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.

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.

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.

Patterns of increased intrinsic functional connectivity in patients with restless legs syndrome are associated with attentional control of sensory inputs.

INTRODUCTION: Potential alterations of intrinsic functional connectivity in idiopathic restless legs syndrome (RLS) are to be assumed since RLS is considered a network disorder. Whole-brain-based investigation of intrinsic functional connectivity networks including the sensorimotor systems in patients with RLS was compared with matched healthy controls. METHODS: 'Resting-state' functional MRI (1.5 T) from 26 patients with RLS and 26 matched controls were analyzed using standardized seed-based analysis procedures. The motor/sensorimotor, sensory thalamic, ventral and dorsal attention, basal ganglia-thalamic, cingulate, and brainstem networks were used for voxel-based group comparisons between RLS patients and controls. RESULTS: Significantly increased connectivities were observed in the sensory thalamic, ventral and dorsal attention, basal ganglia-thalamic, and cingulate networks in RLS patients, whereas no differences could be demonstrated for the motor/sensorimotor and the brainstem system. The pattern of functional connectivity alterations was positively correlated with increasing symptom severity. CONCLUSIONS: Abnormally increased regional BOLD synchronization appears to be a key feature of intrinsic brain architecture in RLS. Alterations in cortical and sub-cortical functional networks support the notion that the underlying pathophysiology of RLS is beyond the sensorimotor and the brainstem system and may be also associated with altered attentional control of sensory inputs.

Microstructure of the Midbrain and Cervical Spinal Cord in Idiopathic Restless Legs Syndrome: A Diffusion Tensor Imaging Study.

STUDY OBJECTIVES: Diffusion tensor imaging (DTI) allows the study of white matter microstructure in the central nervous system. The aim of this study was to examine the DTI metrics of the cervical spinal cord and the brainstem up to the midbrain in patients with idiopathic restless legs (RLS) compared to matched healthy controls. METHODS: DTI analysis of the cervical spinal cord and the brainstem up into the midbrain was performed in 25 patients with idiopathic RLS and 25 matched healthy controls. Data analysis in the brain was performed by voxelwise comparison of fractional anisotropy (FA) maps at group level. Cervical spinal cord data analysis was performed by slicewise analysis of averaged FA values in axial slices along the spinal cord. RESULTS: Voxelwise comparison of FA maps in the brainstem showed significant microstructural alterations in two clusters in the midbrain bilaterally. Slicewise comparison of the FA maps in the cervical spinal cord showed a trend for lower FA values at the level of the second and third vertebra area in the patient sample. CONCLUSIONS: The imaging data suggest that significant alterations in the midbrain in RLS can be visualized by DTI and might correlate to a macroscopically subtle process with changes of the tissue microstructure in the corresponding tracts. An additional area of interest is regionally clustered in the upper cervical spinal cord with a tendency toward altered diffusion metrics. These results might be addressed by further studies, e.g., at higher magnetic field strengths.

Prevalence of restless legs syndrome in an urban population of eastern Africa (Tanzania).

OBJECTIVES: Restless legs syndrome (RLS) is one of the most common neurological disorders in Caucasian populations with prevalence rates between 5% and 15%. A recent study conducted in rural northern Tanzania documented a prevalence of only 0.013%. This result requires further investigation of the epidemiology of RLS in Africa, as prevalence rates seem to vary among different ethnicities. PATIENTS/METHODS: We conducted a community-based door-to-door study in an urban environment in eastern Africa (Kinondoni district, Dar es Salaam, Tanzania), where 35.008 people aged 14 years and above were screened for RLS according to the essential diagnostic criteria. Sampling was performed by the method of cluster sampling with probability-proportional-to-size. RESULTS: One hundred and sixty-four people screened positively for RLS (0.47%). Ninety-two of those were subject to detailed history taking and physical examination. Four people could finally be diagnosed with RLS, yielding a RLS prevalence rate of 0.037% (95% CI 0.015%; 0.059%) among the people in Kinondoni. CONCLUSION: These results support previous findings that RLS has a very low prevalence in Tanzania despite the fact that only part of the questionnaire-positive RLS people could be interviewed face-to-face, and show that this is independent of whether assessed in a rural or an urban population. According to our results it seems that indigenous Tanzanian people (which are considered representative for the population of Eastern Africa) are less prone to RLS compared to Caucasian populations. Whether the reasons for this discrepancy in prevalence are primarily genetic, environmental or have a cultural/social component remains to be determined. In addition, the study points to a limited application of the essential diagnostic criteria in settings of non-Caucasian populations. Irrespective of ethnic origin, we support the necessity of detailed history and physical examination as performed in the second part of our study to exclude RLS mimics and verify the diagnosis of RLS.

