Magdolna Hornyak

Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome

BACKGROUND There is a need for an easily administered instrument which can be applied to all patients with restless legs syndrome (RLS) to measure disease severity for clinical assessment, research, or therapeutic trials. The pathophysiology of RLS is not clear and no objective measure so far devised can apply to all patients or accurately reflect severity. Moreover, RLS is primarily a subjective disorder. Therefore, a subjective scale is at present the optimal instrument to meet this need. METHODS Twenty centers from six countries participated in an initial reliability and validation study of a rating scale for the severity of RLS designed by the International RLS study group (IRLSSG). A ten-question scale was developed on the basis of repeated expert evaluation of potential items. This scale, the IRLSSG rating scale (IRLS), was administered to 196 RLS patients, most on some medication, and 209 control subjects. RESULTS The IRLS was found to have high levels of internal consistency, inter-examiner reliability, test-retest reliability over a 2-4 week period, and convergent validity. It also demonstrated criterion validity when tested against the current criterion of a clinical global impression and readily discriminated patient from control groups. The scale was dominated by a single severity factor that explained at least 59% of the pooled item variance. CONCLUSIONS This scale meets performance criteria for a brief, patient completed instrument that can be used to assess RLS severity for purposes of clinical assessment, research, or therapeutic trials. It supports a finding that RLS is a relatively uniform disorder in which the severity of the basic symptoms is strongly related to their impact on the patients life. In future studies, the IRLS should be tested against objective measures of RLS severity and its sensitivity should be studied as RLS severity is systematically manipulated by therapeutic interventions.

Does REM sleep contribute to subjective wake time in primary insomnia? A comparison of polysomnographic and subjective sleep in 100 patients

Primary insomnia (PI) is characterized by low subjective sleep quality which cannot always be verified using polysomnography (PSG). To shed light on this discrepancy, subjective estimates of sleep and PSG variables were compared in patients with PI and good sleeper controls (GSC). 100 patients with PI (age: 42.57 ± 12.50 years, medication free for at least 14 days) and 100 GSC (41.12 ± 13.99 years) with a sex distribution of 46 men and 54 women in each group were included. Both PSG and questionnaire variables showed clear impairments of sleep quality in PI compared with GSC. The arousal index within total sleep time was increased, which was mainly because of a strong increase within rapid eye movement (REM) sleep. Subjectively, more PI than GSC subjects estimated wake times longer than obtained from PSG. Linear modeling analysis of subjective wake time in terms of PSG parameters revealed that in addition to PSG defined wake time, REM sleep time contributed significantly to subjective wake time. This REM sleep contribution was larger for PI than for GSC subjects. The findings suggest that REM sleep‐related processes might contribute to subjectively disturbed sleep and the perception of waking time in patients with PI.

Restless legs syndrome and periodic limb movement disorder in the elderly

Restless legs syndrome (RLS) is a sensorimotor neurological disorder characterized by an urge to move the extremities, mostly the legs, caused or accompanied by unpleasant sensations in the affected limbs. Symptoms appear or increase in the evening or during the night and at rest. Sleep disturbances are the most frequent reason why patients seek medical aid. The diagnosis of periodic limb movement disorder (PLMD) requires polysomnographic confirmation and relies on the exclusion of other causes of sleep disturbances. The diagnosis of RLS is a clinical one and usually based on the patients history. Diagnosis criteria should be applied in a modified form in the cognitively impaired elderly. The newly revised criteria emphasize behavioral indicators and supportive features in diagnosing RLS in this special population. Prevalence of both disorders increases strongly with age. Epidemiological studies revealed a 9% to 20% prevalence of RLS and an estimated 4% to 11% prevalence of PLMD in the elderly. Recent studies indicate RLS occurring approximately twice as often in older women than in older men. Treatment with dopaminergic drugs, opioids, anticonvulsants or hypnotics are usually well tolerated in the elderly. However, interaction with other medications and the possibility of severe sedation due to slower metabolism in the elderly should be considered.

Impact of Experimentally Induced Serotonin Deficiency by Tryptophan Depletion on Sleep EEG in Healthy Subjects

The tryptophan depletion test is a research strategy to investigate the functional consequences of decreasing the brain serotonin metabolism. Because serotonin is involved in sleep regulation and the regulation of affective states, we studied the acute polysomnographic effects of tryptophan depletion and expected to induce similar changes of sleep EEG as observed in depressed patients. A total of 12 healthy subjects (mean age 34 ± 3 years) had eight polysomnograms, divided in two blocks of 4 consecutive nights. After one adaptation and 1 baseline night, subjects received a low-protein diet on day 3 and 4 until midday. On day 4 at 18.00 h, they drank an amino acid mixture either devoid of tryptophan or containing 2.3 g of tryptophan (placebo control) in randomized and double-blind order, resulting in an 85% decrease (tryptophan depletion) and a 144% increase (placebo control) of serum tryptophan at 22.00 h. After tryptophan depletion but not placebo, significant effects on sleep EEG were observed in terms of decreased non-rapid eye movement (non-REM) stage 2, increase of wake %, and of rapid eye movement (REM) density compared with baseline. REM latency was not altered, however the first and second REM period interval were significantly shorter after tryptophan depletion. This study underlines the impact of the serotonergic system on sleep maintenance and on REM sleep.

