Epidemiology, impact, and treatment options of restless legs syndrome in end-stage renal disease patients: an evidence-based review

Transcription

1 & 2013 International Society of Nephrology mini review Epidemiology, impact, and treatment options of restless legs syndrome in end-stage renal disease patients: an evidence-based review Christoforos D. Giannaki 1,2, Georgios M. Hadjigeorgiou 3, Christina Karatzaferi 2,4, Marios C. Pantzaris 5, Ioannis Stefanidis 6 and Giorgos K. Sakkas 2,4,6 1 Department of Life and Health Sciences, University of Nicosia, Nicosia, Cyprus; 2 Institute of Research and Technology Thessaly, Centre for Research and Technology Hellas, LIVE Lab, Thessaly, Greece; 3 Department of Neurology, Faculty of Medicine, University of Thessaly, Larissa, Greece; 4 Department of PE and Sport Science, University of Thessaly, Trikala, Greece; 5 The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus and 6 Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa, Greece Restless legs syndrome (RLS) (or Willis Ekbom disease) is a neurological disorder with high prevalence among the endstage renal disease population. This is one of the most predominant types of secondary RLS, and it is called uremic RLS. Despite the fact that uremic RLS has been less studied compared to idiopathic RLS, recent studies now shed light in many aspects of the syndrome including clinical characteristics, impact, epidemiology, and treatment options. The current review discusses the above topics with special emphasis given on the management of uremic RLS, including the management of symptoms that often appear during a hemodialysis session. Uremic RLS symptoms may be ameliorated by using pharmacological and nonpharmacological treatments. Evidence so far shows that both approaches may be effective in terms of reducing the RLS symptom s severity; nevertheless, more research is needed on the efficiency of treatments for uremic RLS. Kidney International (2013) 85, ; doi: /ki ; published online 9 October 2013 KEYWORDS: dopamine agonists; exercise; hemodialysis; quality of life; secondary RLS; sleep disorders During the past two decades, the scientific interest regarding restless legs syndrome (RLS) has significantly grown while, continuously, new evidence related to the clinical significance of this syndrome is coming to light. RLS is very common among the end-stage renal disease (ESRD) population. 1 This type of secondary RLS, called uremic RLS, appears to provoke further impairments in the already diminished quality of life (QoL) and health status of the uremic patients. 2 WHAT IS UREMIC RLS? Terminology RLS (also known as Willis Ekbom disease) is a sensorimotor neurological disorder characterized by an urgent need to move the limbs, which is usually accompanied by unpleasant sensations. This disorder mainly affects the lower body, but there are cases where patients also complained of upper body discomfort. 3 The symptoms begin or worsen during periods of rest and inactivity (usually at night), resulting in a significant sleep disturbance. RLS is a disorder with both primary (idiopathic) and secondary causation, with the latter including ESRD, resulting in the diagnosis of uremic RLS. Prevalence The prevalence of uremic RLS in the ESRD population is significantly higher than in the general population. When the International RLS Study Group (IRLSSG) questionnaire was used as the main diagnostic tool, the prevalence reached approximately 30% of the ESRD population (range 7 45%). 1,2,4 Correspondence: Giorgos K. Sakkas, Institute of Research and Technology Thessaly, Centre for Research and Technology Hellas, LIVE Lab, Trikala, Thessaly, Greece. gsakkas@med.uth.gr Received 20 May 2013; revised 30 July 2013; accepted 15 August 2013; published online 9 October 2013 Pathophysiology of uremic RLS The precise pathogenic mechanisms responsible for uremic RLS are still unknown. According to the most widely accepted hypothesis for idiopathic RLS, a dysfunction of the dopaminergic system and reduced iron stores in specific regions in the brain are implicated. 5,6 Studies reporting that treatment with dopamine agonists have been beneficial to uremic RLS patients 7 indicated that dopaminergic dysfunction may be implicated in the pathophysiology of uremic Kidney International (2014) 85,

2 mini review CD Giannaki et al.: Restless legs syndrome in ESRD RLS as well. Moreover, calcium/phosphate imbalance is also reported to be involved in the pathophysiology of uremic RLS. 8,9 Finally, in a recent study by Marconi and coworkers, 10 subclinical peripheral nerve abnormalities were present in the majority of the uremic RLS patients, in contrast to the idiopathic ones, indicating a potential role of damaged peripheral nerves in the pathophysiology of uremic RLS. However, we should note that other studies did not confirm the association between peripheral neuropathy and uremic RLS. 11 Still, it is noteworthy to mention that for the majority of uremic RLS sufferers the symptoms disappear after kidney transplantation, 12 a fact that points to an involvement of uremic toxicity in the pathogenesis of RLS in the ESRD patients. In contrast to idiopathic RLS, the familial component is significantly lower in uremic RLS. Winkelmann et al. 13 classify cases as being definite positive hereditary in 42.3% of the idiopathic RLS patients, but only in 11.7% of the uremic RLS patients. 13 In a more recent study by members of this and our groups, 4 the BTBD9 gene was found to be significantly associated with RLS in ESRD patients from Germany and Greece, showing a genetic contribution to susceptibility in ESRD. It is evident that more studies covering various regions worldwide are needed in order to explore in more depth the issue of genetic influence on uremic RLS. RLS symptoms during the hemodialysis session Uremic RLS patients may experience both sensory 11,14 and motor 15 symptoms during a hemodialysis (HD) session. Because of that, approximately 20% of HD patients reported a premature discontinuation of their therapy owing to the presence of RLS symptoms. 