Restless legs syndrome (RLS) is a sensorimotor disorder that is characterized by motor restlessness resulting in an uncontrolled urge to move the affected body parts. The symptoms are accentuated during rest, later in the day, and during the early night and are usually, but not always, associated with disagreeable leg sensations.1,2 The diagnostic features for RLS according to the International RLS study group (IRLSSG) consensus are 1) desire to move the extremities that is usually associated with some definable discomfort, 2) motor restlessness, 3) worsening of symptoms at rest with at least temporary relief by activity, and 4) worsening of symptoms later in the day or at night2,3 (Table 1). Although RLS affects approximately 10% of the adult population, it is very much an unknown syndrome to health care providers and seldom diagnosed.4 The origin of RLS could be idiopathic, and it is associated with family history, multiparity, sedentary life style, and older age,5 or secondary to, among others, iron deficiency, renal failure, pregnancy, and certain types of medication.6 The prevalence of RLS in patients on dialysis reported in previous studies varies between 10% and 60%.7,8 These large variations may be dependent on the heterogeneity of the study population and on differences in the diagnostic tool of RLS in each study. The etiology of uremia-induced RLS is probably different compared with RLS of idiopathic origin and could be related to anemia and to uremic toxicity. So far RLS in patients on dialysis has been treated using dopamine agonists with satisfactory results in reducing RLS symptoms and improving sleep quantity; however, side effects and even rebound phenomena have been commonly reported in the literature.6,8 Side effects are just one reason why there is an argument to be made for the clinical use of nonpharmacological treatments or for studies combining low dosage of medication and alternative therapies.
Exercise training has been used in patients on dialysis as a mean of counteracting the catabolic effect and the myopathy–neuropathy symptoms of uremia.9,10 So far, previous dialysis exercise studies have not examined specifically patients with RLS and therefore it is not known whether exercise can have an effect on the severity of RLS symptoms in patients with uremia-induced RLS undergoing dialysis. Therefore, the aims of this pilot study were to examine the effects of a 16-week supervised aerobic exercise training program in the RLS severity score, quality of life, exercise and functional capacity, and in sleep quality in patients with uremia-related RLS undergoing hemodialysis (HD). This study was designed with the intention to explore methodological issues in preparation for a randomized controlled trial.
Study Subjects and Design
This study was undertaken between August 2005 and August 2006 in clinically stable patients on long-term dialysis who were dialyzed at the University Hospital of Larissa. All patients gave written informed consent for study participation after full explanation of the procedure. The study conformed to the principles enumerated in the Helsinki Declaration of 1975 and was approved by the Human Research and Ethics Committee at the University Hospital of Larissa.
Fourteen patients of 46 (30%) were diagnosed with RLS symptoms as defined by the standard criteria11 (Table 1) and recruited for being part of the study. The recruited patients were offered the option to exercise (Ex-group) or not to exercise (Con-group) for the period of 16 weeks. Patients, who decided to exercise, participated in a 16 weeks aerobic exercise training regime, three times a week during the HD session.
The causes of renal failure were diabetic nephropathy (2), glomerulonephritis (4), polycystic kidneys (1), renovascular disease (1), hypertension (2), and unknown etiology (4). Entry criteria for the study were RLS diagnosis and receipt of chronic HD for 6 months or more with adequate dialysis delivery (KT/V >1). Patients were excluded whether they had reasons for being in a catabolic state (including malignancies, HIV, opportunistic infections, infections that required intravenous antibiotics, etc.), within 3 months before enrollment. Patients with polyneuropathy or vascular disease of lower extremities or with ankle to brachial index (ABI) <0.95 were also excluded.
Clinical findings and routine laboratory results were recorded monthly for all subjects and additionally a single-pool KT/V was calculated from pre- and postdialysis urea measurements using the Daugirdas II equation.12 The ABI was calculated using an oscillometric method as described previously.13 The ABI was measured only once during the recruitment period. Ankle to brachial index <0.9, acute illnesses requiring hospitalization or inadequacy of HD treatment (access inadequacy or KT/V <1 present twice during the study) were further exclusion criteria. None of our patients were alcoholic or consuming more than 5 units of alcohol per week. Hemodialysis sessions were a minimum of 4 hours for each patient.