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.

What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications.

BACKGROUND: At the time of writing only dopamine agonists are licensed for the treatment of restless legs syndrome (RLS) in various countries, but randomized controlled trials (RCTs) have been performed with other treatments. We performed comprehensive meta-analyses and indirect comparisons of RCTs for all currently recommended treatments of RLS. METHODS: We searched the Central, Medline, Embase, PsycINFO and CINAHL databases. Outcome measures were the international RLS study group severity scale (IRLS), clinical global impression-improvement, (CGI-I), periodic limb movement index (PLMI), and psychosocial parameters such as quality of life (QoL). We also conducted indirect comparisons by testing for heterogeneity between the substance groups. RESULTS: Placebo (58 trials) and actively (4 trials) controlled RCTs with dopamine agonists (38 trials), levodopa (4 trials), anticonvulsants (13 trials), most of them with α2δ ligands (11 trials), opioids (1 trial), and iron treatments (6 trials) were included (9596 patients). Although treatment effects showed large variations, changes in the IRLS in the substance groups were comparable (P = 0.78), with a mean reduction in the IRLS of -5.47 points for dopamine agonists, -5.12 points for anticonvulsants (α2δ ligands and levetiracetam), and -4.59 points for iron treatments. The CGI-I indicated slightly different treatment effects between the substance groups, while PLMI changes during treatment differed (P = 0.002), showing a marked decrease with dopamine agonists (-22.50/h), levodopa (-26.01/h), and oxycodone (-34.46/h) compared with a slight decrease for anticonvulsants (α2δ ligands and levetiracetam; -8.48/h) and iron treatments (-13.10/h). Quality of sleep and QoL improved moderately in most of the RCTs investigating these parameters (standardized mean difference, SMD) 0.40 and 0.33, respectively). In the few studies evaluating the change of depressive (n = 4) or anxiety symptoms (n = 3), these symptoms improved slightly (SMD -0.24, and -0.21). Adverse effects and dropouts were comparable in number across all substance groups. In meta-regressions, the treatment effect was predicted by the design of the trial (the more sites involved in a trial the lower the effect) and by the duration of action of a medication (the longer the duration of action, expressed as the half-life time of a substance, the greater the improvement), the latter indicating potential superiority of treatments with stable blood concentration. CONCLUSION: This first meta-analysis of all RCTs for the pharmacological treatment of RLS provides evidence that, besides the well-defined efficacy of dopaminergic treatment, other treatments with different pharmacological principles show efficacy in small samples and may be well-tolerated alternatives for the treatment of RLS. In the group of anticonvulsants, only the trials performed with α2δ ligands such as gabapentin, gabapentin enacarbil, and pregabalin showed good efficacy. This indicates a specific mechanism of action of these substances in RLS. The group of iron treatments consisted of a few trials with different compounds in oral and intravenous application form, respectively. For a more differentiated evaluation of the efficacy of iron treatments further studies are necessary. The large efficacy of one opioid RCT in RLS has to be confirmed in further studies.

Long-Term treatment of a patient with severe restless legs syndrome using intrathecal morphine.

Restless legs syndrome (RLS) is a common sensorimotor disorder.(1) The symptoms have a strong circadian rhythmicity and are most severe at night and at rest. In the most severe cases, symptoms are accompanied by serious sleep disturbances and unbearable paresthesias. First-line treatments of RLS are dopamine agonists, but GABAergic anticonvulsants and opioids are also effective.(2,3) Patients with the most severe RLS are often treated with oral opioids.(4) The use of these may, however, be limited due to side effects. The intrathecal administration of opioids results in better pain relief and fewer side effects in severe chronic pain. Case reports of 4 patients have documented excellent results with short-term use of intrathecal opioids also in RLS.

Investigating the response to intravenous iron in restless legs syndrome: an observational study.

