Treatment of Restless Legs Syndrome

Restless legs syndrome (RLS) is a common disorder diagnosed by the clinical characteristics of restlessness in the legs associated often with abnormal sensations that start at rest and are improved by activity, occurring with a diurnal pattern of worsened symptoms at night and improvement in the morning. RLS is the cause of impaired quality of life in those more severely afflicted. Treatment of RLS has undergone considerable change over the last few years. Several classes of medications have demonstrated efficacy, including the dopaminergic agents and the alpha-2-delta ligands. Levodopa was the first dopaminergic agent found to be successful. However, chronic use of levodopa is frequently associated with augmentation that is defined as an earlier occurrence of symptoms frequently associated with worsening severity and sometimes spread to other body areas. The direct dopamine agonists, including ropinirole, pramipexole, and rotigotine patch, are also effective, although side effects, including daytime sleepiness, impulse control disorders, and augmentation, may limit usefulness. The alpha-2-delta ligands, including gabapentin, gabapentin enacarbil, and pregabalin, are effective for RLS without known occurrence of augmentation or impulse control disorders, although sedation and dizziness can occur. Other agents, including the opioids and clonazepam do not have sufficient evidence to recommend them as treatment for RLS, although in an individual patient, they may provide benefit.     

Prevalence and profile of Restless Legs Syndrome in Parkinson's disease and other neurodegenerative disorders: A case-control study

BackgroundRestless Legs Syndrome (RLS) is associated with impaired central dopaminergic neurotransmission. Though a link between RLS and parkinsonism has been proposed, the prevalence of RLS in parkinsonian disorders is poorly documented.ObjectiveTo determine the prevalence of RLS in patients with Parkinson's Disease (PD), Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB).MethodsWe evaluated 187 consecutive patients with parkinsonian disorders (PD = 134, PSP = 27, MSA = 21, DLB = 5) and 172 healthy controls. RLS was diagnosed using the International RLS Study Group (IRLSSG) criteria and the severity of RLS was assessed in patients with definite RLS. Quality of sleep was evaluated with established scales.ResultsThe prevalence of RLS was higher in patients compared to controls (9.6% vs. 2.9%; p = 0.009) and was highest in PD (11.9%). RLS was present in only one patient each with MSA and PSP and none with DLB. The mean IRLSSG severity score of patients was 16.2 ± 6.5. The global Pittsburgh Sleep Quality Index score and Epworth Sleepiness Scale score were significantly higher in patients compared to controls (p < 0.001). PD patients with RLS had lower Parkinson's Disease Sleep Scale (PDSS) score compared to patients without RLS (p = 0.023). There was no significant difference in gender, age, duration and severity of PD between the two groups.ConclusionsOur study found a higher prevalence of RLS in PD compared to healthy controls or other parkinsonian disorders. Apart from PDSS score, there was no significant difference in the clinical characteristics of PD patients with and without RLS.     

医学史话:不宁腿综合征的认识史

正不宁腿综合征(restless legs syndrome,RLS)似乎是一个颇具神秘色彩的疾病,其症状常难以形容和表述,呈昼夜规律性发作。RLS曾是难治性疾病,目前治疗已有突破。然而,还有许多未知的发病机制、病理和最佳治疗方案仍需探讨,回顾RLS的认识史对攻克这一疾病或有裨益。1类似不宁腿综合征的早期描述不宁腿综合征的第一次描述要追溯到法     

Strategies for the Treatment of Restless Legs Syndrome

Restless legs syndrome (RLS) is a common neurological disorder of unknown etiology that is managed by therapy directed at relieving its symptoms. Treatment of patients with milder symptoms that occur intermittently may be treated with nonpharmacological therapy but when not successful, drug therapy should be chosen based on the timing of the symptoms and the needs of the patient. Patients with moderate to severe RLS typically require daily medication to control their symptoms. Although the dopamine agonists, ropinirole and pramipexole have been the drugs of choice for patients with moderate to severe RLS, drug emergent problems like augmentation may limit their use for long term therapy. Keeping the dopamine agonist dose as low as possible, using longer acting dopamine agonists such as the rotigotine patch and maintaining a high serum ferritin level may help prevent the development of augmentation. The ??2?? anticonvulsants may now also be considered as drugs of choice for moderate to severe RLS patients. Opioids should be considered for RLS patients, especially for those who have failed other therapies since they are very effective for severe cases. When monitored appropriately, they can be very safe and durable for long term therapy. They should also be strongly considered for treating patients with augmentation as they are very effective for relieving the worsening symptoms that occur when decreasing or eliminating dopamine agonists.     

