Identification of Restless Legs Syndrome Genes by Mutational Load Analysis.

OBJECTIVE: Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes. METHODS: We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low-frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth. RESULTS: Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni-corrected significance by the other to show a differential burden of low-frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine-mapping potentially causative domains within these genes. INTERPRETATION: Differential burden with intragenic low-frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2020;87:184-193.

Targeted resequencing and systematic in vivo functional testing identifies rare variants in MEIS1 as significant contributors to restless legs syndrome.

Restless legs syndrome (RLS) is a common neurologic condition characterized by nocturnal dysesthesias and an urge to move, affecting the legs. RLS is a complex trait, for which genome-wide association studies (GWASs) have identified common susceptibility alleles of modest (OR 1.2-1.7) risk at six genomic loci. Among these, variants in MEIS1 have emerged as the largest risk factors for RLS, suggesting that perturbations in this transcription factor might be causally related to RLS susceptibility. To establish this causality, direction of effect, and total genetic burden of MEIS1, we interrogated 188 case subjects and 182 control subjects for rare alleles not captured by previous GWASs, followed by genotyping of ∼3,000 case subjects and 3,000 control subjects, and concluded with systematic functionalization of all discovered variants using a previously established in vivo model of neurogenesis. We observed a significant excess of rare MEIS1 variants in individuals with RLS. Subsequent assessment of all nonsynonymous variants by in vivo complementation revealed an excess of loss-of-function alleles in individuals with RLS. Strikingly, these alleles compromised the function of the canonical MEIS1 splice isoform but were irrelevant to an isoform known to utilize an alternative 3' sequence. Our data link MEIS1 loss of function to the etiopathology of RLS, highlight how combined sequencing and systematic functional annotation of rare variation at GWAS loci can detect risk burden, and offer a plausible explanation for the specificity of phenotypic expressivity of loss-of-function alleles at a locus broadly necessary for neurogenesis and neurodevelopment.

Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction.

Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find new entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 individuals with RLS (cases) and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including three on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (rg = 0.96). Locus annotation prioritized druggable genes such as glutamate receptors 1 and 4, and Mendelian randomization indicated RLS as a causal risk factor for diabetes. Machine learning approaches combining genetic and nongenetic information performed best in risk prediction (area under the curve (AUC) = 0.82-0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up and provided evidence that nonlinear interactions are likely relevant to RLS risk prediction.

ExomeChip-based rare variant association study in restless legs syndrome.

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

Psychological distress of patients suffering from restless legs syndrome: a cross-sectional study.

BACKGROUND: Restless legs syndrome (RLS) is a chronic disorder with substantial impact on quality of life similar to that seen in diabetes mellitus or osteoarthritis. Little is known about the psychological characteristics of RLS patients although psychological factors may contribute to unfavourable treatment outcome. METHODS: In an observational cross-sectional design, we evaluated the psychological features of 166 consecutive RLS patients from three outpatient clinics, by means of the Symptom Checklist 90-R (SCL-90-R) questionnaire. Additionally, the Beck Depression Inventory-II (BDI-II) and the International RLS Severity Scale (IRLS) were measured. Both treated and untreated patients were included, all patients sought treatment. RESULTS: Untreated patients (n = 69) had elevated but normal scores on the SCL-90-R Global Severity Index (GSI; p = 0.002) and on the sub-scales somatisation (p < 0.001), compulsivity (p = 0.003), depression (p = 0.02), and anxiety (p = 0.004) compared with a German representative sample. In the treated group, particularly in those patients who were dissatisfied with their actual treatment (n = 62), psychological distress was higher than in the untreated group with elevated scores for the GSI (p = 0.03) and the sub-scales compulsivity (p = 0.006), depression (p = 0.012), anxiety (p = 0.031), hostility (p = 0.013), phobic anxiety (p = 0.024), and paranoid ideation (p = 0.012). Augmentation, the most serious side effect of dopaminergic, i.e. first-line treatment of RLS, and loss of efficacy were accompanied with the highest psychological distress, as seen particularly in the normative values of the sub-scales compulsivity and anxiety. Generally, higher RLS severity was correlated with higher psychological impairment (p < 0.001). CONCLUSION: Severely affected RLS patients show psychological impairment in multiple psychological domains which has to be taken into account in the treatment regimen.

Levodopa for restless legs syndrome.

