Restless Legs Syndrome

Restless legs syndrome is associated with poor sleep quality and quality of life in patients with ankylosing spondylitis:

a questionnaire-based study

Seden Demirci1 • Kadir Demirci2 • Atalay Dog˘ru3 • Esra Erkol I˙nal4 •

Hasan Rifat Koyuncuog˘lu1 • Mehmet S¸ ahin3

Received: 21 July 2015 / Accepted: 27 October 2015 / Published online: 12 November 2015

© Belgian Neurological Society 2015

Abstract We aimed to investigate the frequency of restless legs syndrome (RLS) and the associations between RLS and quality of sleep and life in patients with anky- losing spondylitis (AS). One hundred and eight AS patients and 64 controls were included in this study. Demographics, clinical, and laboratory data were recorded. The presence of RLS was determined with face-to-face interview by an experienced neurologist based on the International RLS Study Group criteria. RLS severity was evaluated using International RLS Study Group rating scale. Sleep quality and insomnia severity were assessed by Pittsburgh sleep quality index (PSQI) and insomnia severity index (ISI), respectively. Disease-related quality of life was evaluated by AS quality of life questionnaire (ASQoL). The fre- quency of RLS was significantly higher in AS patients than

in controls (36.4 vs. 14.0 %, p = 0.004). RLS severity

score for AS patients was significantly higher than that for controls (p = 0.03). The AS patients had higher scores in the subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep

medication domains of PSQI, and also total PSQI and ISI than controls (p \\ 0.05, for all). ASQoL scores were

higher in AS patients with RLS compared to those without RLS (p \\ 0.001). RLS severity was observed to be inde- pendently associated with total PSQI, ISI and ASQoL (p \\ 0.05, for all). As RLS may adversely affect the sleep and quality of life in AS patients, clinicians should be aware of RLS for early diagnosis and management in AS patients.

Keywords Restless legs syndrome • Ankylosing spondylitis • Sleep • Quality of life Introduction

Restless legs syndrome (RLS), or Willis–Ekbom disease, is a chronic sensorimotor disease that causes unpleasant sensations in the legs associated with an irresistible urge for leg movement to relieve the discomfort. The symptoms appear or increase in the evening or night and during periods of rest or inactivity [1]. Although the pathophysi- ology of RLS remains unclear, there is evidence of disor- dered iron homeostasis and dopaminergic dysfunction [2]. Many studies have reported that the prevalence of RLS

ranges from 2 to 15 % of the general population [3–5]. The

& Seden Demirci [email protected]

1 Department of Neurology, Faculty of Medicine, Su¨leyman Demirel University, Isparta, Turkey

2 Department of Psychiatry, Faculty of Medicine, Su¨ leyman Demirel University, Isparta, Turkey

3 Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Su¨ leyman Demirel University, Isparta, Turkey

4 Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Su¨leyman Demirel University, Isparta, Turkey

most frequent of the RLS cases are classified as primary or idiopathic. Secondary form of RLS has been associated with clinical conditions such as pregnancy, iron deficiency anemia, neurological diseases, renal insufficiency, and the use of certain medications [3]. RLS usually has negative impact on sleep and quality of life. Sleep disturbance is often the cause of the patients’ first requisition for medical advice [6].

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease that affects axial skeleton and peripheral joints, leading to functional impairment and disability. The

disease frequently results in progressive and irreversible fusion of the spine [7]. AS contributes considerably to global health-care expenditure and causes financial costs for the patient, family, and society [8]. Various sleep problems such as poor quality of sleep, sleep onset insomnia, difficulty awakening, and obstructive sleep apnea syndrome have been reported in AS [9]. Sleep problems because of axial pain and stiffness at night are also significant features of AS [10].

Recently, only in a clinical study, an increased fre- quency of RLS has been reported in patients with AS [11]. Moreover, the relationships between RLS and disease- specific variables, sleep quality and quality of life were not investigated before in AS patients. Therefore, the aim of the present study was to investigate the frequency of RLS in patients with AS and evaluate the associations between RLS and disease-specific variables, sleep quality and quality of life in patients with AS.

