Restless Legs Syndrome in Medical Disorders

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Chapter 25 Restless Legs Syndrome in Medical Disorders

Restless legs syndrome (RLS) has been associated with multiple medical conditions in addition to its association with the neurological conditions discussed in Chapter 26. The most noteworthy of these medical conditions are end-stage renal disease (ESRD) and medical conditions that produces iron deficiency (ID). The principal features that link these disorders to RLS are (1) higher rates of RLS in these disorders than those seen in the general population, (2) temporal association of the onset of RLS to the presence of these disease processes, and (3) resolution of the RLS symptoms with treatment of the precipitating condition. For these reasons, RLS associated with either ESRD or ID is defined in “secondary” RLS. However, it should be made clear that the pathophysiology of both primary and secondary RLS is not clearly understood and that those with secondary RLS may share some or all of the various underlying bases for the symptoms occurring in “idiopathic,” or primary, RLS. Similarly, those with RLS associated with a particular medical condition may not form a homogeneous etiological entity. Nevertheless, subtyping of diseases by associated medical conditions is one of the potential means by which more homogeneous groups can be created with which to understand underlying mechanisms of disease development and progress. This chapter focuses first on ESRD and then on the broader concept of the relation of ID to RLS and in particular the occurrence of RLS in medical conditions causing ID. We conclude with a discussion of the relationship between RLS and rheumatic conditions and diabetes.

Approximately one quarter of individuals with ESRD have RLS, which is phenotypically indistinguishable from that of primary RLS. RLS in patients with ESRD interferes with sleep quality and quantity and produces decrements in quality of life. RLS may lead to an increase in dialysis nonadherence and to an increase in mortality. Our understanding of the pathophysiology of ESRD-related RLS is limited. Treatment approaches are very similar to those for primary RLS—dopaminergic agonists, gabapentin, and potentially intravenous iron—and are similarly effective. However, renal failure may require modification of dosing for some agents.

Ekbom1 first recognized the association between RLS and ID more than 50 years ago. More recent work has identified ID as a risk factor for RLS, related to poor nutrition, blood donation, and medical procedures that produce blood loss or hemolysis. Furthermore, ID may be a common thread tying together essentially many of the seemingly diverse secondary causes of RLS other than those that are primarily neurological, such as neuropathy. Given the significance of ID in RLS and our inability to measure central nervous system iron on a clinical basis, the criteria for determining ID also need to be adjusted to a level of ferritin of less than 45 to 50 µg/L or percentage transferrin saturation of less than 16%. Iron treatment should be considered for all RLS patients who are iron deficient (see Chapter 34). Both ESRD and ID-related RLS provide an opportunity to better understand the pathophysiology of all RLS.

Restless Legs Syndrome in End-Stage Renal Disease

The high prevalence and severe nature of RLS in ESRD potentially provide some tantalizing clues as to the pathogenesis of RLS. ESRD is generally defined as the irreversible loss of renal function, to a creatinine clearance of less than 15 ml/min per 1.73 m2. It is present in roughly 400,000 adults in the United States, with an incidence of 260 cases per million per year in whites and 840 per million per year in African Americans. The incidence of ESRD is increasing by 6% per year, probably as a result of the increasing prevalence of diabetes, which accounts for nearly half of all cases of ESRD.2 Unfortunately, the long-term prognosis for ESRD is poor, with mortality rates of roughly 20% per year. Over 80% of individuals with ESRD are on hemodialysis, although some people use peritoneal dialysis and others receive transplanted kidneys, often after a period of receiving one of the types of dialysis.

Roughly 60% to 80% of patients with ESRD describe difficulty with nocturnal sleep quality and quantity and/or excessive daytime sleepiness.3 Multiple causes for sleep disturbance are present in those with ESRD. Depressive and anxiety disorders, poor sleep hygiene (e.g., daytime napping), pain, pruritis, symptoms of heart disease (nocturnal dyspnea or chest pain), and symptoms of diabetes (neuropathic pain, fluctuations in blood sugar) are all common in ESRD, and all may contribute to difficulties with nocturnal sleep. Among primary sleep disorders, central and obstructive sleep apneas and RLS are commonly observed at higher rates than in the general population.3

Prevalence and Characteristics of Restless Legs Syndrome in End-Stage Renal Disease

In 1966, Callaghan4 first described five patients with classic RLS in ESRD, which he thought was related to subclinical neuropathy. He also described RLS in the upper limbs and leg movements during sleep in two of these patients, both of which are common associated symptoms of RLS. A number of studies have reported the association of ESRD and RLS and have further clarified the prevalence, characteristics, and consequences of the disorder in this population.

