Restless Legs Syndrome Subjects Research Articles

0698 Contrasting Painful and Painless Restless Legs Phenotypes: An Adult Twin Family Study

Abstract Introduction Several studies characterized painful and painless restless legs syndrome (RLS) phenotypes based on clinical, topographical, polysomnographic, and genetic background. One pediatric twin family study demonstrated a clear contrast between these two forms of RLS. The painful pediatric RLS being familial, probably genetically influenced, and associated with primary pain disorders (non-migraines headaches; recurrent abdominal pain), the painless pediatric RLS being familial but probably not genetically determined, and associated with iron deficiency, female gender, and persistent/chronic pain disorders. The current study investigated these contrasting painful and painless RLS phenotypes in the adult population. Methods The Twins Research Australia database was used to recruit adult twins and their families. The subjects were surveyed and responded to questions related to their demographics, the Cambridge-Hopkins diagnostic questionnaire for RLS diagnosis and categorization into painful and painless RLS subgroups, the history of physician-confirmed iron deficiency, the presence of selected chronic and primary pain disorders, and also other medical, non-pain conditions associated with RLS. Association analyses, using logistic regression with application of generalized estimating equations to control for twin influences, and adjusting for gender and age, were conducted. Results A total of 1449 adult subjects responded to the RLS diagnostic questionnaire and to pain related and other medical conditions questions (64.4% females). A total of 1327 adult subjects responded to the iron deficiency pertinent questions (65.7% females). Numbers of dizygous twins and painful RLS subjects were insufficient for heritability testing and for association analyses with medical conditions. Painless RLS was associated with iron deficiency (OR= 1.59; p=0.003), while painful RLS was not (OR=1.26; p=0.444). Painful RLS was associated with migraine (OR=2.35; p=0.004), recurrent abdominal pain (OR=1.96; p=0.026), growing pains (OR=2.13; p=0.050), diverse chronic pain (OR=2.88; p=0.017), chronic spinal pain (OR=3.65; p=0.001) and dysmenorrhea (OR=2.46; p=0.009). Painless RLS was not associated with any pain disorder. Conclusion This study further confirmed contrasting associations in adults with painless and painful phenotypes of RLS (association with iron deficiency and multiple pain disorders, respectively). Support (if any) This work was supported by the School of Women's and Children's Health, Medicine, University of New South Wales, Kensington 2052, NSW, Australia; Private donors.

Coexistence of restless legs syndrome and multiple sclerosis aggravates anxiety and depression.

Among the comorbidities that accompany multiple sclerosis (MS), restless legs syndrome (RLS) is one of the most common. Anxiety and depression are common psychological comorbidities that impact the quality of life of patients with MS (PwMS), as well as patients with RLS. To investigate the psychiatric burden of MS and RLS coexistence, we conducted a nationwide, multicenter and cross-sectional survey. Participants were assessed by using demographic and clinical parameters along with the Hamilton Anxiety and Hamilton Depression Scales (HAM-A and HAM-D). Out of the 1,068 participants, 173 (16.2%) were found to have RLS [RLS(+)] and 895 (83.8%) did not [RLS(-)]. The mean scores for HAM-A and HAM-D were significantly higher among RLS(+) subjects than among RLS(-) subjects (p<0.001 for all variables). According to our data, the presence of RLS in PwMS may increase the occurrence of both anxiety and depression symptoms. Awareness and treatment of RLS in PwMS could possibly reduce the symptoms of psychiatric comorbidities originating from RLS.

Working memory deficits in patients with idiopathic restless legs syndrome are associated with abnormal theta-band neural synchrony.

