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Association of anxiety, sleepiness, and sexual dysfunction with restless legs syndrome in hemodialysis patients Suber DIKICI,1 Anzel BAHADIR,2 Davut BALTACI,3 Handan ANKARALI,4 Mustafa EROGLU,5 Nurten ERCAN,1 Tansu SAV6 Medical Faculty, 1Neurology Department, 2Biophysics Department, 3Family Medicine Department, Biostatistics Department, 5Duzkar Dialysis Center, 6Hemodialysis Department, Duzce University; Duzce, Turkey
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Abstract Restless legs syndrome (RLS) is characterized by unpleasant sensations, pain in the legs along with irresistible urges to move the legs when at rest. It is often accompanied by sleep disturbance. The purpose of this study was to assess the association of anxiety and sleepiness with sexual function in hemodialysis patients with and without RLS. Sociodemographic parameters, laboratory data of hemodialysis patients from three dialysis centers were collected prospectively. Anxiety, sleepiness, sexual function, and presence of RLS symptoms were assessed with standardized questionnaires as the RLS Diagnosis and Scale, Hamilton Anxiety Rating Scale, Epworth Sleepiness Scale (ESS), Arizona Sex Experiences Scale (ASEX). Univariate, regression tree method were used for statistical analysis. RLS was observed in 45.9% (n = 113) of hemodialysis patients (n = 246). The mean age of patients and duration of hemodialysis were 59.7 ± 14.0 and 4.9 ± 4.2 years, respectively. The correlation between Arizona Sexual Experiences Scale (ASEX) and sociodemographic features was significant (P < 0.0001). Patients with RLS had higher scores for anxiety (9.4 ± 7.8 with RLS and 6.8 ± 6.0 without), higher ESS (ESS, 6.6 ± 5.2 with RLS and 4.6 ± 4.0 without), and higher ASEX (24.6 ± 5.7 with RLS and 22.5 ± 6.8 without) than did those without RLS. The presence of RLS symptoms in hemodialysis patients was associated with sleepiness, anxiety, and sexual dysfunction. A regression tree method, which is a different statistical method, can help physicians estimate patients ASEX, RLS, ESS, and anxiety scores. Key words: hemodialysis, restless legs syndrome, anxiety, sexual dysfunction, regression tree method
INTRODUCTION Sexual dysfunction (SD) is a common problem in both men and women with end-stage renal disease (ESRD).1 Correspondence to: S. Dikici, MD, Duzce University, Medical Faculty, Neurology Department, Duzce, 81620, Turkey. E-mail: [email protected] Conflict of Interest: The authors have no conflicts of interest to report.
Common disturbances include erectile dysfunction in men, menstrual abnormalities in women, and decreased libido and fertility in both sexes. These abnormalities are primarily organic in nature and are related to uremia and the other comorbid conditions that occur frequently in ESRD patients. Several factors, including hormonal disturbances (hyperprolactinemia, hypothalamic–pituitary dysfunction), anemia, psychosocial factors (depression, anxiety, poor self-esteem, social withdrawal, and fear of disability and death), marital status, loss of employment
© 2014 International Society for Hemodialysis DOI:10.1111/hdi.12175
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and financial difficulties, autonomic neuropathy, some drugs (antihypertensives, antidepressants, histamine receptor blockers), and comorbid illnesses contribute to the occurrence of SD in ESRD patients.2–7 Restless legs syndrome (RLS) is characterized by uncomfortable leg lower-limb sensations that are relieved by leg movements. RLS symptoms are relatively common in the ESRD population, ranging from 12 to 58.3%.8,9 These distressing symptoms are characterized by achy, crawling sensations and paresthesias, typically in the lower extremities, which are relieved by movement of the affected limb. RLS can lead to severe insomnia, depression, anxiety, and greatly impaired quality of life.8 Some epidemiological studies have suggested that a higher prevalence of depressive symptoms is seen in adults with RLS than in those without it.10 Most studies have emphasized anxiety in adults with RLS rather than depression. The purpose of this study was to assess the association of anxiety and sleepiness with sexual function in ESRD patients with RLS. We hypothesized that anxiety, sleepiness, and RLS would be related to a lower level of satisfaction with one’s sex life in ESRD patients.
SUBJECT AND METHODS Ethical review The study was approved by the ethics committee of Duzce University. Before enrollment, all patients received detailed written and verbal information regarding the aims and the protocol of the study and signed an informed consent.
Patient’s selection and data collection Data of dialysis patients were collected from three dialysis centers in Duzce, Turkey, between January and June 2012. Patients were examined by two neurologists. The study was designed in a cross-sectional manner. A structural study consisting of the RLS Diagnosis and Scale, Hamilton Anxiety Rating Scale (HARS), Epworth Sleepiness Scale (ESS), and Arizona Sex Experiences Scale (ASEX) was used, with previously trained physicians interviewing the patients. Additionally, sociodemographic data (age, gender, height, weight, body mass index (BMI), education level, income level, jobs, smoking frequency, and duration of dialysis treatment) were recorded in study questionnaire form with face to face interview. Income level was determined according to Institute of Turkish Statistics (TUIK).11 Inclusion criteria were hemodialysis treatment
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for at least 3 months and informed consent. Exclusion criteria were recent infectious disease; cancer; drug abuse or excessive alcohol intake; severe neurological, pulmonary, hepatic or cardiac disease; recent hospitalization; and confusion or dementia. Also, patients who refused to participate were excluded. Laboratory data collected included hemoglobin, hematocrit, ferritin, phosphorus and calcium levels, parathyroid hormone, (alkaline phosphotase, ALP), high-sensitivity C-reactive protein, and albumin levels.
Assessment of RLS Information about RLS symptoms was obtained using four questions proposed by The International Restless Legs Syndrome Study Group for clinical diagnosis of RLS.12 All four of these criteria must be met for RLS to be diagnosed: 1. Urge to move the legs (usually accompanied or caused by uncomfortable and unpleasant sensations in the legs). 2. Onset of unpleasant sensation or worsening of symptoms at rest or inactivity, as in lying or sitting. 3. Partial or total relief from symptoms by movement. 4. Symptoms are worse in the evening or at night. Supporting clinical features include positive family history, positive response to dopaminergic therapy, and presence of periodic limb movements during wakefulness or during sleep.13 It was determined that all questions should have a similar format. Each question had a set of five response options graded from no RLS or impact (score one-fourth 0) to very severe RLS or impact (score one-fourth 4). This produced a total scale whose overall score could range from 0 to 40 (see list in Appendix 1).
Assessment of anxiety symptoms To assess the presence and degree of anxiety symptoms, we used HARS. HARS consists of 14 items assessing physical, psychological, and behavioral aspects of anxiety. The time reference in this case includes the last few days for all items except the last, which assesses patient state during the actual interview. HARS was administered by an expert clinician. The score on this scale ranges from 0 to 56 points. The recommended cut-off points are as follows: 0–5 points, no symptoms of anxiety; 6–14 points, mild symptoms of anxiety; and >15 points, moderate to severe symptoms of anxiety.14
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Assessment of sleepiness Dialysis patients were asked about symptoms of excessive daytime sleepiness using the ESS, on which a score of more than 10 points indicates increased sleepiness.15
Assessment of sexual activity To assess sexual activity, the Arizona Sexual Experiences Scale (ASEX), which consists of five items, was used. It is a quick scale to administer and requires no special training in terms of interpretation. ASEX may provide advantages as a screening and assessment instrument in hemodialysis patients as it is designed to assess the core elements of sexual function: drive, arousal, penile erection/vaginal lubrication, ability to reach orgasm, and satisfaction with orgasm. Each item is rated with a 6-point Likert system, with higher scores reflecting impaired sexual function. The maximum score is 30. The ASEX score was found to be negatively correlated with SD.16 We used the ASEX scale in this study based on its reliability and validity.17
Statistical analyses Statistical analyses were conducted on a total of 246 patients. Two patients refused to complete the ASEX questionnaire.
Diego, CA, USA) trial software was used for RTM. Five categorical and 16 continuous variables were used to estimate the ASEX score by RTM.