OBJECTIVE: To investigate the effect of intravenous (IV) iron (500 mg ferric carboxymaltose [FCM] as a single dose) on restless legs syndrome (RLS) severity on a day-to-day basis. METHODS: Twenty patients with RLS and absolute or functional iron deficiency or low normal serum ferritin (<45 µg/l) were included. Change of RLS severity was evaluated using the International RLS severity scale (IRLS) and the RLS-severity diary (RLS-SD) which evaluates symptom severity over a 6-h period on an 11-point numerical Likert scale, four times a day. RESULTS: Twelve patients reported that IV FCM improved RLS ("responders"). IRLS score decreased from 30.1 (± 5.9) to 23.07 (± 9.5) (p=0.001) in the whole group and from 28.3 (± 6.1) to 18.3 (± 8.0) (p=0.002) in the responder group three weeks after IV FCM treatment. A clinically relevant effect of IV iron on RLS severity could be seen as early as day eight. The responder group differed from the non-responder group in tendency by being younger (p=0.064), having a lower serum ferritin level at baseline (p=0.097), and presenting a lower number of comorbid conditions. CONCLUSIONS: FCM led to a considerable improvement in RLS in the responder group within about one week. These findings are clinically relevant, especially for patients with severe RLS symptoms and iron deficiency, since a change or uptitration of RLS-specific medication can be avoided or postponed in these patients due to the rapid response to IV FCM treatment.

Efficacy and safety of dopamine agonists in restless legs syndrome.

OBJECTIVE: Restless legs syndrome (RLS) is a common neurological disorder causing considerable impairment to daily living. This article is an overview of a comprehensive Cochrane meta-analysis on the efficacy and safety of dopamine agonists (DAs), the first-line treatment of RLS. METHODS: CENTRAL, MEDLINE, EMBASE, PsycINFO, and CINAHL databases were searched for double-blind randomized controlled trials (RCTs) of DAs vs placebo. RESULTS: Thirty-five placebo-controlled RCTs (total number of patients=6954) were eligible. The likelihood of bias was considered to be low. The mean treatment duration of the RCTs was 10.3 (standard deviation 7.3) weeks, with treatment durations up to seven months. Overall, DAs showed a moderate improvement in the International RLS Severity Scale score (mean difference -5.7 points [95% confidence interval, CI, -6.7 to -4.7; P<0.00001]) and the Clinical Global Impression-Improvement response (risk ratio 1.44 [95% CI 1.34-1.54; P<0.00001]) compared with placebo. Periodic limb movements decreased by -22.38/h (95% CI -27.8 to -16.9; P<0.00001) for DAs compared with placebo. Sleep quality and disease-specific quality of life increased slightly to moderately. Safety data confirmed the established safety characteristics of DAs. Augmentation, a specific side-effect of dopaminergic treatment of RLS, was not assessed adequately. CONCLUSIONS: This meta-analysis showed that DAs have moderate efficacy in the treatment of RLS. Actively controlled and long-term studies are still lacking. Large-scale comparative studies are needed to identify the most efficient treatments for this chronic disorder.

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.

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.

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.

Evaluation of painful sensory symptoms in restless legs syndrome: experience from two clinical trials.

BACKGROUND: Although "uncomfortable and unpleasant" limb sensations are a core symptom of restless legs syndrome (RLS), change in sensory symptomatology is usually not evaluated as a treatment outcome. METHODS: In two double-blind trials, patients with idiopathic RLS (n=357 in trial 615 and 398 in trial 604) were randomized to placebo or pramipexole (optimized at 0.125, 0.25, 0.50, or 0.75 mg/day). For entry, trial 604 also required at least moderate mood disturbance. In both trials, 12-week change in RLS-related limb pain was assessed using a 100-mm visual analogue scale (VAS). RESULTS: At baseline, approximately 75% of patients had limb-pain scores >30. Treatment with pramipexole yielded significant score reduction as early as day 5. At week 12, median score reduction for pramipexole relative to placebo was -33.5 vs. -11.0 (p<0.0001) in trial 615 and -31.0 vs. -11.0 (p<0.0001) in trial 604. CONCLUSIONS: Painful sensations may be more frequent in RLS than has previously been appreciated, and their amelioration may be a facet of pramipexole's benefit even in patients with concurrent mood disturbance. Limb pain assessment, e.g., by a VAS, is a useful measure of change in RLS symptom severity.

Impaired memory consolidation during sleep in patients with functional memory disorder.

Functional memory disorder (FMD) is characterized by mnestic and attentional deficits without symptoms of mild cognitive impairment or dementia. FMD usually develops in subjects with high psychosocial stress level and is classified to the somatoform disorders. We assessed memory performance (procedural mirror tracing task, declarative visual and verbal memory task) and other cognitive functions before and after one night of sleep in 12 FMD patients (mean age: 51.7 yrs, 7 females) and 12 healthy subjects matched for age, gender and IQ. Memory performance and other neurocognitive tasks did not differ between the groups at baseline. After one night of sleep, FMD patients showed an impairment of declarative memory consolidation compared to healthy subjects (visual task: p=0.004; verbal task: p=0.039). Spectral analysis of sleep-EEG indicated an increased cortical excitation in FMD. We hypothesize that a hyperarousal state in FMD might contribute to sleep disturbance implicating negative effects on declarative memory consolidation.