Cognitive impairment, particularly prefrontal function, has been reported in patients with restless legs syndrome. However, working memory performance in patients with restless legs syndrome remains uncertain. The present study aimed to examine working memory performance in patients with restless legs syndrome by investigating electroencephalography theta‐band oscillations within task‐relevant brain regions and the synchronization among oscillations during a working memory task. Twelve female idiopathic patients with restless legs syndrome and 12 female healthy controls participated in this study. Nineteen‐channel electroencephalography data were recorded while participants performed a Sternberg working memory task. We analysed event‐related theta‐band activity and interregional theta‐band phase synchrony during the memory retrieval phase. The spatial pattern of theta‐band phase synchrony was quantified using graph theory measures, including the clustering coefficient, characteristic path length, and small‐world propensity. Considerable increases in theta‐band activity and theta‐band phase synchrony were observed at 600–700 ms in controls and at 650–750 ms in restless legs syndrome subjects after the probe item was presented. During this period, induced theta‐band activity showed lower with borderline significance in the restless legs syndrome subjects than in the controls regardless of channel location (F 4,88 = 3.92, p = .06). Theta‐band phase synchrony between the frontal and posterior regions was significantly reduced in the restless legs syndrome subjects. Inefficiency in both global and local networks in the restless legs syndrome subjects was revealed by the decreased small‐world propensity (t 22 = 2.26, p = .03). Small‐world propensity was negatively correlated with restless legs syndrome severity (r = −.65, p = .02). Our findings suggest that patients with restless legs syndrome have multiple deficits in cognitive processes, including attentional allocation, evaluation of incoming stimuli, and memory manipulation of encoded information during a working memory task. Abnormal local theta‐band neural synchrony and global theta‐band neural synchrony may underlie the neurophysiological mechanism of the working memory dysfunction associated with restless legs syndrome.

Restless Legs Syndrome in Parkinson's Disease Patients: Clinical Features Including Motor and Nonmotor Symptoms.

Background and PurposeWe investigated the frequency and clinical features of restless legs syndrome (RLS) in patients with Parkinson's disease (PD).MethodsThis study included 74 PD patients. RLS was diagnosed in face-to-face assessments of all of the subjects based on diagnostic criteria of the International Restless Legs Syndrome Study Group revised in 2003. We analyzed the clinical features of PD patients with and without RLS and compared the data to idiopathic RLS.ResultsThe frequency of RLS in the cohort was 21.6% (n=16). Two (12.5%) of the patients with RLS were not treated with dopaminergic drugs, while 14 (24.1%) of the 58 patients without RLS received treatment with dopaminergic drugs. Anxiety, depression, and quality of life (QoL) were significantly worst in patients with RLS. PD patients with RLS had significantly worse sleep quality (p=0.003) and worse scores on the cardiovascular subscale of the Scales for Outcomes in Parkinson's Disease for Autonomic Symptoms (p=0.031) compared to those without RLS. In the group of PD patients with RLS, RLS preceding PD onset was related to a lower Hoehn and Yahr stage.ConclusionsWe found that the frequency of RLS in the present patients with PD was higher than that in our previous study of a general population of RLS subjects. Compared to the PD patients without RLS, the present PD patients with RLS suffered from worse sleep quality and QoL, depression, anxiety, and autonomic disturbances, especially those with cardiovascular problems.

Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome.

Restless legs syndrome is a sensorimotor neurological disorder of the limbs that impairs quality of life and disturbs sleep. However, there has been progress in understanding the disease involving the dopaminergic system as well as iron metabolism. The exact pathophysiological mechanisms of restless legs syndrome remain elusive. We tried to elucidate the underlying mechanisms in iron metabolism in restless legs syndrome subjects on a systemic, cellular, and mitochondrial level. We conducted a study prospectively recruiting 168 restless legs syndrome patients and 119 age-matched healthy controls focusing on iron metabolism using human monocytes as surrogates. Evaluation of systemic iron metabolism parameters in the circulation showed no significant difference between patients and controls. We observed a significant reduction in mRNA levels of heme oxygenase 1 and mitochondrial iron genes like mitoferrin 1 and 2 in monocytes isolated from restless legs syndrome patients, indicating mitochondrial iron deficiency. Interestingly, we also observed reduced expression of iron regulatory protein 2 along with impaired activity of mitochondrial aconitase and reduced mitochondrial superoxide formation in restless legs syndrome subjects. Along this line, patients had reduced mitochondrial respiratory capacity that improved in restless legs syndrome subjects under treatment with dopaminergic drugs compared with untreated patients. Our data suggest that restless legs syndrome is linked to mitochondrial iron deficiency and associated impairment of mitochondrial function. This is partly corrected by treatment with dopaminergic drugs compared with untreated patients, which may be linked to an effect of dopamine on cellular iron homeostasis. © 2018 International Parkinson and Movement Disorder Society.