RESULTS Results of univariate analyses In total, 246 patients (aged 19–96 years, mean age 59.74 ± 13.9) were included. Of the patients, 50.2% were male (n = 124) and 49.8% were female (n = 122). Their mean duration of dialysis treatment was 4.87 ± 4.16 years (median = 3, range = 20.5). Clinical and laboratory characteristics of the patients are presented in Table 1. RLS was observed in 45.9% (n = 113) of 246 patients on dialysis. Similar symptoms were recorded in families of 3.7% of patients with RLS. In the patients, comorbid disease were 118 (48.2%) hypertension, 20 (8.1%) diabetes mellitus, 71 (28.7%) both hypertension and diabetes mellitus, 18 (7.3%) renal dysfunction and 19 (7.7%) of the etiology was unknown. The ASEX scores that have only hypertension, only diabetes mellitus, and both hypertension and diabetes mellitus in hemodialysis patients were Table 1 Clinical and laboratory characteristics of patients included in the study Numerical variables
Univariate analysis Descriptive statistics for numerical and categorical variables were computed as means ± standard deviation, and frequencies (count, percentage). Correlation analysis was used for relationships between numerical variables. Oneway analysis of variance followed by a post hoc Tukey’s test was used for differences among the categories for categorical variables with regard to the Arizona scale scores. P values ≤ 0.05 were deemed to indicate statistical significance. PASW software (ver. 18; SPSS Inc., Hong Kong, China) was used for statistical calculations. Regression tree method (RTM) The RTM is a tree-based model that is more useful than traditional methods when the dataset is large and when the number of variables is high. Moreover, RTM does not ignore interactions among factors and is not affected by high correlations among risk factors. Backward pruning was applied to eliminate problems with overfitting. The cost-complexity parameter was taken into consideration in the pruning process. Optimal tree is determined by cross validation.18 Classification and Regression Tree (CART) programme, (ver. Trial, 6.0; Salford Systems, San
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Hb Htc Ferritin Albumin PTH ALP Ca P hsCRP Age Systolic blood pressure Diastolic blood pressure Duration of dialysis (years) Mean ± SD Median (range, IQR) RLS Scale HARS ASEX Scale ESS Scale
Mean ± SD (n = 247) 11.1 ± 1.3 33.6 ± 4.1 754.7 ± 440.5 3.8 ± 0.4 417.5 ± 391.2 142.3 ± 93.3 8.4 ± 0.8 5.1 ± 1.4 18.1 ± 21.2 59.7 ± 14.0 127.7 ± 24.2 77.4 ± 12.4 4.9 ± 4.2 3 (range =20.5, IQR = 5) 8.1 ± 9.7 8.0 ± 7.0 23.4 ± 6.4 5.5 ± 4.7
ALP = alkaline phosphotase; ASEX = Arizona Sex Experiences Scale; Ca = calcium; ESS = Epworth Sleepiness Scale; HARS = Hamilton Anxiety Rating Scale; Hb = hemoglobin; hsCRP = high-sensitivity C-reactive Protein; Htc = hematocrit; IQR = interquartile range; PTH = parathyroid hormone; RLS = restless legs syndrome.
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Table 2 Linear correlations between demographic features and HARS, RLS, ESS, and ASEX scores Scales HARS Demographic features and scales Age BMI Duration of dialysis(years) HARS RLS ESS
r
0.231
RLS P
ESS
r
P
0.136 0.126 0.145 −0.184
.033 .049 .023 .004
.0001
r
ASEX P
0.151 0.206
.017 .001 —
r
P
0.554 0.126
.000 .049
0.260 0.217 0.077
.0001 .0001 .229
ASEX = Arizona Sex Experiences Scale; BMI = body mass index; ESS = Epworth Sleepiness Scale; HARS = Hamilton Anxiety Rating Scale; RLS = restless legs syndrome.
23.3 ± 6.5, 24.6 ± 6.5, and 25.0 ± 5.5, respectively. However, ASEX scores did not show statistically significant differences among them. Correlations between sociodemographic features and scales are presented in Table 2. Scores on the RLS scale were correlated with HARS (r = 0.231, P < 0.001) and ASEX (r = 0.217, P = 0.001) scores, and ASEX was also positively correlated with HARS (r = 0.260, P = 0.001). Furthermore, RLS was positively correlated with age (r = 0.554, P < 0.001) and duration of hemodialysis (r = 0.145, P = 0.023). HARS scores in patients with RLS were higher than were those in patients without RLS (9.4 ± 7.8 vs. 6.8 ± 6.0). ESS and ASEX scores were found to be higher in patients with RLS than in those without RLS. Mean ESS scores were 6.6 ± 5.2 and 4.6 ± 4.0 in patients with and without RLS, respectively, and mean ASEX scores were 24.6 ± 5.7 and 22.5 ± 6.8 in patients with and without RLS, respectively (Table 3). The relationships of ASEX scores with education level, occupation, marital status, and income level were investigated, and these results were significant (P < 0.0001; Table 4). ASEX scores in illiterate patients were significantly higher than in those patients with primary school, high school, and university education levels (P < 0.0001, Table 3 Comparison of HARS, ASEX and ESS in patients with and without RLS Presence of RLS Scales
With RLS
Without RLS
P
HARS ASEX ESS
9.4 ± 7.8 24.6 ± 5.7 6.6 ± 5.2
6.8 ± 6.0 22.5 ± 6.8 4.6 ± 4.0
354.50. 4. The median value of Terminal Node 10 was 18: occupation is not housewife, age >72.50, and RLS >20.50. 5. The median value of Terminal Node 7 was 20: occupation is not a housewife, 53 < age ≤ 72.50, and ESS ≤8.50. 6. The median value of Terminal Node 8 was 26: occupation is not a housewife, 53 < age ≤ 72.50, and ESS >8.50. 7. The median value of Terminal Node 3 was 27. occupation is housewife, married, HARS >3.5, and ALP ≤354.5 8. The median value of Terminal Node 2 was 30: occupation is housewife, married, HARS ≤3.5 and age >58. 9. The median value of Terminal Node 5 was 30: occupation is housewife, marital status is other. 10. The median value of Terminal Node 9 is 30: occupation is not housewife, age >72.50, and RLS ≤20.50 (Figure 1). When the median values of the 10 groups were compared using the Kruskal-Wallis test followed by the non-parametric Dunn’s test, we obtained the results shown in Table 3. Significant differences are marked with an asterisk (Table 5). Additionally, the correlation coefficient between the observed and predicted values obtained from the optimal tree for the ASEX score was found to be 0.80 (P < 0.001). The determination coefficient was 64.0%, and the intraclass correlation coefficient was 0.792. These results indicated that the optimal tree was successful in predicting the ASEX score.
Table 5 Significance of the differences between the terminal nodes Terminal Node Number
2
3
4
5
6
7
8
9
10
1 2 3 4 5 6 7 8 9
*
* —
— — —
* — * *
— * * — *
— * * — * *
* — — — * * *
* — — * — * * —
— — * — * — — — *
*Asterisk indicates significantly different terminal nodes.
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AGE ≤ 58.00 Terminal Node 2 MAD = 3.833 Med = 6.000 W = 9.00 N=6
ALP ≤ 354.50 Terminal Node 3 MAD = 3.041 Med = 27.000 W = 49.00 N = 49
ALP ≤ 354.50 Terminal Node 4 MAD = 1.667 Med = 18.000 W = 3.00 N=3
HAMLTON ≤ 3.50 Node 5 ALP ≤ 354.50 MAD = 3.365 Med = 27.00 W = 52.00 N = 52
MARTAL_STATUS = (2,3) Terminal Node 5 MAD = 0.429 Med = 30.000 W = 49.00 N = 49
AGE ≤ 53.00 Terminal Node 6 MAD = 3,390 Med = 15.000 W = 41.00 N = 41
ESS ≤ 8.50 Terminal Node 7 MAD = 3.535 Med = 20.000 W = 43.00 N = 43
RLS ≤ 20.50 Terminal Node 10 MAD = 2.333 Med = 18.000 W = 3.00 N=3
AGE ≤ 72.50 Node 9 RLS ≤ 20.50 MAD = 3.238 Med = 27.000 W = 21.00 N = 21 RLS ≤ 20.50 Terminal Node 9 MAD = 2.222 Med = 30.000 W = 18.00 N = 18
AGE ≤ 53.00 Node 7 AGE ≤ 72.50 MAD = 4.425 Med = 23.000 W = 87.00 N =87
ESS ≤ 8.50 Terminal Node 8 MAD = 3.087 Med = 26.000 W = 23.00 N = 23
AGE ≤ 72.50 Node 8 ESS ≤ 8.50 MAD = 4.045 Med = 21.000 W = 66.00 N = 66
OCCUPATION = (2,3,4,5,6) Node 4 AGE ≤ 53.00 MAD = 5.141 Med = 20.000 W = 128.00 N = 128
Figure 1 Risk factors of the Arizona Sex Experiences Scale (ASEX) according to optimum regression tree. ALP = alkaline phosphotase; ESS = Epworth Sleepiness Scale; MAD = median absolute differences; Med = median; N = number of observations; RLS = restless legs syndrome; W = weight.
