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Validation of the Restless Legs Syndrome Quality of Life Instrument (RLS-QLI): findings of a consortium of national experts and the RLS Foundation.

UNLABELLED: This study was designed to assess the initial psychometric properties of a new disease-specific health-related quality of life (HRQL) measure, the Restless Legs Syndrome (RLS) Quality of Life Instrument (RLS-QLI). METHODS: Draft items were generated from a literature review, consultation with MD and PhD specialists in the fields of neurology and sleep medicine, and input from two patient focus groups. The initial item reduction was accomplished using a survey of 392 persons with self-reported RLS symptoms from the membership of the RLS Foundation. The final (independent) validation sample consisted of 574 of persons on the RLS Foundation's Interest Group List Serve who also reported having RLS. The mean age of participants was 54.5 (SD 12.3), with a sex ratio of 1M:2F, and the majority was on some form of medication for RLS (66%). RESULTS: Four factors were identified (Daily Function, Social Function, Sleep Quality, and Emotional Well-Being) consisting of 17 items that explained 73.3% of the total variance. Each scale had good internal consistency (Cronbach's alpha's between 0.85 and 0.91) and 2-week test retest stability (Pearson Correlations between 0.81 and 0.93). Convergent validity was demonstrated using related scales on the SF-36 (r = 0.47-0.60) and criterion-related validity was shown using the clinical IRLS Scale of Symptom Severity (r = -0.45 to -0.77). CONCLUSION: The RLS-QLI is a valid disease-specific HRQL instrument that will contribute to our understanding of how RLS impacts the lives of those affected with this CNS disorder.

Adult↗

Clinical symptomatology and treatment of restless legs syndrome and periodic limb movement disorder.

Patients with restless legs syndrome (RLS) suffer from sensory and motor symptoms evoked in the limbs at rest. Symptoms increase in the evening and during the night. The circadian rhythm and the presence of involuntary periodic limb movement in sleep (PLMS) which are frequently associated with arousals probably cause the leading symptom of sleep disturbances in RLS. Patients who do not have typical RLS symptoms but whose polysomnography shows PLMS that either impact on sleep continuity or daytime functioning are diagnosed as having the periodic limb movement disorder (PLMD). Dopaminergic agents such as levodopa/dopa decarboxylase inhibitor (DDI) and dopamine agonists are considered the treatment of choice for RLS and PLMS. This article gives an overview of the epidemiology, pathophysiology, clinical symptomatology and diagnosis of RLS and PLMD and focuses on treatment strategies in both disorders.

Corpus Striatum↗

Dopaminergic neurotransmission and restless legs syndrome: a genetic association analysis.

In order to examine the genetic substrate of the dopamine hypothesis in restless legs syndrome, we analyzed eight genes coding for receptors and enzymes related to dopaminergic transmission, using a population of 92 patients with restless legs syndrome and 182 controls matched for ethnic background. No significant differences were found in the genotypic or allelic distributions between groups. Furthermore, no effect of the loci examined was observed with stratification using clinical parameters such as age at onset or periodic leg movements during sleep index.

Adult↗

Gabapentin versus ropinirole in the treatment of idiopathic restless legs syndrome.

Dopaminergic agents such as ropinirole are the drugs of first choice in treating restless legs syndrome (RLS). Recently, gabapentin, a structural analogue of gamma-aminobutyric acid, has also been shown to improve sensorimotor symptoms in RLS. Therefore, the tolerability and efficacy of randomized treatment with either gabapentin or ropinirole in patients with idiopathic RLS was evaluated in this 4-week open clinical trial. Patients with idiopathic RLS were treated with either 300 mg of gabapentin (n = 8) or 0.5 mg of ropinirole (n = 8) as the initial dose, and the dose was up-titrated until relief of symptoms was achieved (gabapentin mean dosage 800 +/- 397 mg, range 300-1,200 mg; ropinirole mean dosage 0.78 +/- 0.47 mg, range 0.25-1.50 mg). In both groups, International Restless Legs Syndrome Study Group questionnaire scores improved significantly (p < or = 0.018), whereas the scores of the Epworth sleepiness scale remained unchanged within normal limits. Polysomnographic data showed a reduction of periodic leg movements during sleep (PLMS; p < 0.03) and PLMS index (p < 0.02) in both groups. Side effects were only mild and mostly transient. After 6-10 months of follow-up, in most patients, RLS symptoms were still improved. We conclude that gabapentin and ropinirole provide a similarly well-tolerated and effective treatment of PLMS and sensorimotor symptoms in patients with idiopathic RLS.

Acetates↗

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↗

A comparison of self-reported symptoms and DSM-III-R criteria for cocaine withdrawal.