Estimates of the prevalence of RLS in ESRD vary between 15% and 70% in the published studies (Table 25-1). A number of potential factors contribute to this variability, including the method of patient recruitment, method of diagnosing RLS (questionnaire versus interview), the ethnicity of the population, adequacy of the anemia treatment, use of intravenous iron in treatments, and the severity of RLS required for a diagnosis. There does not appear to be any difference between rates of RLS in those receiving hemodialysis from those getting peritoneal dialysis.5 There are no data on individuals with acute renal failure or on rates of RLS before dialysis dependence.

The RLS phenotype in ESRD appears to be very similar to that of primary RLS. There is some suggestion, from studies including both ESRD-related and primary RLS, that the daytime symptoms and nocturnal sleep disruption are more severe in the former and in particular the leg movements in sleep may be more pronounced.6 Nevertheless, diagnosis of RLS in ESRD is complicated by comorbid disease commonly observed in those with ESRD, particularly peripheral neuropathy. For instance, one Italian study demonstrated that a questionnaire similar to that usually used as a screening tool for RLS had modest specificity (81.6%) with low sensitivity (44.7%), giving a low positive predictive value of 47.4% in identifying ESRD patients with RLS.7 Less than half of the patients identified as having RLS by the questionnaire actually had the disorder. This raises some uncertainty about the true prevalence of RLS in dialysis, but even with these limits the best estimates indicate a very high RLS prevalence.

Dramatic ethnic variation has been reported for prevalence of ESRD-related RLS, with northern Europeans generally demonstrating higher rates than those reported in India,8 Japan,9 and Hungary.10 However, the wide variability in prevalence rates found across all ethnicities in Table 25-1 casts doubt on the validity of the often reported regional or ethnic differences in RLS prevalence. Similarly, it is unclear whether African American patients with ESRD have lower11 or the same12 rates as whites living in the same areas.

Etiology of Restless Legs Syndrome in End-Stage Renal Disease

The pathogenesis of RLS in ESRD is largely unknown, although treatment studies suggest that iron and anemia status are significant factors. A number of studies have assessed large groups of such patients and compared a variety of variables in ESRD patients with and without RLS, looking for factors that might distinguish the two groups. The majority of such analyses have been negative. Although Collado-Seidel and colleagues13 found higher parathyroid hormone (PTH) levels in ESRD patients with RLS than in those without RLS, Stepaniski and colleagues14 found the opposite result, with lower PTH levels in ESRD-related RLS patients, suggesting that this finding and that by Collado-Seidel and colleagues were probably type 1 errors resulting from inadequate statistical correction for the number of factors evaluated. Walker and colleagues15 found that BUN and creatinine levels were higher in those with RLS and ESRD, but again these results did not use statistics with adequate control for the multiple comparisons and the elevation in creatinine levels did not meet the usual criteria for statistical significance (p >.05). These results, not surprisingly, have not been confirmed in other studies. Similarly, some authors have found that duration of dialysis dependence or number of dialysis sessions predicts RLS in ESRD, whereas others have not.16,17 This disagreement cannot be explained by the problem of not correcting for multiple comparisons, but there are significant confounding factors affecting dialysis duration that likely differ between dialysis programs. Of note is that most studies have not found a consistent relationship between ESRD-related RLS and other common predictors of RLS in the general population such as age, gender, and iron indices.10,15,18,19 Similarly, although some authors have found a higher prevalence of (only) severe RLS in diabetics with ESRD,5,16 others have not.18,20 One study found an increased history of use of calcium channel blockers.21

Given the inconsistency and negative findings of the majority of investigations into correlates of RLS in ESRD, our understanding of the pathogenesis of RLS in this condition is limited to treatment studies. Extrapolation of theories regarding primary RLS pathophysiology to ESRD-related RLS seems reasonable, although little work has been performed testing such theories. For instance, no neuroimaging or neuroendocrine assessments of dopamine function have been performed in ESRD-related RLS. Although rates of familial RLS in those with ESRD appear to be similar to those in the general population,22 genetic studies, which have been of value in defining chromosomal markers in familial primary RLS, may still help define an underlying genetic predisposition to develop ESRD-related RLS.

