Eight things you should know about restless legs syndrome.
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Humans↗
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Opioid and dopamine antagonist drug challenges in untreated restless legs syndrome patients.
Background: The restless legs syndrome (RLS) is a common sensomotor disorder associated with severe sleep disturbances. Symptoms clearly improve following treatment with dopaminergic or opioidergic agonists.Objective: To further elucidate the involvement of opioidergic and dopaminergic mechanisms in the pathophysiology of RLS, the effects of specific antagonists on motor (periodic leg movements) and subjective (sensory) RLS-symptoms during daytime were assessed.Methods: A modified suggested immobilization test was performed in eight drug-naive RLS-patients. An infusion of either naloxone, metoclopramide or placebo was administered. In addition, the hormonal levels of adrenocorticotropic hormone, cortisol, prolactin and growth hormone were determined, to elucidate a possible involvement of the hypothalamic-pituitary-adrenocortical (HPA) system in RLS.Results: RLS sensory or motor symptoms could not be provoked. Hormonal responses showed no abnormal profiles.Conclusions: Rather than a general alteration of the opioidergic/dopaminergic tone and an involvement of the HPA system, it is more likely that specific neuronal dopaminergic or opioidergic pathways are altered in the pathophysiology of RLS.
Journal Article↗
Prehension patterns in restless legs syndrome patients.
The pathogenesis of restless legs syndrome (RLS) is poorly understood. Previously we have shown that a reach-to-grasp task can be used to differentiate Parkinson's disease (PD) patients from healthy age-matched control subjects. The aim of this study was to determine if performance on this task could be used to differentiate between patients with RLS, PD patients, and healthy control subjects. Results indicated that RLS and control participants produced movement patterns that were nearly identical to one another, while movement patterns produced by the PD patients were significantly different from the other two groups. These results suggest RLS patients do not show any abnormalities in the performance of upper extremity prehension movements. Thus, these movements can be used to effectively differentiate between patients with Parkinson's Disease and Restless Legs Syndrome. While RLS patients respond favorably to dopaminergic therapies, this study suggests that PD and RLS may not share the same basal ganglia pathophysiology.
Journal Article↗
Restless red legs: an association of the restless legs syndrome with arborizing telangiectasia of the lower limbs.
Two patients are reported with Ekbom's syndrome of "restless legs" occurring in association with arborizing telangiectasia of the lower limbs. Sensory complaints have previously been reported in this skin condition but not described in detail. The co-existence of the two conditions is discussed in the context of previous explanations of the restless legs syndrome.
Adult↗
Autosomal dominant restless legs syndrome maps on chromosome 14q.
Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible desire to move the extremities associated with paraesthesia/dysaesthesia. These symptoms occur predominantly at rest and worsen at night, resulting in nocturnal insomnia and chronic sleep deprivation. In this paper, we show significant evidence of linkage to a new locus for RLS on chromosome 14q13-21 region in a 30-member, three-generation Italian family affected by RLS and periodic leg movements in sleep (PLMS). This is the second RLS locus identified so far and the first consistent with an autosomal dominant inheritance pattern. The new RLS critical region spans 9.1 cM, between markers D14S70 and D14S1068. The maximum two-point log of odds ratio score value, of 3.23 at theta = 0.0, was obtained for marker D14S288. The accurate clinical evaluation of RLS-affected, as well as unaffected, family members allowed for the configuring of RLS as a phenotypic spectrum ranging from PLMS to RLS. Motor component, both while awake and during sleep, was an important aspect of the phenotype in the family analysed. The complementary clinical and genetic studies on multiplex families are likely to be of the utmost importance in unfolding the complete expressivity of RLS phenotype spectrum.
Adolescent↗
Restless Leg Syndrome and Periodic Limb Movements of Sleep.
