Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study

AimThe aim of this study is to assess the effect of switching to rotigotine transdermal patch on severity of restless legs syndrome (RLS) in patients who experienced acute augmentation with previous oral dopaminergics.MethodsIn this 13-month observational study, adults with moderate-to-severe RLS and augmentation were switched to rotigotine per the physician’s independent decision. Assessments included Clinical Global Impression severity score (CGI-1); (primary), treatment regimen for switching (secondary), RLS-6, International RLS Study Group Rating Scale (IRLS), and augmentation severity rating scale (ASRS).ResultsA total of 99 patients received rotigotine, of whom 46 completed observational period, and 43 were assessed for effectiveness. A total of 5 patients switched to rotigotine after a >1-day drug holiday, 23 switched overnight, 9 had an overlapping switch, and 6 received ongoing oral dopaminergics with rotigotine for ≥28 days. Of the 99 patients, 57 took concomitant RLS medications (excluding switching medications) on at least 1 day. At the final visit, median change in CGI-1 (Hodges–Lehman estimate [95% CI]) was −2.0 (–2.5, −1.50); 37 of the 43 patients improved by ≥1 CGI-1 category, and 16 of 43 were responders (≥50% improvement). RLS-6 and IRLS scores also improved. Patients had median ASRS of 0 at the final visit indicating “no worsening/occurrence of augmentation.” ASRS item 1 showed a shift in mean time of symptom onset (24-h clock) from 12:38 (baseline) to 18:25 (final visit). Most common reasons for withdrawal of rotigotine were adverse events (26 patients) and lack of efficacy (14 patients).ConclusionsSwitching from oral therapies to rotigotine was effective in improving RLS symptoms in 37 of the 43 patients (from the original population of 99 patients) who remained in the study over 13 months.Clinical trial registrationClinicalTrials.gov NCT01386944.     

Polysomnographic and pharmacokinetic findings in levodopa-induced augmentation of restless legs syndrome.

Augmentation, defined as a loss of circadian recurrence with progressively earlier daily onset and increase in the duration, intensity, and anatomy of symptoms, not compatible with the half-life of the drug, is associated with dopaminergic treatment in restless legs syndrome (RLS) patients. The pathogenesis of augmentation is unclear. We describe a patient with idiopathic RLS who developed augmentation after 8 months of levodopa treatment. Videopolysomnographic and pharmacokinetic studies with monitoring of plasma levodopa levels demonstrated marked motor hyperactivity during augmentation, with anarchic discharges of motor unit potentials, tonic grouped discharges and flexor spasms, associated with painful dysesthesia. Symptoms and signs of augmentation were related to low plasma levodopa levels, abating 75 minutes after oral levodopa administration and reappearing after 3 hours, closely mirroring the rapid rise and fall of plasma levodopa concentration. This case is the first report in which RLS augmentation is shown to be characterized by motor hyperkinesias paralleling levodopa plasma pharmacokinetic profile.     

继发性不宁腿综合征

本文回顾继发性不宁腿综合征的相关研究结果,介绍其常见病因。经研究显示,有多种因素可能与继发性不宁腿综合征的发生发展和严重程度相关,如肾衰竭、脊髓和周围神经病变、妊娠所致铁和叶酸缺乏及相应性激素变化;帕金森病多巴胺能系统功能紊乱;某些药物（抗抑郁药、抗精神病药、组胺受体阻断药）;吸烟、饮酒;咖啡因;偏头痛等。临床应详细询问病史,去除病因,提高患者生活质量。     