Peripheral Dopamine in Restless Legs Syndrome.

Restless Legs Syndrome (RLS) is a dopamine-dependent disorder characterized by a strong urge to move. The objective of this study was to evalulate blood levels of dopamine and other catecholamines and blood D2-subtype dopamine receptors (D2Rs) in RLS. Dopamine levels in blood samples from age-matched unmedicated RLS subjects, medicated RLS subjects and Controls were evaluated with high performance liquid chromatography and dopamine D2R white blood cell (WBC) expression levels were determined with fluorescence-activated cell sorting and immunocytochemistry. Blood plasma dopamine levels, but not norepinepherine or epinephrine levels, were significantly increased in medicated RLS subjects vs unmedicated RLS subjects and Controls. The percentage of lymphocytes and monocytes expressing D2Rs differed between Control, RLS medicated and RLS unmedicated subjects. Total D2R expression in lymphocytes, but not monocytes, differed between Control, RLS medicated and RLS unmedicated subjects. D2Rs in lymphocytes, but not monocytes, were sensitive to dopamine in Controls only. Downregulation of WBCs D2Rs occurs in RLS. This downregulation is not reversed by medication, although commonly used RLS medications increase plasma dopamine levels. The insensitivity of monocytes to dopamine levels, but their downregulation in RLS, may reflect their utility as a biomarker for RLS and perhaps brain dopamine homeostasis.

Association between restless legs syndrome and hypertension: a meta-analysis of nine population-based studies.

Previous population-based studies evaluating the association between restless legs syndrome (RLS) and cardiovascular risk factors have showed inconsistent results, especially for the relationship between RLS and hypertension. We, therefore, aimed to meta-analyze to assess the association between RLS and hypertension. PubMed and Embase databases were systematically searched to identify eligible studies. Nine population-based cross-sectional studies were selected for inclusion, involving 102,408 individuals. Overall, the prevalence of hypertension in RLS subjects was higher than those without RLS (OR=1.36, 95% CI, 1.18-1.57, P=0.043). Our findings indicate that RLS is associated with increased blood pressure. More large-scale and prospective studies are warranted to further clarify the relationship and its potential mechanism.

Turkish version of the Johns Hopkins restless legs syndrome quality of life questionnaire (RLS- QoL): Validity and reliability study

Restless legs syndrome (RLS), as well as problems secondary to RLS, may worsen the quality of life. Our aim was to modify the Restless Legs Syndrome Quality of Life (RLS-QoL) questionnaire advanced by Abetz (Health Qual Life Outcomes 3:79, 2005) and to analyse the validity and reliability of the questionnaire. Two hundred and one consecutive patients with RLS and forty-three control subjects were included in the study. Permission regarding the translation and validation of the RLS-QoL questionnaire was obtained. The translation was conducted according to the guidelines provided by the publisher. For the RLS subjects, the mean Insomnia Severity Index (ISI) score, the International Restless Legs Syndrome Severity Rating Scale (IRLSSG) score and the computed score of the RLS-QoL questionnaire were 22.60 ± 3.39, 24.83 ± 5.28 and 45.93 ± 17.62, respectively. Among the RLS subjects without insomnia, the mean (±standard deviation) ISI score, IRLSSG score and computed score of the RLS-QoL questionnaire were 6.67 ± 2.34, 15.11 ± 4.03 and 41.93 ± 16.12, respectively. A significant difference was identified between both groups on all scores (ISI: p = 0.001, RLS: p = 0.001). The groups with and without insomnia were similar regarding the computed score of the RLS-QoL questionnaire (p = 0.140). According to a correlation analysis, a significant correlation was identified between the ISI and IRLSSG or RLS-QoL scores (r = 0.513, p = 0.001 and r = −0.383, p = 0.001, respectively). Although the coefficient of correlation is significant between IRLSSG score and RLS-QoL scale score, it should not be considered as a powerful enough correlation (r = 0.190, p = 0.007). Most items also exhibited a strong correlation with each other. The internal consistency determined by Cronbach’s alpha indicated an extremely good correlation (0.975). These findings suggest the Turkish version of the RLS-QoL questionnaire is a valid and reliable tool for the assessment of the quality of life in patients with RLS.