AGE ≤ 58.00 Terminal Node 1 MAD = 4.444 Med = 16.000 W = 9.00 N=9
HAMLTON ≤ 3.50 Node 4 AGE ≤ 58.00 MAD = 5.800 Med = 20.000 W = 15.00 N = 15
MARTAL_STATUS = (1) Node 3 HAMLTON ≤ 3.50 MAD = 4.537 Med = 26.000 W = 67.00 N = 67
OCCUPATION = (1) Node 2 MARTAL_STATUS = (1) MAD = 3.474 Med = 30.000 W = 116.00 N = 116
Node 1 OCCUPATION = (1) MAD = 5.496 Med = 25.000 W = 244.000 N = 244
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DISCUSSION RLS is a common disorder in Europe and North America.19 In contrast, the prevalence of RLS in Asia was estimated to be less than 4%,19 and the prevalence in Turkey was found to be 3.19%.20 In this study, patients were asked about RLS-related symptoms in their families. Similar symptoms were observed in the families of 3.7% of the patients with RLS. This was consistent with the previously reported prevalence in Turkey. We detected RLS in 45.9% of the patients enrolled in the present study. Szenykiralyi et al. found that depressive symptoms were twice as common in patients with RLS as in those without RLS symptoms in a large cohort of patients with ESRD.21 In our study, a high ESS score was associated with increased RLS frequency, and high ASEX scores in patients with RLS indicated that their sex lives were adversely affected. According to RTM, when occupation = housewife, marital status = married, and HARS > 3.5, the ASEX score was low (median = 27), but when the HARS < 3.5, the ASEX score was high (median = 20). According to this result, it appeared that when HARS increased, the ASEX score also increased. Furthermore, we demonstrated that this association was independent of insomnia, and the presence of RLS symptoms was still significantly associated with anxiety. The relationship between RLS symptoms and anxiety is not completely explained by impaired sleep; sleep-independent mechanisms likely contribute to this relationship too. Insomnia is a risk factor for anxiety, and RLS contributes to insomnia.22 Poor sleep quality could be considered an independent risk factor for the development of anxiety. Some potential mechanisms may help explain the sleepindependent relationship between RLS and anxiety. Concerns about physical safety, security, the sense of freedom, fatigue, social isolation, helplessness, and pain are common symptoms of RLS, and these problems may predispose patients to anxiety. Failure to receive appropriate diagnosis and treatment for RLS may also contribute to frustration, anxiety, and depression with ESRD.22,23 Based on the RTM data, the ASEX score was 20.0 in 43 patients aged >53 and ≤72.5, and their ESS score was ≤8.50. The ASEX score was 26.0 in 23 patients whose ESS was >8.50. Accordingly, low ESS was associated with low ASEX score. This suggests that increased sleepiness during the daytime negatively affects patients’ sex lives. Correspondingly, based on the RTM data, the ASEX score was 21 in 62 patients aged >53 and ≤72.5, and it was 27 in 21 patients aged >72.0. Accordingly, ASEX was negatively affected by increased age. Age is an important
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factor for sexual satisfaction.2,3 SD was determined to be more prevalent in women (43%) than in men (31%) and was associated with a variety of demographic characteristics. Although the survey examined a variety of demographic and lifetime experiences in the participants of the study, it did not examine any impact of medications. Some information is available for individuals with ESRD treated with hemodialysis.24 Mean ASEX scores for women and men in our study were 26.3 ± 5.4 and 20.6 ± 6.1, respectively. Lower ASEX scores in male vs. female patients in this study were consistent with previous reports.7,23 In the present study, the frequency of RLS increased with age and dialysis duration. This led us to consider that dialysis could be a facilitating factor in RLS development. The highest ASEX scores (median = 30) were seen in those aged >72, people with an occupation other than housewife, and RLS values 20.5, the ASEX score was lower. However, the numbers of subjects was too small to make generalizations. Our results are consistent with these conclusions. RLS was associated with increased ESS, PSQ, and ASEX scores, and insomnia showed a strong, independent relationship with anxiety and SD. It has been reported that dopamine levels decrease in anxiety disorders.25 It is possible that the relationship between anxiety and RLS symptoms may be explained by an as-yet unknown confounding cause. Abnormalities in dopaminergic neurotransmission in the brain may be involved in the pathomechanism of RLS and anxiety. The sexual act involves central and peripheral mechanisms. Several mediators are involved in the central mechanisms. It is well established that noradrenaline, serotonin, and dopamine are involved in the central mechanisms.26 Decreases in dopamine levels, responsible for central mechanisms, could also be involved in the etiopathogenesis of RLS and SD. SD is a frequent finding in ESRD patients. Uremiaassociated hypogonadism is multifactorial in origin and rarely improves with the initiation of dialysis, although it usually normalizes after renal transplantation. Experimental and clinical evidence suggest that testosterone may have important clinical implications with regards to kidney disease progression; changes in sexual drive, libido, and erectile function; development of anemia; impairment of muscle mass and strength; and the progression of atherosclerosis and cardiovascular disease. Dopamine agonist therapy is one treatment option.27 It has been reported that plasma dopamine-βhydroxylase levels are lower in patients with ESRD than in healthy individuals, suggesting lowered sympathetic
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activity and/or abnormalities in release, distribution, or metabolism in RLS.28 This may explain why RLS was frequently seen in patients with ESRD accompanied by anxiety. In our study, 61.9% of patients had HARS scores above 5. Furthermore, anxiety was observed in 62.2% of patients with RLS. Meanwhile, the ASEX scores in patients with RLS were higher than in those without RLS. This may be explained by a high dopamine level. It is well known that sleep disturbances increase the risk of anxiety. Indeed, experiences associated with ESRD include stress, waiting for diagnostic procedures, time spent in ambulatory care and/or a day hospital, and new therapies or therapy switches, and it is well known that these conditions may be associated with alterations in mood and with anxiety. The present results suggest the importance of investigating the possible causative role of comorbid conditions in the development of anxiety in ESRD patients. The relationships between ASEX scores and education level, occupation, marital status, and income level are shown in Table 4. An inverse relationship between ASEX score and education level was observed. In particular, patients with lower educational levels had higher ASEX scores. Similar findings have been reported in other cultural settings.23,29 A low educational level can prevent patients from implementing suggested changes, resulting in low quality of life and sexual dissatisfaction.30 Also, low income levels were correlated with high ASEX scores. In the present study, ASEX was significantly higher in female than in male patients. This may be explained by conditions unique to women. Hormonal changes are more evident in women. Childbirth, loss of self-esteem, insufficient social support, and work overload could also be reasons for higher ASEX scores in women. Furthermore, the mean score for anxiety in female patients was significantly higher than that in male patients. This could be due to generally higher anxiety in women compared with men. The most determinative factor for SD in male patients was sexual performance. Moreover, lack of knowledge, misconceptions and overblown stories are other factors that may trigger or maintain SD. Concern for high sexual performance can trigger anxiety.26 In this study, male patients who had high scores for anxiety also had high ASEX scores. Interestingly, BMI was observed to be significantly higher in patients who had higher ASEX scores. Patients with high BMI might consider themselves unattractive, and high BMI could decrease self-esteem and be accompanied by many other health problems, such as diabetes mellitus, hypertension, and obstructive sleep apnea syndrome.23
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This study has several limitations. First, assessing RLS with questionnaires does not provide clinical diagnosis of the syndrome; the results obtained should be interpreted cautiously. Also, we did not conduct an electromyographic investigation, but two neurologists examined all patients. Finally, our subject group was small and the mean age was old. In conclusion, the effects of RLS on SD were objectively assessed based on ASEX scores using RTM. In this way, SD could be assessed even in patients who refrained from sharing information about their sex lives using sociodemographic features and HARS, ESS, RLS, and ASEX scores. Thus, physicians may be able to predict the likelihood of SD in such patients.