Electrophysiological findings in patients with restless legs syndrome

BackgroundRestless legs syndrome (RLS) manifests as an urge to move the body to relieve the discomfortable sensations, primarily when resting, sitting, laying down, or sleeping. Diagnosis of RLS relies on clinical criteria, and the immobilization test was the only instrumental tool with equivocal results.ObjectivesTo assess different electrophysiological findings in patients with RLS, and compare the diagnostic values of these parameters in the diagnosis of RLS.Methods30 patients with primary RLS and 30 controls who were matched for age and gender were studied. Participant's demographics, laboratory findings, and electrophysiological test, namely nerve conduction studies (NCS), cutaneous silent period (CSP), H reflex and sympathetic skin response (SSR), F-wave latency, amplitude, F-wave duration (FWD), and the ratio between FWD and duration of the corresponding compound muscle action potential (FWD/CMAPD) were analyzed.ResultsNone of the patients showed altered NCS data. FWD of upper (12.37 ± 2.77 ms) and lower limb (21.71 ± 5.24 ms) were significantly longer in patients. Also, FWD/CMAP duration of the upper (1.03 ± 0.2) and lower limb (2.02 ± 0.55) was longer in patients. Likewise, they exhibited delayed CSP latency from TA (110.62 ± 13.73 ms) and APB (77.35 ± 12.16 ms) whereas the CSP duration from TA and APB was decreased (37.36 ± 11.59 ms; 42.55 ± 7.97 ms, respectively). The SSR latency was not different, and right-sided H reflex amplitude (5.07 ± 3.98 mV) and H/M ratio (0.65 ± 1.81) were significantly increased in the patient group.ConclusionThe data suggest that there may be a dysfunction of the inhibitory/excitatory circuits at a spinal level; and no pathology in the peripheral nerves. The unilateral difference of H reflex amplitude and H/M ratio may suggest asymmetrical central inhibitory dysfunction. Further prospective studies with larger cohorts are now needed to evaluate the pathophysiology of RLS with different neurophysiological assessment tools.     

Childhood and adult factors associated with restless legs syndrome (RLS) diagnosis

BACKGROUND AND PURPOSE: RLS appears to be caused by a complex interaction of genetic and environmental factors. This study sought to identify some environmental risk factors significantly associated with the occurrence of RLS. PATIENTS AND METHODS: Three adult behaviors and 10 childhood factors potentially related to development of RLS were evaluated for significant association with the occurrence of RLS in a large case-controlled family history study. All available family members of the probands in this study were evaluated for RLS using a validated diagnostic telephone interview that included a background questionnaire covering factors potentially associated with the development of RLS. Where possible, the mothers of the subjects were also interviewed regarding developmental factors that might affect the child's health and perhaps occurrence of RLS. All family members with a definite diagnosis of RLS or Not-RLS were included in the study. Of a total of 973 participants, 262 (27%) had RLS and 711 did not. RESULTS: An odds ratio (OR) with 95% confidence limits (CI) was calculated for the relationship of each factor to RLS diagnosis. Restless sleep in childhood was associated with an increased risk of developing RLS later in life for both men (OR=2.64; 95% CI: 1.31-5.29) and women (OR=2.54; 95% CI: 1.41-4.59). Blood donation was also significantly associated with an increased risk of developing RLS among men only (OR=1.99; 95% CI: 1.10-3.58), which was more pronounced for those donating blood more than the median number of donations for this group of five (OR=2.3, 95% CI: 1.16-4.43). No other factor was significantly associated with the occurrence of RLS. CONCLUSIONS: This is the first case-controlled study that demonstrates a significant association between blood donation and the occurrence of RLS in males. The association was most significant for those men donating five or more times. Smoking and alcohol use were not related to the occurrence of RLS. Neither childhood growing pains nor attention-deficit hyperactivity disorder (ADHD) was related to RLS. The only consistent factor found related to prevalence of RLS for both men and women was the report of 'restless sleep' in childhood.     