0741 PREVALENCE AND CHARACTERISTICS OF RESTLESS LEGS SYNDROME IN KOREAN ADULTS: THE STUDY ON TWO-INDEPENDENT POPULATIONS

Restless legs syndrome (RLS) is regarded as a common sleep disorder with a significant impact on quality of life and with a genetic background, more frequently occurring in Caucasian than Asian population. RLS prevalence in Korean adult population is 3.9 - 14.3%, higher than those reported in other Asian countries. A wide range of reported prevalence derives from the differences in the population characteristics and in the methods to define RLS. We aimed to provide the RLS prevalence estimate in Korean adults, compared with previous reports in Korea, Asian and western countries. In this study, we included two independent samples of Korean adult populations: group-1 was a nation-wide stratified random sample of adult population (n = 2,824; aged 19 - 79 years) and group-2 was a community based cohort (n = 2,685; aged 47 - 79 years). The presence of RLS was evaluated with the Cambridge-Hopkins diagnostic questionnaire for RLS (CH-RLSq). We compared sleep profiles, sleep-related symptoms, mood/anxiety, and comorbid medical conditions between RLS and non-RLS groups. RLS prevalence was 0.42% in the group-1 and 0.86% in the group-2. There were no significant differences of age, sex, and body mass index between RLS and non-RLS groups. In group-1, RLS subjects have depression and insomnia more frequently than those without RLS (p < 0.05). In group-2, RLS subjects were more sleepy and depressive with shorter sleep duration, worse sleep quality and more severe insomnia symptom (p < 0.05). Underlying comorbidities including smoking, alcohol, hypertension, diabetes, hyperlipidemia, anemia, neurological disorder, or kidney disease were not statistically different between RLS and non-RLS groups. RLS prevalence in Korean adult was less than 1%, which contrasts with previously reported ones in Korea. Considering the ethnic difference and genetic background of RLS, and the RLS prevalence depending on the diagnostic metrics, a high prevalence of RLS in Korea is questionable. None

Restless leg syndrome as co-morbidity in type 2 diabetes mellitus

B ackground: Diabetes is a global epidemic with India estimated to have the highest prevalence of 79.4 million by 2030. RLS is a common yet undiagnosed comorbidity causing significant distress. We aimed to analyze association between restless legs syndrome (RLS) and type 2 diabetes. Methods: One hundred fifty six type 2 diabetes mellitus (T2DM) and eighty eight non-diabetic controls were assessed at Mahatma Gandhi Medical College & Hospital, Jaipur, India for RLS using the international RLS study group rating scale. Several patient clinical profiles along with laboratory parameters were compared in both groups. Diabetic polyneuropathy was evaluated for its role as risk factor in diabetic RLS subjects. Results: RLS was diagnosed in 35 diabetic patients (22.44%) and in only 7 non diabetic controls (7.95%). RLS was independently associated with type 2 diabetes (P<0.04). A clinical diagnosis of polyneuropathy was made in only 22.86% of diabetic patients with comorbid RLS. In multivariate logistic regression, polyneuropathy was the only variable associated with RLS in diabetics (P<0.03). RLS manifested in diabetics after the diagnosis of diabetes was made. Conclusions: An association between RLS and type 2 diabetes is established in Indian subpopulation. In diabetic patients, polyneuropathy is the main risk factor for RLS. But, polyneuropathy only partially explains the increased prevalence of RLS in type 2 diabetics.

