescribed antidepressant, has been linked to weight gain and dyslipidemia. Whether dyslipidemia occurs secondary to increased appetite due to antidepressant treatment, or due to direct pharmacological effects of mirtazapine is unknown. The aim of this analysis is to complement our previously published results of the effect of mirtazapine on metabolism and energy substrate partitioning from a proof-of-concept, open-label clinical study (ClinicalTrials.gov NCT00878540) in 12 healthy males (20-25 years). We report the effect of a seven-day administration of mirtazapine 30 mg per day on weight and lipid metabolism in healthy men under highly standardized conditions with respect to diet, physical activity and day-night-rhythm and under continuous clinical observation. After a 7-day administration of mirtazapine 30 mg, we observed a statistically significant increase in triglyceride levels (mean change + 4.4 mg/dl; 95% CI [- 11.4; 2.6]; p = 0.044) as well as TG/HDL-C ratio (mean change + 0.2; 95% CI [- 0.4; 0.1]; p = 0.019) and a decrease in HDL-cholesterol (mean change - 4.3 mg/dl; 95% CI [2.1; 6.5]; p = 0.004), LDL-cholesterol (mean change - 8.7 mg/dl; 95% CI [3.8; 13.5]; p = 0.008), total cholesterol (mean change - 12.3 mg/dl; 95% CI [5.4; 19.1]; p = 0.005), and non-HDL-C (mean change - 8.0 mg/dl; 95% CI [1.9; 14.0]; p = 0.023). Notably, weight (mean change - 0.6 kg; 95% CI [0.4; 0.8]; p = 0.002) and BMI (mean change - 0.2; 95% CI [0.1; 0.2]; p = 0.002) significantly decreased. No change in waist circumference (mean change - 0.4 cm; 95% CI [- 2.1; 2.9]; p = 0.838) or waist-to-hip-ratio (mean change 0.0; 95% CI [- 0.0; 0.0]; p = 0.814) was observed. This is the first study showing unfavorable changes in lipid metabolism under mirtazapine in healthy individuals despite highly standardized conditions including dietary restriction, and despite the observation of a decrease of weight. Our findings support the hypothesis that mirtazapine has direct pharmacological effects on lipid metabolism. ClinicalTrials.gov: NCT00878540.

Restless legs syndrome: Over 50 years of European contribution.

Restless legs syndrome (RLS) is a sensorimotor neurological disorder characterised by an urge to move the limbs with a circadian pattern (occurring in the evening/at night), more prominent at rest, and relieved with movements. RLS is one of the most prevalent sleep disorders, occurring in 5%-10% of the European population. Thomas Willis first described RLS clinical cases already in the 17th century, and Karl-Axel Ekbom described the disease as a modern clinical entity in the 20th century. Despite variable severity, RLS can markedly affect sleep (partly through the presence of periodic leg movements) and quality of life, with a relevant socio-economic impact. Thus, its recognition and treatment are essential. However, screening methods present limitations and should be improved. Moreover, available RLS treatment options albeit providing sustained relief to many patients are limited in number. Additionally, the development of augmentation with dopamine agonists represents a major treatment problem. A better understanding of RLS pathomechanisms can bring to light novel treatment possibilities. With emerging new avenues of research in pharmacology, imaging, genetics, and animal models of RLS, this is an interesting and constantly growing field of research. This review will update the reader on the current state of RLS clinical practice and research, with a special focus on the contribution of European researchers.

Cortico-autonomic local arousals and heightened somatosensory arousability during NREMS of mice in neuropathic pain.