普拉克索治疗原发性不宁腿综合征的疗效和安全陛观察

目的 观察普拉克索对我国原发性不宁腿综合征(RLS)患者的治疗效果以及可能发生的不良反应. 方法 选择自2009年5月至11月在哈尔滨医科大学第二附属医院神经内科就诊的10例中到重度原发性RLS患者,给予普拉克索0.125～0.75mg/d,每日睡前2～3h顿服,持续治疗6周.利用国际RLS研究小组的RLS严重程度量表(mLS)、临床总体印象改善量表(CGI-I)、患者总体印象量表(PGI)和Epworth嗜睡量表(ESS)对患者治疗前后的RLS症状严重程度和嗜睡程度进行评估.并对结果进行统计学分析,同时记录不良反应.结果 (1)治疗后患者的IRLS评分较治疗前平均降低73.7%,比较差异有统计学意义(P<0.05),9例患者IRLS评分降低在50%以上;(2)治疗结束时,8例患者PGI评估选择很好或非常好,9例患者CGI-I评估为明显改善或非常明显改善;(3)患者ESS评分在治疗后较治疗前平均降低3.80±1.75,比较差异有统计学意义(P<0.05);(4)1例患者在治疗末期加量至0.5mg/d时出现轻度恶心,胃区不适,治疗结束停药2 d后症状自行消失;(5)1例患者首次用药后双下肢感觉异常和睡眠障碍即有明显改善.结论 为期6周的临床实验表明,在每日口服剂量为0.125～0.75 mg时,普拉克索对于我国原发性RLS的治疗是安全有效的.     

不宁腿综合征40例临床分析

目的 探讨不宁腿综合征(RLS)的临床表现,观察吡贝地尔对RLS的治疗效果.方法 对40例不宁腿综合征患者的临床特征和治疗结果 进行回顾性分析.结果 40例患者均有肢体不能忍受的不适感,迫切希望活动肢体,夜间症状加重,常伴失眠.根据国际不宁腿综合征研究组(IRLSSG)的诊断标准,平均得分24分.40例患者均给予吡贝地尔50mg睡前口服,治疗4周后,大多数患者主观症状明显改善,IRLSSG评分明显减少(平均得分11分).结论 不宁腿综合征常表现下肢不适,夜间加重,活动后减轻,常伴睡眠障碍,诊断主要依据临床表现,吡贝地尔治疗有一定效果.     

The Frontal Assessment Battery in RLS patients with and without augmentation

ObjectiveWe assessed frontal executive functions in patients with RLS/WED with and without augmentation and compared the results to healthy controls.MethodsWe recruited 38 patients with RLS/WED. A total of 23 patients were treated with dopaminergic therapy and showed no signs of augmentation and 15 patients had a history of augmentation (AUG). Results were compared to 21 healthy controls. All individuals were assessed by the Frontal Assessment Battery (FAB) and the MMSE. Furthermore, impulsivity was assessed during a semi-structured interview.ResultsPatients with AUG performed worse in the FAB than healthy controls and RLS/WED patients without AUG (p = 0.001, η² = 0.201). When we assessed the subtests of the FAB separately, we found a significant difference in the subtest assessing inhibitory control (p = 0.008, η² = 0.138).ConclusionsOur findings suggest an impaired executive function in RLS/WED patients with augmentation compared to RLS/WED patients without augmentation and healthy controls. Long term neuroplastic changes within the prefrontal cortex may be the underlying cause for these results. However, further studies in a larger sample size and with a more extensive neuropsychological test battery are needed to confirm our preliminary results.     

Clinical characteristics of Korean pediatric patients with restless legs syndrome

ObjectivesRestless legs syndrome (RLS) is a common neurological disorder but it is not sufficiently recognized in children and adolescents. It often overlaps with growing pains in children, and as a result the clinical characteristics of pediatric RLS are not well studied, especially in Asia. The purpose of this study is to investigate the clinical characteristics of pediatric RLS patients in Korea and compare it to those of adult RLS patients.MethodsWe retrospectively reviewed the medical records of all pediatric RLS patients (≤18 years) from January 2015 to December 2018 in a regional tertiary hospital sleep center. We randomly selected adult primary RLS patients without comorbid medical disorders from our sleep center's dataset as controls. The number of controls was determined to be twice the number of pediatric RLS patients according to sample size calculation. The clinical and polysomnographic (PSG) characteristics of both groups were compared. The independent t-test, chi-squared test, and Fisher's exact test were used for analyzing quantitative data between the two groups and p < 0.05 was considered statistically significant.ResultsTwenty-nine primary pediatric RLS patients and 57 adult RLS patients were enrolled. Pediatric RLS patients showed equal prevalence between sexes, as opposed to adults where there is female predominance. Ferritin level was significantly lower in pediatric patients, although it remained within the normal range. Also, pediatric RLS patients showed less severe RLS symptoms and had better sleep quality than adults did in both objective and subjective measures. In addition, PLMS was shown to be less common in pediatric RLS patients compared to adults.ConclusionsPediatric RLS patients showed relatively mild to moderate RLS symptoms and a smaller likelihood of experiencing PLMS than adult patients, which is comparable to similar western studies. Long-term evaluation of a patient's clinical course through multicenter clinical studies is strongly suggested for the future.     