Only cursory examination of peripheral nerve functioning has been performed in ESRD patients with RLS. The almost universal, complete, and immediate relief from RLS produced by renal transplantation does not occur for peripheral neuropathy associated with ESRD. Thus, peripheral nerve status does not seem likely to be a significant factor explaining the high rate of RLS in ESRD.

Finally, although normalization of the hematocrit with supplemental erythropoietin has been shown to reduce the PLM index during sleep,22 serum iron measures do not predict those patients with ESRD who develop RLS.15,18 However, some of the usual serum measures of iron status (e.g., ferritin) are distorted by the disease process in ESRD. Alternative evaluations available for iron as significant factors in the pathogenesis of RLS are the clinical responses to aggressive iron treatment (combined with erythropoietin) and the post-transplantation status. Fortunately, here we have better data. First, there is a blinded, placebo-controlledation study of intravenous iron administration that showed effective an dramatic reduction in RLS symptoms,23 even though iron markers were normal before intravenous iron treatment. Second, there is and anecdotal impression that rates of RLS in ESRD have decreased since the widespread adoption of supplemental intravenous iron administration combined with erythropoietin. Third, RLS rarely occurs among post-transplantation patients, but the small number with RLS have significantly lower hemoglobin levels and more ID than those without RLS.24 Further work in this area, in particular with assessment of central nervous system indices of iron storage and function, will be important. At this point, iron insufficiency is the only putative cause of RLS in ESRD that has some experimental support.

Restless Legs Syndrome Morbidity in End-Stage Renal Disease

RLS has been associated with a number of adverse outcomes in ESRD: interference with sleep, excess daytime sleepiness, premature dialysis sign-offs, reduced quality of life, increased rates of depression and anxiety disorders, and increased mortality rates. Unfortunately, most of the studies are open to the criticism of not controlling for confounding factors, and thus it is possible that some of these adverse outcomes may not be caused by RLS.

Although it is not a criterion for RLS, sleep disturbance is one of the most salient symptoms of RLS, and the one that often drives patients to seek treatment. All studies examining self-reported sleep in patients with RLS in ESRD have demonstrated severe impairments in sleep, including difficulty falling asleep, frequent nocturnal awakenings, early morning awakening, and shortened total sleep time, with some data suggesting worsened sleep with increasing severity of RLS.3 Studies using polysomnography to assess sleep in ESRD patients with RLS have generally shown prolonged sleep latency, increases in the percentage of light sleep (stages I and II), and reductions in total sleep time and sleep efficiency,22,25 which is similar to the sleep of RLS patients in general.25 ESRD patients with RLS also consistently take more hypnotic medications than those without RLS.5,14,16,17

The sleep disturbance in these patients is certainly a result of the sensory dysesthesia and motor restlessness present during wake but may also be related to periodic leg movements of sleep (PLMS), which are present in the majority of RLS patients but also in some patients with ESRD without RLS. In those with ESRD and RLS, the index of PLM per hour of sleep has been noted to be higher than in idiopathic RLS and to be inversely correlated with reports of subjective sleep quality,24 as well as to quality of life.26

Excessive daytime sleepiness (EDS) is present in 30% to 50% of patients with ESRD, by either physiologic (Multiple Sleep Latency Test [MSLT]) or subjective (Epworth Sleepiness Scale [ESS]) measurement.27,28 Although other features of ESRD, such as blood urea nitrogen,22 and obstructive sleep apnea, certainly relate to this finding, it appears that RLS and/or PLMS is closely associated to patients’ EDS. Both Hui and coworkers29 and Gigli and coworkers20 found an association between ESRD patients with RLS and excessive daytime sleepiness, the latter reporting that scores on the ESS greater than 9 were over five times (16% versus 3%) as likely for those patients reporting RLS as for those without these symptoms. Nevertheless, the average ESS values reported (of ≅4) are certainly within the normal range. PLMS may also relate to daytime sleepiness. Hanly and coworkers28 investigated 24 patients with ESRD and found that the PLM index was significantly and substantially higher in those with EDS than those without EDS (57 versus 6 per hour of sleep), whereas multiple indices of sleep apnea severity were not significantly associated with measures of daytime sleepiness. Stepanski and coworkers,14 in a smaller group of ESRD patients without obstructive sleep apnea, found similar results.