BACKGROUND: Levodopa plus dopamine decarboxylase inhibitor is a common treatment for restless legs syndrome (RLS). OBJECTIVES: To evaluate efficacy and safety of levodopa for RLS compared to placebo and other active agents. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2008, Issue 4), MEDLINE, EMBASE, PsycINFO and CINAHL, from January 1985 to December 2008, reference lists of articles, and contacted pharmaceutical companies. SELECTION CRITERIA: We included double-blind randomised controlled trials (RCT) investigating levodopa treatment versus placebo or other treatment for at least seven days in patients with RLS (age ≥ 18 years). Outcomes included symptom severity, CGI-I, objective as well as self rated sleep parameters, quality of life, and safety parameters. DATA COLLECTION AND ANALYSIS: Two authors extracted data, assessed risk of bias, and contacted pharmaceutical companies and authors for additional information. We collected dropouts due to adverse events and patients experiencing adverse events. MAIN RESULTS: Six placebo controlled and three active controlled RCTs were included (521 participants). Symptom severity (11 point rating scale, 0 points indicating no symptoms, 10 points indicating maximally severe symptoms) was more reduced with levodopa than placebo in two studies (mean difference (MD) -1.34, 95% confidence interval (CI) -2.18 to -0.5, P = 0.002). Periodic limb movements in sleep per hour of sleep (PLMS-Index; PLMSI) improved by -26.28/h compared to placebo (95% CI -30.53 to -22.02, P < 0.00001).The CGI-I changed more with levodopa than placebo in two studies (MD -1.25, 95% CI -1.89 to -0.62, P = 0.0001). In two studies, sleep quality (sleep questionnaire, visual analogue scale) showed a large effect (standardised mean difference (SMD) 0.92, 95% CI 0.52 to 1.33, P < 0.00001) whereas quality of life (50 mm Visual Analogue Scales) improved by 3.23 compared to placebo (95% CI 1.64 to 4.82, P < 0.0001). Few patients dropped out of treatment (3 of 218 patients) but more levodopa treated patients experienced adverse events than with placebo (odds ratio 2.61, 95% CI 1.35 to 5.04, P = 0.004). Two dopamine agonist controlled studies showed smaller effects with levodopa than cabergoline and pramipexole on the IRLS (MD 5.25, 95% CI 2.10 to 8.40, P =0.001), CGI-I (MD 0.62, 95% CI 0.37 to 0.87, P < 0.00001), and quality of life (MD 5.54, 95% CI 2.65 to 8.43, P = 0.0002). AUTHORS' CONCLUSIONS: Levodopa is efficacious for the short-term treatment of RLS. Augmentation, the clinically most relevant adverse event, was not investigated sufficiently.

Dopamine agonists for restless legs syndrome.

BACKGROUND: According to clinical guidelines, dopamine agonists are the first-line treatment of restless legs syndrome (RLS). OBJECTIVES: To evaluate efficacy and safety of dopamine agonists for RLS. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue 4), MEDLINE, EMBASE, PsycINFO and CINAHL, from January 1985 to December 2008, plus reference lists of articles. We contacted pharmaceutical companies. SELECTION CRITERIA: We included double-blind randomised controlled trials (RCTs) of dopamine agonist treatment versus placebo or other treatment for a period of at least seven days in patients with RLS (≥ 18 years). Outcomes included the International RLS Severity Rating Scale (IRLS), Clinical Global Impressions (CGI-I), polysomnography and self rated sleep quality, quality of life, daytime functioning, and safety parameters. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data separately; assessed risk of bias; and contacted pharmaceutical companies and authors for additional information. We collected dropout rates due to adverse events and experience of adverse events. MAIN RESULTS: We included 35 placebo controlled and three active controlled RCTs (N = 7365). The mean reduction on the IRLS was -5.7 points lower in dopamine agonist treatment compared to placebo (95% confidence interval (CI) -6.7 to -4.7). Periodic limb movements in sleep per hour of sleep (PLMS-Index; PLMSI) were -22.4/h lower than in placebo (95% CI -27.8 to -16.9). Self rated quality of sleep and disease specific quality of life were improved by a standardised mean difference (SMD) of 0.40 (95% CI 0.33 to 0.47) and 0.34 (95% CI 0.23 to 0.44), respectively. Patients were more likely to drop out (odds ratio (OR) 1.82, 95% CI 1.35 to 2.45) and experienced more adverse events under dopamine agonist treatment than with placebo (OR 1.82, 95% CI 1.59 to 2.08). Visual inspection of forest plots showed the highest efficacy in three studies investigating cabergoline and pergolide (N = 3). Active controlled trials investigated effects of cabergoline, pergolide, and pramipexole in a number of outcomes. The IRLS score was lower with cabergoline and pramipexole compared to levodopa (MD -5.3, 95% CI -8.4 to -2.1). Only four studies investigated treatment efficacy up to seven months. The most severe side effect, augmentation, was not assessed reliably. AUTHORS' CONCLUSIONS: The meta-analyses show the superiority of dopamine agonists over placebo in RCTs up to seven months. Cabergoline and pramipexole showed larger efficacy compared to levodopa in some but not all outcomes.