The frequencies of 15 self-reported symptoms of cocaine withdrawal were compared in 75 subjects to the symptoms listed as criteria by DSM-III and DSM-III-R for either amphetamine or cocaine withdrawal. Three of the four most frequently reported symptoms, depression (75%), sleep disturbance (71%), and fatigue (69%), corresponded to DSM-III and DSM-III-R criteria. The only other DSM-III symptom, increased dreaming (33%), was infrequently reported, lending support to its deletion by DSM-III-R. Physical withdrawal symptoms, which are generally unappreciated in cocaine withdrawal, were reported by 64% of the sample. Neither the DSM-III criteria nor the new DSM-III-R criteria include other frequent symptoms which might contribute to relapse and impaired functioning, such as craving (69%), apathy/amotivation (67%), and restlessness (64%). Thus, these criteria may be too narrowly defined for treatment purposes.

Cocaine↗

Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective.

Restless legs syndrome (RLS) involves abnormal limb sensations that diminish with motor activity, worsen at rest, have a circadian peak in expression in the evening and at night, and can severely disrupt sleep. Primary treatment is directed at CNS dopaminergic systems, particularly activation of D(2)-like (D(2), D(3), and D(4)) receptors. Although RLS affects 2% to 15% of the general population, the neural circuitry contributing to RLS remains speculative, and there is currently no accepted animal model to enable detailed mechanistic analyses. Traditional views suggest that RLS arises from supraspinal sources which favor facilitation of the flexor reflex and emergence of the RLS phenotype. The authors forward the hypothesis that RLS reflects a dysfunction of the little-studied dorsoposterior hypothalamic dopaminergic A11 cell group. They assert that, as the sole source of spinal dopamine, reduced drive in this system can lead to spinal network changes wholly consistent with RLS. The authors summarize their recent investigations on spinal cord dopamine dysfunction that rely on lesions centered on A11, and on studies in D(3) receptor knockout (D(3)KO) mice. Excessive locomotor behavior is evident in both sets of animals, and D(3)KO mice exhibit facilitation rather than the expected depression of spinal reflexes in the presence of dopamine as well as a reversal in their circadian expression of the rate-limiting enzyme for dopamine synthesis, tyrosine hydroxylase. Taken together, these findings are consistent with an involvement of spinal dopamine dysfunction in the etiology of RLS, and they argue that the D(3)KO mouse might serve as a relevant animal model to study the underlying mechanisms of RLS.

Animals↗

Sleepless nights: obstructive sleep apnea in the pediatric patient.

Obstructive sleep apnea syndrome (OSAS) is a subtle but severe sleep disorder of early childhood. It occurs in 1.6%-3.4% of children between 6 months and 6 years of age. OSAS is often difficult to detect, and may have long-term consequences, including failure to thrive, behavioral disturbances, developmental delay, and cor pulmonale. Pediatric nurses are pivotal in assessing the clinical symptoms of OSAS so that prompt evaluation and treatment can be initiated. Early symptoms of OSAS include awakening with a startle or gasp, restlessness, retractions, inspiratory stridor, mouth breathing, and excessive sweating. Treatments vary, and include adenotonsilectomy, nasal continuous positive airway pressure (NCPAP), behavior modification, and tracheostomy.

Child↗

[No difference in efficacy of hydroquinine and placebo in restless legs syndrome].

OBJECTIVE: Determination of the efficacy of hydroquinine treatment of the restless legs syndrome. DESIGN: Double blind cross-over trial. SETTING: University Hospital Leiden. PATIENTS AND METHODS: Selection through an announcement in the press and followed by structured interview. Inclusion criteria according to the international classification of sleep disorders. Exclusion criteria defined by medication risks. Patients used either hydroquinine (200 mg in the evening and 200 mg before going to bed) or placebo in the second and fourth of four periods of two weeks duration. Severity of complaints was assessed using a daily questionnaire and a Suggested Immobilization Test (SIT) twice weekly, in which they noted the severity of complaints as experienced during a 15-minute period of immobilization. RESULTS: The study was completed by 59 out of 68 patients. Analysis of variance showed no significant differences between the two groups of patients (those starting with placebo and those starting with hydroquinine) for any of the questions of the daily questionnaire or of the SIT. McNemar's test showed no significant differences between the proportions of patients who wished to continue the use of either placebo or hydroquinine. CONCLUSION: This study showed no significant differences between the efficacy of placebo or hydroquinine in the restless legs syndrome.

Adult↗

Emerging drugs for restless legs syndrome.