Frequent nightly arousals typical for sleep disorders cause daytime fatigue and present health risks. As such arousals are often short, partial, or occur locally within the brain, reliable characterization in rodent models of sleep disorders and in human patients is challenging. We found that the EEG spectral composition of non-rapid eye movement sleep (NREMS) in healthy mice shows an infraslow (~50 s) interval over which microarousals appear preferentially. NREMS could hence be vulnerable to abnormal arousals on this time scale. Chronic pain is well-known to disrupt sleep. In the spared nerve injury (SNI) mouse model of chronic neuropathic pain, we found more numerous local cortical arousals accompanied by heart rate increases in hindlimb primary somatosensory, but not in prelimbic, cortices, although sleep macroarchitecture appeared unaltered. Closed-loop mechanovibrational stimulation further revealed higher sensory arousability. Chronic pain thus preserved conventional sleep measures but resulted in elevated spontaneous and evoked arousability. We develop a novel moment-to-moment probing of NREMS vulnerability and propose that chronic pain-induced sleep complaints arise from perturbed arousability.

Periodic Leg Movements During Sleep.

Periodic leg movements during sleep (PLMS) are a frequent finding in nocturnal sleep registrations that include tibialis anterior electromyographic signals. Different PLMS scoring rules exist and can have a major impact on PLMS frequency, which tends to be underappreciated. There is no consistent evidence that frequent PLMS are a causal risk factor for clinically significant outcomes. Several critical open questions are identified that need to be addressed, including but not limited to the consideration of the full range of all sleep-related leg movement activity.

We need to do better: A systematic review and meta-analysis of diagnostic test accuracy of restless legs syndrome screening instruments.

This systematic review and meta-analysis evaluated the diagnostic accuracy of screening instruments for restless legs syndrome (RLS) and reports sensitivity, specificity, positive (PPV) and negative predictive values (NPV). Searches for primary studies were conducted in electronic databases. Of the 1541 citations identified, 52 were included in the meta-analysis. The methodological quality of each study was evaluated using QUADAS-2. Only 14 studies assessed the reference standard in all participants or in all screen-positives and a selection of screen-negatives. Bivariate meta-analysis of these 14 studies estimated median sensitivity to be 0.88 (0.72-0.96) and specificity 0.90 (0.84-0.93); based on a population prevalence of 5%, the calculated PPV was 0.31 (0.27-0.34). For all 52 studies, with either full or partial verification of RLS status, we constructed best-case scenario sensitivities and specificities at pre-defined levels of prevalence: across all samples, when prevalence is 5%, the median best-case scenario PPV is 0.48 with significant between-study heterogeneity. No RLS screening instruments can currently be recommended for use without an expert clinical interview in epidemiological studies. For conditions with statistically low prevalence such as RLS, the specificity, not the sensitivity, of a screening instrument determines true prevalence. Therefore, future instruments should maximize specificity. We provide guidelines on RLS ascertainment in epidemiological studies that requires a two-step process with clinical interview following a screening test, and given the poor reporting quality of many RLS epidemiological studies, we include an RLS reporting checklist.

Sleep-related leg movements in obstructive sleep apnea: definitions, determinants, and clinical consequences.

STUDY OBJECTIVES: To investigate (1) the effect of different scoring rules on leg movement (LM) classification in patients with obstructive sleep apnea (OSA); (2) determinants of respiratory event related leg movements (rLM); and (3) to relate LM parameters to clinical outcomes. METHODS: (1) LM classification was compared between the World Association of Sleep Medicine (WASM) 2006 and the WASM 2016 rules in 336 participants with apnea hypopnea index (AHI) ≥ 5; (2) determinants and features of rLM were investigated with logistic mixed regression in 172 participants with AHI ≥ 10 and respiratory disturbance index (RDI) ≥ 15, and (3) LM parameters were compared for patients with and without cardiovascular events and related to continuous positive airway pressure (CPAP) adherence. RESULTS: WASM-2016 scoring significantly reduced periodic limb movements of sleep (PLMS) frequency in OSA participants even when only considering the new periodicity criteria. Probability of rLM was strongly increased when respiratory events ended with an arousal, but rLM probability was lower for hypopneas and respiratory effort-related sleep arousal (RERAs) than for obstructive apneas. In participants with frequent non-respiratory PLMS, rLM were more frequent and behaved more PLMS-like. In participants without PLMS, rLM probability mostly depended on respiratory event features. LM parameters were neither related to cardiovascular event risk nor to CPAP-adherence. CONCLUSIONS: It is likely that the PLMS frequency in OSA populations has been previously overestimated. Our results suggest that there are two types of rLM, true periodic ones that happen to synchronize with the respiratory events, and periodic appearing but respiratory driven LM, and that the presence of non-respiratory PLMS is instrumental in distinguishing between the two.

