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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2016  |  Volume : 27  |  Issue : 4  |  Page : 685-691
Prevalence and correlates of Willis-Ekbom's disease/restless legs syndrome in patients undergoing hemodialysis


1 Department of Medicine, Himalayan Institute of Medical Sciences, Swami Ram Nagar, Doiwala, Dehradun, India
2 Department of Psychiatry and Sleep Clinic, Himalayan Institute of Medical Sciences, Swami Ram Nagar, Doiwala, Dehradun, India
3 Department of Nephrology, Himalayan Institute of Medical Sciences, Swami Ram Nagar, Doiwala, Dehradun, India

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Date of Web Publication5-Jul-2016
 

   Abstract 

Willis-Ekbom's disease/restless legs syndrome (WED/RLS) has been described in subjects undergoing hemodialysis (HD). Different studies have reported varying prevalence rates and different factors associated with this condition; however, the results are inconsistent. Thus, this study was conducted to assess the prevalence of WED/RLS in patients undergoing HD. Another aim of the study was to identify if any comorbidities or biochemical factors were associated with this condition. A total of 194 adult patients undergoing maintenance HD were included in this study. They were screened for WED/RLS using International RLS Study Group criteria on the face-to-face interview and clinical examination. Most recent laboratory parameters were gathered from the medical records. In addition, seroreactivity to hepatitis B and C was also recorded. The mean age of all the subjects included in the study was 54.4 ± 15 years (range: 18-92 years); 58.2% were males. The mean duration on HD was 36.6 ± 19.3 months. WED/RLS was seen in 5.2% of the study subjects. Subjects with and without WED/RLS were comparable with regard to gender (P = 0.23), adequacy of dialysis (P = 0.82), shift of dialysis (P = 0.93), presence of diabetes mellitus (P = 0.91), hypertension (P = 0.26), smoking (P = 0.22), alcohol use (P = 0.45), and reactivity to hepatitis C (P = 0.19) and hepatitis B (P = 0.80), as well as various hematological and biochemical parameters. The prevalence of WED/RLS of 5% in the HD group was higher than in the general population. However, this study could not find any correlation between RLS and any biochemical parameters or comorbidities. This is an important area to be considered in future and requires more work with larger sample size.

How to cite this article:
Bathla N, Ahmad S, Gupta R, Ahmad S. Prevalence and correlates of Willis-Ekbom's disease/restless legs syndrome in patients undergoing hemodialysis. Saudi J Kidney Dis Transpl 2016;27:685-91

How to cite this URL:
Bathla N, Ahmad S, Gupta R, Ahmad S. Prevalence and correlates of Willis-Ekbom's disease/restless legs syndrome in patients undergoing hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2021 Dec 8];27:685-91. Available from: https://www.sjkdt.org/text.asp?2016/27/4/685/185224

   Introduction Top


Restless legs syndrome (RLS), recently named as Willis-Ekbom's disease (WED), is a common, yet unrecognized, disorder affecting 7-11% of the adult population. [1],[2] Certain conditions pre-dispose a person to have WED/RLS including increasing age, female gender, anemia, pregnancy, rheumatoid arthritis, and chronic kidney disease (CKD). [2],[3] Studies have reported a prevalence of 21-60% of WED/ RLS in patients on hemodialysis (HD), which is higher than in the general population. [4],[5],[6],[7]

Conflicting data exist regarding the higher, [8] or comparable, [9] prevalence of RLS in renal failure not managed by dialysis and the general population. These contradictory reports question the contribution of CKD in the development of WED/RLS, as well as the factors that can be implicated. As already mentioned, the prevalence of WED/RLS is higher among CKD patients, and it further increases among patients on dialysis. [4],[5],[6],[7],[10] Frequency may vary with the type of dialysis and patients on peritoneal dialysis have been reported to have a higher frequency of WED/RLS as compared to those on HD. [11]

The biochemical factors and medical comorbidities that predispose the development of WED/RLS among dialysis patients are yet to be confirmed. Some factors thought to be associated with WED/RLS are diabetes mellitus, use of coffee, afternoon shift of dialysis, female gender, lower hemoglobin (Hb), and homocysteine. [4],[6],[12] However, a recent meta-analysis reported that WED/RLS in dialysis patients was associated with diabetes mellitus among Asians while in Caucasians, the association was strong with low Hb and low iron. [13] This meta-analysis failed to find any association between gender, age, duration of dialysis, creatinine, phosphorus, calcium, parathyroid hormone, blood urea nitrogen, albumin and body mass index, and risk of RLS/WED among dialysis patients. [13]

Recognition and screening of WED/RLS in CKD are important since this entity is associated with depression, anxiety, and sleep disturbances and with high cardiovascular morbidity. [6],[8],[11],[14],[15],[16] The difference in the methodology used to diagnose WED/RLS appears to be the cause of the contradictory findings reported in the earlier studies. Few studies have used the International RLS Study Group (IRLSSG) criteria through questionnaire, while others have used the standardized questionnaire; some others have relied on the clinical diagnosis of WED/RLS. [4],[8],[9],[13]

Considering the inconsistent literature in this area, we planned to study to find out the prevalence of WED/RLS among subjects under-going maintenance HD. We also analyzed the risk factors associated with WED/RLS in these patients.