16 A possible explanation for the above phenomenon may lie in the procedure of the HD therapy itself, during which patients are instructed to avoid movement for 3 4 h. As RLS symptoms begin or worsen during inactivity periods such as lying down or sitting, the HD procedure per se provides one of the main triggers of RLS, that is, inactivity. FACTORS AFFECTING RLS STATUS AND SEVERITY Factors affecting RLS status and severity include hypertension, 14 female gender, 11,14,17 increased body weight, and dialysis vintage. 18 In addition, age and diabetes mellitus were associated with the severity of RLS symptoms in a epidemiological study by Unruh and co-workers 19 in a sample of 894 HD patients. 19 The association between HD modality, adequacy, time of delivery of the HD session, and RLS severity remains controversial. In a recent multicenter study by Jabera nd coworkers, 20 short home-hd sessions (six sessions per week) resulted both in significant improvements in RLS symptoms severity score and reductions of sleep disturbances. However, we should note that the percentage of patients who were prescribed RLS-related medication did not significantly change. Inadequate dialysis has been reported to be related to the presence and the severity of uremic RLS. 21 However, we should note that no significant differences in dialysis adequacy were noted in studies comparing uremic RLS HD patients with RLS-free HD patients. 2,11,17 Moreover, in the same or other studies, no associations were reported between RLS and biochemical indices of dialysis adequacy, such as urea and creatinine levels. 2,8,9 Interestingly, receiving the HD treatment later during the day was independently associated with an increased risk of reporting RLS symptoms. 22 Merlino et al., 11 in a perhaps inadequately powered study comparing HD and continuous ambulatory peritoneal dialysis, observed that both the frequency (3.0±0.0 vs. 2.8±0.3 sessions per week) and the duration (4.0±0.5 vs. 3.8±0.4 h per session) of HD sessions were significantly higher in the uremic RLS patients compared with their RLS-free counterparts. 11 Finally, in a very recent multicenter study by Lin and co-workers, 23 longer duration of HD dependence (i.e. years in HD) was associated with RLS prevalence and correlated with its severity, confirming previous data by Gigli et al. 24 DIAGNOSIS OF UREMIC RLS For idiopathic and secondary forms of RLS alike, the four essential diagnostic criteria of RLS, developed by the IRLSSG, 3 are considered the gold standard diagnostic tool for the diagnosis of the syndrome (see Table 1). The diagnosis is mainly based on an interview with the patient that includes various questions based on the four diagnostic criteria (Table 2). The clinician should be aware that RLS is positively Table 1 Diagnostic criteria of RLS according to the International Restless Legs Syndrome Study Group 3 Essential criteria Restless legs syndrome is defined by the presence of the following four essential clinical criteria 1. An urge to move the legs, usually accompanied or caused by uncomfortable or unpleasant sensations in the legs 2. The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting 3. The urge to move or unpleasant sensations are partially or totally relieved by movement such as walking or stretching, at least as long as the activity continues 4. The urge to move or unpleasant sensations are worse in the evening or night than during the day or occur only in the evening or night Note: The occurrence of the RLS symptoms should not be solely accounted for by another condition Supportive criteria Supportive clinical features that can help resolve any diagnostic uncertainty 1. Positive family history of restless legs syndrome 2. Response to dopaminergic drugs 3. Periodic limb movements during sleep or wakefulness Associated features of RLS Significant clinical features that have been identified as being associated with the restless legs syndrome 1. The natural clinical course of the disorder is in general chronic and progressive 2. Significant sleep disturbance induced by restless legs syndrome 3. Medical evaluation and physical examination (mainly used for idiopathic patients and not for secondary restless legs syndrome patients) 1276 Kidney International (2014) 85,

3 CD Giannaki et al.: Restless legs syndrome in ESRD mini review Table 2 Questions that could be used by the clinician as a first step in order to diagnose RLS as suggested by the National Sleep Foundation and the RLS Foundation When you sit or lie down, do you have a strong desire to move your legs? Does your desire to move your legs feel impossible to resist? Have you ever used the words unpleasant, creepy crawly, creeping, itching, pulling, or tugging to describe your symptoms? Does your desire to move often occur when you are resting or sitting still? Does moving your legs make you feel better or slow down the symptoms? Do you have more of these symptoms at night? Have you kept your bed partner awake with jerking movements in your legs? Do you ever have involuntary leg movements while you are awake? Are you tired or unable to concentrate during the day? Do any of your family members have similar symptoms? Has a trip to the health-care professional not revealed any physical cause for your discomfort? Abbreviation: RLS, restless legs syndrome. Answering yes to the majority of the following questions reflects increased possibility of having RLS; however, a further examination by an RLS specialist is required in order to diagnose RLS by using the four essential criteria of the International RLS Study Group (adapted from: article/rls-restless-legs-syndrome-diagnosis). diagnosed only if the interviewee gives four positive answers in all of the four criteria, while the occurrence of RLS symptoms must not be solely result of other conditions such as low sleep quality, neurological and behavioral disorders, leg cramps, positional discomfort, leg swelling, arthritis, and medication or substance use. Supportive criteria for RLS diagnosis include a positive family history of RLS, a positive response to dopaminergic drugs, and an increased presence of symptoms of a condition called periodic limb movements in sleep (PLMS). 