Patients underwent HD therapy (Fresenius 4008B, Oberursel, Germany) 3 times/wk with hollow-fiber dialysers and bicarbonate buffer. Low-flux cellulose triacetate dialysers (FB 210T, Nipro, Osaka, Japan) were used in eight patients and high-flux polysulfone dialysers (F 60S, Fresenius, Oberursel, Germany) in six patients throughout the study period. Low molecular weight heparin (Enoxaparin, Clexane, Sanofi-Aventis, Strasbourg, France) was applied for anticoagulation. Enoxaparin dose of 40–60 mg was administered intravenously before the beginning of HD treatment. The dialysate temperature was set at 37°C in all sessions.
The waist-to-hip ratio (WHR) was calculated as waist circumference at the midway between the iliac crest and the lowermost margins of the ribs over the hip circumference at the maximum circumference of buttocks. Whole body fat (% fat) and lean body mass (LBM) were measured by a dual energy X-ray absorptiometry (DEXA) system (Lunar model DPX Madison, WI).14
General physical condition was assessed (at week-0 and end-point week-16) by using the North Staffordshire Royal Infirmary (NSRI) walk test.15 Briefly, the NSRI walk test consists of the time in seconds taken to complete a task of 50 m continuous walking, climbing up 22 stairs (total elevation 3.3 m), climbing down 22 stairs, and walking back 50 m to the starting point. Exercise capacity was assessed by using a modified version of the Astrand Bicycle Ergometer Test Protocol at bedside during dialysis session.16
The nutritional status of the patients was assessed using the seven-point subjective global assessment (SGA) scale. This method classifies the patients into seven categories (A, A−, B+, B, B−, C, or C−) starting from well nourished (A) to seriously malnourished (C−). The validity and reliability of this method of nutritional assessment has previously been reported in patients on dialysis.17
For the assessment of the quality of life and related parameters at the baseline and at the end of the 16 weeks of exercise training, we used the following questionnaires; the Sort Form 36 Quality of Life, the Epworth Sleepiness Scale, the Massachusetts Sleep Diary, and the Zung self-rating Depression Scale. Briefly, quality of life was assessed by using the SF36 QOL questionnaire adjusted and validated in patients on dialysis.18 The Epworth Sleepiness Scale (ESS)19 was used to assess daily sleepiness. Quality of sleep was estimated using a 7-day sleep diary adapted from the University of Massachusetts Medical School website (http://healthnet.umassmed.edu/mhealth/WeeklySleepQuestionnaire.pdf). The sleep diary contained questions about how often during the last week the patients experienced on dialysis: 1) difficulties in falling asleep, 2) number of nocturnal awakenings, 3) difficulties remaining asleep, 4) the sensation of waking up tired and fatigued, 5) day time stress, and 6) how often they felt refreshed after a night's sleep. The sleep diary scored as “never” (0 points), “1–2 times a week” (1 point), “3–5 times a week” (2 points), and “6–7 times a week” (3 points). For question number 6, the scoring was reversed with three points for the answer “never,” and 0 points for the answer “6–7 times a week.” The sleep diary score was calculated as the sum of the total points with the minimum at zero points and the maximum score at 18. We have previously observed that patients on dialysis with normal sleep quality have scored 3.5 ± 3.0 in the sleep diary scale, whereas patients on dialysis with sleep disorders have scored 8.3 ± 5.6 in the same scale.20 The Zung self-rating Depression Scale21 was used to assess levels of depression.
Restless legs syndrome were identified by using the RLSQ, a patient-completed instrument that has been shown to be a reliable screening tool for RLS.22 Diagnosis of RLS was confirmed in all cases by an RLS specialist (G.M.H.). Restless legs syndrome severity was assessed using the International RLS (IRLS) study group rating scale 3 at baseline, week 0, 1, 2, 3, 4, 8, 12, and at the end of the study (week 16) by an RLS specialist (G.M.H.) in a blind fashion. SF 36-QOL, ESS, 7-d sleep diary, and Zung depression scale were administered at week-0 and end-point week-16. We assessed for possible augmentation23 every week according to National Institute of Health criteria for augmentation.24 The questionnaire materials were completed by the interview method by experienced personnel. All interviewers and personnel who handled the questionnaires were blinded to study allocation of the participants.