   Patients and Methods Top


This study was conducted after obtaining approval from the Ethics Committee in the dialysis unit of a teaching hospital. Consecutive adult patients (age >18 years) attending the dialysis unit for maintenance dialysis were included in this study. All patients undergoing HD were requested to participate in the study after explaining them the rationale of the study. A written informed consent was acquired from those who agreed to participate in this study. However, subjects who were unwilling to participate, having chronic pain for any reason, were using hypnotic medications or taking any drug that could induce sleep, those with impaired cognition, unable to respond to the questionnaire, having psychotic illness, and having a previous diagnosis of sleep apnea or parasomnia were excluded from the study.

Demographic data of the subjects were recorded and their weight was recorded. Diagnosis and staging of CKD were made according to the standard criteria. [17] Details regarding the etiology and duration of CKD, the presence of comorbidities such as smoking, alcohol consumption, diabetes, and cardiovascular disorders were recorded. In addition, data related to the shift of dialysis (day/evening/night), frequency of dialysis per week, and duration of dialysis were retrieved from the records of the patients. Most recent laboratory data (within last 14 days), for example, Hb, albumin, total iron binding capacity (TIBC), serum iron, kidney function tests [blood urea nitrogen (BUN) and serum creatinine (SCr)], serum albumin, calcium, phosphorous, and potassium were also gathered from the medical records. In addition, seroreactivity to hepatitis B and C was also recorded.

Diagnosis of WED/RLS was made according to the criteria proposed by IRLSSG on clinical interview and examination. [18] Severity of WED/RLS was assessed using the Hindi version of international RLS severity rating scale (IRLS). [19],[20]


   Statistical Analysis Top


The analysis was performed using Statistical Package for the Social Science (SPSS) software version 21 (IBM Corp. Released 2012, IBM SPSS Statistics for Windows, version 21.0. Armonk, NY, USA). Differences between categorical variables were analyzed using the Chi-square test or the two-tailed Fisher's exact test as appropriate. Independent sample t-test was used to compare the means between those with and without WED/RLS. However, wherever the data were skewed, for example, serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum TIBC, and serum iron, Mann-Whitney U-test was used.


   Results Top


A total of 194 patients undergoing maintenance HD were included in this study. The mean age of all the subjects included in the study was 54.4 ± 15 years (range: 18-92 years). Exactly 58.2% of the subjects were males; 45.4% had diabetes mellitus, 76.3% had a history of hypertension, 25.8% were smokers, and 17.5% were social drinkers.

The mean duration on HD was 36.6 ± 19.3 months. The mean glomerular filtration rate (GFR) using the Cockcroft formula was 14.9 ± 8.8 mL/min/1.73 m 2 suggesting that 63.9% of the subjects fell under stage-5 CKD.17 Of the 194 subjects studied, only 56.7% were undergoing adequate dialysis in terms of duration and frequency. The scheduling of dialysis was in three sessions a day, 46.4% were dialyzed in the daytime, 18% in the evening, and 35.6% in the night shift.

Willis-Ekbom's disease/restless legs syndrome in the study population

WED/RLS was seen in 5.2% of subjects in this study. Subjects with WED/RLS and the control group were comparable with regard to gender (P = 0.23), adequacy of dialysis (P = 0.82), shift of dialysis (P = 0.93), presence of diabetes mellitus (P = 0.91), hypertension (P = 0.26), smoking (P = 0.22), alcohol use (P = 0.45), reactivity to hepatitis C (P = 0.19), and hepatitis B (P = 0.80). Interestingly, all WED/RLS cases were nonreactive to hepatitis B and C. Seven subjects had moderately severe WED/ RLS, while the others had severe WED/ RLS.

Serum iron was available for 91 subjects without WED/RLS and seven subjects with these symptoms. However, we did not observe any difference between the two groups (76.2 ± 30.8 μg/dL with WED/RLS vs. 84.7 ± 36 μg/dL in controls; P = 0.85). Similarly, TIBC was available for seven cases with WED/RLS and 90 controls. This also did not show any difference (267.8 ± 96.7 μg/dL with WED/RLS vs. 271 ± 135.4 μg/dL in controls; P = 0.87) [Table 1]).
Table 1: Comparison of hematological and biochemical characteristics of patients with and without WED/RLS.

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   Discussion Top


This study showed that WED/RLS was seen in a small proportion of patients undergoing HD. Moreover, none of the factors that have been described earlier in association with WED/RLS were found in this study group.

Many of the studies performed earlier in this patient group have used the questionnaire to diagnose the WED/RLS, and this could be one reason behind the high reported the prevalence of WED/RLS. [14].[21],[22] It was reported earlier that the diagnosis of WED/RLS fell to 4.5% after clinical examination and face-to-face interview from 21% on the questionnaire based results. [9]

Similar results have been reported in an epidemiological study as well. [23] Although, limb pain has been reported by a significant proportion of dialysis patients, yet the prevalence of WED/RLS is low. [24] Hence, there is a higher chance of false diagnosis of WED/RLS upon questionnaire-based screening. The low prevalence in the present study could be related to the clinical diagnosis of WED/RLS instead of using the questionnaire. However, to suggest that the technique used to diagnose WED/RLS is the only reason for varied results reported across studies is questionable as the studies which have followed a similar method of assessment have reported different prevalence rates. [23] Thus, some other factors are also thought to play a role.