3 Briefly, PLMS includes stereotypical leg movements occurring during sleep and can be assessed by using polysomnography (overnight sleep study). PLMS and RLS share common pathogenesis, and approximately 80% of RLS patients present with PLMS. 3 The suggested immobilization test (a test that requires patients to remain still for 1 h while sitting on a bed with their legs outstretched while motor and sensory symptoms of RLS are evaluated) and examination by actigraphy can be also used for RLS diagnosis, supporting further the essential diagnostic criteria. Finally, despite the essential and supportive criteria, some associated features may help the clinician to be more successful in the diagnosis of RLS. These features include the following: (a) a natural clinical course of the disorder, which usually is chronic and progressive; (b) significant sleep disturbance, which is considered to be a common characteristic of the condition; and (c) medical evaluation and physical examination in order to exclude any other neurological conditions or biochemical-related parameters that may exacerbate the RLS symptoms, such as low ferritin levels. 3 We should note that the latter feature could be helpful mainly in the diagnosis of idiopathic RLS and not for uremic RLS, as peripheral neuropathy and iron deficiency are common and have been reported to be associated with uremic RLS. 10 Table 3 International RLS severity scale 25 1 Overall, how would you rate the RLS discomfort in your legs or arms? 2 Overall, how would you rate the need to move around because of your RLS symptoms? 3 Overall, how much relief of your RLS arm or leg discomfort did you get from moving around? (4) No relief (3) Slight relief (2) Moderate relief (1) Either complete or almost complete relief (0) No RLS symptoms to be relieved 4 Overall, how severe was your sleep disturbance due to your RLS symptoms? 5 How severe was your tiredness or sleepiness due to your RLS symptoms? 6 How severe was your RLS as a whole? 7 How often did you get RLS symptoms? (4) Very often [6 7 days/w] (3) Often [4 5 days/wk] (2) Sometimes [2 3 days/w] (1) Occasionally [p1 day/w] (0) Never 8 When you had RLS symptoms, how severe were they on average? (4) Very severe [X8 h/24 h] (3) Severe [3 8 h/24 h] (2) Moderate [1 3 h/24 h] (1) Mild [o1 h/24 h] (0) None 9 Overall, how severe was the impact of your RLS symptoms on your ability to carry out your daily affairs for example, carrying out a satisfactory family, home, social, or work life? 10 How severe was your mood disturbance due to your RLS symptoms for example, angry, depressed, sad, anxious, or irritable? Abbreviation: RLS, restless legs syndrome. Scoring mild: RLS 0 10 points; moderate: RLS points; severe: RLS points; very severe RLS: points. As already mentioned, the gold standard diagnostic tool is the four criteria developed by the IRLSSG. These have been formulated in the IRLSSG severity scale, consisting of 10 questions, for assessing RLS severity, as well as for evaluating the effects of RLS treatment, 25 presented in Table 3. Other instruments such as the Clinical Global Impression Scale, the John Hopkins RLS Severity Scale, the RLS-6 scale, and indices such as the PLMS index derived from an overnight polysomnographic evaluation and the multiple suggested immobilization test test could also be used for the assessment of the severity and treatment efficacy of the RLS patients. There are no specific diagnostic criteria exclusively for the diagnosis of uremic RLS, and there is a debate regarding that issue. Many nephrologists and neurologists believe that the development of specific diagnostic criteria could help for an early and accurate diagnosis of RLS in the ESRD population (personal communication). In a recent pilot study from Kume and co-workers, 26 a Holter-monitored suggested immobilization test during HD session was used successfully for the diagnosis of uremic RLS; however, further research is needed in order to increase the sensitivity of this method. Differential diagnosis of RLS Many other conditions (mainly neurological based) may induce unpleasant sensations in the limbs similar to RLS. As it was mentioned above, positive RLS diagnosis includes the presence of all four IRLSSG criteria. This should be the Kidney International (2014) 85,