Hemochromatosis and iron therapy of Restless Legs Syndrome

Restless legs syndrome (RLS) occurs in some persons with iron deficiency, and some persons with RLS benefit from oral iron therapy. Approximately one in 200 persons of northern European ancestry have hemochromatosis attributable to inheritance of two common mutations of the hemochromatosis-associated HFE gene on chromosome 6. We evaluated and treated a 46-year-old man with RLS who was diagnosed as having hemochromatosis after he developed new symptoms associated with taking iron therapy for RLS. He had transferrin saturation 88%, serum ferritin 658 ng/ml, and C282Y homozygosity. Therapeutic phlebotomy of one unit of blood (450-500 ml) weekly (total 24 units) relieved his non-RLS symptoms, caused RLS symptoms to occur more frequently, and was associated with transient fatigue and mild dependent edema. His sister, who also has RLS, was subsequently diagnosed as having hemochromatosis. We conclude that serum transferrin saturation and ferritin levels should be measured before initiation of iron therapy of RLS. Patients with a history of iron deficiency or low serum iron parameters should undergo evaluation for iron deficiency; patients who have histories suggestive of hemochromatosis or iron overload or elevated pre-treatment transferrin saturation or serum ferritin levels should undergo evaluation to determine the cause of these abnormalities before they are treated with iron. In all persons with RLS treated with oral iron, serum iron parameters should be re-measured once or twice yearly during therapy.     

Increased Frequency of Restless Legs Syndrome in Myasthenia Gravis

Background/Aims: The objective of this study was to assess the prevalence of restless legs syndrome (RLS) in patients with myasthenia gravis (MG). Methods: We interviewed 73 MG patients and 65 healthy controls by using a structured diagnostic questionnaire based on the International Restless Legs Syndrome Study Group diagnostic criteria. We also collected data about the course of MG therapy, the presence of other comorbidities, sleep complaints, and demographic characteristics. All of the MG patients underwent neurological assessment. Results: RLS was present in 43.2% of the MG patients and in 20% of the controls (p = 0.0029). We failed to identify a relationship between the prevalence of RLS and the duration and type of MG therapy, other comorbidities, age or sex of the patients. Patients with MG more frequently reported daytime sleepiness. For 9.4% of the RLS-positive MG patients, RLS symptoms represented the most disturbing health problem; for 46.9% of them, RLS was as problematic as other diseases. Conclusions: RLS is common in MG patients. MG patients consider RLS symptoms as a troublesome health problem.     

Validation of an algorithm for the diagnosis of Restless Legs Syndrome: The Restless Legs Syndrome-Diagnostic Index (RLS-DI)

BackgroundThere is a need for structured methods to improve sensitivity and specificity of diagnostic decision making in Restless Legs Syndrome (RLS). We present the RLS-Diagnostic Index (RLS-DI), a diagnostic algorithm which combines essential and supportive diagnostic criteria from patient interviews, polysomnography and neurological examination in an adaptive procedure.MethodThe RLS-DI consists of 10 items which are related to the essential diagnostic criteria established by the International RLS Study Group (five items) as well as their supportive criteria (3 items) and features associated with RLS (2 items). Items have to be completed using three categories per item that address frequency of occurrence of symptoms or certainty of presence or absence of other diagnostic information. Negative weights were given when the clinically most relevant items were not present. The RLS-DI was administered in a telephone interview to 179 patients (86 with RLS, 93 with other sleep disorders) of the 21 month cohort of one sleep center in Germany.ResultsWith receiver-operating characteristics, a cut-off of ?11 points on a scale ranging from ?22 (no RLS) to 20 (definite RLS) was identified by comparing the RLS-DI total score to the diagnosis of two independent sleep experts. Sensitivity was 93.0%, specificity was 98.9%, and 96.1% of the patients could be correctly diagnosed. Specificity was higher in items related to supportive or associated diagnostic information (95.7%) than in those related to the essential diagnostic criteria (81.7%). Patients with RLS scored a higher RLS-DI than those with primary insomnia or other neurological or psychiatric disorders (p < .001).ConclusionThe RLS-DI demonstrated the ability to validly diagnose an actual and persistently present Restless Legs Syndrome in patients of a sleep lab population and to exclude those patients whose sleep disturbances have other causes.     