Cognitive behavioural group therapy to improve patients’ strategies for coping with restless legs syndrome: a proof-of-concept trial

Background: Restless legs syndrome (RLS) is a usually chronic disorder accompanied by clinically relevant psychosocial impairment. To date, no psychologically based approach is available to improve the coping strategies and quality of life of RLS sufferers. Objective: To develop cognitive behavioural therapy tailored to this disorder (the RELEGS coping therapy programme) and present the results of this proof-of-concept study. Methods: Twenty-five patients (five men, 20 women; 15 medicated, 10 unmedicated; mean (SD) age 56.1 (12.3) years) with subjective psychosocial impairment due to RLS participated in one of three consecutive therapy groups. The severity scales (IRLS and RLS-6) indicated moderate to severe RLS symptoms at baseline. Exclusion criteria were secondary RLS, foreseeable change of RLS medication during the study period, serious physical or psychiatric comorbidity, and severe cognitive deficits. Each group took part in eight group sessions (90 min each with a break). Results: At the end of the treatment, both the RLS-related quality of life and the mental health status of the subjects had improved significantly (QoL-RLS scale: from 28.6 (12.8) to 23.4 (13.1); SCL-90-R: from 51.3 (37.0) to 45.9 (32.9)). The improvement remained at follow-up 3 months later. Subjective ratings of RLS severity had improved at the end of therapy and at follow-up. Psychometric scales not specific for RLS-related impairment remained unaffected by the treatment. Conclusions: The study establishes the feasibility and high acceptance of the newly devised therapy programme. The application of RLS-oriented specific psychological strategies is a step toward an integrated treatment approach in RLS.

Clinical significance of RLS.

While the restless legs syndrome (RLS) may have been known in antiquity, it has only recently come to medical attention. Individuals with RLS fall along a spectrum from mild, infrequent symptoms to those with severe daily life‐impairing discomforts and sleep disruption. These problems can cause impaired mood, daytime fatigue, cognitive difficulties, and inability to participate in a variety of quiet activities. This leads to a general reduction in quality of life similar to other significant psychiatric and medical disorders. Recent studies suggest that RLS may be a risk factor for developing both psychiatric disorders (such as major depression and anxiety) and somatic diseases (such as hypertension and cardiovascular disease). In dialysis patients, RLS has been found to be a risk factor for mortality. Therefore, those with RLS who have clinically significant symptoms suffer increased morbidity and are at risk for impaired long‐term medical outcomes.

Randomized trial of pramipexole for patients with restless legs syndrome (RLS) and RLS-related impairment of mood

OBJECTIVES Patients with restless legs syndrome (RLS) have an elevated prevalence of mood disorders compared with the general population. We investigated the change of RLS-related mood impairment during treatment of RLS with pramipexole, a dopamine D(3)/D(2) agonist. METHODS Adults with moderate to very severe RLS were enrolled in a 12-week, double-blind, placebo-controlled Phase IV pramipexole trial. A moderate to very severe RLS-related mood disturbance at baseline (score ≥2 on Item 10 of the International RLS Study Group Rating Scale [IRLS]) was also required. Pramipexole (0.125 to 0.75 mg once daily) was flexibly titrated over the first 4 weeks. RESULTS The intent-to-treat population comprised 199 patients on placebo and 203 on pramipexole. At week 12, adjusted mean total-score changes on IRLS were -14.2±0.7 for pramipexole and -8.1±0.7 for placebo (p<0.0001), and on the Beck Depression Inventory version II, -7.3±0.4 for pramipexole and -5.8±0.5 for placebo (p=0.0199). For IRLS item 10, the 12-week responder rate (reduction to no or mild mood disturbance) was 75.9% for pramipexole and 57.3% for placebo (p<0.0001). Study withdrawal rates were higher for placebo (20.5%) than for pramipexole (12.8%). CONCLUSIONS In patients with RLS-related mood disturbance, pramipexole improved RLS while also improving RLS-related mood impairment. Tolerability of pramipexole was similar to that in previous studies.