No persisting effect of partial sleep curtailment on cognitive performance and declarative memory recall in adolescents.

Growing evidence indicates that sleep facilitates learning and memory processing. Sleep curtailment is increasingly common in adolescents. The aim of this study was to examine the effects of short-term sleep curtailment on declarative memory consolidation in adolescents. A randomized, cross-over study design was chosen. Twenty-two healthy subjects, aged 14-16 years, spent three consecutive nights in the sleep laboratory with a bedtime of 9 h during the first night (adaptation), 4 h during the second (partial sleep curtailment) and 9 h during the third night (recovery). The control condition consisted of three consecutive nights with bedtimes of 9 h. Both experimental conditions were separated by at least 3 weeks. The acquisition phase for the declarative tests was between 16:00 and 18:00 hours before the second night. Memory performance was examined in the morning after the recovery night. Executive function, attention and concentration were also assessed to control for any possible effects of tiredness. During the 4-h night, we observed a curtailment of 50% of non-rapid eye movement (non-REM), 5% of slow wave sleep (SWS) and 70% of REM sleep compared with the control night. Partial sleep curtailment of one night did not influence declarative memory retrieval significantly. Recall in the paired-associate word list task was correlated positively with percentage of non-REM sleep in the recovery night. Declarative memory consolidation does not appear to be influenced by short-term sleep curtailment in adolescents. This may be explained by the high ability of adolescents to compensate for acute sleep loss. The correlation between non-REM sleep and declarative memory performance supports earlier findings.

Cerebral correlates of heart rate variations during a spontaneous panic attack in the fMRI scanner.

We report the first published case study of a suddenly occurring panic attack in a patient with no prior history of panic disorder during combined functional magnetic resonance imaging (fMRI, 1.5 Tesla) and electrocardiogram (ECG) recording. The single case was a 46-year-old woman who developed a panic attack near the planned end of the fMRI acquisition session, which therefore had to be aborted. Correlational analysis of heart rate fluctuations and fMRI data revealed a significant negative association in the left middle temporal gyrus. Additionally, regions-of-interest (ROI) analyses indicated significant positive associations in the left amygdala, and trends towards significance in the right amygdala and left insula.

Effect of illicit recreational drugs upon sleep: cocaine, ecstasy and marijuana.

The illicit recreational drugs cocaine, ecstasy and marijuana have pronounced effects upon sleep. Administration of cocaine increases wakefulness and suppresses REM sleep. Acute cocaine withdrawal is often associated with sleep disturbances and unpleasant dreams. Studies have revealed that polysomnographically assessed sleep parameters deteriorate even further during sustained abstinence, although patients report that sleep quality remains unchanged or improves. This deterioration of objective sleep measures is associated with a worsening in sleep-related cognitive performance. Like cocaine, 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy") is a substance with arousing properties. Heavy MDMA consumption is often associated with persistent sleep disturbances. Polysomnography (PSG) studies have demonstrated altered sleep architecture in abstinent heavy MDMA users. Smoked marijuana and oral Delta-9-tetrahydrocannabinol (THC) reduce REM sleep. Moreover, acute administration of cannabis appears to facilitate falling asleep and to increase Stage 4 sleep. Difficulty sleeping and strange dreams are among the most consistently reported symptoms of acute and subacute cannabis withdrawal. Longer sleep onset latency, reduced slow wave sleep and a REM rebound can be observed. Prospective studies are needed in order to verify whether sleep disturbances during cocaine and cannabis withdrawal predict treatment outcome.

Cerebral correlates of muscle tone fluctuations in restless legs syndrome: a pilot study with combined functional magnetic resonance imaging and anterior tibial muscle electromyography.

BACKGROUND: The pathology of restless legs syndrome (RLS) is still not understood. To investigate the pathomechanism of the disorder further we recorded a surface electromyogram (EMG) of the anterior tibial muscle during functional magnetic resonance imaging (fMRI) in patients with idiopathic RLS. METHODS: Seven subjects with moderate to severe RLS were investigated in the present pilot study. Patients were lying supine in the scanner for over 50 min and were instructed not to move voluntarily. Sensory leg discomfort (SLD) was evaluated on a 10-point Likert scale. For brain image analysis, an algorithm for the calculation of tonic EMG values was developed. RESULTS: We found a negative correlation of tonic EMG and SLD (p <0.01). This finding provides evidence for the clinical experience that RLS-related subjective leg discomfort increases during muscle relaxation at rest. In the fMRI analysis, the tonic EMG was associated with activation in motor and somatosensory pathways and also in some regions that are not primarily related to motor or somatosensory functions. CONCLUSIONS: By using a newly developed algorithm for the investigation of muscle tone-related changes in cerebral activity, we identified structures that are potentially involved in RLS pathology. Our method, with some modification, may also be suitable for the investigation of phasic muscle activity that occurs during periodic leg movements.