Putting the periodicity back into the periodic leg movement index: an alternative data-driven algorithm for the computation of this index during sleep and wakefulness

ObjectiveTo evaluate an alternative index for periodic leg movements during sleep (PLMS) and wakefulness (PLMW) expected to be similar to the standard index when leg movement activity is genuinely periodic, but significantly lower when periodicity is low. Subjects and methodsOne-hundred-and-seven subjects with restless legs syndrome (RLS) were retrospectively identified and included (47 males, 60 females, mean age 56.9 years), along with 63 controls (33 males, 30 females, 42.2 years). Night-to-night variability was analysed in a subgroup of 17 subjects with RLS. PLMW were evaluated in a subgroup of 66 RLS subjects. Two ‘alternative’ PLMS/PLMW indices were calculated: one increased the lower limit of the inter-movement intervals from 5 to 10 s (‘Alt1’) and another additionally considered only series not interrupted by LMs with a short inter-movement interval (‘Alt2’). ResultsDespite a high correlation between methods, only the Alt2 algorithm provided significantly different results, with PLMS/PLMW indices being consistently lower than those provided by the other two methods. The difference was more evident in the controls and during wakefulness, when periodicity was lower. The difference between the Alt2 and the standard PLMS index showed a significantly negative correlation with the Periodicity Index. Night-to-night variability was similar for all PLMS indices and significantly higher than the variability seen in the Periodicity Index. ConclusionThis methodological study introduces an alternative to the standard PLMS/PLMW indices, initiating the validation process for a new way of computing the PLMS/PLMW index, more adherent to the parameters that allows a reliable evaluation of their periodicity.

Turkish version of the Johns Hopkins Restless Legs Syndrome Quality of Life Questionnaire (RLS-QoL): validity and reliability study.

Restless legs syndrome (RLS), as well as problems secondary to RLS, may worsen the quality of life. Our aim was to modify the Restless Legs Syndrome Quality of Life (RLS-QoL) questionnaire advanced by Abetz (Health Qual Life Outcomes 3:79, 2005) and to analyse the validity and reliability of the questionnaire. Two hundred and one consecutive patients with RLS and forty-three control subjects were included in the study. Permission regarding the translation and validation of the RLS-QoL questionnaire was obtained. The translation was conducted according to the guidelines provided by the publisher. For the RLS subjects, the mean Insomnia Severity Index (ISI) score, the International Restless Legs Syndrome Severity Rating Scale (IRLSSG) score and the computed score of the RLS-QoL questionnaire were 22.60 ± 3.39, 24.83 ± 5.28 and 45.93 ± 17.62, respectively. Among the RLS subjects without insomnia, the mean (±standard deviation) ISI score, IRLSSG score and computed score of the RLS-QoL questionnaire were 6.67 ± 2.34, 15.11 ± 4.03 and 41.93 ± 16.12, respectively. A significant difference was identified between both groups on all scores (ISI: p = 0.001, RLS: p = 0.001). The groups with and without insomnia were similar regarding the computed score of the RLS-QoL questionnaire (p = 0.140). According to a correlation analysis, a significant correlation was identified between the ISI and IRLSSG or RLS-QoL scores (r = 0.513, p = 0.001 and r = -0.383, p = 0.001, respectively). Although the coefficient of correlation is significant between IRLSSG score and RLS-QoL scale score, it should not be considered as a powerful enough correlation (r = 0.190, p = 0.007). Most items also exhibited a strong correlation with each other. The internal consistency determined by Cronbach's alpha indicated an extremely good correlation (0.975). These findings suggest the Turkish version of the RLS-QoL questionnaire is a valid and reliable tool for the assessment of the quality of life in patients with RLS.

Gray matter alteration in patients with restless legs syndrome: a voxel-based morphometry study

The purpose of this study was to demonstrate whether or not restless legs syndrome (RLS) is associated with any morphological change in gray matter. Forty-six RLS subjects and 46 controls were enrolled. We performed voxel-based morphometry analysis and compared the results of the two groups. The RLS subjects showed significant regional decreases of gray matter volume in the left hippocampal gyrus, both parietal lobes, medial frontal areas and cerebellum (uncorrected, P<.001). We found that RLS patients showed structural alteration in the brain and alterations in certain parts of the brain in RLS patients are relevant to RLS.

Augmentation in restless legs syndrome patients in Korea.