Ultradian modulation of cortical arousals during sleep: effects of age and exposure to nighttime transportation noise.

STUDY OBJECTIVES: The present study aimed at assessing the temporal non-rapid eye movement (NREM) EEG arousal distribution within and across sleep cycles and its modifications with aging and nighttime transportation noise exposure, factors that typically increase the incidence of EEG arousals. METHODS: Twenty-six young (19-33 years, 12 women) and 16 older (52-70 years, 8 women) healthy volunteers underwent a 6-day polysomnographic laboratory study. Participants spent two noise-free nights and four transportation noise exposure nights, two with continuous and two characterized by eventful noise (average sound levels of 45 dB, maximum sound levels between 50 and 62 dB for eventful noise). Generalized mixed models were used to model the time course of EEG arousal rates during NREM sleep and included cycle, age, and noise as independent variables. RESULTS: Arousal rate variation within NREM sleep cycles was best described by a u-shaped course with variations across cycles. Older participants had higher overall arousal rates than the younger individuals with differences for the first and the fourth cycle depending on the age group. During eventful noise nights, overall arousal rates were increased compared to noise-free nights. Additional analyses suggested that the arousal rate time course was partially mediated by slow wave sleep (SWS). CONCLUSIONS: The characteristic u-shaped arousal rate time course indicates phases of reduced physiological sleep stability both at the beginning and end of NREM cycles. Small effects on the overall arousal rate by eventful noise exposure suggest a preserved physiological within- and across-cycle arousal evolution with noise exposure, while aging affected the shape depending on the cycle.

Effect of mirtazapine on metabolism and energy substrate partitioning in healthy men.

BACKGROUND: Weight gain and metabolic changes during treatment with antidepressant drugs have emerged as an important concern, particularly in long-term treatment. It is still a matter of ongoing debate whether weight gain and metabolic perturbations with antidepressant use are the consequence of increased appetite and weight gain, respectively, or represents direct pharmacological effects of the drug on metabolism. METHODS: We therefore conducted a proof-of-concept, open-label clinical trial, hypothesizing that in exceptionally healthy men no change of metabolic parameters would occur under mirtazapine, when environmental factors such as nutrition, sleep, and physical exercise were controlled and kept constant. Over a 3-week preparation phase, 10 healthy, young men were attuned to a standardized diet adjusted to their individual caloric need, to a regular sleep/wake cycle and moderate exercise. Continuing this protocol, we administered 30 mg mirtazapine daily for 7 days. RESULTS: While no significant weight gain or changes in resting energy expenditure were observed under these conditions, hunger and appetite for sweets increased with mirtazapine, accompanied by a shift in energy substrate partitioning towards carbohydrate substrate preference as assessed by indirect calorimetry. Furthermore, with mirtazapine, insulin and C-peptide release increased in response to a standardized meal. CONCLUSION: Our findings provide important insights into weight-independent metabolic changes associated with mirtazapine and allow a better understanding of the long-term metabolic effects observed in patients treated with antidepressant drugs. CLINICALTRIALS: gov NCT00878540. FUNDING: Nothing to declare.

Characteristics and Determinants of Respiratory Event-Associated Leg Movements.