4 mini review CD Giannaki et al.: Restless legs syndrome in ESRD Table 4 Overview of the pharmacological treatment of uremic RLS Drug Daily dose Adverse effects Efficacy on IRLS severity scale score Ropinirole mg per day No considerable adverse effects 54 75% improvement in RLS severity Pramipexole mg 0.75 mg per day No considerable adverse effects 70% improvement in RLS severity Pergolide Initially 0.05 mg per day, Nausea, headache, somnolence, 60% improvement in increased gradually with 0.05 mg emesis, vomiting, and nightmares RLS severity per day Gabapentin mg three times per week Lethargy and somnolence. Severe adverse effects presented in one patient (unclarified) Intravenous iron Levodopa mg per day Vomiting, general weakness, Wegener s, and granulomatosis 82% improvement in RLS severity Iron Dextran 1000 mg Nausea, vomiting, and headache No IRLSSG severity scale score was provided % improvement in RLS severity Abbreviations: IRLSSG, International RLS Study Group; RLS, restless legs syndrome. Reference 7, , ,47 benchmark by which the clinician will discriminate RLS from other RLS-mimic conditions. Furthermore, as the sensations that accompany RLS are unusual, patients may present with difficulty in properly describing their symptoms. Thus, they may use a diverse wording such as uncomfortable, pain, creeping, burning, itching, pulling, or creepy-crawly to describe the sensation in their legs. Phrases such as soda running through the veins and electricity running through the legs are also common attempts made by patients to better express their uncomfortable sensations. 3 Interestingly, pruritus, which is known to be one of the most bothersome side effects of renal failure, is also commonly reported as one of the main complaints by RLS patients. 3 Indeed, a significant correlation was found between RLS prevalence and pruritus in ESRD patients. 16 It is reported that both pruritus and uremic RLS could impair sleep quality and QoL in ESRD patients. 27 The clinician should keep in mind that RLS symptoms usually follow a circadian pattern, appearing during the evening or at night and during inactivity or rest periods, with the unpleasant sensation being produced mainly deep inside the legs instead of being restricted to the skin and the surface of the legs as in uremic pruritus. Therefore, in order to distinguish RLS symptoms from other disorders or conditions with RLS-like symptoms, various parameters that are known to favor RLS should be ruled out. Thus, biochemical, neurological, neurophysiological, and physical examinations should be performed by specialized personnel in order to have an accurate diagnosis of the presence and severity of the syndrome. EPIDEMIOLOGY OF UREMIC RLS Effect on sleep-related parameters Sleep disturbances in ESRD patients are associated with factors that can promote insulin resistance such as fatty liver, central adiposity, physical inactivity, and reduced functional capacity, 28 thus affecting morbidity and mortality. Uremic RLS can impair both sleep quality and quantity. It has been reported that uremic patients with RLS experienced further impairments in sleep quality compared with uremic patients without RLS, 2 whereas RLS severity was associated with poorer sleep quality. 19 The RLS symptoms could induce difficulties in sleep initiation, therefore reducing total sleep time, whereas the presence of PLMS, found in the majority of the RLS patients, could significantly impair both sleep quality and quantity through their associated arousals and increased leg movement activity. It is noteworthy that sleep quality 14,29 and motor activity during sleep, expressed by the PLMS index, were more affected in uremic RLS patients compared with idiopathic RLS patients. 29,30 It seems that renal disease itself can exacerbate the sleep-related symptoms of RLS. Effect on QoL It is well known that idiopathic RLS is negatively associated with QoL. 31 Interestingly, it has been reported that the QoL score was 25% lower in the uremic RLS patients compared with idiopathic RLS patients, 32 part at least of this difference reflecting the overall detrimental effect of ESRD on QoL. Uremic patients with RLS reported poorer QoL scores compared with their RLS-free counterparts, mainly owing to increased insomnia, anxiety, poor quality of sleep, worse depression levels, and inadequate rest, whereas the severity of the uremic RLS symptoms negatively correlated with QoL score. 2 It seems that the key factor responsible for the effects of uremic RLS on QoL may be its detrimental effect on sleep, a well-known component of QoL and well-being (Figure 1). It is still unclear whether the further impairments in QoL are due to mental or physical-related parameters; however, recent data from our group revealed that mental health and sleeprelated aspects were mostly responsible for the low QoL scores reported by uremic RLS patients. 2 Effects on skeletal muscle So far, there is only one report on the muscle status of uremic RLS patients, by our group, assessing the size and composition of thigh muscles via computed tomography scans. In uremic RLS patients, we observed a 15% reduction in thigh muscle size compared with their RLS-free counterparts 1278 Kidney International (2014) 85,

5 CD Giannaki et al.: Restless legs syndrome in ESRD mini review Effect on mental-related parameters Depression Mental fatigue Psychological distress Insomnia Inadequate rest Daily sleepiness Uremia and hemodialysis therapy Uremic RLS Sleep deprivation Effect on physical-related parameters Muscle atrophy Physical fatigue Cardiovascular abnormalities Hypertension Reductions of quality of life and general health Further reductions of quality of life and overall health Figure 1 The effect of uremic restless legs syndrome (RLS) on overall health and quality-of-life parameters. (without alterations in muscle composition). Sleep deprivation caused by RLS was hypothesized to contribute to the evidence of muscle atrophy in uremic RLS patients, as it could induce alterations in anabolic hormone secretion and circulation levels, including growth hormone (GH) and insulin-like growth factor I (IGF-I). 