加巴喷丁治疗不安腿综合征的疗效观察

目的：探讨加巴喷丁治疗不安腿综合征（RLS）的疗效。方法：回顾性分析10例应用加巴喷丁治疗RLS患者的临床资料，以2RLS病情严重程度评定量表（IRLS）及匹兹堡睡眠质量指数（PSQI）评估疗效。结果：RLS患者用药前后IRLS及PSQI评分差异有统计学意义（P〈0．05）；在主观睡眠质量、入睡时间、睡眠时间、睡眠效率、日间功能障碍及总分评定差异有统计学意义（P〈0．05），疗效与病程成正相关（P〈0．05）。结论：加巴喷丁用于治疗RLS有效。     

Consensus Guidelines on Rodent Models of Restless Legs Syndrome

Restless legs syndrome (RLS) is a chronic sensorimotor disorder diagnosed by clinical symptoms. It is challenging to translate the diagnostic self-reported features of RLS to animals. To help researchers design their experiments, a task force was convened to develop consensus guidelines for experimental readouts in RLS animal models. The RLS clinical diagnostic criteria were used as a starting point. After soliciting additional important clinical features of RLS, a consensus set of methods and outcome measures intent on capturing these features—in the absence of a face-to-face interview—was generated and subsequently prioritized by the task force. These were, in turn, translated into corresponding methods and outcome measures for research on laboratory rats and mice and used to generate the final recommendations. The task force recommended activity monitoring and polysomnography as principal tools in assessing RLS-like behavior in rodents. Data derived from these methods were determined to be the preferred surrogate measures for the urge to move, the principal defining feature of RLS. The same tools may be used to objectively demonstrate sleep-state features highly associated with RLS, such as sleep disturbance and number and periodicity of limb movements. Pharmacological challenges and dietary or other manipulations that affect iron availability are desirable to aggravate or improve RLS-like behavior and lend greater confidence that the animal model being proffered replicates key clinical features of RLS. These guidelines provide the first consensus experimental framework for researchers to use when developing new rodent models of RLS. © 2020 International Parkinson and Movement Disorder Society     

Alterations of Functional Connectivity in Patients With Restless Legs Syndrome

Restless legs syndrome (RLS) is a common neurological illness marked by a strong desire to move one’s legs, usually in association with uncomfortable sensations. Recent studies have investigated brain networks and connectivity in RLS. The advent of network analysis has greatly improved our understanding of the brain and various neurological disorders. A few studies have investigated alterations in functional connectivity in patients with RLS. This article reviews functional connectivity studies of patients with RLS, which have identified significant alterations relative to healthy controls in several brain networks including thalamic, salience, default-mode, and small-world networks. In addition, network changes related to RLS treatment have been found, including to repetitive transcranial magnetic stimulation, transcutaneous spinal cord direct-current stimulation, and dopaminergic drugs. These findings suggest that the underlying pathogenesis of RLS includes alterations in the functional connectivity in the brain and that RLS is a network disorder.     

Imaging Brain Functional and Metabolic Changes in Restless Legs Syndrome

Even though the pathophysiology of restless legs syndrome is not completely understood, several imaging studies have contributed to our understanding of the disease. Functional and metabolic impairment seems to be the pathophysiological core, tied to a single brain network or multiple connected brain networks, via neurotransmitter modifications. Positron emission tomography and single photon emission computed tomography studies support a dysfunction of dopaminergic pathways, involving not only the nigrostriatal pathway but also the mesolimbic pathway. Furthermore, a possible role of serotonergic neurotransmission has been suggested. Functional magnetic resonance imaging studies have demonstrated in restless legs syndrome patients a pathologic activation of cerebral areas belonging to both the sensorimotor and the limbic networks. Proton magnetic resonance spectroscopy has confirmed abnormality of the limbic system and suggested the presence of a glutamatergic disorder. Finally magnetic resonance studies using iron-sensitive sequences have demonstrated reduced iron content in several regions of the brain of restless legs syndrome patients. In this review we attempt to integrate all current imaging study results into a convergent pathophysiological interpretation.