Restless leg syndrome is one of the most common causes of severe insomnia, and is easily diagnosed by patient history alone. Formal sleep studies are rarely, if ever, indicated. The only routine laboratory study indicated is a serum ferritin level. The majority of patients with restless leg syndrome obtain substantial relief with a variety of medications. Although the majority of restless leg syndrome patients demonstrate periodic limb movements on polysomnographic study, the true clinical significance, if any, of periodic limb movements identified by polysomnographic study in the absence of restless leg syndrome symptoms remains to be determined.
Journal Article↗
Randomized, Double-Blind, Placebo-Controlled Study of Clonidine in Restless Legs Syndrome.
Ten patients with idiopathic restless leg syndrome (RLS) were asked to rate their symptoms at baseline during 2 weeks of placebo and 2 weeks of clonidine treatment by using a four-point scale. On two consecutive nights of each treatment period, polysomnography (PSG) and actigraphic studies were performed. Patients subjectively reported improvement in leg sensations (p = 0.02) and motor restlessness (p = 0.001) while receiving clonidine (mean = 0.5 mg/day). On PSG testing, sleep onset occurred faster with clonidine (12 minutes) compared with placebo (30 minutes) and baseline (47 minutes) (p = 0.006). Adverse findings associated with clonidine treatment included decreased percent REM sleep in the clonidine group (4%) compared with placebo (16%) and baseline (16%) (p = 0.001) and increased REM latency in the clonidine group (195 minutes) compared to the placebo (70 minutes) and baseline groups (89 minutes) (p = 0.028). There were no significant changes in total sleep time, stage 1 and 2 sleep, sleep efficiency, awakenings, arousals or periodic limb movements in sleep. There was a nonstatistical trend toward and increase in stage 3 and 4 sleep and a decrease in motor activity as measured by actigraphic recordings. Globally, seven out of 10 patients felt clonidine was more effective than placebo. Four patients chose to continue clonidine after the study. Clonidine may be an effective treatment for RLS patients who don't have large numbers of sleep-disrupting periodic limb movements but have delayed sleep onset due to leg sensations and subsequent motor restlessness.
Adrenergic Agonists↗
Sex differences in cerebrospinal fluid proteomics of patients with restless legs syndrome.
STUDY OBJECTIVES: The pathobiology of restless legs syndrome (RLS) remains poorly understood, complicating effective treatment. This observational cross-sectional study aimed to identify a cerebrospinal fluid proteomic signature of RLS and to explore sex-specific differences in cerebrospinal fluid proteomics. METHODS: Cerebrospinal fluid samples were collected from 22 untreated RLS patients and 18 controls, matched for age, body mass index, and sex. Proteomic analysis was conducted using the SOMAscan platform, assessing over 7000 peptides. RESULTS: Eight proteins were differentially abundant between patients and controls, with CRP and JAML increased, and TAPBPL and IL1RL1 decreased. Pathway analysis highlighted significant involvement in immune response, coagulation, and cytoskeletal regulation. Analyses were then carried out using sex stratification, comparing men and women separately. Sex-specific analyses revealed more pronounced proteomic alterations in males (68 differentially abundant proteins vs. control males) than in females (17 proteins). Gene enrichment analysis revealed that men with RLS had more involvement in gene regulation and epigenetic factors than control males and women with restless legs syndrome had greater involvement in systemic inflammatory and vascular processes than control females. CONCLUSIONS: This study identified a cerebrospinal fluid proteomic signature in RLS, implicating immune and inflammatory pathways in the disease's pathophysiology. Significant sex differences in protein level suggest potential sex-specific mechanisms in RLS, warranting further investigation. These findings contribute to the current understanding of RLS and could inform future therapeutic strategies.
Humans↗
Restless legs syndrome in childhood and adolescence.
Restless legs syndrome (RLS) is believed to be a condition primarily of middle to older age. However, it can have its onset in childhood. Five illustrative case histories with an autosomal dominant mode of inheritance are described. A mother and her 3 children (age: 6 1/2, 4 and 1 1/2 years) as well as a 16-year-old patient from a second family have typical RLS signs of leg discomfort (paresthesias) and motor restlessness prevalent at night and at rest, with temporary relief by activity. Polysomnography or videotaping revealed periodic limb movements in sleep (PLMS) and, in some cases, involuntary jerking of the legs was present during wakefulness as well. Clinicians should be aware that RLS can occur in childhood and adolescence and may be more common than heretofore recognized. "Growing pains" and attention deficit hyperactivity disorder (ADHD) are in the differential diagnosis of RLS in childhood.