Randomized trial of pramipexole for patients with restless legs syndrome (RLS) and RLS-related impairment of mood.

OBJECTIVES: Patients with restless legs syndrome (RLS) have an elevated prevalence of mood disorders compared with the general population. We investigated the change of RLS-related mood impairment during treatment of RLS with pramipexole, a dopamine D(3)/D(2) agonist. METHODS: Adults with moderate to very severe RLS were enrolled in a 12-week, double-blind, placebo-controlled Phase IV pramipexole trial. A moderate to very severe RLS-related mood disturbance at baseline (score ≥2 on Item 10 of the International RLS Study Group Rating Scale [IRLS]) was also required. Pramipexole (0.125 to 0.75 mg once daily) was flexibly titrated over the first 4 weeks. RESULTS: The intent-to-treat population comprised 199 patients on placebo and 203 on pramipexole. At week 12, adjusted mean total-score changes on IRLS were -14.2±0.7 for pramipexole and -8.1±0.7 for placebo (p<0.0001), and on the Beck Depression Inventory version II, -7.3±0.4 for pramipexole and -5.8±0.5 for placebo (p=0.0199). For IRLS item 10, the 12-week responder rate (reduction to no or mild mood disturbance) was 75.9% for pramipexole and 57.3% for placebo (p<0.0001). Study withdrawal rates were higher for placebo (20.5%) than for pramipexole (12.8%). CONCLUSIONS: In patients with RLS-related mood disturbance, pramipexole improved RLS while also improving RLS-related mood impairment. Tolerability of pramipexole was similar to that in previous studies.

Ropinirole improves depressive symptoms and restless legs syndrome severity in RLS patients: a multicentre, randomized, placebo-controlled study.

Comorbid depressive symptoms in restless legs syndrome (RLS) remain a treatment challenge, as some antidepressants aggravate RLS symptoms. Preliminary data in depressive patients suggest antidepressant properties of ropinirole. The present study investigates the effects of ropinirole immediate release (IR) on depressive symptoms and RLS severity. A multicenter, placebo-controlled, double-blind randomized (3:1) study was performed including patients with moderate to severe idiopathic RLS and at least mild depressive symptoms. Ropinirole IR (in flexible doses up to 4 mg/day) or placebo was given for 12 weeks including an uptitration phase of 7 weeks. Visits were scheduled at screening, baseline, and weeks 1, 4, and 12 with additional telephone contacts for dosing decisions. The modified intent to treat population comprised 231 patients (171 ropinirole, 60 placebo). The MADRS (Montgomery-Asberg Depression Rating Scale) scores decreased from baseline to week 12 from 18.8 to 8.7 in the ropinirole group and from 18.4 to 12.1 in the placebo group (primary endpoint, adjusted mean treatment difference -3.6 (95% CI: -5.6 to -1.6, significance in favor of ropinirole: P < 0.001). The superiority of ropinirole compared to placebo was confirmed by the Hamilton Scale for Depression and Beck Depression Inventory-II scores. RLS severity scores (IRLS) decreased by 14.7 (ropinirole) and by 9.9 (placebo, P < 0.001) points. Three out of four subdomains of the Medical Outcomes Study Sleep Scale improved significantly. The findings indicate that mild to moderate depressive symptoms should not be treated before sufficient therapy for RLS. Antidepressant medication can be necessary if depression symptoms still persist even if RLS symptoms are ameliorated.

Depressive disorders in restless legs syndrome: epidemiology, pathophysiology and management.

Epidemiological studies report a 2- to 4-fold risk of a depressive disorder in patients with restless legs syndrome (RLS) compared with healthy controls. The high prevalence rates of depression in RLS indicate an association between the two disorders. Severe sleep disturbance due to the nightly occurrence of RLS symptoms is a common complaint of patients with moderate or severe RLS and may substantially contribute to the emergence of depressive symptoms. Difficulty in the diagnosis of a depressive disorder in patients with RLS may arise from the overlap of symptoms in the two disorders, as sleep-related complaints are frequent both in RLS and depression. The treatment of depression in RLS has some unique aspects, as several antidepressants have been reported to trigger or worsen RLS. To date, no studies have been published regarding the course of depression in untreated and treated patients with RLS. On the other hand, the presence of co-morbid depression can have a substantial impact on the global treatment outcome. In patients with co-morbid moderate/severe depression, antidepressant therapy in parallel with or shortly after commencing RLS treatment is usually necessary. Data from recent trials with dopamine receptor agonists indicate that mild to moderate depressive symptoms are often relieved with improvement of RLS symptoms.