Neurological disorders: towards a mechanistic understanding of restless legs syndrome

Restless legs syndrome is a curious neurological disorder of unknown aetiology. A new study has found that Drosophila mutants in the fly homologue of a human gene, BTBD9, that has been implicated as a risk factor for restless legs display important features of the syndrome.     

不宁腿综合征遗传学研究进展

不宁腿综合征(Restless legs syndrome, RLS)遗传学研究近年来获得了许多重要的进展, 极大地丰富了对于这种疾病分子机制的认识。RLS是一种常见的复杂疾病, 几个遗传流行病学和双生子研究对RLS遗传组分进行了剖析, 说明RLS是一个遗传性很强的性状, 其遗传力约为50%。采用基于模型的连锁分析方法或者是不依赖于模型的连锁分析方法目前已定位了5个重要的RLS疾病连锁位点: 12q13-23, 14q13-21, 9p24-22, 2q33和20p13, 为定位克隆RLS致病基因或者易感基因提供了连锁图谱。最新基于高通量的SNPs分型平台开展的全基因组分析确立3个与RLS显著关联的区域: 6p21.2, 2p14和15q23。文章结合作者近年来从事不宁腿综合征遗传学的研究工作, 对该领域的重要成果进行了汇总和评述。     

Erratum to: Pathogenetic heterogeneity of restless legs syndrome in Parkinson’s disease

Sleep and Biological Rhythms -     

Prevalence of restless legs syndrome in pregnant women: a meta-analysis

Sleep and Biological Rhythms - Restless legs syndrome is a neuromotor problem which is more common among pregnant women. Several studies have reported different prevalences for this disorder....     

Genetic influences in self-reported symptoms of obstructive sleep apnoea and restless legs: a twin study.

Sleep disorders, such as obstructive sleep apnoea (OSA) and restless legs syndrome (RLS), are very common. The relative importance of genetic and nongenetic (environmental) influences on the symptomatology of these conditions has not been well studied. This study uses the twin design to examine this by evaluating OSA and RLS symptoms in monozygotic (MZ) and dizygotic (DZ) twins. Six thousand six hundred unselected female twin pairs, identified from a national volunteer twin register, were asked to complete a medical questionnaire. This questionnaire included questions on OSA and RLS symptoms, as well as questions on subject demographics, past medical history, smoking history and menopausal status. Responses were obtained from 4503 individuals (68% response rate). A total of 1937 twin pairs were evaluable: 933 MZ pairs (mean [range] age 51 [20-76] years) and 1004 DZ pairs (age 51 [20-80] years). Concordance rates were higher for MZ than DZ twins for OSA and RLS symptoms. Multifactorial liability threshold modeling suggests that additive genetic effects combined with unique environmental factors provide the best model for OSA and RLS symptoms. Heritability was estimated to be 52% (95% confidence interval 36% to 68%) for disruptive snoring, 48% (37% to 58%) for daytime sleepiness, 54% (44% to 63%) for restless legs, and 60% (51% to 69%) for legs jerking. These estimates dropped only slightly after adjustment for potential confounding influences on the symptoms of snoring and daytime sleepiness. These results suggest a substantial genetic contribution to the symptomatology of OSA and RLS. More research is needed to identify the genes responsible, and may ultimately lead to new therapies.     

Case control polysomnographic studies of sleep disorders in Parkinson's disease

Background

The relationship between a number of primary sleep disorders and Parkinson''s disease (PD) is still debated. There are limited case control polysomnographic studies in PD and most of these study sample sizes are small.

Methodology/Findings

We conducted one of the largest case-control studies involving overnight polysomnographic evaluation, with prospective recruitment of unselected Parkinson''s disease patients and healthy controls from an Asian population. The cases were recruited from the specialized movement disorder outpatient clinics in a tertiary referral center, and controls from the same geographical locations. All subjects underwent an overnight polysomnographic study and a multiple sleep latency test.A total of 124 subjects including 56 patients and 68 controls frequency-matched for age and sex were included. Multivariate analysis revealed that patients had significantly shorter total sleep time than controls (p = 0.01), lower sleep efficiency (p = 0.001) and increased REM latency (p = 0.007). In patients, multivariate analysis showed that reduced total sleep time was significantly associated with increased age (p = 0.001) and increased levodopa dose (p = 0.032). The mean Insomnia Severity Index was higher in PD patients (9.0±7.1) compared to controls (3.3±3.9, p<0.001). The mean Epworth Sleepiness Scale score was higher in PD patients (9.3±5.9 vs. 5.7±4.8, p<0.001). Nocturnal arousals, obstructive sleep apnea, periodic leg movements and objective abnormal sleepiness were not increased in our patients.

Conclusions/Significance

Our case-control polysomnographic study, the first-ever performed in an Asian population, revealed altered sleep architecture and reduced sleep in PD patients compared to controls. Reduced total sleep time was associated with increased age and levodopa dose. However, nocturnal arousals, primary sleep disorders and abnormal sleepiness were not increased in our PD patients suggesting that ethnic/genetic differences may be a factor in the pathophysiology of these conditions.     

Treatment of the restless legs syndrome with carbamazepine: a double blind study.

One hundred and seventy four patients suffering from the restless legs syndrome were examined in a double blind, between patient, placebo controlled study in general practice for five weeks to investigate the effects of carbamazepine and placebo on the syndrome. The syndrome was more common among middle aged women with relatively low systolic blood pressure. The median haemoglobin concentration was about average for the population, but the severity of the symptoms seemed to increase with decreasing concentrations of haemoglobin. Both placebo and carbamazepine showed a significant therapeutic effect (p less than 0.01). Carbamazepine was significantly more effective than placebo (p less than or equal to 0.03). The significant therapeutic effect of placebo in restless legs showed that only double blind controlled trials can confirm the efficacy of suggested treatments.     