AUTHOR CONTRIBUTIONS SD, AB, and DB carried out the design, coordinated the study, and prepared the article. HA provided statistical consultation on the study design and analysis; ME, TS, and NE contributed to the study. All authors played active parts in each stage of the study, and their roles overlapped in all domains.
Manuscript received November 2013; revised February 2014.
REFERENCES 1 Alleyne S, Dillard P, McGregor C, Hosten A. Sexual function and mental distress status of patients with end-stage renal disease on hemodialysis. Transplant Proc. 1989; 21:3895–3898. 2 Palmar BF. Sexual function in uremia. J Am Soc Nephrol. 1999; 10:1381–1388. 3 Anantharaman P, Schmidt RJ. Sexual function in chronic kidney disease. Adv Chronic Kidney Dis. 2007; 14:119– 125. 4 Finkelstein F, Shirani S, Wuerth D, Finkelstein SH. Therapy insight: Sexual dysfunction in patients with chronic kidney disease. Nat Clin Pract Nephrol. 2007; 3:200–207. 5 Kutner NG. Quality of life and daily hemodialysis. Semin Dial. 2004; 17:92–98. 6 Campese VM. Autonomic nervous system dysfunction in uraemia. Nephrol Dial Transplant. 1990; 5:98–101. 7 Naya Y, Soh J, Ochiai A, et al. Significant decrease of the International Index of Erectile Function in male renal failure patients treated with hemodialysis. Int J Impot Res. 2002; 14:172–177.
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8 Tuncel D, Orhan FO, Sayarlioglu H, Isık IO, Utku U, Dinc A. Restless legs syndrome in hemodialysis patients: Association with depression and quality of life. Sleep Breath. 2011; 15:311–315. 9 Rijsman RM, de Weerd AW, Stam CJ, Kerkhof GA, Rosman JB. Periodic limb movement disorder and restless legs syndrome in dialysis patients. Nephrology (Carlton). 2004; 9:353–361. 10 Lee HB, Hening WA, Allen RP, et al. Restless legs syndrome is associated with DSM-IV major depressive disorder and panic disorder in the community. J Neuropsychiatry Clin Neurosci. 2008; 20:101–105. 11 TUIK, Statistics. (Income, Consumption, Poverty), 2013. Available from: http://www.tuik.gov.tr/PreTablo.do?alt _id=1011 (accessed date: May 11, 2013). 12 Walters AS. Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord. 1995; 10:634–642. 13 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; 4:101–119. 14 Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959; 32:50–55. 15 Johns MW. A new method for measuring daytime sleepiness: The Epworth Sleepiness Scale. Sleep. 1991; 14:540– 545. 16 McGahuey CA, Delgado LP, Geleberg AJ. Assessment of sexual dysfunction using the Arizona Sexual Experience Scale (ASEX) and implications for the treatment of depression. Psychiatr Ann. 1999; 29:39–45. 17 Soykan A. The reliability and validity of Arizona Sexual Experiences Scale in Turkish ESRD patients undergoing hemodialysis. Int J Impot Res. 2004; 16:531–534. 18 Camdeviren H, Mendes M, Ozkan MM, Toros F, Sasmaz T, Oner S. Determination of depression risk factors in children and adolescents by regression tree methodology. Acta Med Okayama. 2005; 59:19–26. 19 Garcia-Borreguero D, Egatz R, Winkelmann J, Berger K. Epidemiology of restless legs syndrome: The current status. Sleep Med Rev. 2006; 10:153–167. 20 Sevim S, Dogu O, Camdeviren H, et al. Unexpectedly low prevalence and unusual characteristics of RLS in Mersin, Turkey. Neurology. 2003; 61:1562–1569. 21 Szentkiralyi A, Molnar MZ, Czira ME, et al. Association between restless legs syndrome and depression in patients with chronic kidney disease. J Psychosom Res. 2009; 67:173–180. 22 Theofilou PA. Sexual functioning in chronic kidney disease: The association with depression and anxiety. Hemodial Int. 2012; 16:76–81. 23 Bahar A, Savas AH, Yıldızgordu E, Barlioglu H. Anxiety, depression and sexual life of hemodialysis patients. Anatolian J Psychiatry 2007; 8:287–292.
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24 Lopes AA, Bragg-Gresham JL, Satayathum S, McCullough K, et al. Health-related quality of life and associated outcomes among haemodialysis patients of different ethnicities in the United States: The Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2003; 41:605–615. 25 Davis MM, Olausson P, Greengard P, Taylor JR, Nairn AC. Regulator of calmodulin signaling knockout mice display anxiety-like behavior and motivational deficits. Eur J Neurosci. 2012; 35:300–308. 26 Hull EM, Muschamp JW, Sato S. Dopamine and serotonin: Influences on male sexual behavior. Physiol Behav. 2004; 83:291–307. 27 Iglesias P, Carrero JJ, Díez JJ. Gonadal dysfunction in men with chronic kidney disease: Clinical features, prognostic implications and therapeutic options. J Nephrol. 2012; 25:31–42. 28 Spohr U, Ritz F, Kaden F. Dopamin-betahydroxylaseaktivität im Plasma von Dialysepatienten (author’s transl). Klin Wochenschr. 1977; 55:1089–1093. 29 Coelho-Marques FZ, Wagner MB, Poli de Figueiredo CE, d’Avila DO. Quality of life and sexuality in chronic dialysis female patients. Int J Impot Res. 2006; 18:539– 543. 30 Shifren JL, Monz BU, Russo PA, Segreti A, Johannes CB. Sexual problems and distress in United States women: Prevalence and correlates. Obstet Gynecol. 2008; 112:970–978.