STUDY OBJECTIVES: To (1) replicate the recently described distribution of respiratory event-associated leg movements (rLMs) in participants with mild-to-moderate obstructive sleep apnea syndrome (OSAS), (2) explore global and local factors associated with the presence of rLMs, and (3) investigate differences related to OSAS severity and periodic leg movements during sleep (PLMS) status. METHODS: We randomly selected six groups of participants without restless legs syndrome (12-15 participants in each group), stratified by apnea-hypopnea index (AHI) severity (AHI 10-20, 20-30, and 30-40) and PLMS status (PLMS index <15 and >15 per hr) from the population-based HypnoLaus study that assessed full polysomnography at home in participants aged 40 to 80 years, randomly selected from the population register of the city of Lausanne, Switzerland. RESULTS: Our results confirmed the distribution of leg movement activity at the end of respiratory events (-2.0 to +10.25 s). Mixed effects logistic regression modeling rLM-probability showed that rLMs were more frequent in participants with high-PLMS, at the end of obstructive apneas (vs. hypopneas) and in the presence of arousals at the end of the events. In participants with high-PLMS, rLM-probability decreased with time of night and was more reduced during REM sleep (vs. NREM sleep), whereas the duration of the respiratory event had a significant effect only in participants with low-PLMS. CONCLUSIONS: We confirm the previously reported distribution of rLMs in participants with mild-to-moderate OSAS and our results suggest that rLMs are sensitive to both sleep-related and respiratory-related factors in a complex interaction with the PLMS status.

Bilateral leg movements during sleep: detailing their structure and features in normal controls and in patients with restless legs syndrome.

OBJECTIVE: The aim of this study was to analyze statistically the number of single leg movements (LMs) forming bilateral LMs during sleep, along with their combined duration, to eventually provide evidence-based data for the adjustment of the current scoring rules defining bilateral LMs. METHODS: Polysomnographic recordings of 111 untreated patients with RLS with a median age of 56.0 years, along with 42 normal controls with a mean age of 60.0 years, were included. In each recording, we identified all LMs that were considered as bilateral when two or more LMs were overlapping or the onset of the following movement was <0.5 second after the offset of the preceding LM. The remaining LMs were classified as monolateral. A series of parameters were computed for both bilateral and monolateral LMs. RESULTS: The duration of monolateral LMs in RLS patients was significantly longer than that of normal controls. For bilateral LMs, the maximum number of single LMs forming a bilateral movement and the maximum duration were slightly higher in RLS patients; however, the distribution of the number of individual LMs forming a single bilateral LM was similar. Only 0.12% and 0.27% of bilateral LMs consisted of >4 individual movements, and only 0.16% and 1.90% of bilateral LMs were >15 seconds in RLS patients and healthy controls, respectively. CONCLUSION: Our results strongly suggest that bilateral LMs during sleep should be constituted by no more than four individual LMs and should have a maximum duration of 15 seconds.

Intervening Leg Movements Disrupt PLMS Sequences.

Study Objectives: Periodic leg movements during sleep (PLMS) occur within a subject as a series with a remarkably stable period defined by the intermovement interval (IMI). Sometimes a non-PLMS movement occurs intervening between two PLMS. PLMS scoring rules totally ignore these intervening leg movements (iLM). This implicitly assumes an iLM results from a process sufficiently independent from the periodic process producing PLMS that it does not affect the periodicity of the surrounding PLMS. This study for the first time tests this basic assumption and explores characteristics of iLM as a potentially significant class of leg movements during sleep. Methods: Leg movements were analyzed from two nights of polysomnography recordings from 27 RLS patients and 22 controls using the validated MATPLM1.1 program. All periods (IMI) between PLMS containing an iLM were compared to the local PLMS period defined as the immediately preceding PLMS IMI using pairwise two-sided Wilcoxon sign-rank tests. Similarly, iLM were tested to see if they started a new PLMS series by having the same period as the subsequent PLMS. Results: The periods (IMIs) containing iLM were longer than the previous periods in RLS subjects, but not controls (p < .05). The periods beginning with the iLM were shorter than the subsequent periods in both RLS and controls (p < .05). Conclusions: iLM as a separate type of LM distort PLMS periodicity and do not restart PLMS series. iLM end PLMS series.