2 The effects that a chronically augmented sympathetic activity may have on skeletal muscle status cannot be excluded (refer, e.g., to an animal study by Bacurau et al, 33 discussing vasoconstriction, oxidative stress, and proinflammatory cytokines), especially because, as discussed in the next session, uremic RLS patients may be more prone to developing heart failure. Clearly, further research is needed, possibly combining noninvasive with invasive methods, in the assessment of uremic RLS effects on skeletal muscle. Uremic RLS and increased risk for cardiovascular disease Both RLS and PLMS are associated with an increased risk for the development of new, or aggravation of existing, cardiovascular disease in both uremic 17,34,35 and nonuremic populations. 36,37 This increased risk might be, at least partially, related to an augmentation of sympathetic nervous system activity, evidenced by high blood pressure (nondipping), and heart rate levels reported during the night in patients suffering from the idiopathic form of the syndrome 35 and in the general population as well. 38 The latter mechanism could induce an excessive hemodynamic stimulus, which in turn could result in cardiac structure abnormalities such as left ventricular hypertrophy. Indeed, in a very recent study by our group, left ventricular internal diameter in diastole was found to be significantly enlarged in uremic RLS patients with PLMS, leading to a significantly increased left ventricular mass compared with uremic RLS patients without PLMS. 39 Taking all into account, recent data reveal that uremic RLS can potentially contribute to the development of cardiovascular disease through both metabolic and physiological mechanisms (Figure 2). Such evidence bear high clinical significance, as cardiovascular disease is considered to be the main cause of mortality in the ESRD population. 40 Association between uremic RLS and mortality In the ESRD population, uremic RLS severity has been associated with lower survival 19 and higher short-term mortality. 17 Moreover, PLMS, which is very common among uremic RLS sufferers, has been reported to be an independent predictor of mortality. 41 The fact that RLS and PLMS are associated with significant impairments in various vital health aspects including metabolic and cardiovascular health, as described above, could explain, in part if not fully, the observed effect of uremic RLS/PLMS on mortality. Future research should focus on investigating the effects of the available treatment options on the management of cardiovascular risk factors in patients with uremic RLS, in parallel with the amelioration of the syndrome s symptoms severity. MANAGEMENT OF UREMIC RLS Unfortunately, few data are available with regard to the treatment options for uremic RLS sufferers (Table 4). In addition, the majority of the available published studies involved short treatment periods, small sample sizes, and thus inadequate statistical power. In the following text, the available treatments are being discussed, and are divided into pharmacological and nonpharmacological interventions for the management of uremic RLS. PHARMACOLOGICAL TREATMENTS Currently, the first-line treatment for idiopathic RLS is the administration of dopamine agonists. These include the nonergot dopamine agonists such as cabergoline and pergolide, and the non-ergot dopamine agonists ropinirole, pramipexole, and rotigotine, which have been officially approved by both the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) for use in treating RLS. Unfortunately, there is a lack of strong evidence regarding the use of dopamine agonists in ESRD patients with RLS, as only few studies with small sample size have so far examined this issue. The substance levodopa (L-DOPA) was used successfully in studies conducted mainly in the 90s. 42 Kidney International (2014) 85,

6 mini review CD Giannaki et al.: Restless legs syndrome in ESRD Metabolic factors Insulin resistance Muscle atrophy Uremic RLS Cardiovascular factors Sympathetic overactivity during the night Nocturnal blood pressure Cardiac structure abnormalities Increased cardiovascular risk Figure 2 Factors that may contribute to an increased cardiovascular risk in patients with uremic restless legs syndrome (RLS). In one randomized crossover trial conducted by Pelletier and co-workers, 7 11 HD patients with RLS were treated with ropinirole ( mg per day) or levodopa ( mg day) for 14 weeks. The results showed that ropinirole was more effective than levodopa for the treatment of uremic RLS, reducing the severity of the symptoms by 75%. The effectiveness of ropinirole was confirmed in a recent randomized, placebo-controlled study by our group, where 6 months of ropinirole administration (0.25 mg per day) resulted in significant improvements in uremic RLS symptoms (54% improvement in the RLS severity scale score), sleep quality, and depression score. 43 In the study by Miranda et al., 44 the dopamine agonist pramipexole ( mg per day, 2 h before sleep) was effective in reducing uremic RLS symptoms by 70% and improving PLMS and during wakefulness. In the study of Pita and co-workers, 45 pergolide ( mg per day before bedtime) was effective in reducing uremic RLS symptoms in eight patients. However, we should note the high dropout rates in that study, as well as that some patients reported a series of adverse effects, such as vomiting, nausea, emesis, and nightmares. In the study of Kume et al., 26 pergolide with an initial dose of 0.05 mg per day at night (which was increased gradually with 0.05 mg per day steps until satisfactory amelioration of the RLS symptoms) for 4 weeks was found to significantly ameliorate uremic RLS symptoms by approximately 60%. 26 However, even though uremic patients find relief from RLS symptoms with dopamine agonist treatments, one study reported that these patients present a decreased response to this kind of drugs compared with the patients with idiopathic RLS, implying a type of drug resistance. 