Augmentation has been known as the major complication of long-term dopaminergic treatment of restless legs syndrome (RLS). However, there have been no reports on the prevalence of augmentation in Korea. Thus, we aimed to assess the rate of augmentation and evaluate related factors in Korean RLS patients. Ninety-four idiopathic RLS patients who have been treated over a period of at least 6 months were enrolled. Thirty subjects were treated with a dopamine agonist only, and 64 were treated with a dopamine agonist and alpha two delta ligands. We assessed the clinical characteristics of those RLS subjects and evaluated the rate of augmentation. Augmentation was assessed using the NIH criteria for augmentation by two RLS experts independently. Eleven subjects (11.7%) were classified as having definitive or highly suggestive clinical indication of augmentation. In comparing the augmentation group with the non-augmentation group, there were no significant differences of baseline clinical characteristics. Four (13.3%) of the dopamine agonists monotherapy group and seven (10.9%) of the combination therapy group were categorized as augmentation. There was no significant difference in the augmentation rate between these two groups. We found an 11.7% augmentation rate in Korean RLS subjects. There was no difference in the rate of RLS augmentation between the dopaminergic monotherapy group and the combined treatment group. It may be related with using a similar dosage of dopaminergic drugs.

Comparison of Cognitive Function between Patients with Restless Legs Syndrome and Healthy Controls

Recent studies have reported that moderate to severe restless legs syndrome (RLS) patients may have significant cognitive deficits, primarily in executive functioning, compared with healthy control subjects.1-4 Electrophysiological studies also support the existence of cognitive dysfunction in RLS patients. For example, a recent event-related potential (ERP) study showed that underlying cognitive dysfunction, associated with a working memory deficit characterized by increased reaction time and lower amplitude of the P300 component, was evident in patients with severe RLS.5,6 In contrast, other studies found no difference in cognitive function between RLS patients and controls. RLS subjects performed better than sleep-restricted controls on a test of verbal fluency.7 In middle-aged and elderly subjects, individuals with mild RLS were found to have no differences in multiple domains of cognitive functioning when compared to those without RLS.8,9 This discrepancy may be attributable to several factors, such as differences in study samples, the use of different age groups (patients of middle vs. older age), the types of neuropsychological tests administered (full batteries vs. selected tests of frontal function), and medication effects (unmedicated vs. medicated). It has been reported that comorbid psychiatric conditions such as depression and anxiety are common in patients with RLS.10-12 Epidemiological studies report a 2to 4-fold risk of a deReceived: November 22, 2014 Revised: December 10, 2014 Accepted: December 15, 2014

Restless legs syndrome and central nervous system gamma-aminobutyric acid: preliminary associations with periodic limb movements in sleep and restless leg syndrome symptom severity

BackgroundPrevious research has demonstrated abnormalities in glutamate and N-acetyl aspartate (NAA) in the thalamus in individuals with restless legs syndrome (RLS) compared with healthy matched controls. However, levels of these transmitters in other RLS-related brain areas and levels of the most common inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), have not been assessed. MethodsThis study examined GABA, glutamate, and NAA levels in the dorsal anterior cingulate cortex (ACC), thalamus and cerebellum with the use of proton magnetic resonance spectroscopy (1H-MRS) at 4 tesla (4 T) and Megapress difference-editing in 18 subjects with RLS and a matched control group without RLS. Actigraphy was performed on the nights before scans to assess periodic limb movements of sleep (PLMS). ResultsLevels of GABA, glutamate, and NAA were no different between RLS and control subjects in any of the three voxels of interest. However, GABA levels were positively correlated with both PLM indices and RLS severity in the thalamus and negatively with both of these measures in the cerebellum in RLS subjects. In addition, NAA levels were higher in the ACC in RLS than in controls. ConclusionOur preliminary data suggest that known cerebellar–thalamic interactions may modulate the intensity of RLS sensory and motor symptoms. In addition, anterior cingulate cortex may be associated with the affective components of the painful symptoms in this disorder.

Altered white matter integrity in primary restless legs syndrome patients: diffusion tensor imaging study

Objectives:A prior diffusion tensor imaging (DTI) of restless legs syndrome (RLS) subjects found alterations in brain white matter (WM). The aim of this study was to explore the possible mechanism of altered integrity of brain WM in RLS patients.Methods:The DTI measurement was performed in 22 subjects with RLS and 22 age-matched control subjects. Using a voxel-based analysis, fractional anisotropy (FA) and axial and radial diffusivities (AD and RD) were compared between RLS and control subjects with a two-sample t-test, and correlation analysis was performed in RLS subjects.Results:RLS subjects demonstrated decreased FA in the genu of the corpus callosum and frontal WM adjacent to the inferior frontal gyrus compared with the control subjects. For areas of decreased FA, both the AD and RD were higher than that in the control subjects.Discussion:Our findings suggest that loss of axonal density and myelin may account for WM changes seen in a prior study of RLS subjects.