Efficacy and safety of dopamine agonists in restless legs syndrome

OBJECTIVE Restless legs syndrome (RLS) is a common neurological disorder causing considerable impairment to daily living. This article is an overview of a comprehensive Cochrane meta-analysis on the efficacy and safety of dopamine agonists (DAs), the first-line treatment of RLS. METHODS CENTRAL, MEDLINE, EMBASE, PsycINFO, and CINAHL databases were searched for double-blind randomized controlled trials (RCTs) of DAs vs placebo. RESULTS Thirty-five placebo-controlled RCTs (total number of patients=6954) were eligible. The likelihood of bias was considered to be low. The mean treatment duration of the RCTs was 10.3 (standard deviation 7.3) weeks, with treatment durations up to seven months. Overall, DAs showed a moderate improvement in the International RLS Severity Scale score (mean difference -5.7 points [95% confidence interval, CI, -6.7 to -4.7; P<0.00001]) and the Clinical Global Impression-Improvement response (risk ratio 1.44 [95% CI 1.34-1.54; P<0.00001]) compared with placebo. Periodic limb movements decreased by -22.38/h (95% CI -27.8 to -16.9; P<0.00001) for DAs compared with placebo. Sleep quality and disease-specific quality of life increased slightly to moderately. Safety data confirmed the established safety characteristics of DAs. Augmentation, a specific side-effect of dopaminergic treatment of RLS, was not assessed adequately. CONCLUSIONS This meta-analysis showed that DAs have moderate efficacy in the treatment of RLS. Actively controlled and long-term studies are still lacking. Large-scale comparative studies are needed to identify the most efficient treatments for this chronic disorder.

Psychological distress of patients suffering from restless legs syndrome: a cross-sectional study

BackgroundRestless legs syndrome (RLS) is a chronic disorder with substantial impact on quality of life similar to that seen in diabetes mellitus or osteoarthritis. Little is known about the psychological characteristics of RLS patients although psychological factors may contribute to unfavourable treatment outcome.MethodsIn an observational cross-sectional design, we evaluated the psychological features of 166 consecutive RLS patients from three outpatient clinics, by means of the Symptom Checklist 90-R (SCL-90-R) questionnaire. Additionally, the Beck Depression Inventory-II (BDI-II) and the International RLS Severity Scale (IRLS) were measured. Both treated and untreated patients were included, all patients sought treatment.ResultsUntreated patients (n = 69) had elevated but normal scores on the SCL-90-R Global Severity Index (GSI; p = 0.002) and on the sub-scales somatisation (p < 0.001), compulsivity (p = 0.003), depression (p = 0.02), and anxiety (p = 0.004) compared with a German representative sample. In the treated group, particularly in those patients who were dissatisfied with their actual treatment (n = 62), psychological distress was higher than in the untreated group with elevated scores for the GSI (p = 0.03) and the sub-scales compulsivity (p = 0.006), depression (p = 0.012), anxiety (p = 0.031), hostility (p = 0.013), phobic anxiety (p = 0.024), and paranoid ideation (p = 0.012). Augmentation, the most serious side effect of dopaminergic, i.e. first-line treatment of RLS, and loss of efficacy were accompanied with the highest psychological distress, as seen particularly in the normative values of the sub-scales compulsivity and anxiety. Generally, higher RLS severity was correlated with higher psychological impairment (p < 0.001).ConclusionSeverely affected RLS patients show psychological impairment in multiple psychological domains which has to be taken into account in the treatment regimen.

Transient total sleep loss in cerebral Whipple's disease: a longitudinal study

A case with transient, almost complete sleep loss caused by cerebral manifestation of Whipples disease (WD) is presented. Cerebral WD is rare and in most cases occurs after gastrointestinal infection. In our case, a progressive and finally almost complete sleep loss was the initial and predominant symptom. Polysomnographic studies in several consecutive nights and over 24 h showed a total abolition of the sleep–wake cycle with nocturnal sleep duration of less than 15 min. Endocrine tests revealed hypothalamic dysfunction with flattening of circadian rhythmicity of cortisol, TSH, growth hormone and melatonin. Cerebrospinal fluid (CSF) hypocretin was reduced. [18F]Deoxyglucose positron emission tomography (FDG‐PET) revealed hypermetabolic areas in cortical and subcortical areas including the brainstem, which might explain sleep pathology and vertical gaze palsy. In the course of treatment with antibiotics and additional carbamazepine for 1 year, insomnia slowly and gradually improved. Endocrine investigations at 1‐year follow‐up showed persistent flattening of circadian rhythmicity. The FDG‐PET indicated normalized metabolism in distinct regions of the brain stem which paralleled restoration of sleep length. The extent of sleep disruption in this case of organic insomnia was similar to cases of familial fatal insomnia, but was at least partially reversible with treatment.