29 Uremic RLS symptom severity was significantly reduced after treatment with the anticonvulsant gabapentin ( mg three times per week after the end of the HD session). 46 In addition, 4 weeks of treatment with gabapentin (200 mg after the HD session) was found to be superior to levodopa in terms of effectiveness in uremic RLS symptoms, as well as in sleep quality, sleep latency, sleep disturbances, and various QoL-related scales in an open-label study of Micozkadioglu et al. 47 The Food and Drug Administration-approved gabapentin for the treatment of RLS in 2011, whereas a combination of dopamine agonists (talipexole) with a benzodiazepine derivative (clonazepam) and a combination of two types of dopamine agonists (talipexole and pergolide) were effective in reducing RLS symptoms (47.7% improvement in the RLS severity scale score) in the study of Enomoto et al. 29 in Japanese uremic RLS patients. A common characteristic of many secondary forms of RLS is their association with iron deficiency and anemia. Therefore, some studies examined the effect of iron supplementation 48 or erythropoietin 49 on the reduction of RLS symptoms in ESRD patients, with satisfactory results. However, we should note that despite 82% of the patients administered a high dose of iron dextran reporting significant improvements in RLS severity, this improvement was unfortunately transient, as iron dextran appeared to be superior to placebo at 2 weeks, but not at 4 weeks, after the initiation of treatment. 48 Independently from the above findings, many studies have reported that serum iron, ferritin, and anemia were not associated with RLS in ESRD patients. 9 This seems logicalbecause, after the introduction of erythropoietin therapy as standard care in the HD units, severe anemia is usually eliminated. AUGMENTATION AND ADVERSE EFFECTS According to the literature, idiopathic RLS treatment with dopaminergic drugs (especially with levodopa) and mainly long-term treatment is often associated with side effects specific to RLS, such as an increase in symptoms severity, earlier onset of symptoms at night, appearance of daytime symptoms, and spread of symptoms to other parts of the body, collectively described as augmentation. 3 To our knowledge, no significant augmentation phenomena have been reported in uremic RLS patients after treatment with dopaminergic drugs. In contrast, some adverse effects have been reported after treatment with other agents. In particular, treatment with gabapentin was associated with somnolence and lethargy 46 and severe side effects in one patient (no details were provided); 47 levodopa was associated with vomiting, 7 general weakness, and Wegener s granulomatosis; 42 and pergolideuse was associated with nausea, headache, somnolence, emesis, vomiting, and nightmares at least at the initial phase of the treatment. 26,45 No considerable adverse effects were reported with ropinirole 7 or pramipexole treatment. 44 NONPHARMACOLOGICAL TREATMENTS Chronic exercise training Recently, intradialytic exercise training was successfully applied in patients with uremic RLS as a means of improving 1280 Kidney International (2014) 85,

7 CD Giannaki et al.: Restless legs syndrome in ESRD mini review RLS symptoms. Intradialytic aerobic exercise training (cycling for 45 min per HD session) for and weeks reduced symptoms by 42% and 58%, respectively, compared with the control groups. Moreover, significant improvements in QoL, sleep quality, depression, and functional capacity related parameters were also observed. The exercise-induced improvements in RLS symptoms severity occurred with no adverse effects, nor any augmentation phenomena. These results, in combination with the fact that aerobic exercise confers improvements in or halts the deterioration of cardiovascular and metabolic health in ESRD patients, 52 indicate that intradialytic exercise training could constitute a safe and effective alternative treatment option in patients with uremic RLS. Exercise therapy could be administered either as a monotherapy or in combination with appropriate medication, and future studies should explore optimal combination treatments. MANAGEMENT OF RLS SYMPTOMS DURING THE HD SESSION Minimal evidence exists regarding the management of RLS symptoms that occur during the HD session. In one study, 4 weeks of treatment with the dopamine agonist pergolide (initial dose of 0.05 mg per day at night, increased gradually by 0.05 mg per day steps) was found to be effective in reducing, among others, the PLM during HD session. 26 In a recent study by our group, even acute intradialytic exercise (cycling), independently of intensity, was effective in the amelioration of RLS motor symptoms expressed as PLM/ index per hour of HD. 15 Thus, it seems that both dopamine agonists and intradialytic exercise training (whether acute or chronic) could be effective as interventions for the management of uremic RLS symptoms appearing during the HD sessions. Still, larger, randomized placebo-controlled studies are needed in order to verify the above findings. TRANSPLANTATION It seems that the best treatment for uremic RLS is kidney transplantation, which has a strong and positive influence on uremic RLS, resulting even in complete relief from RLS symptoms. 