A pilot study to evaluate simulated driving performance and cognitive function in healthy subjects and patients with restless legs syndrome

A pilot study to evaluate simulated driving performance and cognitive function in healthy subjects and patients with restless legs syndrome Dan Chen,1 Paula Shaw,2 Daniel M Canafax,1,3 James Catesby Ware4 1XenoPort, Inc., Santa Clara, CA, USA; 2Charles River Northwest, Tacoma, WA, USA; 3Theravance Inc., South San Francisco, CA, USA; 4Division of Sleep Medicine, Eastern Virginia Medical School, Norfolk, VA, USA Objective: Symptoms of restless legs syndrome (RLS) usually occur during the evening and night time, resulting in disrupted sleep and subsequent daytime fatigue. This study compared simulated driving performance, alertness, and cognitive function between healthy subjects and patients with a diagnosis of RLS. Methods: Fifteen healthy subjects and 15 untreated RLS subjects were enrolled and completed two driving tests. The first test occurred at 4 PM followed by the second test at 8 AM the next morning. Outcome measures included lane position variability (LPV), speed variability, frequency of simulated crashes (off-road events or collision), and brake reaction time. Other assessments included visual analog scale (VAS) of alertness and the Brief Assessment of Cognition (BAC). Results: Overall, RLS patients and healthy subjects performed similarly on driving assessments. Two subjects within each group experienced off-road events. RLS patients had less alertness on the VAS than healthy subjects before and after driving assessments. Both groups scored similarly on the cognitive function assessments. Conclusion: Despite reported diminished alertness, RLS patients did not demonstrate impairment in driving or cognitive performance. Keywords: restless legs syndrome, simulated driving performance, cognitive function