APPENDIX 1 INTERNATIONAL RESTLESS LEGS SYNDROME RATING SCALE FOR SEVERITY (IRLSSGRS) THIS SCALE IS COPYRIGHTED BY THE INTERNATIONAL RESTLESS LEGS SYNDROME STUDY GROUP 2002. Rate your symptoms for the following ten questions. Unless otherwise instructed, you should rate the average symptoms that you have experienced for the most recent two week period. (1) Overall, how would you rate the RLS discomfort in your legs or arms? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None
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(2) Overall, how would you rate the need to move around because of your RLS symptoms? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None (3) Overall, how much relief of your RLS arm or leg discomfort do 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 and therefore question does not Apply (4) Overall, how severe is your sleep disturbance from your RLS symptoms? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None (5) How severe is your tiredness or sleepiness from your RLS symptoms? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None (6) Overall, how severe is your RLS as a whole? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None
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(7) How often do you get RLS symptoms? (4) Very severe (This means 6 to 7 days a week) (3) Severe (This means 4 to 5 days a week) (2) Moderate (This means 2 to 3 days a week) (1) Mild (This means 1 day a week or less) (0) None (8) When you have RLS symptoms how severe are they on an average day? (4) Very severe (This means 8 hours per 24 hour day or more) (3) Severe (This means 3 to 8 hours per 24 hour day) (2) Moderate (This means 1 to 3 hours per 24 hour day) (1) Mild (This means less than 1 hour per 24 hour day) (0) None (9) Overall, how severe is the impact of your RLS symptoms on your ability to carry out your daily affairs, for example carrying out a satisfactory family, home, social, school or work life? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None (10) How severe is your mood disturbance from your RLS symptoms—for example angry, depressed, sad, anxious or irritable? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None
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Association of anxiety, sleepiness, and sexual dysfunction with restless legs syndrome in hemodialysis patients Suber DIKICI,1 Anzel BAHADIR,2 Davut BALTACI,3 Handan ANKARALI,4 Mustafa EROGLU,5 Nurten ERCAN,1 Tansu SAV6 Medical Faculty, 1Neurology Department, 2Biophysics Department, 3Family Medicine Department, Biostatistics Department, 5Duzkar Dialysis Center, 6Hemodialysis Department, Duzce University; Duzce, Turkey
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Abstract Restless legs syndrome (RLS) is characterized by unpleasant sensations, pain in the legs along with irresistible urges to move the legs when at rest. It is often accompanied by sleep disturbance. The purpose of this study was to assess the association of anxiety and sleepiness with sexual function in hemodialysis patients with and without RLS. Sociodemographic parameters, laboratory data of hemodialysis patients from three dialysis centers were collected prospectively. Anxiety, sleepiness, sexual function, and presence of RLS symptoms were assessed with standardized questionnaires as the RLS Diagnosis and Scale, Hamilton Anxiety Rating Scale, Epworth Sleepiness Scale (ESS), Arizona Sex Experiences Scale (ASEX). Univariate, regression tree method were used for statistical analysis. RLS was observed in 45.9% (n = 113) of hemodialysis patients (n = 246). The mean age of patients and duration of hemodialysis were 59.7 ± 14.0 and 4.9 ± 4.2 years, respectively. The correlation between Arizona Sexual Experiences Scale (ASEX) and sociodemographic features was significant (P < 0.0001). Patients with RLS had higher scores for anxiety (9.4 ± 7.8 with RLS and 6.8 ± 6.0 without), higher ESS (ESS, 6.6 ± 5.2 with RLS and 4.6 ± 4.0 without), and higher ASEX (24.6 ± 5.7 with RLS and 22.5 ± 6.8 without) than did those without RLS. The presence of RLS symptoms in hemodialysis patients was associated with sleepiness, anxiety, and sexual dysfunction. A regression tree method, which is a different statistical method, can help physicians estimate patients ASEX, RLS, ESS, and anxiety scores. Key words: hemodialysis, restless legs syndrome, anxiety, sexual dysfunction, regression tree method
INTRODUCTION Sexual dysfunction (SD) is a common problem in both men and women with end-stage renal disease (ESRD).1 Correspondence to: S. Dikici, MD, Duzce University, Medical Faculty, Neurology Department, Duzce, 81620, Turkey. E-mail: [email protected] Conflict of Interest: The authors have no conflicts of interest to report.
Common disturbances include erectile dysfunction in men, menstrual abnormalities in women, and decreased libido and fertility in both sexes. These abnormalities are primarily organic in nature and are related to uremia and the other comorbid conditions that occur frequently in ESRD patients. Several factors, including hormonal disturbances (hyperprolactinemia, hypothalamic–pituitary dysfunction), anemia, psychosocial factors (depression, anxiety, poor self-esteem, social withdrawal, and fear of disability and death), marital status, loss of employment
© 2014 International Society for Hemodialysis DOI:10.1111/hdi.12175
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and financial difficulties, autonomic neuropathy, some drugs (antihypertensives, antidepressants, histamine receptor blockers), and comorbid illnesses contribute to the occurrence of SD in ESRD patients.2–7 Restless legs syndrome (RLS) is characterized by uncomfortable leg lower-limb sensations that are relieved by leg movements. RLS symptoms are relatively common in the ESRD population, ranging from 12 to 58.3%.8,9 These distressing symptoms are characterized by achy, crawling sensations and paresthesias, typically in the lower extremities, which are relieved by movement of the affected limb. RLS can lead to severe insomnia, depression, anxiety, and greatly impaired quality of life.8 Some epidemiological studies have suggested that a higher prevalence of depressive symptoms is seen in adults with RLS than in those without it.10 Most studies have emphasized anxiety in adults with RLS rather than depression. The purpose of this study was to assess the association of anxiety and sleepiness with sexual function in ESRD patients with RLS. We hypothesized that anxiety, sleepiness, and RLS would be related to a lower level of satisfaction with one’s sex life in ESRD patients.
SUBJECT AND METHODS Ethical review The study was approved by the ethics committee of Duzce University. Before enrollment, all patients received detailed written and verbal information regarding the aims and the protocol of the study and signed an informed consent.
Patient’s selection and data collection Data of dialysis patients were collected from three dialysis centers in Duzce, Turkey, between January and June 2012. Patients were examined by two neurologists. The study was designed in a cross-sectional manner. A structural study consisting of the RLS Diagnosis and Scale, Hamilton Anxiety Rating Scale (HARS), Epworth Sleepiness Scale (ESS), and Arizona Sex Experiences Scale (ASEX) was used, with previously trained physicians interviewing the patients. Additionally, sociodemographic data (age, gender, height, weight, body mass index (BMI), education level, income level, jobs, smoking frequency, and duration of dialysis treatment) were recorded in study questionnaire form with face to face interview. Income level was determined according to Institute of Turkish Statistics (TUIK).11 Inclusion criteria were hemodialysis treatment
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for at least 3 months and informed consent. Exclusion criteria were recent infectious disease; cancer; drug abuse or excessive alcohol intake; severe neurological, pulmonary, hepatic or cardiac disease; recent hospitalization; and confusion or dementia. Also, patients who refused to participate were excluded. Laboratory data collected included hemoglobin, hematocrit, ferritin, phosphorus and calcium levels, parathyroid hormone, (alkaline phosphotase, ALP), high-sensitivity C-reactive protein, and albumin levels.
Assessment of RLS Information about RLS symptoms was obtained using four questions proposed by The International Restless Legs Syndrome Study Group for clinical diagnosis of RLS.12 All four of these criteria must be met for RLS to be diagnosed: 1. Urge to move the legs (usually accompanied or caused by uncomfortable and unpleasant sensations in the legs). 2. Onset of unpleasant sensation or worsening of symptoms at rest or inactivity, as in lying or sitting. 3. Partial or total relief from symptoms by movement. 4. Symptoms are worse in the evening or at night. Supporting clinical features include positive family history, positive response to dopaminergic therapy, and presence of periodic limb movements during wakefulness or during sleep.13 It was determined that all questions should have a similar format. Each question had a set of five response options graded from no RLS or impact (score one-fourth 0) to very severe RLS or impact (score one-fourth 4). This produced a total scale whose overall score could range from 0 to 40 (see list in Appendix 1).
Assessment of anxiety symptoms To assess the presence and degree of anxiety symptoms, we used HARS. HARS consists of 14 items assessing physical, psychological, and behavioral aspects of anxiety. The time reference in this case includes the last few days for all items except the last, which assesses patient state during the actual interview. HARS was administered by an expert clinician. The score on this scale ranges from 0 to 56 points. The recommended cut-off points are as follows: 0–5 points, no symptoms of anxiety; 6–14 points, mild symptoms of anxiety; and >15 points, moderate to severe symptoms of anxiety.14
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Assessment of sleepiness Dialysis patients were asked about symptoms of excessive daytime sleepiness using the ESS, on which a score of more than 10 points indicates increased sleepiness.15
Assessment of sexual activity To assess sexual activity, the Arizona Sexual Experiences Scale (ASEX), which consists of five items, was used. It is a quick scale to administer and requires no special training in terms of interpretation. ASEX may provide advantages as a screening and assessment instrument in hemodialysis patients as it is designed to assess the core elements of sexual function: drive, arousal, penile erection/vaginal lubrication, ability to reach orgasm, and satisfaction with orgasm. Each item is rated with a 6-point Likert system, with higher scores reflecting impaired sexual function. The maximum score is 30. The ASEX score was found to be negatively correlated with SD.16 We used the ASEX scale in this study based on its reliability and validity.17
Statistical analyses Statistical analyses were conducted on a total of 246 patients. Two patients refused to complete the ASEX questionnaire.
Diego, CA, USA) trial software was used for RTM. Five categorical and 16 continuous variables were used to estimate the ASEX score by RTM.