Olanzapine-induced restless legs syndrome

Only nine patients with olanzapine-induced restless legs syndrome (RLS) have been reported in the literature to our knowledge. We describe two patients with olanzapine-induced RLS treated at our hospital and review the nine reported patients. There were five women and six men aged between 28 and 62 years in the overall group. RLS symptoms emerged at olanzapine doses between 2.5 and 20 mg. The symptoms improved in all patients when the dose was reduced and immediately disappeared when the medication was stopped. International Restless Legs Scale (IRLS) scores ranged from 10 to 35. Three patients had a family history of idiopathic RLS. Supplemental drugs were administered to control RLS symptoms in five patients. Ropinirole was effective in one patient, while two patients did not respond to the drug. Propoxyphene effectively relieved symptoms in one patient who did not respond to ropinirole or clonazepam. RLS symptoms did not recur following substitution of other antipsychotic drugs for olanzapine. In conclusion, olanzapine can induce RLS, particularly in patients with a family history of idiopathic RLS. More than half of the patients experienced severe to very severe symptoms. A dose-dependent relationship was observed between olanzapine and RLS symptoms. A gradual increase in dose may prevent olanzapine-induced RLS. The optimal treatment for olanzapine-induced RLS is discontinuation of olanzapine.     

High prevalence of restless legs syndrome/Willis Ekbom Disease (RLS/WED) among people living at high altitude in the Indian Himalaya

BackgroundAt high altitude, prevalence of restless legs syndrome has been found to be greater than expected in small population-based studies, which did not use validated tools for identification of RLS. However, it is not known as to whether this increased prevalence is associated with altitude or increased risk factors for RLS in these populations or errors in identification of RLS.MethodThis population based, door-to-door study was conducted at low altitude (400 m above sea level) and high altitudes (1900–2000 m and 3200 m above sea level) using random stratified sampling in Himalayan and sub-Himalayan region of India. Subjects between 18 and 84 years were screened for restless-legs-syndrome using the validated Cambridge–Hopkins RLS diagnostic questionnaire. Medical comorbidities were ascertained from their medical records. Their anthropometric measurements were obtained and wake resting oxygen saturation was monitored using finger pulse-oximeter. Physical activity during leisure time was evaluated by using the Goldin leisure time exercise questionnaire.ResultsA total of 1689 subjects were included. Average age of the included subjects was 35.2 years; 55.2% were women. RLS was identified in 9.4% subjects with higher prevalence among women (13.6% women vs. 4.1% men; P < 0.001). RLS was significantly more prevalent at higher altitudes (12.2% at 1900–2000 m and 11.8% at 3200 m) compared to low altitude (2.5% at 400 m). The low altitude prevalence matched that reported in prior studies of RLS in India. Subjects with medical disorders sometimes related to RLS (eg, peripheral neuropathy, COPD, varicose veins and anemia) also had higher prevalence of RLS. Binary logistic regression controlling for female gender, number of pregnancies, peripheral neuropathy, varicose veins, anemia showed that high altitude independently significantly increased the likelihood of RLS (OR: 5.4, 95% CI: 2.8, 10.4).ConclusionRLS is about five times more prevalent at high than low altitudes even when controlling for effects of other medical conditions associated with increased risk of RLS.     