Materials and methods

Participants

One hundred and eight patients with AS who applied con- secutively to the outpatient clinics of Physical Medicine and Rehabilitation and Rheumatology were enrolled in this study. 64 healthy volunteers admitted to our hospital for routine check-ups were included as control. Written informed consent was obtained from all subjects according to the ethical prin- ciples of the Declaration of Helsinki. The study was approved by the local ethics committee. All patients were diagnosed with AS according to modified New York classification cri- teria [12]. The patients who had diabetes mellitus, other rheumatologic diseases, kidney, liver or thyroid diseases, amyloidosis, chronic heart failure, respiratory disease, malignancies, chronic alcoholism or neurological diseases were excluded from the study. Patients who were pregnant and taking drugs that could potentially interfere with RLS were also excluded. All participants completed a psychiatric examination with the Structured Clinical Interview for DSMIV-R Axis I (SCID-I). The psychiatric examination was performed by the psychiatrist. Participants with psychiatric disorders were also excluded from the study. Complete neu- rologic and rheumatologic examinations were performed for all participants. Patients with abnormal neurological exami- nation, including sensory or motor impairments, were not included in the study. Medical history, demographic data, presence of smoking, and medications of the patients were recorded. Laboratory data including hemoglobin level, blood levels of iron, ferritin, C reactive protein (CRP), erythrocyte sedimentation rate (ESR), vitamin B12 and D, and folic acid were evaluated in patients with AS.

Restless legs syndrome diagnosis and sleep assessment

Based on the International Restless Legs Syndrome Study Group (IRLSSG) criteria, the presence of RLS was deter- mined with face to face interview by an experienced neu- rologist. The diagnosis of RLS was made according to the revised IRLSSG criteria [13]. Participants fulfilling all five updated IRLSSG criteria were diagnosed with RLS. The severity of RLS was investigated using IRLSSG rating scale (IRLSSG-RS) [14]. IRLSSG-RS consists of ten questions linked to symptom severity, impact on daily functions, mood, sleep, and symptoms intensity and fre- quency which are rated on a 4-point Likert scale, with a maximum total score of 40 (maximal RLS severity).

Sleep quality was evaluated using the Pittsburgh sleep quality index (PSQI). This scale is a standard index for assessing the sleep quality and widely used in both clinical settings and public health practice. It measures the sub- jective sleep quality in the past month and consists of seven component scores—subjective sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction [15]. The sum of these seven scores is the total PSQI score with a range from 0 to 21. PSQI scores of above five were considered poor sleep quality. Adaptation to Turkish society of the scale was conducted by Agargun et al. [16]. Insomnia severity was assessed using insomnia severity index (ISI) [17]. The index consists of seven-item self-report ques- tionnaire evaluating the nature, severity, and impact of insomnia symptoms over the past month. Total scores range from 0 to 28 points. Higher scores indicate more severe sleep disturbance. The reliability and validity of the Turkish version of the ISI was conducted by Boysan et al. [18].

Quality of life

The disease-related quality of life was assessed by the AS quality of life questionnaire (ASQoL) [19]. This scale contains 18 items with dichotomous responses (yes/no) and higher scores indicate poor quality of life in AS patients. Turkish version of ASQoL was verified in point of relia- bility and validity by Duruo¨z et al. [20].

Measurements of disease variables

The disease activity of AS is usually evaluated as a com- bination of pain, fatigue, stiffness, and discomfort. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was chosen as the standard tool used in both daily practice and clinical trials. The BASDAI is a self- administered questionnaire that includes six questions relating five major

symptoms (fatigue, spinal pain, joint pain/swelling, areas of localized tenderness, and morning stiffness). Patients were asked to rate their disturbance that they felt over the previous week on a 10-cm horizontal visual analog scale (VAS) in each one the questions. Total BASDAI score is the mean of total of five scores with higher scores indi- cating higher disease activity [21].

Functional disability was assessed using the Turkish version of the Bath Ankylosing Spondylitis Functional Index (BASFI). The BASFI consists of ten questions related to daily activities and patients’ ability to cope with everyday life. Patients were asked to rate each question on 0–10 cm VAS reflecting status over previous month. Total score is mean of total of the ten scores, with higher scores indicating more severe impairment [22].

The patient’s global assessment of AS over the past week was evaluated by VAS recording from 0 cm (none) to 10 cm (very severe).

Statistical analysis

Statistical analysis was performed using SPSS software (version 15 SPSS; Chicago, IL, USA). The Kolmogorov– Smirnov test was used to test the normality of distribution

of all continuous variables. Mean ± SD was used to pre-

sent normally distributed continuous data and median and interquartile ranges (IQR; the range of values lying between the 25th and 75th centiles) were used to represent non-normally. Chi square test was used to compare cate- gorical variables which were shown as frequencies. Com- parisons of two groups were performed with Student’s t test and Mann–Whitney U test for parametric and non-para- metric data, respectively. Spearman’s or Pearson’s corre- lation tests were performed to determine the relationships between continuous variables for parametric or non-para- metric data, respectively. Multivariate linear regression analysis was performed to find out the predictor effect of the RLS severity on the scores of the total PSQI, ISI and ASQoL. Age, sex, RLS severity, and BASDAI were included in all models. p Values \\ 0.05 were accepted as significant.