RESULTS Results of univariate analyses In total, 246 patients (aged 19–96 years, mean age 59.74 ± 13.9) were included. Of the patients, 50.2% were male (n = 124) and 49.8% were female (n = 122). Their mean duration of dialysis treatment was 4.87 ± 4.16 years (median = 3, range = 20.5). Clinical and laboratory characteristics of the patients are presented in Table 1. RLS was observed in 45.9% (n = 113) of 246 patients on dialysis. Similar symptoms were recorded in families of 3.7% of patients with RLS. In the patients, comorbid disease were 118 (48.2%) hypertension, 20 (8.1%) diabetes mellitus, 71 (28.7%) both hypertension and diabetes mellitus, 18 (7.3%) renal dysfunction and 19 (7.7%) of the etiology was unknown. The ASEX scores that have only hypertension, only diabetes mellitus, and both hypertension and diabetes mellitus in hemodialysis patients were Table 1 Clinical and laboratory characteristics of patients included in the study Numerical variables
Univariate analysis Descriptive statistics for numerical and categorical variables were computed as means ± standard deviation, and frequencies (count, percentage). Correlation analysis was used for relationships between numerical variables. Oneway analysis of variance followed by a post hoc Tukey’s test was used for differences among the categories for categorical variables with regard to the Arizona scale scores. P values ≤ 0.05 were deemed to indicate statistical significance. PASW software (ver. 18; SPSS Inc., Hong Kong, China) was used for statistical calculations. Regression tree method (RTM) The RTM is a tree-based model that is more useful than traditional methods when the dataset is large and when the number of variables is high. Moreover, RTM does not ignore interactions among factors and is not affected by high correlations among risk factors. Backward pruning was applied to eliminate problems with overfitting. The cost-complexity parameter was taken into consideration in the pruning process. Optimal tree is determined by cross validation.18 Classification and Regression Tree (CART) programme, (ver. Trial, 6.0; Salford Systems, San
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Hb Htc Ferritin Albumin PTH ALP Ca P hsCRP Age Systolic blood pressure Diastolic blood pressure Duration of dialysis (years) Mean ± SD Median (range, IQR) RLS Scale HARS ASEX Scale ESS Scale
Mean ± SD (n = 247) 11.1 ± 1.3 33.6 ± 4.1 754.7 ± 440.5 3.8 ± 0.4 417.5 ± 391.2 142.3 ± 93.3 8.4 ± 0.8 5.1 ± 1.4 18.1 ± 21.2 59.7 ± 14.0 127.7 ± 24.2 77.4 ± 12.4 4.9 ± 4.2 3 (range =20.5, IQR = 5) 8.1 ± 9.7 8.0 ± 7.0 23.4 ± 6.4 5.5 ± 4.7
ALP = alkaline phosphotase; ASEX = Arizona Sex Experiences Scale; Ca = calcium; ESS = Epworth Sleepiness Scale; HARS = Hamilton Anxiety Rating Scale; Hb = hemoglobin; hsCRP = high-sensitivity C-reactive Protein; Htc = hematocrit; IQR = interquartile range; PTH = parathyroid hormone; RLS = restless legs syndrome.
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Table 2 Linear correlations between demographic features and HARS, RLS, ESS, and ASEX scores Scales HARS Demographic features and scales Age BMI Duration of dialysis(years) HARS RLS ESS
r
0.231
RLS P
ESS
r
P
0.136 0.126 0.145 −0.184
.033 .049 .023 .004
.0001
r
ASEX P
0.151 0.206
.017 .001 —
r
P
0.554 0.126
.000 .049
0.260 0.217 0.077
.0001 .0001 .229
ASEX = Arizona Sex Experiences Scale; BMI = body mass index; ESS = Epworth Sleepiness Scale; HARS = Hamilton Anxiety Rating Scale; RLS = restless legs syndrome.
23.3 ± 6.5, 24.6 ± 6.5, and 25.0 ± 5.5, respectively. However, ASEX scores did not show statistically significant differences among them. Correlations between sociodemographic features and scales are presented in Table 2. Scores on the RLS scale were correlated with HARS (r = 0.231, P < 0.001) and ASEX (r = 0.217, P = 0.001) scores, and ASEX was also positively correlated with HARS (r = 0.260, P = 0.001). Furthermore, RLS was positively correlated with age (r = 0.554, P < 0.001) and duration of hemodialysis (r = 0.145, P = 0.023). HARS scores in patients with RLS were higher than were those in patients without RLS (9.4 ± 7.8 vs. 6.8 ± 6.0). ESS and ASEX scores were found to be higher in patients with RLS than in those without RLS. Mean ESS scores were 6.6 ± 5.2 and 4.6 ± 4.0 in patients with and without RLS, respectively, and mean ASEX scores were 24.6 ± 5.7 and 22.5 ± 6.8 in patients with and without RLS, respectively (Table 3). The relationships of ASEX scores with education level, occupation, marital status, and income level were investigated, and these results were significant (P < 0.0001; Table 4). ASEX scores in illiterate patients were significantly higher than in those patients with primary school, high school, and university education levels (P < 0.0001, Table 3 Comparison of HARS, ASEX and ESS in patients with and without RLS Presence of RLS Scales
With RLS
Without RLS
P
HARS ASEX ESS
9.4 ± 7.8 24.6 ± 5.7 6.6 ± 5.2
6.8 ± 6.0 22.5 ± 6.8 4.6 ± 4.0
354.50. 4. The median value of Terminal Node 10 was 18: occupation is not housewife, age >72.50, and RLS >20.50. 5. The median value of Terminal Node 7 was 20: occupation is not a housewife, 53 < age ≤ 72.50, and ESS ≤8.50. 6. The median value of Terminal Node 8 was 26: occupation is not a housewife, 53 < age ≤ 72.50, and ESS >8.50. 7. The median value of Terminal Node 3 was 27. occupation is housewife, married, HARS >3.5, and ALP ≤354.5 8. The median value of Terminal Node 2 was 30: occupation is housewife, married, HARS ≤3.5 and age >58. 9. The median value of Terminal Node 5 was 30: occupation is housewife, marital status is other. 10. The median value of Terminal Node 9 is 30: occupation is not housewife, age >72.50, and RLS ≤20.50 (Figure 1). When the median values of the 10 groups were compared using the Kruskal-Wallis test followed by the non-parametric Dunn’s test, we obtained the results shown in Table 3. Significant differences are marked with an asterisk (Table 5). Additionally, the correlation coefficient between the observed and predicted values obtained from the optimal tree for the ASEX score was found to be 0.80 (P < 0.001). The determination coefficient was 64.0%, and the intraclass correlation coefficient was 0.792. These results indicated that the optimal tree was successful in predicting the ASEX score.
Table 5 Significance of the differences between the terminal nodes Terminal Node Number
2
3
4
5
6
7
8
9
10
1 2 3 4 5 6 7 8 9
*
* —
— — —
* — * *
— * * — *
— * * — * *
* — — — * * *
* — — * — * * —
— — * — * — — — *
*Asterisk indicates significantly different terminal nodes.
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AGE ≤ 58.00 Terminal Node 2 MAD = 3.833 Med = 6.000 W = 9.00 N=6
ALP ≤ 354.50 Terminal Node 3 MAD = 3.041 Med = 27.000 W = 49.00 N = 49
ALP ≤ 354.50 Terminal Node 4 MAD = 1.667 Med = 18.000 W = 3.00 N=3
HAMLTON ≤ 3.50 Node 5 ALP ≤ 354.50 MAD = 3.365 Med = 27.00 W = 52.00 N = 52
MARTAL_STATUS = (2,3) Terminal Node 5 MAD = 0.429 Med = 30.000 W = 49.00 N = 49
AGE ≤ 53.00 Terminal Node 6 MAD = 3,390 Med = 15.000 W = 41.00 N = 41
ESS ≤ 8.50 Terminal Node 7 MAD = 3.535 Med = 20.000 W = 43.00 N = 43
RLS ≤ 20.50 Terminal Node 10 MAD = 2.333 Med = 18.000 W = 3.00 N=3
AGE ≤ 72.50 Node 9 RLS ≤ 20.50 MAD = 3.238 Med = 27.000 W = 21.00 N = 21 RLS ≤ 20.50 Terminal Node 9 MAD = 2.222 Med = 30.000 W = 18.00 N = 18
AGE ≤ 53.00 Node 7 AGE ≤ 72.50 MAD = 4.425 Med = 23.000 W = 87.00 N =87
ESS ≤ 8.50 Terminal Node 8 MAD = 3.087 Med = 26.000 W = 23.00 N = 23
AGE ≤ 72.50 Node 8 ESS ≤ 8.50 MAD = 4.045 Med = 21.000 W = 66.00 N = 66
OCCUPATION = (2,3,4,5,6) Node 4 AGE ≤ 53.00 MAD = 5.141 Med = 20.000 W = 128.00 N = 128
Figure 1 Risk factors of the Arizona Sex Experiences Scale (ASEX) according to optimum regression tree. ALP = alkaline phosphotase; ESS = Epworth Sleepiness Scale; MAD = median absolute differences; Med = median; N = number of observations; RLS = restless legs syndrome; W = weight.