Exercise Training Regime
The exercise training regime was always supervised and consisted of 45 minutes continuous cycling using a bedside cycle ergometer (Model 881 Monark Rehab Trainer, Monark Exercise AB, Varberg, Sweden) at 45–50 rpm between the second and third hour of a 4-hour HD session. The exercise resistance was set between 65% and 75% of their maximum power capacity (watts) assessed at the beginning of the training and reassessed and adjusted every 2 weeks by a submaximal cycling test.25 Each training session included 5 minutes warm up and 5 minutes cool down periods according to American College of Sports Medicine (ACSM) guidelines.26 Blood pressure and heart rate were monitored constantly as standard procedure during HD therapy. The exercise ergometers were calibrated every week and before every test.
Total transferrin, ferritin, hematocrit (Hct), and hemoglobin (Hb) analyses were performed at the clinical lab of the University Hospital of Larissa under standard hospital procedures.
The primary aim of this study was to compare the changes in IRLS score from baseline to week 4, week 8, week 12, and at the end of the 16-week period (month 4) in the two groups. Secondary aims were to compare changes of functional ability, exercise capacity, quality of life, and sleep quality. Within-group changes from baseline to month 4 were evaluated using paired t tests. Absolute changes (baseline to month 4) in the Ex-group were compared with those in the Con-group using unpaired t tests. All statistical analyses were performed using Statview (SAS Institute Inc., Cary, NC). Data are the mean ± SD. Two-tailed p-values <0.05 were considered statistically significant.
Patients’ demographic characteristics, body composition, and biochemical values are shown in Table 2. There was no familial predisposition and all were sporadic RLS cases. In all patients, symptoms of RLS had begun after diagnosis of advanced nephropathy (Table 2). Seven patients on HD were recruited and completed the 16 weeks exercise training regimen, whereas seven patients decided for personal reasons not to follow the exercise training and served as the control group at the two time points. The exercise group (Ex-group) was younger with higher levels of LBM compared with the control group (Con-group) (p < 0.05). None of our patients had been treated with any RLS specific agents at the time of the study. All patients were receiving weekly doses of erythropoietin and iron as standard care. There were no differences in body mass index and % total body fat between the two groups.
At baseline, the Ex-group performed better in the functional tests (Table 3) compared with the Con-group. A significant reduction in IRLS score was found after the 16 weeks of exercise training for the Ex-group with no statistical differences at week 4, 8, and 12 time points (Figure 1). Exercise training did not have any acute effect on IRLS score or augmentation during the first 3 weeks (1, 2, 3 weeks time points) of the training program (data not shown). The total score was reduced by 42% in the Ex-group compared with no changes in the Con-group. The score for quality of life was significantly increased by 25% in the Ex-group, by moving up both physical health and mental health parameters compared with the Con-group. Sleep diary score decreased by 50% only in the Ex-group, with no changes in ESS and Zung Depression Scale scores. Functional capacity was improved by 28% and exercise capacity was improved by twofold in the Ex-group against no changes in the Con-group. Blood chemistry was similar at baseline between the two groups with exception of Hct and Hb values that significantly increased in the Ex-group compared with baseline (Table 3). None of the patients with RLS in Ex-group showed signs of augmentation related to exercise training during the study period. In agreement with previous exercise in dialysis studies, there were no intradialytic complications (e.g., needle displacement or disconnection, hypotension, cardiac arrhythmias) during the study period.
An aerobic training regimen of 16 weeks ameliorates RLS symptoms, improves functionality, and exercise capacity leading to a significant improvement in the quality of life of patients with RLS undergoing dialysis. This is the first study to show that exercise training could be a significant and overall safe intervention in the treatment of this disease reducing significantly the severity of the syndrome in patients receiving HD therapy.
The improvement in RLS symptoms in the Ex-group reached 42%. Recently and in agreement with our data, another study that used a combination of aerobic and resistance exercise training with the currently prescribed RLS medication showed an improvement of 39% in the RLS total score in a nondialysis population.27 In patients on dialysis so far, the treatment of RLS has been either through dopamine precursors or dopamine agonists showing improvements from 33% to 73% for the former and the latter, respectively.8 Promising results have been also presented by a small scale study using gamma-aminobutyric acid (GABA) analogues with significant improvements in the quality of life and the severity of RLS.28
To our knowledge, our study is the first to show that a 4-month aerobic exercise training program can improve RLS symptoms in a way similar to the pharmacological intervention in patients who have never received any kind of therapy for the treatment of RLS. Despite close monitoring, none of patients with RLS in Ex-group showed any signs of augmentation.