Microstructural changes in the basal ganglia in restless legs syndrome and migraine

Sleep and Biological Rhythms -     

Algorithms for the diagnosis and treatment of restless legs syndrome in primary care

Background

Restless legs syndrome (RLS) is a neurological disorder with a lifetime prevalence of 3-10%. in European studies. However, the diagnosis of RLS in primary care remains low and mistreatment is common.

Methods

The current article reports on the considerations of RLS diagnosis and management that were made during a European Restless Legs Syndrome Study Group (EURLSSG)-sponsored task force consisting of experts and primary care practioners. The task force sought to develop a better understanding of barriers to diagnosis in primary care practice and overcome these barriers with diagnostic and treatment algorithms.

Results

The barriers to diagnosis identified by the task force include the presentation of symptoms, the language used to describe them, the actual term "restless legs syndrome" and difficulties in the differential diagnosis of RLS.

Conclusion

The EURLSSG task force reached a consensus and agreed on the diagnostic and treatment algorithms published here.     

Rifaximin antibiotic treatment for restless legs syndrome: a double-blind,placebo-controlled study

Sleep and Biological Rhythms - The purpose was to evaluate rifaximin antibiotic therapy for restless legs syndrome (RLS) patients who have small intestinal bacterial overgrowth (SIBO). Patients...     

Association between restless legs syndrome and CLOCK and NPAS2 gene polymorphisms in schizophrenia

Previous studies have suggested that there is a genetic basis to restless legs syndrome (RLS) development. Occurrence of antipsychotic-induced RLS could also be due to differences in genetic susceptibility. We investigated whether CLOCK and NPAS2 gene polymorphisms are associated with RLS in schizophrenic patients on antipsychotics because RLS symptoms usually manifest during the evening and night. We assessed symptoms of RLS in 190 Korean schizophrenic patients on antipsychotics and divided the subjects into two groups according to the International Restless Legs Syndrome Study Group diagnostic criteria: (i) subjects who met all the criteria and (ii) the remaining subjects who did not meet all the criteria. We found a significant difference in the number of subjects with different genotype and allele carrier frequencies for the CLOCK gene (rs2412646) between the two groups (p?=?0.031 and 0.010, respectively). Distribution of CLOCK haplotypes (rs2412646–rs1801260) was significantly different between schizophrenic patients with and without RLS (p?=?0.021). However, the distributions of allelic, genotypic, and haplotypic variants of NPAS2 (rs2305160 and rs6725296) were not significantly different between the two groups. Our results suggest that CLOCK polymorphisms are associated with increased susceptibility of schizophrenic patients to RLS. We hypothesize that RLS in schizophrenia patients treated with antipsychotics may be a very mild akathisia that manifests during the night and is under control of circadian oscillation.     

Ethnic differences in periodic limb movements during sleep in patients with restless legs syndrome: a preliminary cross-sectional study of Austrian and Japanese clinical population

Periodic limb movements during sleep (PLMS) are identified as a common finding in patients with restless legs syndrome (RLS). Although PLMS are observed in more than 80% of RLS patients in Western countries, little is known about Asian RLS patients and no data are available about Japanese patients. This cross-sectional study aimed to investigate ethnic differences in clinical information and polysomnographic variables including PLMS between Austrian and Japanese RLS patient undergoing nocturnal polysomnography (n-PSG). One hundred Austrian and 139 Japanese consecutive patients diagnosed with RLS who underwent n-PSG were included [Austrian 54.5 ± 13.6 years, 40 females (40%); Japanese 50.2 ± 18.9 years, 88 females (63.3%)]. Medical records and n-PSG data were reviewed retrospectively. Epidemiological, clinical and n-PSG variables were compared between the two groups. Rate of patients with PLMS ≥ 5/h and those with PLMS ≥ 15/h were higher in Austrian than in Japanese RLS patients (80.0 vs. 56.1%, P < 0.001; 55.0 vs. 41.7%, P = 0.043). Accordingly, Japanese RLS patients showed lower PLMS index than Austrian patients (21.3 vs. 33.6/h, P = 0.008). Japanese RLS patients showed higher female predominance, lower BMI, lower systolic/diastolic blood pressure, lower ferritin level and higher International restless legs syndrome severity scale than Austrian patients. None of these variables were associated with PLMS in both groups. Japanese RLS patients showed significantly lower comorbidity rate and lower indices of PLMS compared to Austrian RLS patients. This cross-sectional study on ethnic differences in PLMS in patients with RLS may provide a bridge to a future genetic comparative study between European and Asian RLS patients.

     

Frequency of impulse control behaviours associated with dopaminergic therapy in restless legs syndrome

Background  

Low doses of dopamine agonists (DA) and levodopa are effective in the treatment of restless legs syndrome (RLS). A range of impulse control and compulsive behaviours (ICBs) have been reported following the use of DAs and levodopa in patients with Parkinson's disease. With this study we sought to assess the cross-sectional prevalence of impulse control behaviours (ICBs) in restless legs syndrome (RLS) and to determine factors associated with ICBs in a population cohort in Germany.     

The prevalence and associated risk factors of restless legs syndrome among Saudi adults

Sleep and Biological Rhythms - The aim of this cross-sectional study was to determine the prevalence, risk factors, other associated sleep disorders and commodities of Restless Legs Syndrome (RLS)...     

Therapeutic experience of deep vein thrombosis prevention system for restless legs syndrome

Sleep and Biological Rhythms - The present paper reports a case of restless legs syndrome (RLS) in which the Flowtron DVT (Huntleigh Technologies, Luton, UK) was used as a deep vein thrombosis...