Adolescent↗
Cortical involvement in the generation of "involuntary" movements in restless legs syndrome.
The pathophysiology of the restless legs syndrome (RLS) is poorly understood. One index symptom is the urge to move, increasing at night. It is largely accepted that movement in RLS is "involuntary" and that the generators are below the level of the neocortex. Here the authors provide evidence that characteristic leg movements in RLS are preceded by preparatory cortical activation that cannot be attributed to sensory processing or to the expectancy of movement.
Adult↗
Risk factors for restless legs syndrome in dialysis patients.
BACKGROUND: Restless legs syndrome (RLS) is a movement disorder that affects 6.6-62% of dialysis patients. The aims of this multicentre cross-sectional study were to document the frequency, prevalence and severity of RLS in patients attending 5 dialysis centres for chronic hospital haemodialysis (HHD) and to identify associated risk factors. METHODS: The diagnosis of RLS was made using the criteria of The International Restless Legs Study Group. The following data were collected: age; gender; duration of renal replacement therapy (RRT); current smoking status; urea reduction ratio; weekly erythropoietin dose; weekly intravenous iron dose; prescribed beta blocker; prescribed renin/angiotensin system inhibitors and pre-dialysis blood concentrations of haemoglobin, ferritin, total calcium (corrected for albumin), albumin, phosphate, parathyroid hormone. Associations with RLS were analysed by univariate and multivariate logistic regression. RESULTS: Data relating to 277 of 295 patients who had been attending for regular HHD for > 3 months were collected. RLS was present in 127 (45.8%). 82 (29.6%), 27 (9.7%) and 18 (6.5%) patients had mild, moderate and severe RLS, respectively. 39 patients (14.1%) were prescribed medicines aimed at reducing RLS. 30 (76.9%) of these 39 patients still had RLS. Female gender (RR 2.17; p = 0.01), increasing duration since first dialysis (RR 1.06 per year; p = 0.03) and increasing body weight (RR 1.02 per kg; p = 0.02) were independent risk factors for RLS by multivariate analysis. In contrast to previous studies, we found no association with iron status, haemoglobin, serum phosphate or smoking. CONCLUSIONS: There is a high prevalence of RLS in our population and therapeutic intervention appears to have limited efficacy. The associations with female gender, duration of RRT and body weight deserve further study.
Adult↗
Restless legs syndrome: a review for the renal care professionals.
Restless legs syndrome is a common neurological disorder with an estimated prevalence between 2 and 10%. It is characterised by an imperative desire to move the extremities associated with paraesthesias, motor restlessness, worsening of symptoms at rest with at least partial relief by activity, and worsening of symptoms in the evening or at night. As a consequence, patients suffer from severe sleep disturbances and, less frequently, from daytime sleepiness. The cause of restless legs syndrome remains unknown. It has been divided into idiopathic and symptomatic (secondary, e.g. uraemic restless legs syndrome) forms. Based on pharmacological, neurophysiological and imaging studies it is suggested that it is a disease of the subcortical central nervous system with involvement of the brainstem and spinal chord. Dopaminergic agents are regarded as the first choice of treatment; however, the development of augmentation of symptoms especially under levodopa therapy may be a major problem. Alternative medications are opioids and benzodiazepines. In secondary restless legs syndrome the underlying illness should be treated first, but dopaminergic drugs may also be helpful.
Dopamine Agents↗
Restless legs syndrome in pregnancy. Case reports.
Restless legs syndrome is a common complaint in pregnancy affecting up to one in every three women. The exact pathophysiology is poorly understood. The majority of patients respond to simple explanation and reassurance, however, a small proportion may suffer debilitating symptoms requiring drug therapy. We describe two such cases.