Periodic leg movements during sleep: phenotype, neurophysiology, and clinical significance.

Periodic leg movements during sleep (PLMS) are the most important objective finding in restless legs syndrome (RLS). During the last decade, PLMS have been very important for the assessment and comprehension of their pathophysiological correlates, which have been paralleled by the emergence of new computer-assisted and data-driven rules for their identification, scoring, and analysis. The present article focused on the most relevant PLMS-related findings of the last decade, and sought to provide a coherent and comprehensive overview on this enigmatic motor phenomenon. First, a clear description was made on the identification, quantification, and scoring of PLMS and their associated events. This was followed by a description of the current knowledge of their neurophysiologic aspects. Then, the typical phenotype of genuine PLMS in RLS and other clinical conditions was described, allowing for their careful separation from other sleep leg motor activities. In addition, the most recent findings on the genetics of PLMS were briefly summarized, followed by the current evidence on their clinical correlates, which is another rapidly advancing field of research. The description of the specific aspects of PLMS in children was also carefully reported, with important clues on their evaluation in this age group. Finally, further research was proposed, which may lead to consideration of PLMS as a clinically significant concern, independent of the association with RLS.

Defining morphology of periodic leg movements in sleep: an evidence-based definition of a minimum window of sustained activity.

OBJECTIVE: Current standard guidelines for scoring periodic leg movements (PLM) define the start and end of a movement but fail to explicitly specify the movement morphology necessary to classify an EMG event as a PLM, rather than some other muscle event. This is currently left to the expert visual scorer to determine. This study aimed to define this morphology to provide a consistent standard for visual scoring and to improve automatic periodic leg movements in sleep scoring. METHODS: A review of expert PLM scoring produced a hypothesized morphology criterion: a window of high EMG activity within the movement lasting at least 0.5 s. Two diverse expert visual scorers were independently presented with images of EMG tracings from candidate leg movements (CLM) that either passed or failed this requirement (aka "full" or "empty" movements, respectively), and indicated whether each should be scored as CLM. The 0.5-s window was compared with alternatives of 0.25 and 0.75 windows. RESULTS: Expert scorers on average identified 94 % of "full" movements as CLM in contrast to only 8.5 % of "empty" movements. The proposed minimum window of 0.5 s also resulted in the highest agreement between visual scorers and between scorers and an automatic program. CONCLUSION: An added criterion requiring 0.5 s of high EMG activity within a valid CLM improves the accuracy of automatic scoring algorithms in relation to the gold standard of expert visual scorers. Our results suggest that this rule is an accurate representation of the morphology feature used by experts. This new rule has the potential to improve consistency and accuracy of visual and automatic scoring of PLM.

Principles of practice parameters for the treatment of sleep disordered breathing in the elderly and frail elderly: the consensus of the International Geriatric Sleep Medicine Task Force.

Sleep disordered breathing (SDB) is a leading cause of morbidity worldwide. Its prevalence increases with age. Due to the demographic changes in industrial societies, pulmonologists and sleep physicians are confronted with a rapidly growing number of elderly SDB patients. For many physicians, it remains unclear how current guidelines for SDB management apply to elderly and frail elderly patients. The goal of this consensus statement is to provide guidance based on published evidence for SDB treatment in this specific patient group.Clinicians and researchers with expertise in geriatric sleep medicine representing several countries were invited to participate in a task force. A literature search of PubMed from the past 12 years and a systematic review of evidence of studies deemed relevant was performed.Recommendations for treatment management of elderly and frail elderly SDB patients based on published evidence were formulated via discussion and consensus.In the last 12 years, there have been surprisingly few studies examining treatment of SDB in older adults and even fewer in frail older adults. Studies that have been conducted on the management of SDB in the older patient population were rarely stratified for age. Studies in SDB treatment that did include age stratification mainly focused on middle-aged and younger patient groups. Based on the evidence that is available, this consensus statement highlights the treatment forms that can be recommended for elderly SDB patients and encourages treatment of SDB in this large patient group.