In addition to the reason mentioned above, the difference in results could be related to many other demographic factors as even in the general population, the prevalence of WED/ RLS has varied to a great extent. [23] Studies on the prevalence of WED/RLS in HD patients are varied in terms of age-groups, gender distribution and ethnicity, geographical areas of the study subjects, their etiologies, and severity of CKD in addition to the duration on HD. [4],[21],[22],[25],[26] While studies from East Asia have reported lower prevalence like ours, [8],[25] studies from Arab countries have reported a higher prevalence, similar to studies from the Western world. [4],[22],[27] Thus, besides race/ethnicity, lesser recognition of WED/RLS as a disturbing medical condition and hence, lower reporting to the health professionals might be additional reasons for its low prevalence in our study. [1] Although the prevalence of WED/RLS among patients on HD was lower in the present study as compared to similar studies, it was higher than in the general population in similar geographical region, suggesting an association between CKD and/or HD and WED/RLS. [28]

In our study, the mean age was 56 years with a slight male preponderance, nearly half had diabetes and were on maintenance HD on an average for three years. An earlier study with similar prevalence as ours also had younger subjects with shorter duration on dialysis, [25] while another study observed that patient characteristics were almost similar to ours, except for a higher frequency of diabetes mellitus. [21]

Yet another study with higher prevalence of WED/RLS had included older subjects with longer duration on HD. [26] Thus, it appears that although age, gender, duration of dialysis, and diabetes mellitus in isolation may not significantly contribute to the development of WED/RLS in HD patients, they interact in a yet unidentified manner within themselves and with other unknown factors.

Contradictory data exist for the role of Hb, serum iron, serum TIBC, and serum ferritin in causing/contributing to WED/ RLS in CKD subjects. While some studies have shown that reduced iron stores and low Hb were associated with WED/RLS in patients with CKD, [22] others failed to find this association. [21],[22],[25],[26] Iron is an important factor for the synthesis of dopamine, [29],[30] but results reported across many studies suggest that depleted iron stores alone may not have a role in the pathogenesis of WED/RLS, especially in HD patients. This is further corroborated by the observation that the prevalence of WED/RLS in CKD patients was comparable to the general population, despite the observation that CKD patients have higher chances to be iron deficient as compared to general population. [9],[31] A few studies used ferritin, an acute phase reactant as a biomarker for iron deficiency, which may also lead to an under-estimation of the prevalence. [32] Thus, the relationship between the WED/RLS and iron metabolism in CKD and HD is confounded by many variables, and this issue requires further research.

A recent meta-analysis has found an association between diabetes mellitus and WED/RLS among Asian patients with CKD; we did not observe any such association. [13] Theoretically, diabetes mellitus may influence the expression of WED/RLS as it influences dopamine synthesis; however, in view of the contradictory evidence, it cannot be considered a causal pathway. [13],[4],[9],[26],[27]

Like some other studies, this study did not find any difference in the biochemical profile including BUN and SCr between subjects with and without WED/RLS, negating the proposed association with uremia through the development of uremic neuropathy as reported in some studies. [21],[26],[27]

Dialysis leads to a large amount of electrolyte shift and can directly or indirectly affect dopamine synthesis by influencing the cellular and subcellular process. [29],[33] This could be one reason behind the increased frequency of WED/RLS symptoms seen in dialysis patients as compared to patients with chronic renal failure but not on dialysis and also between HD and continuous peritoneal dialysis. [34]

The pathway between HD and WED/RLS remains obscure, and a multicenter study following the clinical diagnosis of WED/RLS may throw some light on this issue, taking multiple other covariates such as age, gender, substance abuse, iron stores, family history of WED/ RLS, comorbidities, and medications into account. One more potential area is to look for the membrane that has been used during HD. The type of membrane in the dialyzer has been found to affect various constituents such as hepcidin, amino-acid, and albumin. [35],[36] Such an effect has never been studied, and this might unfold the underlying association between HD and WED/RLS. Alternatively, HD may induce an antigen-antibody reaction which may elucidate this association. [37] Thus, a number of yet to be defined pathways need to be investigated.

The limitations of our study were a small study population and, lack of consideration of the family history of WED/RLS due to the recall bias.


   Conclusion Top


This study showed that WED/RLS is seen in 5% of the patients undergoing HD which is more than the prevalence in the general population. Moreover, no correlation was seen between the biochemical parameters and comorbidities, and the presence of WED/RLS. This is an important area to be considered in future and requires more work with larger sample size.

Conflict of interest: None declared.

 
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Correspondence Address:
Ravi Gupta
Department of Psychiatry and Sleep Clinic, Himalayan Institute of Medical Sciences, Swami Ram Nagar, Doiwala, Dehradun - 248 140
India
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DOI: 10.4103/1319-2442.185224

PMID: 27424684

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