Various factors that might induce or simply aggravate RLS symptoms in patients on HD (i.e., the iron status or the dialysis quality) remained principally unchanged after the 4-month aerobic exercise training program in the Ex-group. A statistically significant rise in KT/V as a measure of dialysis quality was observed in the Con-group after the 16 weeks study period, which, however, did not influence the RLS symptoms as the severity scale remained unchanged in this group. KT/V did not change significantly during the study in the Ex-group. In addition, the Ex-group showed a significant improvement in Hct and Hb after the 16 weeks of exercise training compared with baseline. Nevertheless, the iron status, which influences RLS symptoms principally independent from the existence of anemia,1,29 remained unchanged in both groups. Iron deficiency was not present in any patient. In addition, none of the participants had been treated with RLS specific agents during the study.
Restless legs syndrome has been shown to have a significant impact on the quality of life of the patients on HD30 mainly because of the poor quality of sleep and inadequate rest.7 Exercise training is known to improve functional capacity and quality of life in patients on dialysis.9 In agreement, our data showed a 25% improvement in Ex-group patients’ quality of life mainly because of changes in the domains of the physical rather than mental health. Mental health did not change significantly from baseline values as a result of the exercise program in agreement also with our findings from the Zung depression scale. On the other hand, the 16 weeks period was not enough to induce any negative changes in the aforementioned variables for the Con-group.
The reduced quality of life in patients on RLS-dialysis is possible because of inadequate sleep quality and quantity.7 Although we did not perform a polysomnography test to accurately evaluate the sleep patterns of our patients, the sleep diary score revealed that the Ex-group showed a 50% improvement in sleep quality compared with no changes in the Con-group. Studies have shown that improvements in sleep quality and quantity can induce changes in physical and cognitive performance as well as valuable improvement in the quality of life.31 In agreement with other studies, the improvement in sleep quality and quantity could explain the 25% improvement in quality of life found in our patients after the exercise intervention.
Apart from important change in IRLS score, patients on dialysis who participated in the Ex-group showed an improvement in muscle functional and exercise capacity. The Ex-group scored a 28% increase in functional ability and a twofold increase in exercise capacity after the 16 weeks intensive aerobic exercise training, compared with no-changes in the Con-group. The only study in which exercise training was tested in patients with idiopathic RLS did not report any data regarding the improvement in exercise capacity,27 and therefore to the best of our knowledge, the current study is the first to show that patients with RLS benefited by an exercise program, not only by improving the RLS symptoms but also increasing exercise capacity and functional ability after 16 weeks of aerobic training.
Placebo effect was reported in many RLS double-blind randomized trials on the efficacy and side effects of dopaminergic agents from the first month of the treatment and therefore we currently cannot exclude the possibility of a placebo effect in our study.2 However, the improvement in IRLS scale found in our study occurred after the third month of the exercise training regime (Figure 1), in agreement with current knowledge that a minimum of 3 months of exercise training is needed to achieve any neuromuscular adaptations to exercise.26 Moreover, with existing data, we cannot make a concrete statement whether the exercise or the leg movements per se contributed to the improvement of RLS symptoms in the current study. Therefore, a long-term randomized placebo controlled study, i.e., comparing progressive resistance exercise versus unresisted leg movement, is needed to clarify the aforementioned issues. It has been reported that strenuous activities like exercise could augment RLS symptoms later in the day and therefore should be avoided.32 In contrary, we have shown that medium to high intensity exercise training for 4 months could ameliorate RLS symptoms significantly without any signs of augmentation.
In conclusion, for the first time, we have shown that an aerobic exercise training is a safe and an effective approach in reducing RLS symptoms in patients with RLS undergoing HD. It additionally improves the quality of life in this group. Aerobic training for 16 weeks had a positive effect in patients on RLS-dialysis probably by increasing their exercise capacity and improving their functional capacity and quality of sleep. Whether long-term exercise training could be equally safe and effective in reducing RLS symptoms in patients on HD deserves further exploration with a randomized trial.
Supported by the Greek Scholarship Foundation (IKY) and by the 03ED375 research project, implemented within the framework of the “Reinforcement Programme of Human Research Manpower” (PENED) and co-financed by National and Community Funds (25% from the Greek Ministry of Development-General Secretariat of Research and Technology and 75% from E.U.-European Social Fund). The authors thank the nursing staff at the hemodialysis unit of the University Hospital of Larissa for their cooperation, and all hemodialysis patients for participating in this study.
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