AGE ≤ 58.00 Terminal Node 1 MAD = 4.444 Med = 16.000 W = 9.00 N=9
HAMLTON ≤ 3.50 Node 4 AGE ≤ 58.00 MAD = 5.800 Med = 20.000 W = 15.00 N = 15
MARTAL_STATUS = (1) Node 3 HAMLTON ≤ 3.50 MAD = 4.537 Med = 26.000 W = 67.00 N = 67
OCCUPATION = (1) Node 2 MARTAL_STATUS = (1) MAD = 3.474 Med = 30.000 W = 116.00 N = 116
Node 1 OCCUPATION = (1) MAD = 5.496 Med = 25.000 W = 244.000 N = 244
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DISCUSSION RLS is a common disorder in Europe and North America.19 In contrast, the prevalence of RLS in Asia was estimated to be less than 4%,19 and the prevalence in Turkey was found to be 3.19%.20 In this study, patients were asked about RLS-related symptoms in their families. Similar symptoms were observed in the families of 3.7% of the patients with RLS. This was consistent with the previously reported prevalence in Turkey. We detected RLS in 45.9% of the patients enrolled in the present study. Szenykiralyi et al. found that depressive symptoms were twice as common in patients with RLS as in those without RLS symptoms in a large cohort of patients with ESRD.21 In our study, a high ESS score was associated with increased RLS frequency, and high ASEX scores in patients with RLS indicated that their sex lives were adversely affected. According to RTM, when occupation = housewife, marital status = married, and HARS > 3.5, the ASEX score was low (median = 27), but when the HARS < 3.5, the ASEX score was high (median = 20). According to this result, it appeared that when HARS increased, the ASEX score also increased. Furthermore, we demonstrated that this association was independent of insomnia, and the presence of RLS symptoms was still significantly associated with anxiety. The relationship between RLS symptoms and anxiety is not completely explained by impaired sleep; sleep-independent mechanisms likely contribute to this relationship too. Insomnia is a risk factor for anxiety, and RLS contributes to insomnia.22 Poor sleep quality could be considered an independent risk factor for the development of anxiety. Some potential mechanisms may help explain the sleepindependent relationship between RLS and anxiety. Concerns about physical safety, security, the sense of freedom, fatigue, social isolation, helplessness, and pain are common symptoms of RLS, and these problems may predispose patients to anxiety. Failure to receive appropriate diagnosis and treatment for RLS may also contribute to frustration, anxiety, and depression with ESRD.22,23 Based on the RTM data, the ASEX score was 20.0 in 43 patients aged >53 and ≤72.5, and their ESS score was ≤8.50. The ASEX score was 26.0 in 23 patients whose ESS was >8.50. Accordingly, low ESS was associated with low ASEX score. This suggests that increased sleepiness during the daytime negatively affects patients’ sex lives. Correspondingly, based on the RTM data, the ASEX score was 21 in 62 patients aged >53 and ≤72.5, and it was 27 in 21 patients aged >72.0. Accordingly, ASEX was negatively affected by increased age. Age is an important
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factor for sexual satisfaction.2,3 SD was determined to be more prevalent in women (43%) than in men (31%) and was associated with a variety of demographic characteristics. Although the survey examined a variety of demographic and lifetime experiences in the participants of the study, it did not examine any impact of medications. Some information is available for individuals with ESRD treated with hemodialysis.24 Mean ASEX scores for women and men in our study were 26.3 ± 5.4 and 20.6 ± 6.1, respectively. Lower ASEX scores in male vs. female patients in this study were consistent with previous reports.7,23 In the present study, the frequency of RLS increased with age and dialysis duration. This led us to consider that dialysis could be a facilitating factor in RLS development. The highest ASEX scores (median = 30) were seen in those aged >72, people with an occupation other than housewife, and RLS values 20.5, the ASEX score was lower. However, the numbers of subjects was too small to make generalizations. Our results are consistent with these conclusions. RLS was associated with increased ESS, PSQ, and ASEX scores, and insomnia showed a strong, independent relationship with anxiety and SD. It has been reported that dopamine levels decrease in anxiety disorders.25 It is possible that the relationship between anxiety and RLS symptoms may be explained by an as-yet unknown confounding cause. Abnormalities in dopaminergic neurotransmission in the brain may be involved in the pathomechanism of RLS and anxiety. The sexual act involves central and peripheral mechanisms. Several mediators are involved in the central mechanisms. It is well established that noradrenaline, serotonin, and dopamine are involved in the central mechanisms.26 Decreases in dopamine levels, responsible for central mechanisms, could also be involved in the etiopathogenesis of RLS and SD. SD is a frequent finding in ESRD patients. Uremiaassociated hypogonadism is multifactorial in origin and rarely improves with the initiation of dialysis, although it usually normalizes after renal transplantation. Experimental and clinical evidence suggest that testosterone may have important clinical implications with regards to kidney disease progression; changes in sexual drive, libido, and erectile function; development of anemia; impairment of muscle mass and strength; and the progression of atherosclerosis and cardiovascular disease. Dopamine agonist therapy is one treatment option.27 It has been reported that plasma dopamine-βhydroxylase levels are lower in patients with ESRD than in healthy individuals, suggesting lowered sympathetic
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activity and/or abnormalities in release, distribution, or metabolism in RLS.28 This may explain why RLS was frequently seen in patients with ESRD accompanied by anxiety. In our study, 61.9% of patients had HARS scores above 5. Furthermore, anxiety was observed in 62.2% of patients with RLS. Meanwhile, the ASEX scores in patients with RLS were higher than in those without RLS. This may be explained by a high dopamine level. It is well known that sleep disturbances increase the risk of anxiety. Indeed, experiences associated with ESRD include stress, waiting for diagnostic procedures, time spent in ambulatory care and/or a day hospital, and new therapies or therapy switches, and it is well known that these conditions may be associated with alterations in mood and with anxiety. The present results suggest the importance of investigating the possible causative role of comorbid conditions in the development of anxiety in ESRD patients. The relationships between ASEX scores and education level, occupation, marital status, and income level are shown in Table 4. An inverse relationship between ASEX score and education level was observed. In particular, patients with lower educational levels had higher ASEX scores. Similar findings have been reported in other cultural settings.23,29 A low educational level can prevent patients from implementing suggested changes, resulting in low quality of life and sexual dissatisfaction.30 Also, low income levels were correlated with high ASEX scores. In the present study, ASEX was significantly higher in female than in male patients. This may be explained by conditions unique to women. Hormonal changes are more evident in women. Childbirth, loss of self-esteem, insufficient social support, and work overload could also be reasons for higher ASEX scores in women. Furthermore, the mean score for anxiety in female patients was significantly higher than that in male patients. This could be due to generally higher anxiety in women compared with men. The most determinative factor for SD in male patients was sexual performance. Moreover, lack of knowledge, misconceptions and overblown stories are other factors that may trigger or maintain SD. Concern for high sexual performance can trigger anxiety.26 In this study, male patients who had high scores for anxiety also had high ASEX scores. Interestingly, BMI was observed to be significantly higher in patients who had higher ASEX scores. Patients with high BMI might consider themselves unattractive, and high BMI could decrease self-esteem and be accompanied by many other health problems, such as diabetes mellitus, hypertension, and obstructive sleep apnea syndrome.23
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This study has several limitations. First, assessing RLS with questionnaires does not provide clinical diagnosis of the syndrome; the results obtained should be interpreted cautiously. Also, we did not conduct an electromyographic investigation, but two neurologists examined all patients. Finally, our subject group was small and the mean age was old. In conclusion, the effects of RLS on SD were objectively assessed based on ASEX scores using RTM. In this way, SD could be assessed even in patients who refrained from sharing information about their sex lives using sociodemographic features and HARS, ESS, RLS, and ASEX scores. Thus, physicians may be able to predict the likelihood of SD in such patients.