12 However, it is not known whether the symptoms may reoccur later in life, whether as a result of the chronic immunosuppressive medication or because of the normal aging of the transplanted kidney, or other reasons. RECOMMENDATIONS FOR THE MANAGEMENT OF RLS SYMPTOMS IN ESRD PATIENTS Currently, there are no specific published guidelines regarding the treatment of uremic RLS symptoms. Therefore, the prescription given in the clinical practice for the uremic patients is primarily based on the published instructions for the treatment of patients with idiopathic RLS. The first approach is the re-evaluation of the blood biochemical profile, especially for those indices related to iron deficiency and anemia (iron, ferittin, hemoglobin, and hematocrit levels), as low levels of those indices could increase or induce RLS symptoms. If appropriate, anemia and iron deficiency should be corrected by using intravenous iron and erythropoietin therapy. The second approach for the amelioration of uremic RLS symptoms is to improve sleep habits. In parallel with the improvements in sleep hygiene, a re-evaluation of the medication taken by the patients, in order to explore whether some drugs may induce RLS symptoms, is recommended. For instance, dopamine antagonists, tricyclic antidepressants, selective serotonin uptake inhibitors, and lithium have been reported to exacerbate or unmask RLS symptoms and should be probably replaced. The consumption of substances that contain caffeine, nicotine, and alcohol should be reduced as well, especially in the hours before bedtime. Changing the shift of the HD session from late to early morning could be proven beneficial in some patients. 22 Moreover, application of home short daily HD when possible could be also beneficial in terms of reducing the uremic RLS symptoms and improving sleep and QoL-related parameters. In patients with severe RLS symptoms, which could significantly impair the patients health and QoL, dopamine agonists should constitute the first-line treatment. In case of failure or inability to prescribe dopamine agonists, an alternative scenario is to use gabapentin (after the end of the HD session), clonidine, and benzodiazepines in order to relieve patients from uremic RLS symptoms. Aerobic exercise could be used independently as a complementary treatment option, which in turn could promote many other healthrelated parameters in parallel to RLS symptom improvement. Exercise could also be used in patients who suffer from mild/ intermittent RLS or in patients who experience RLS symptoms mainly during the HD sessions. CONCLUSIONS Prevalence of RLS is high in ESRD. Uremic RLS causes significant impairments on the QoL and overall healthrelated parameters, and therefore it should be carefully managed. Both pharmacological and nonpharmacological treatment approaches have been used successfully for the reductions of uremic RLS symptoms. Future research should focus on unfolding the mechanisms underlying the high prevalence of RLS in the uremic patients. However, in parallel, efforts should also continue in improving the effectiveness and safety of treatment options to reduce the syndrome s severity and improve the patients quality of life and general health. DISCLOSURE All the authors declared no competing interests. REFERENCES 1. Murtagh FE, Addington-Hall J, Higginson IJ. The prevalence of symptoms in end-stage renal disease: a systematic review. Adv Chronic Kidney Dis 2007; 14: Giannaki CD, Sakkas GK, Karatzaferi C et al. Evidence of increased muscle atrophy and impaired quality of life parameters in patients with uremic Restless Legs Syndrome. PLoS One 2011; 6: e Kidney International (2014) 85,

8 mini review CD Giannaki et al.: Restless legs syndrome in ESRD 3. Allen RP, Picchietti D, Hening WA et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003; 4: Schormair B, Plag J, Kaffe M et al. MEIS1 and BTBD9: genetic association with restless leg syndrome in end stage renal disease. J Med Genet 2011; 48: Zucconi M, Manconi M, Ferini Strambi L. Aetiopathogenesis of restless legs syndrome. Neurol Sci 2007; 28(Suppl 1): S47 S Allen RP. Controversies and challenges in defining the etiology and pathophysiology of restless legs syndrome. Am J Med 2007; 120: S13 S Pellecchia MT, Vitale C, Sabatini M et al. Ropinirole as a treatment of restless legs syndrome in patients on chronic hemodialysis: an open randomized crossover trial vs. levodopa sustained release. Clin Neuropharmacol 2004; 27: Takaki J, Nishi T, Nangaku M et al. Clinical and psychological aspects of restless legs syndrome in uremic patients on hemodialysis. Am J Kidney Dis 2003; 41: Collado-Seidel V, Kohnen R, Samtleben W et al. Clinical and biochemical findings in uremic patients with and without restless legs syndrome. Am J Kidney Dis 1998; 31: Marconi S, Scaglione C, Pizza F et al. Group I nonreciprocal inhibition in restless legs syndrome secondary to chronic renal failure. Parkinsonism Relat Disord 2012; 18: Merlino G, Lorenzut S, Romano G et al. Restless legs syndrome in dialysis patients: a comparison between hemodialysis and continuous ambulatory peritoneal dialysis. Neurol Sci 2012; 33: Winkelmann J, Stautner A, Samtleben W et al. Long-term course of restless legs syndrome in dialysis patients after kidney transplantation. Mov Disord 2002; 17: Winkelmann J, Wetter TC, Collado-Seidel V et al. Clinical characteristics and frequency of the hereditary restless legs syndrome in a population of 300 patients. Sleep 2000; 23: Araujo SM, de Bruin VM, Nepomuceno LA et al. Restless legs syndrome in end-stage renal disease: clinical characteristics and associated comorbidities. Sleep Med 2010; 11: Giannaki CD, Sakkas GK, Hadjigeorgiou GM et al. Non-pharmacological management of periodic limb movements during hemodialysis session in patients with uremic restless legs syndrome. Asaio J 2010; 56: Winkelman JW, Chertow GM, Lazarus JM. Restless legs syndrome in endstage renal disease. Am J Kidney Dis 1996; 28: La Manna G, Pizza F, Persici E et al. Restless legs syndrome enhances cardiovascular risk and mortality in patients with end-stage kidney disease undergoing long-term haemodialysis treatment. Nephrol Dial Transplant 2011; 26: Siddiqui S, Kavanagh D, Traynor J et al. Risk factors for restless legs syndrome