Restless legs syndrome (RLS) is a common, but often underdiagnosed, neurological disorder, which is characterised by an imperative urge to move the extremities associated with paraesthesias, worsening of symptoms at rest and in the evening or at night, and, as a consequence, sleep disturbances. RLS affects 1-10% of the population. The aetiology of RLS is unknown, but besides genetic factors the dopaminergic and opioidergic system may play a crucial role and new developments also point to an exciting iron-dopamine connection in the pathophysiology of this burdening disorder. Due to the limited disease-specific knowledge, current treatment strategies are not curative, but nevertheless may produce an effective and lasting relief of symptoms. Although clinically based treatment has focused on levodopa, opioids and benzodiazepines for a long time, evidence-based and clinical guidelines identify dopamine agonists as a first-line treatment for daily restless legs symptoms. These substances are now in the process of registration for this indication. Ropinirole is the first dopamine agonist that has been approved by the FDA in May 2005. In addition, several promising new therapies with nondopamine profiles are under development for RLS.

Clinical Trials as Topic↗

Modeling the causal relationships between symptoms associated with restless legs syndrome and the patient-reported impact of RLS.

The objective of this study is to examine the causal relationships between the symptoms of restless legs syndrome (RLS) and specific clinical and subjective health-related, quality of life consequences. Structural equation modeling was applied to data from a questionnaire-based observational study. The RLS morbidities of decreased functional alertness and emotional distress in our sample of patients appear to be mostly secondary to the sleep disturbance associated with RLS. There was no clear indication of any other feature of RLS affecting these two aspects of RLS morbidity. A primary treatment goal should be the reduction of the sleep disturbance of RLS, both to decrease the RLS-related nocturnal distress and to improve daytime functioning.

Adult↗

[Restless legs syndrome in a patient with amputation of both legs].

INTRODUCTION: We present the case of a patient who, after amputation of both legs, suffered restless legs syndrome (RLS). This syndrome is characterised by a feeling of agitation in the legs and an overwhelming need to move them. CASE REPORT: A 62-year-old male patient who visited because of sleep onset and maintenance insomnia. The aetiology of the insomnia was interpreted as being an anxiety-dysthymic syndrome, which improved with suitable medication. Five months later, the patient returned with the same symptoms (onset insomnia). On questioning the patient again, we noticed that he displayed clear symptoms of RLS, despite the absence of both lower limbs. The clinical features were resolved with the administration of ropinirole. CONCLUSIONS: We do not know of any similar cases, but the scarce amount of knowledge available about RLS makes it likely that many patients with amputations present this problem without any proper diagnosis.

Amputation, Surgical↗

Efficacy and safety of pramipexole in restless legs syndrome.

OBJECTIVE: To evaluate the efficacy and safety of pramipexole in patients with moderate to severe restless legs syndrome (RLS) METHODS: The authors conducted a 12-week, double-blind, randomized, placebo-controlled trial of fixed doses of pramipexole (0.25, 0.50, and 0.75 mg/day). Patients (N = 344) were up-titrated to their randomized dose over 3 weeks. The primary efficacy endpoints were patient ratings of symptom severity on the International RLS Study Group Rating Scale (IRLS) and clinician ratings of improvement on the Clinical Global Impressions-Improvement (CGI-I) scale. Secondary efficacy endpoints included visual analogue ratings of sleep and quality of life (QOL) RESULTS: By both primary measures, pramipexole was superior to placebo. For IRLS, the adjusted mean (SE) change from baseline to week 12 was -9.3 (1.0) for placebo, -12.8 (1.0) for 0.25 mg/day, -13.8 (1.0) for 0.50 mg/day, and -14.0 (1.0) for 0.75 mg/day (all p < 0.01). Similarly, pramipexole increased the percentage of patients with a CGI-I rating of "very much improved" or "much improved" at the end of the trial (51.2% for placebo and 74.7%, 67.9%, and 72.9% for pramipexole; all p < 0.05). Pramipexole significantly improved ratings of symptom severity, day and night, and also ratings of sleep satisfaction and QOL. Pramipexole was well tolerated: The most frequent adverse events with higher occurrence in the pramipexole group were nausea (19.0% vs 4.7%) and somnolence (10.1% vs 4.7%) CONCLUSION: As rated by patients and by clinicians, pramipexole was efficacious and safe in reducing the symptoms of restless legs syndrome.

Adolescent↗

Periodic limb movement disorder in children.

Periodic limb movement disorder (PLMD) has been reported in children and is more prevalent in certain conditions such as attention deficit hyperactivity disorder. The International Restless Legs Syndrome Group has recently developed the criteria for diagnosis of PLMD in children. These criteria include both specific clinical features and polysomnographic findings. Exclusion of other causes especially sleep-disordered breathing is essential. Several medications including benzodiazepine and dopaminergic medication have been used in children, although these medications have not been adequately studied in this age group. Some PLMD children have evidence of low iron storage and response favorably to iron therapy.