임상현장에서 하지불안증후군 환자의 수면다원검사결과의 특징과 약물처방현황

목 적: 임상실제에서 하지불안증후군(restless legs syndrome, RLS) 환자들의 수면다원검사 결과의 특징과 약물치료의 현황을 자연적인 후향성 연구로 조사하는 것이다. 방 법: 임상적으로 RLS의 진단기준을 만족하며 수면다원검사를 시행 받고 치료받은 18세 이상 환자들의 의무기록을 검토하여 분석하였다. 대상자들에 대해 초진시 International Restless Legs Syndrome Study Group(IRLSSG)의 4가지 진단기준과 국제하지불안척도(International Restless Legs Scale, IRLS)를 평가하고 야간수면다원검사와 제안부동검사(suggested immobilization test, SIT)를 시행하였고, 도파민효현제로 한 달간 약물치료 후 IRLS를 재평가하였다. 결 과: 분석에 포함된 총 대상자수는 211명으로 남자가 94명(44.5%), 여자가 117명(55.5%)이었고 평균연령은 46.9세였다. 폐쇄성수면무호흡증이 136명(64.5%), PLMD가 53명(25.1%)에서 동반되어 다른 수면장애를 동반한 환자의 수는 185명(87.7%)이었다. 수면다원검사결과 수면효율은 78.0%, 수면중각성시간(wake after sleep onset)는 86.8분, N3는 3.4%였다. 평균 무호흡저호흡지수(apnea hypopnea index)는 시간당 12.4회, PLMS는 시간당 14.8회, SIT 중 PLMW는 시간당 41.2회였다. 수면중 총 각성지수는 시간당 21.6회였다. 전체 환자 중 ropinirole을 복용한 환자는 149명(70.6%), pramipexole을 복용한 환자수는 47명(22.3%)이었고 ropinirole은 평균 0.9 mg(용량범위 0.125~5 mg), pramipexole은 평균 0.5 mg(용량범위 0.125~4 mg)을 사용하였다. Ropinirole의 용량은 연령과 유의한 양의 상관관계를 보였고(r=0.25, p=0.002), IRLS와도 유의한 양의 상관관계를 보였다(r=0.23, p=0.038). IRLS는 초진시 24.9점에서 1달 뒤 13.4점으로 감소하였다. 결 론: 본 연구의 분석결과 임상적으로 RLS 진단이 가능한 환자 중에 다른 수면장애를 동반하는 경우가 대다수였다. PLMD에 해당되는 사람은 25.1%로 기존 보고보다 적었고 평균 PLMS도 시간당 14.8회로 높지 않았다. 사용하는 도파민효현제의 용량은 한국에서 허가용량으로 승인받은 용량보다 더 높은 경우가 많았다. 향후 이 주제에 대한 전향적이고 통제된 대규모의 연구가 필요하다. Objectives: The aim of this study is to evaluate the polysomnographic characteristics and prescription status of restless legs syndrome (RLS) patients in naturalistic setting. Methods: We reviewed medical record of the patients over 18 years olds who (i) satisfied the clinical RLS diagnostic criteria and (ii) had the polysomnography and got treatment related thereto. As a baseline, we evaluated the four diagnostic criteria of the International Restless Legs Syndrome Study Group (IRLSSG) and the International Restless Legs Scale (IRLS) of the subjects. Then the polysomnography and the suggested immobilization test (SIT) were conducted and, after one month of pharmacotherapy using dopamine agonist, the IRLS was evaluated again. Results: A total of 211 subjects participated in this analysis and 94 (44.5%) of them were male and the other 117 (55.5%) were female and the average age of the 211 subjects was <TEX>$46.9{\pm}14.2$</TEX>. Out of such 211 subjects, 136 subjects (64.5%) also had the obstructive sleep apnea (OSA), and 53 subjects (25.1%) also had the periodic limb movement disorder (PLMD). 185 subjects (87.7%) out of the 211 subjects had some other sleep disorders except RLS. The results of the polysomnography were as follows : 78.0% of sleep efficiency, 86.8 min of wake after sleep onset, and 3.4% of N3. More specifically, 12.4/h of the average apnea hypopnea index, 14.8/h of the periodic limb movement during sleep (PLMS), 41.2/h of the periodic limb movement during wake during SIT and 21.6/h of total arousal index during sleep. Out of the total subjects, 149 (70.6%) of them took the ropinirole and 47 (22.3%) of them took the pramipexole, and the average dosage of ropinirole was 0.9mg(dosage range 0.125-5 mg) while the average dosage of pramipexole was 0.5 mg (dosage range 0.125-4 mg). The dosage of the ropinirole showed a significant positive correlation with the age (r=0.25, p=0.002) and also with the IRLS (r=0.23, p=0.038). The IRLS at the baseline was 24.9 while the same was decreased down to 13.4 after one month. Conclusions: Analyzing the result of this study, a majority of clinical RLS subjects demonstrated comorbidity with some other sleep disorder such as the OSA or PLMD. 25.1% of the subjects showed a PLMD, which was less than in previous researches and the average PLMS was not very high as 14.8/h. The dosage of dopamine agonist taken was often a bit more than the amount recommended in Korea. A prospective research using a large scale controlled subjects will be necessary with respect to this topic.

Postural control in restless legs syndrome with medication intervention using pramipexole

Central dopamine regulation is involved in postural control and in the pathophysiology of restless legs syndrome (RLS) and Parkinson's disease (PD). Postural control abnormalities have been detected in PD, but there are no earlier studies with regard to RLS and postural control. Computerized force platform posturography was applied to measure the shift and the velocity (CPFV) of center point of forces (CPF) with eyes open (EO) and eyes closed (EC) in controls (n = 12) and prior and after a single day intervention with pramipexole in RLS subjects (n = 12). CPFV (EO) was significantly lower in the RLS group (p < 0.05) than in controls. After pramipexole intake, the difference disappeared and the subjective symptom severity diminished. Pramipexole did not significantly influence CPFV (EC) or CPF shift direction. Subjects with RLS used extensively visual mechanisms to control vestibule-spinal reflexes to improve or compensate the postural stability. Further research is needed to clarify altered feedback in the central nervous system and involvement of dopamine and vision in the postural control in RLS.