Does REM sleep contribute to subjective wake time in primary insomnia? A comparison of polysomnographic and subjective sleep in 100 patients.

Primary insomnia (PI) is characterized by low subjective sleep quality which cannot always be verified using polysomnography (PSG). To shed light on this discrepancy, subjective estimates of sleep and PSG variables were compared in patients with PI and good sleeper controls (GSC). 100 patients with PI (age: 42.57 +/- 12.50 years, medication free for at least 14 days) and 100 GSC (41.12 +/- 13.99 years) with a sex distribution of 46 men and 54 women in each group were included. Both PSG and questionnaire variables showed clear impairments of sleep quality in PI compared with GSC. The arousal index within total sleep time was increased, which was mainly because of a strong increase within rapid eye movement (REM) sleep. Subjectively, more PI than GSC subjects estimated wake times longer than obtained from PSG. Linear modeling analysis of subjective wake time in terms of PSG parameters revealed that in addition to PSG defined wake time, REM sleep time contributed significantly to subjective wake time. This REM sleep contribution was larger for PI than for GSC subjects. The findings suggest that REM sleep-related processes might contribute to subjectively disturbed sleep and the perception of waking time in patients with PI.

Restless legs syndrome in older adults.

Restless legs syndrome (RLS) is a common neurological disorder characterized by an urge to move the legs. The symptoms show a strong circadian rhythmicity, with onset or increase in the evening or at night; thus, sleep disturbances are the most frequent reason for patients seeking medical aid. The prevalence of the disorder increases strongly with age, with an estimated 9% to 20% of sufferers being among the elderly. Dopaminergic drugs are the first-line treatment option in RLS; opioids and anticonvulsants can also be used either as add-on or stand alone therapy options. Secondary forms of RLS and possible interaction with other medications require particular consideration in the elderly.

Polysomnography findings in patients with restless legs syndrome and in healthy controls: a comparative observational study.

STUDY OBJECTIVES: Sleep disturbances and their sequelae are the most common complaints of patients with restless legs syndrome (RLS). We compared polysomnography (PSG) findings in a large cohort of patients with idiopathic RLS and of healthy subjects. DESIGN: Comparative observational study. SETTING: University hospital sleep laboratory. PATIENTS: Age- and sex-matched patients with idiopathic but untreated RLS versus healthy controls. INTERVENTIONS: N/A RESULTS: Each group consisted of 29 females and 16 males. RLS subjects and controls were 47.4 +/- 10.9 and 47.3 +/- 10.5 years old, respectively. RLS severity was 24.0 +/- 6.2 points on the IRLS scale, indicating moderately severe RLS symptoms. We found strong multivariate group effects on PSG parameters (Wilks' lambda, P <0.001): RLS patients exhibited prolonged sleep onset latencies (according to the 10-min criterion but not to the one-epoch criterion), shorter total sleep time, lower sleep efficiency, higher arousal index, higher number of stage shifts, and longer REM sleep latency. During the sleep period time, percentage of wake and sleep stage 1 were increased, and sleep stage 2 and REM sleep were decreased in RLS patients. The PLMS indices and the sleep fragmentation index were markedly increased in the RLS group. CONCLUSIONS: We present the largest polysomnography study to date that compares patients with idiopathic RLS with age- and sex-matched healthy subjects. The findings demonstrate markedly fragmented sleep with deterioration of both NREM and REM sleep in RLS patients.

Chronic insomnia and MRI-measured hippocampal volumes: a pilot study.