Child↗

Mania caused by a diencephalic lesion.

We describe the case of a young male patient, SN, who suffered a MR-documented ischaemic lesion of both dorsomedial thalami and presented with a transient maniform syndrome. SN's neuropsychological, structural and functional imaging findings are compared with similar reported cases and are discussed in the framework of fronto-subcortical circuits and their proposed behavioural disorders. SN's mania was characterized by restlessness, mood elevation, a tendency for pleasurable activities, inflated self-esteem and loss of disease awareness. Other symptoms were sexual disinhibition, tactlessness, abnormal discourse, and reduced need for food and sleep. His neuropsychological assessment revealed an anterograde amnesia, and an impairment of frontal-executive functions. A SPECT-study showed diaschisis-related areas of hypoperfusion in both prefrontal regions which were interpreted as equivalents of SN's frontal-dysexecutive syndrome. In addition, there was a perfusion deficit in the right orbitofrontal cortex, which was taken as the imaging correlate of SN's secondary mania and personality disorder. These findings suggest that SN's mania and his other symptoms result from the twofold disruption of fronto-subcortical connections, namely of the right orbitofrontal loop which is concerned with mood regulation and socially appropriate behaviour, and of the dorsolateral prefrontal loop which mediates executive cognitive functions.

Adult↗

Symptoms of attention-deficit/hyperactivity disorder in adults with restless legs syndrome.

OBJECTIVE: To determine the occurrence of symptoms of attention-deficit/hyperactivity disorder (ADHD) in adults with restless legs syndrome (RLS), normal controls, and controls with insomnia. SETTING: University-based hospital. METHODS: The occurrence and severity of current ADHD symptoms were determined in a prospective study of sequential adult patients with RLS (n = 62) or insomnia (n = 32) and adult controls (n = 77) using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) ADHD criteria, the Brown Attention-Deficit Disorder (ADD) Scale for adults, and a structured psychological interview. RLS severity was assessed using the International RLS Study Group Rating Scale (IRLS). RESULTS: Only 1 experimental subject had previously been diagnosed with ADHD. More RLS patients (26%) than insomnia patients (6%) or controls (5%) had ADHD symptoms using age-adjusted total DSM-IV ADHD scores (P < .01). The mean Brown ADD score was greater in RLS patients (37 +/- 28) than in patients with insomnia (24 +/- 18) or controls (21 +/- 18) (P < .01). The RLS symptom severity (0-40 scale) was greater in RLS patients with ADD symptoms (26 +/- 9) than in those without ADD (21 +/- 10) (P < .04). Of the subjects with a Brown ADD score > 40, all reported ADD symptoms in 2 settings, and the majority had had ADHD symptoms since childhood. For subjects with a Brown ADD score > 40, there were no differences between the RLS, insomnia control, and normal control groups in quality of life or the level of anxiety or depression. CONCLUSIONS: ADHD symptoms are more common in RLS patients than in patients with insomnia or controls. RLS leg discomfort or poor quality of sleep may theoretically lead to hyperactivity and lack of concentration. Alternatively, RLS and ADHD may be part of a single symptom complex, and dopaminergic deficiency may play a role in both disorders.

Anxiety↗

Low-dose pramipexole in the management of restless legs syndrome. An open label trial.

Dopaminergic agents are considered the treatment of choice for restless legs syndrome (RLS); levodopa is the only substance licensed for this disorder in some European countries. However, in a substantial proportion of patients symptoms are not adequately controlled for a whole night due to the short half-life of levodopa or because symptom augmentation may develop. To further investigate the impact of pramipexole on the management of RLS we performed a short-term open label trial with pramipexole in 17 patients who were being insufficiently treated with levodopa or for whom pramipexole was primarily being considered because of the severity of the RLS symptoms. A single dose of 0.125-0.75 mg pramipexole (mean 0.3 +/- 0.2 mg) in the evening resulted in a significant improvement of subjective RLS symptoms as rated by the International RLS Study Group Severity Scale (IRLS scores: 29.8 +/- 4.7 baseline vs. 7.3 +/- 5.9 endpoint; p = 0.0001). Polysomnographic recordings showed a significant improvement of the periodic leg movements (PLM) index, PLM sleep arousal index, sleep-onset latency, total sleep time and sleep efficiency. All patients who had developed a worsening of RLS symptoms under levodopa recovered from daytime symptoms after their medication was switched to pramipexole. Since pramipexole was well tolerated, an ideal dosage to control RLS symptoms could be reached rapidly. Pramipexole has proven a suitable alternative in patients with moderate to severe RLS, particularly when their therapy has to be switched to a dopamine agonist.

Administration, Oral↗