不安腿综合征的诊治

目的 探讨不安腿综合征(RLS)的临床特征,为早期诊断和治疗提供参考.方法 结合相关文献,对16例确诊的不安腿综合征患者的临床表现、治疗、转归进行回顾性分析.结果 RLS是一种以双下肢感觉异常不适为主要症状的病因未明的疾病,可能与贫血、铁缺乏、糖尿病史、肾功能不全等有关.多巴胺受体激动剂为治疗该病的首选药,阿片类、抗惊厥药物、苯二氮类药物及铁剂治疗对部分患者有效.结论 RLS预后较好,及时的诊断和治疗可明显改善患者的生活质量.     

Effect of pramipexole on cutaneous-silent-period parameters in patients with restless legs syndrome

Objective

The aim of this study was to investigate cutaneous-silent-period (CSP) parameters in patients with restless legs syndrome (RLS) and examine the effects of treatment on CSP which, to our knowledge, have not been investigated till date.

Methods

A total of 25 patients with RLS and 25 healthy volunteers were studied. CSP latency and duration in the upper and lower extremities were examined in the two groups. In RLS patients, the variables were examined before and after pramipexole treatment.

Results

Lower-extremity CSP latency was longer (106.22 ± 11.69 ms vs. 91.67 ± 8.53 ms; p < 0.001) and CSP duration was shorter (35.50 ± 10.91 ms vs. 49.47 ± 6.43 ms; p < 0.001) in patients, compared with controls. In the patient group, CSP durations in the upper (40.88 ± 7.95 ms vs. 46.84 ± 10.22 ms; p = 0.006) and lower extremities (35.50 ± 10.91 ms vs. 44.91 ± 6.43 ms; p = 0.005) were prolonged after treatment, compared with pre-treatment values.

Conclusions

Small-fibre neuropathy may exist in RLS. In addition, we suggest that pramipexole may regulate cortical and spinal inhibitory mechanisms.

Significance

The use of CSP may aid in the diagnosis of RLS and may be used as a measure of treatment effectiveness.     

Connectome and molecular pharmacological differences in the dopaminergic system in restless legs syndrome (RLS): plastic changes and neuroadaptations that may contribute to augmentation

Restless legs syndrome (RLS) is primarily treated with levodopa and dopaminergics that target the inhibitory dopamine receptor subtypes D3 and D2. The initial success of this therapy led to the idea of a hypodopaminergic state as the mechanism underlying RLS. However, multiple lines of evidence suggest that this simplified concept of a reduced dopamine function as the basis of RLS is incomplete. Moreover, long-term medication with the D2/D3 agonists leads to a reversal of the initial benefits of dopamine agonists and augmentation, which is a worsening of symptoms under therapy. The recent findings on the state of the dopamine system in RLS that support the notion that a dysfunction in the dopamine system may in fact induce a hyperdopaminergic state are summarized. On the basis of these data, the concept of a dynamic nature of the dopamine effects in a circadian context is presented. The possible interactions of cell adhesion molecules expressed by the dopaminergic systems and their possible effects on RLS and augmentation are discussed. Genome-wide association studies (GWAS) indicate a significantly increased risk for RLS in populations with genomic variants of the cell adhesion molecule receptor type protein tyrosine phosphatase D (PTPRD), and PTPRD is abundantly expressed by dopamine neurons. PTPRD may play a role in the reconfiguration of neural circuits, including shaping the interplay of G protein-coupled receptor (GPCR) homomers and heteromers that mediate dopaminergic modulation. Recent animal model data support the concept that interactions between functionally distinct dopamine receptor subtypes can reshape behavioral outcomes and change with normal aging. Additionally, long-term activation of one dopamine receptor subtype can increase the receptor expression of a different receptor subtype with opposite modulatory actions. Such dopamine receptor interactions at both spinal and supraspinal levels appear to play important roles in RLS. In addition, these interactions can extend to the adenosine A₁ and A_2A receptors, which are also prominently expressed in the striatum. Interactions between adenosine and dopamine receptors and dopaminergic cell adhesion molecules, including PTPRD, may provide new pharmacological targets for treating RLS. In summary, new treatment options for RLS that include recovery from augmentation will have to consider dynamic changes in the dopamine system that occur during the circadian cycle, plastic changes that can develop as a function of treatment or with aging, changes in the connectome based on alterations in cell adhesion molecules, and receptor interactions that may extend beyond the dopamine system itself.     