STUDY OBJECTIVES: Morphometric analysis of magnetic resonance imaging brain scans was used to investigate possible neuroanatomic differences between patients with primary insomnia compared to good sleepers. DESIGN: MRI images (1.5 Tesla) of the brain were obtained from insomnia patients and good sleepers. MRI scans were analyzed bilaterally by manual morphometry for different brain areas including hippocampus, amygdala, anterior cingulate, orbitofron-tal and dorsolateral prefrontal cortex. SETTING: University Hospital Sleep Center and Radiology Department PARTICIPANTS: 8 unmedicated physician-referred patients with chronic primary insomnia (3 males, 5 females; 48.4 + 16.3 years) and 8 good sleepers matched for age, sex, body mass index, and education. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Patients with primary insomnia demonstrated significantly reduced hippocampal volumes bilaterally compared to the good sleepers. None of the other regions of interest analyzed revealed differences between the 2 groups. CONCLUSIONS: These pilot data raise the possibility that chronic insomnia is associated with alterations in brain structure. Replication of the findings in larger samples is needed to confirm the validity of the data. The integration of structural, neuropsychological, neuroendocrine and polysomnographic studies is necessary to further assess the relationships between insomnia and brain function and structure.

Voxel-based morphometry in unmedicated patients with restless legs syndrome.

BACKGROUND: The pathophysiology of restless legs syndrome (RLS) is not yet understood. A prior voxel-based morphometry (VBM) study reported gray matter increase in the pulvinar of the thalamus in a group of patients, most of whom were on medical treatment. Since there is evidence that medication can change the volume of cerebral structures, the question arises as to whether the reported morphometric alterations are caused by the RLS itself or, alternatively, are a consequence of drug treatment. To address this issue, we performed VBM in unmedicated RLS patients. METHODS: Fourteen patients with idiopathic RLS with no (n=11) or only minimal (n=3) treatment exposure in the past and 14 age- and sex-matched healthy subjects were investigated. All subjects were free of psychotropic drugs for at least 4 months. Morphological data were analyzed by using optimized VBM. RESULTS: We did not detect any structural changes except for slightly increased gray matter density in the ventral hippocampus (p=0.046 on the left and p=0.055 on the right side) and in the middle orbitofrontal gyrus (p=0.046 on the right and p=0.097 on the left side). CONCLUSION: Our study could not confirm the findings of a prior study. A possible explanation for the divergent findings is the difference between the populations examined. Since, in our study, essentially treatment-naïve patients were investigated, it is possible that the prior findings reflect treatment-induced effects on cerebral morphology in RLS.

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.

Relationship of periodic leg movements and severity of restless legs syndrome: a study in unmedicated and medicated patients.

OBJECTIVE: To evaluate the relationship of the severity of restless legs syndrome (RLS) as assessed by a subjective, patient-rated scale (International RLS Study Group Rating Scale, IRLS), and of periodic leg movements in sleep (PLMS) as an objective parameter, in two different patient populations. METHODS: Data of 200 unmedicated patients with idiopathic RLS were evaluated. Group 1 (n=100) consisted of selected patients participating in the Pergolide European Australian RLS (PEARLS) study. Group 2 (n=100) represented an outpatient RLS population investigated in a Sleep Disorders Center. Additionally, Group 1 was also evaluated after a 6 week double-blind treatment period, where 47 patients received pergolide and 53 patients placebo. RESULTS: In unmedicated patients, IRLS scores correlated with the PLMS-arousal index (r=0.22, p=0.033) but not with the PLMS index in Group 1 while no correlation was found in Group 2. The change of the IRLS score under treatment in Group 1 correlated significantly both with the change of the PLMS index (r=0.42, p<0.001) and the change of the PLMS-arousal index (r=0.38, p<0.001). CONCLUSIONS: The IRLS adequately reflects treatment changes of PLMS indices. In unmedicated patients, the IRLS correlates with PLMS indices probably only in selected RLS populations with predefined PSG criteria and high PLM activity. SIGNIFICANCE: The IRLS is an appropriate subjective rating scale for measuring treatment effects in RLS.

Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis.

BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. METHODS: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10-8) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. FINDINGS: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). INTERPRETATION: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. FUNDING: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.

Sleep and sleep disorders in adults with attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a frequent disorder that often persists in adulthood. Persistent ADHD is known to be a serious risk factor for other disorders in adulthood, and adults with ADHD often report on sleep disorders. Despite this, only few studies have investigated the subjective and objective quality of sleep in adults suffering from ADHD. Previous studies have revealed seriously impaired subjective sleep quality and increased nocturnal motor activity in spite of essentially normal standard polysomnographic parameters in this patient group. However, primary sleep disorders such as sleep apnea syndrome or restless legs syndrome (RLS) may be misdiagnosed as ADHD. Moreover, ADHD and primary sleep disorders may occur as comorbidities. In particular, RLS was suggested to be highly associated with ADHD, indicating a probable common central nervous dopaminergic dysfunction. To date, larger studies with adequate sample sizes that compare sleep in adult patients with ADHD, healthy control groups and patients with other primary sleep disorders are still lacking.