Diagnostic accuracy of the standard and alternative periodic leg movement during sleep indices for restless legs syndrome.

OBJECTIVE: To evaluate the diagnostic accuracy of the standard periodic leg movement during sleep (PLMS) index, a recently introduced alternative one, and the periodicity index (PI) for restless legs syndrome (RLS). SUBJECTS AND METHODS: A total of 107 patients with RLS were retrospectively identified and included (47 males and 60 females, mean age 56.9 years), along with 48 normal controls (24 males and 24 females, mean age 52.0 years). The standard PLMS index, the alternative PLMS index, and the PI were calculated from polysomnographic recordings. In order to establish the best performing threshold for the diagnosis of RLS, sensitivity and specificity were calculated with a series of threshold values ranging from 5 to 20/hour for the two PLMS indices, and from 0.2 to 0.9 for the PI. RESULTS: The optimal threshold was found to be between 15 and 16/hour for the standard PLMS index, close to 13/hour for the alternative index, and around 0.5 for the periodicity index. With these thresholds, all methods showed high values of sensitivity and specificity, with corresponding high positive and negative predictive values and accuracy; the receiver operating characteristic (ROC) curve areas were similar, and the Kappa coefficient of agreement indicated a 'very good' agreement between the PLMS indices. CONCLUSIONS: This study assessed the cut-off values of the standard (15-16/hour) and alternative (13/hour) PLMS indices, and of the PI (0.5). The diagnostic accuracy of all indices for RLS vs controls was found to be acceptably high, with the new alternative PLMS index performing slightly higher than the other two indices.

A Data-Driven Analysis of the Rules Defining Bilateral Leg Movements during Sleep.

STUDY OBJECTIVES: The aim of this study was to describe and analyze the association between bilateral leg movements (LMs) during sleep in subjects with restless legs syndrome (RLS), in order to eventually support or challenge the current scoring rules defining bilateral LMs. METHODS: Polysomnographic recordings of 100 untreated patients with RLS (57 women and 43 males, mean age 57 y) were included. In each recording, we selected as reference all LMs that occurred during sleep and that were separated from another ipsilateral LM by at least 10 sec of EMG inactivity. For each reference LM and an evaluation interval from 5 sec before the onset to 5 sec after the offset of the reference LM, we evaluated (1) the presence or absence of contralateral leg movement activity and (2) the distribution of the onset-to-onset and (3) the offset-to-onset differences between bilateral LMs. RESULTS: We selected a mean of 368 (± 222 standard deviation [SD]) reference LMs per subject. For 42% (± 22%) of the reference LMs no contralateral leg movement activity was observed within the evaluation interval. In 55% (± 22%) exactly one and in 3% (± 2%) more than one contralateral LM was observed. A further evaluation of events where exactly one contralateral LM was observed showed that in most (1) the two LMs were overlapping (93% ± 9% SD) and (2) were classified as bilateral according to the World Association of Sleep Medicine and the International Restless Legs Syndrome Study Group (WASM/ IRLSSG) (96% ± 6% SD) and (3) the American Academy of Sleep Medicine scoring rules (99% ± 2% SD). Although there was a systematic and statistically significant difference in standard LM indices during sleep based on the two different definitions of bilateral LMs, the size of the difference was not clinically meaningful (maximum individual, absolute difference in LM indices ± 2.5). In addition, we found that the duration of LMs within bilateral LM pairs was longer compared to monolateral LMs and that the duration of the single LMs in bilateral LM pairs tended to correlate. CONCLUSIONS: The results of this study indicate that the two current standard scoring rules for the definition of bilateral LMs during sleep provide largely corresponding classifications in subjects with RLS and, in a clinical context, can be considered to be equivalent.