Compliance with hemodialysis (hemodialysis) treatments, which requires relative immobility for 4 hours, 3 times per week, is suboptimal for the general group of patients with ESRD. Roughly 8% of patients in the United States miss at least one hemodialysis session per month, and nearly 20% shorten a session by at least 10 minutes.30 However, for those with RLS, adherence to hemodialysis is one of the most frustrating and uncomfortable aspects of their life. Winkelman and coworkers18 found that reported premature discontinuation of dialysis was substantially more likely in patients with ESRD-related RLS compared with those without RLS (p <.0001). Nonadherence with the dialysis prescription has been associated with a variety of poor intermediate outcomes (e.g., hospitalization), as well as with premature mortality, the latter being 14% to 30% more likely with just one skipped session per month.24,26,3032

The studies with an adequate sample size (more than 10 RLS patients) have shown that multiple features of quality of life are worse in patients with ESRD-related RLS than in those without RLS.5,26 Unruh’s5 epidemiologic study of 145 patients with RLS found that mental health composite scores and vitality were substantially worse in those with RLS, even after controlling for sleep quality. Mucsi and associates33 also found that a kidney disease–specific quality of life was impaired in those with RLS, compared with those without RLS, even after controlling for sleep quality.

The two reports of increased mortality in ESRD-related RLS and a similar finding in ESRD patients with PLMS are possibly the most important and surprising findings related to consequences of RLS. Winkelman and associates18 first reported a significantly higher mortality rate (odds ratio = 1.85) at 2-year follow-up in ESRD patients with at least moderate RLS compared with those without RLS (total N = 204), which remained significant even after controlling for age, gender, and duration of dialysis (p <.02) (Fig. 25-1). Unruh and associates5 replicated this finding in a study of 894 patients with ESRD, even after controlling for multiple potential confounds including coincident disease burden, although the increased mortality risk was present only for those with severe RLS (hazard ratio = 1.39). Benz and associates34 also found elevated mortality rates in those ESRD patients with elevated rates of PLMS by overnight polysomography.

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FIGURE 25-1. Increased mortality in those end-stage renal disease patients with restless legs syndrome compared with those without restless legs syndrome.

Reprinted with permission from Winkelman JW, Chertow GM, Lazarus JM. Restless legs syndrome in end-stage renal disease. Am J Kidney Dis 1996;28:372-378.

The causes of this increased mortality in ESRD-related RLS are unclear. The deaths in the Unruh study were not accounted for by an increased mortality from cardiovascular disease or withdrawal of dialysis. Possibilities include a direct effect of RLS, PLMS or poor sleep on longevity, increased rates of sign-offs in RLS leading to increased mortality, or that RLS is a marker for more advanced ESRD. Although the connection with dialysis nonadherence is tantalizing, Unruh’s patients with severe RLS had the same adequacy of dialysis as those without RLS, suggesting that underdialysis was not related to their increased mortality. These issues are obviously of substantial importance in this population, and future studies should address whether effective treatment of RLS improves both hemodialysis adherence and long-term survival.

Work-up of the End-Stage Renal Disease Patient With Restless Legs Syndrome

Once the diagnosis of RLS is made in a patient with ESRD, an evaluation for potential underlying causes and/or important comorbidities is recommended. The primary reversible causes of RLS in this population are ID and medications. Iron deficiency is common in patients on hemodialysis and is believed to be related to chronic phlebotomy, dialysis-related blood loss, and hemolysis.35 It may have become more pronounced since the introduction of erythropoietin administration. Its importance is underscored by its association as an independent predictor of dialysis sign-offs.18 Iron deficiency is assessed in different ways in patients with ESRD than in those with primary RLS, given the unreliability of a ferritin determination as a reflection of underlying iron status, due to its role as an acute phase reactant. For this reason, morning fasting serum iron and transferrin saturation are commonly used.36

A variety of medications can exacerbate RLS, including serotonergic antidepressants,37 dopaminergic antagonists,38

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