AUTHOR CONTRIBUTIONS SD, AB, and DB carried out the design, coordinated the study, and prepared the article. HA provided statistical consultation on the study design and analysis; ME, TS, and NE contributed to the study. All authors played active parts in each stage of the study, and their roles overlapped in all domains.
Manuscript received November 2013; revised February 2014.
REFERENCES 1 Alleyne S, Dillard P, McGregor C, Hosten A. Sexual function and mental distress status of patients with end-stage renal disease on hemodialysis. Transplant Proc. 1989; 21:3895–3898. 2 Palmar BF. Sexual function in uremia. J Am Soc Nephrol. 1999; 10:1381–1388. 3 Anantharaman P, Schmidt RJ. Sexual function in chronic kidney disease. Adv Chronic Kidney Dis. 2007; 14:119– 125. 4 Finkelstein F, Shirani S, Wuerth D, Finkelstein SH. Therapy insight: Sexual dysfunction in patients with chronic kidney disease. Nat Clin Pract Nephrol. 2007; 3:200–207. 5 Kutner NG. Quality of life and daily hemodialysis. Semin Dial. 2004; 17:92–98. 6 Campese VM. Autonomic nervous system dysfunction in uraemia. Nephrol Dial Transplant. 1990; 5:98–101. 7 Naya Y, Soh J, Ochiai A, et al. Significant decrease of the International Index of Erectile Function in male renal failure patients treated with hemodialysis. Int J Impot Res. 2002; 14:172–177.
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8 Tuncel D, Orhan FO, Sayarlioglu H, Isık IO, Utku U, Dinc A. Restless legs syndrome in hemodialysis patients: Association with depression and quality of life. Sleep Breath. 2011; 15:311–315. 9 Rijsman RM, de Weerd AW, Stam CJ, Kerkhof GA, Rosman JB. Periodic limb movement disorder and restless legs syndrome in dialysis patients. Nephrology (Carlton). 2004; 9:353–361. 10 Lee HB, Hening WA, Allen RP, et al. Restless legs syndrome is associated with DSM-IV major depressive disorder and panic disorder in the community. J Neuropsychiatry Clin Neurosci. 2008; 20:101–105. 11 TUIK, Statistics. (Income, Consumption, Poverty), 2013. Available from: http://www.tuik.gov.tr/PreTablo.do?alt _id=1011 (accessed date: May 11, 2013). 12 Walters AS. Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord. 1995; 10:634–642. 13 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; 4:101–119. 14 Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959; 32:50–55. 15 Johns MW. A new method for measuring daytime sleepiness: The Epworth Sleepiness Scale. Sleep. 1991; 14:540– 545. 16 McGahuey CA, Delgado LP, Geleberg AJ. Assessment of sexual dysfunction using the Arizona Sexual Experience Scale (ASEX) and implications for the treatment of depression. Psychiatr Ann. 1999; 29:39–45. 17 Soykan A. The reliability and validity of Arizona Sexual Experiences Scale in Turkish ESRD patients undergoing hemodialysis. Int J Impot Res. 2004; 16:531–534. 18 Camdeviren H, Mendes M, Ozkan MM, Toros F, Sasmaz T, Oner S. Determination of depression risk factors in children and adolescents by regression tree methodology. Acta Med Okayama. 2005; 59:19–26. 19 Garcia-Borreguero D, Egatz R, Winkelmann J, Berger K. Epidemiology of restless legs syndrome: The current status. Sleep Med Rev. 2006; 10:153–167. 20 Sevim S, Dogu O, Camdeviren H, et al. Unexpectedly low prevalence and unusual characteristics of RLS in Mersin, Turkey. Neurology. 2003; 61:1562–1569. 21 Szentkiralyi A, Molnar MZ, Czira ME, et al. Association between restless legs syndrome and depression in patients with chronic kidney disease. J Psychosom Res. 2009; 67:173–180. 22 Theofilou PA. Sexual functioning in chronic kidney disease: The association with depression and anxiety. Hemodial Int. 2012; 16:76–81. 23 Bahar A, Savas AH, Yıldızgordu E, Barlioglu H. Anxiety, depression and sexual life of hemodialysis patients. Anatolian J Psychiatry 2007; 8:287–292.
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24 Lopes AA, Bragg-Gresham JL, Satayathum S, McCullough K, et al. Health-related quality of life and associated outcomes among haemodialysis patients of different ethnicities in the United States: The Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2003; 41:605–615. 25 Davis MM, Olausson P, Greengard P, Taylor JR, Nairn AC. Regulator of calmodulin signaling knockout mice display anxiety-like behavior and motivational deficits. Eur J Neurosci. 2012; 35:300–308. 26 Hull EM, Muschamp JW, Sato S. Dopamine and serotonin: Influences on male sexual behavior. Physiol Behav. 2004; 83:291–307. 27 Iglesias P, Carrero JJ, Díez JJ. Gonadal dysfunction in men with chronic kidney disease: Clinical features, prognostic implications and therapeutic options. J Nephrol. 2012; 25:31–42. 28 Spohr U, Ritz F, Kaden F. Dopamin-betahydroxylaseaktivität im Plasma von Dialysepatienten (author’s transl). Klin Wochenschr. 1977; 55:1089–1093. 29 Coelho-Marques FZ, Wagner MB, Poli de Figueiredo CE, d’Avila DO. Quality of life and sexuality in chronic dialysis female patients. Int J Impot Res. 2006; 18:539– 543. 30 Shifren JL, Monz BU, Russo PA, Segreti A, Johannes CB. Sexual problems and distress in United States women: Prevalence and correlates. Obstet Gynecol. 2008; 112:970–978.
APPENDIX 1 INTERNATIONAL RESTLESS LEGS SYNDROME RATING SCALE FOR SEVERITY (IRLSSGRS) THIS SCALE IS COPYRIGHTED BY THE INTERNATIONAL RESTLESS LEGS SYNDROME STUDY GROUP 2002. Rate your symptoms for the following ten questions. Unless otherwise instructed, you should rate the average symptoms that you have experienced for the most recent two week period. (1) Overall, how would you rate the RLS discomfort in your legs or arms? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None
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(2) Overall, how would you rate the need to move around because of your RLS symptoms? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None (3) Overall, how much relief of your RLS arm or leg discomfort do 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 and therefore question does not Apply (4) Overall, how severe is your sleep disturbance from your RLS symptoms? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None (5) How severe is your tiredness or sleepiness from your RLS symptoms? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None (6) Overall, how severe is your RLS as a whole? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None
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(7) How often do you get RLS symptoms? (4) Very severe (This means 6 to 7 days a week) (3) Severe (This means 4 to 5 days a week) (2) Moderate (This means 2 to 3 days a week) (1) Mild (This means 1 day a week or less) (0) None (8) When you have RLS symptoms how severe are they on an average day? (4) Very severe (This means 8 hours per 24 hour day or more) (3) Severe (This means 3 to 8 hours per 24 hour day) (2) Moderate (This means 1 to 3 hours per 24 hour day) (1) Mild (This means less than 1 hour per 24 hour day) (0) None (9) Overall, how severe is the impact of your RLS symptoms on your ability to carry out your daily affairs, for example carrying out a satisfactory family, home, social, school or work life? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None (10) How severe is your mood disturbance from your RLS symptoms—for example angry, depressed, sad, anxious or irritable? (4) Very severe (3) Severe (2) Moderate (1) Mild (0) None
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