Carbamazepine↗
Restless legs syndrome: treatment with dopaminergic agents.
Restless legs syndrome (RLS) is a common neurologic disorder that affects 5 to 10% of the population and increases in prevalence with aging. The clinical hallmarks of RLS include dysesthesias or paresthesias in the legs and sometimes the arms, occurring primarily at rest, which are usually worse in the evening and are alleviated by movement. RLS can be a disabling disorder, causing sleep disturbance at night and excessive sleepiness during the day. Although treatment with levodopa alleviates symptoms, many RLS patients develop rebound (occurrence of symptoms during the night) or augmentation (occurrence of symptoms before levodopa dosing in the evening). Augmentation occurs in up to 82% of patients treated with levodopa, limiting the long-term usefulness of this agent. The direct dopamine receptor agonists are long-acting drugs often administered as a single dose at bedtime. Among these agents, pergolide, pramipexole, ropinirole, and cabergoline have all been shown to alleviate RLS symptoms in 70 to 100% of patients. The most common adverse effect is nausea. Augmentation, although it may be associated with chronic agonist use, is usually mild and responsive to additional dosing. The direct dopamine receptor agonists have largely replaced levodopa as the most effective treatment for RLS.
Clinical Trials as Topic↗
Periodic limb movements and restless legs syndrome.
The criteria that characterize restless legs syndrome (RLS) and the differential diagnoses are discussed. Clinical signs include sleep disturbance, involuntary movements in sleep or wakefulness, a normal neurologic examination, a chronic clinical course, and, in some cases, a positive family history. Periodic limb movements during sleep, which also may occur as an isolated finding, may or may not cause frequent arousals or awakenings. Clinical diagnosis of idiopathic or symptomatic forms of RLS can be supported with polysomnography. Treatment of first choice consists of dopaminergic drugs or dopamine agonist followed by opioids or benzodiazepines.
Adult↗
Management of restless legs syndrome in patients on dialysis.
Restless legs syndrome (RLS) is characterised by an urge to move the legs, uncomfortable sensations in the legs and worsening of these symptoms during rest with at least temporary relief brought on by activity. RLS occurs in 3-15% of the general population and in 10-30% of patients on maintenance dialysis. RLS may lead to severe sleep onset or maintenance insomnia, and greatly impaired quality of life. Current recommendations suggest dopaminergic therapy (levodopa or dopamine receptor agonists: pramipexol, ropinirole, pergolide or cabergoline) as the first-line treatment for RLS. This group of medications is effective in reducing RLS symptoms in the general population; limited information is available on the effect of these drugs in patients with renal failure. However, it must be noted that most published studies in uraemic patients had short treatment periods and insufficient statistical power because of small sample size. Frequent adverse effects of levodopa, seen mainly with continuous use, may limit its use significantly. Rebound and augmentation, problems relatively frequently seen with levodopa, seem to be less prevalent with the use of dopamine receptor agonists, although properly designed comparative trials are still needed to address this question. Alternative treatment options for RLS are gabapentin, benzodiazepines and opioids. For all of these medications, there are only very limited data available on their effectiveness and safety profile in patients on maintenance dialysis. Referral to a specialist for RLS management should be considered for patients with refractory RLS.
Amines↗
Restless legs syndrome associated with primary hyperparathyroidism.
Restless legs syndrome (RLS) is a poorly understood sleep-related movement disorder which can be primary or associated with other conditions, most commonly iron deficiency, uremia and peripheral nerve disease. We present a case of RLS with an unusual secondary cause: primary hyperparathyroidism with hypercalcemia. This patient experienced complete and sustained relief of RLS symptoms immediately after parathyroidectomy, with normalization of her serum parathyroid hormone (PTH) and calcium levels. Early recognition and treatment of this uncommonly detected underlying cause is important because it is potentially curative in this frequently disabling condition for which usually only symptomatic treatment is available.
Female↗