in dialysis patients. Nephron Clin Pract 2005; 101: c155 c Unruh ML, Levey AS, D Ambrosio C et al. Restless legs symptoms among incident dialysis patients: association with lower quality of life and shorter survival. Am J Kidney Dis 2004; 43: Jaber BL, Schiller B, Burkart JM et al. Impact of short daily hemodialysis on restless legs symptoms and sleep disturbances. Clin J Am Soc Nephrol 2011; 6: Chen WC, Lim PS, Wu WC et al. Sleep behavior disorders in a large cohort of chinese (Taiwanese) patients maintained by long-term hemodialysis. Am J Kidney Dis 2006; 48: Kutner NG, Zhang R, Szczech LA et al. Restless legs syndrome reported by incident haemodialysis patients: is treatment time of day relevant? Nephrology (Carlton) 2012; 17: Lin CH, Wu VC, Li WY et al. Restless legs syndrome in end-stage renal disease: a multicenter study in Taiwan. Eur J Neurol 2013; 20: Gigli GL, Adorati M, Dolso P et al. Restless legs syndrome in end-stage renal disease. Sleep Med 2004; 5: Walters AS, LeBrocq C, Dhar A et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003; 4: Kume A, Sato H, Nonomura H et al. An intradialysis diagnostic test for restless legs syndrome: a pilot study. Am J Kidney Dis 2009; 54: Lerma EV. Are restless legs syndrome, pruritus or hiccoughs surrogates for inadequate dialysis? Semin Dial 2011; 24: Sakkas GK, Karatzaferi C, Zintzaras E et al. Liver fat, visceral adiposity, and sleep disturbances contribute to the development of insulin resistance and glucose intolerance in nondiabetic dialysis patients. Am J Physiol Regul Integr Comp Physiol 2008; 295: R1721 R Enomoto M, Inoue Y, Namba K et al. Clinical characteristics of restless legs syndrome in end-stage renal failure and idiopathic RLS patients. Mov Disord 2008; 23: ; quiz Wetter TC, Stiasny K, Kohnen R et al. Polysomnographic sleep measures in patients with uremic and idiopathic restless legs syndrome. Mov Disord 1998; 13: Allen RP, Walters AS, Montplaisir J et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005; 165: Gkizlis V, Giannaki CD, Karatzaferi C et al. Uremic vs. idiopathic restless legs syndrome: impact on aspects related to quality of life. Asaio J 2012; 58: Bacurau AV, Jardim MA, Ferreira JC et al. Sympathetic hyperactivity differentially affects skeletal muscle mass in developing heart failure: role of exercise training. J Appl Physiol 2009; 106: Lindner A, Fornadi K, Lazar AS et al. Periodic limb movements in sleep are associated with stroke and cardiovascular risk factors in patients with renal failure. J Sleep Res 2012; 21: Portaluppi F, Cortelli P, Buonaura GC et al. Do restless legs syndrome (RLS) and periodic limb movements of sleep (PLMS) play a role in nocturnal hypertension and increased cardiovascular risk of renally impaired patients? Chronobiol Int 2009; 26: Li Y, Walters AS, Chiuve SE et al. Prospective study of restless legs syndrome and coronary heart disease among women. Circulation 2012; 126: Schlesinger I, Erikh I, Avizohar O et al. Cardiovascular risk factors in restless legs syndrome. Mov Disord 2009; 24: Pennestri MH, Montplaisir J, Fradette L et al. Blood pressure changes associated with periodic leg movements during sleep in healthy subjects. Sleep Med 2013; 14: Giannaki CD, Zigoulis P, Karatzaferi C et al. Periodic limb movements in sleep contribute to further cardiac structure abnormalities in hemodialysis patients with restless legs syndrome. J Clin Sleep Med 2013; 9: Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol 1998; 9: S16 S Benz RL, Pressman MR, Hovick ET et al. Potential novel predictors of mortality in end-stage renal disease patients with sleep disorders. Am J Kidney Dis 2000; 35: Trenkwalder C, Stiasny K, Pollmacher T et al. L-dopa therapy of uremic and idiopathic restless legs syndrome: a double-blind, crossover trial. Sleep 1995; 18: Giannaki CD, Sakkas GK, Karatzaferi C et al. Effect of exercise training and dopamine agonists in patients with uremic restless legs syndrome: a sixmonth randomized, partially double-blind, placebo-controlled comparative study. BMC Nephrol 2013; 14: Miranda M, Kagi M, Fabres L et al. Pramipexole for the treatment of uremic restless legs in patients undergoing hemodialysis. Neurology 2004; 62: Pieta J, Millar T, Zacharias J et al. Effect of pergolide on restless legs and leg movements in sleep in uremic patients. Sleep 1998; 21: Thorp ML, Morris CD, Bagby SP. A crossover study of gabapentin in treatment of restless legs syndrome among hemodialysis patients. Am J Kidney Dis 2001; 38: Micozkadioglu H, Ozdemir FN, Kut A et al. Gabapentin vs. levodopa for the treatment of Restless Legs Syndrome in hemodialysis patients: an open-label study. Ren Fail 2004; 26: Sloand JA, Shelly MA, Feigin A et al. A double-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome. Am J Kidney Dis 2004; 43: Benz RL, Pressman MR, Hovick ET et al. A preliminary study of the effects of correction of anemia with recombinant human erythropoietin therapy on sleep, sleep disorders, and daytime sleepiness in hemodialysis patients (The SLEEPO study). Am J Kidney Dis 1999; 34: Sakkas GK, Hadjigeorgiou GM, Karatzaferi C et al. Intradialytic aerobic exercise training ameliorates symptoms of restless legs syndrome and improves functional capacity in patients on hemodialysis: a pilot study. Asaio J 2008; 54: Giannaki CD, Hadjigeorgiou GM, Karatzaferi C et al. A single-blind randomized controlled trial to evaluate the effect of 6 months progressive aerobic exercise training in patients with uraemic restless legs syndrome. Nephrol Dial Transplant; e-pub ahead of print 8 August Bronas UG. Exercise training and reduction of cardiovascular disease risk factors in patients with chronic kidney disease. Adv Chronic Kidney Dis 2009; 16: Kidney International (2014) 85,