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-na?ve patients were investigated, it is possible that the prior findings reflect treatment-induced effects on cerebral morphology in RLS.     

不宁腿综合征

不宁腿综合征为临床常见中枢神经系统感觉运动障碍性疾病,发病机制尚不明确,与遗传因素或多巴胺能系统功能失调有关。发病原因与缺铁性贫血、妊娠、免疫系统疾病、肾衰竭、糖尿病、周围神经病等有关。临床主要表现为感觉障碍、运动症状,并于休息时、傍晚或夜间出现或加重。以铁离子、多巴胺制剂、多巴胺受体激动药、抗癫痂药及阿片类药物为主要治疗药物,     

Cognitive behavioral therapy for insomnia in restless legs syndrome patients

ObjectivesThe purpose of this study was to investigate the effects of cognitive behavioral therapy for insomnia (CBTI) in patients with Restless Legs Syndrome (RLS).MethodsThis is a randomized controlled study. The patients were sequentially selected and randomly assigned to either a CBTI group or a non-CBTI group. A total of 25 RLS patients with comorbid insomnia were recruited from a tertiary university hospital sleep center. Twelve were assigned to the CBTI group, and 13 were assigned to the non-CBTI group. The CBTI group received 4 sessions of behavioral therapy, while the non-CBTI group received one informative session on sleep hygiene. All patients completed sleep and psychiatric-related questionnaires. In addition, each individual completed a one-week sleep log for collecting subjective sleep data and actigraphy for objective sleep data.ResultsAfter conducting the CBTI, there were significant improvements in severity of insomnia symptoms, subjective sleep efficiency, total sleep time, latency to sleep onset, wake after sleep onset, objective latency to sleep onset, and anxiety in the CBTI group as compared to the non-CBTI group. The effect of CBTI on sleep-related data was maintained for up to three months.ConclusionsCBTI was effective in RLS patients by improving sleep quality and anxiety symptoms. CBTI may be considered in clinical practice for RLS patients with comorbid insomnia.     

普拉克索治疗不宁腿综合征的Meta分析

目的 系统评价普拉克索治疗不宁腿综合征(restless legs syndrome,RLS)的疗效与安全性.方法 检索中国期刊全文数据库( CNKI)、美国国立医学生物信息中心PubMed数据库( PubMed)、荷兰医学文摘数据库(Embase)、Cochrane Library数据库关于普拉克索治疗RLS的随机、双盲、安慰剂对照研究.对符合条件的研究结果用RevMan 5.0软件进行Meta分析.以普拉克索组和安慰剂组在国际不宁腿研究组评分量表( International RLS Study Group rating scale,IRLS)评分变化方面的加权均数差(weighted mean difference,WMD)和普拉克索组相对于安慰剂组在临床疗效总评(clinical global impression-improvement,CGI-I)方面疗效显著率的相对危险度(relative risk,RR)为指标进行疗效评价,以其在不良事件方面的相对危险度为指标进行安全性评价.结果 共纳入5项研究,1776例患者被随机分配,其中普拉克索组945例,安慰剂组831例.Meta分析结果显示,普拉克索组相对于安慰剂组在IRLS评分变化方面的WMD=-6.34 (Z=12.76,P＜0.01),在CGI-I显著性评估方面的RR=1.65 (Z=10.39,P＜0.01);两组在不良事件方面的RR=1.14 (Z=1.87,P=0.06).结论 普拉克索是治疗RLS的有效且安全的药物.