Results

One hundred and eight patients with AS (76 males and 32 females) and 64 healthy controls (38 males and 26 females) were included in this study. There was no significant dif- ference between the patients with AS and controls in terms of age and sex. Demographic and clinical characteristics and quality of sleep and life of all participants were sum- marized in Table 1. No difference was observed between the AS patients with and without RLS regarding the age,

sex, smoking, onset of first symptom, disease duration, the history of peripheral arthritis and uveitis, anti-TNF usage, hemoglobin level, serum level of iron, ferritin, vitamin B12 and D, folic acid, CRP, and ESR. However, there were significantly higher levels of the VAS patient’s global assessment of disease, the BASDAI, and the BASFI in AS patients with RLS compared to those without RLS. The subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication domains, daytime dysfunction, total PSQI scores, and the scores of ISI and ASQoL were significantly higher in AS patients with RLS than those without RLS (Table 1).

The frequency of RLS and mean RLS severity score were significantly higher in patients with AS than in controls. The AS patients had higher scores in the sub- jective sleep quality, sleep latency, sleep duration, habit- ual sleep efficiency, sleep disturbances, use of sleep medication domains, and also higher total PSQI scores than controls. 64.8 % of the AS patients were classified as poor sleepers (PSQI total score [ 5). The severity of insomnia was significantly higher in AS patients than controls (Table 1). AS patients with RLS had higher scores in the sleep latency, sleep duration, sleep distur- bances, and also total PSQI than controls with RLS. These data are presented in Table 2.

There was no significant correlation between the RLS severity score and age, onset of first symptom, disease duration, serum level of iron, ferritin, vitamin B12 and D, folic acid, CRP, and ESR (p [ 0.05, for all). There was a negative correlation between the RLS severity score and hemoglobin (r = -0.252, p = 0.009). The score of the RLS

severity was found to correlate positively with the VAS patient’s global assessment of disease, BASFI, BASDAI, total PSQI and each of the PSQI components, ISI, and ASQoL (p \\ 0.05 for all). Correlations of the scores of RLS severity with disease parameters, quality of sleep, and life parameters in patient with AS were shown in Table 3. Also, the scores of total PSQI was positively correlated with

BASDAI, BASFI, VAS patient’s global assessment of dis- ease, ISI, and ASQoL (r = 0.527, p \\ 0.001, r = 0.468, p \\ 0.001, r = 0.460, p \\ 0.001, r = 0.848, p \\ 0.001, and

r = 0.519, p \\ 0.001, respectively).

Multivariate linear regression analysis was performed to find out the predictor effect of the RLS severity score on the total PSQI scores, ISI and ASQoL in AS patients. The scores of the total PSQI, ISI, and ASQoL scores were taken as dependent variables in model 1, 2, and 3, respectively. Age, gender, BASDAI, and score of the RLS severity were taken as possible predictors for the models. The results are presented in Table 4. RLS severity was observed to be independently associated with total PSQI and ISI when controlling for age, gender, and BASDAI. Also, age and

Table 1 Demographic and clinical characteristics and quality of sleep and life of all participants

AS patients with RLS AS patients without p All AS patients Controls p

(n = 39) RLS (n = 69) (n = 108) (n = 64)

Age 44.0 (34.0–53.0) 40.0 (29.5–49.0) 0.21 41.0 (32.0–50.0) 37.0 (26.0–50.0) 0.18

Sex (male/female) 24/15 52/17 0.13 76/32 38/26 0.14

Smoking [n (%)] 14 (35.9) 37 (53.6) 0.10 51 (47.2) 21 (32.8) 0.12

Onset of first symptom (months) 120.0 (72.0–240.0) 120.0 (78.0–240.0) 0.71 120.0 (75.0–240.0) – –

Disease duration (months) 72.0 (32.0–144.0) 76.0 (24.0–144.0) 0.98 74.0 (26.0–144.0) – –

Peripheral arthritis [n (%)] 18 (46.2) 25 (36.2) 0.31 43 (39.8) – –

Uveitis [n (%)] 7 (17.9) 14 (20.3) 0.76 21 (19.4) – –

Anti-TNF usage [n (%)] 23 (59.0) 42 (60.9) 0.84 65 (60.2) – –

Hemoglobin (g/dl) 13.5 ± 1.89 14.1 ± 1.25 0.09 13.9 ± 1.53 – –

Iron (lg/dl) 60.7 ± 36.1 66.5 ± 37.5 0.47 64.4 ± 36.9 – –

Ferritin (ng/ml) 34.2 (15.7–69.7) 50.1 (19.3–83.7) 0.15 46.5 (17.9–74.0) – –

Vitamin B12 (pg/ml) 320.0 (249.0–504.0) 315.0 (258.0–397.0) 0.32 319.0 (258.0–425.5) – –

Vitamin D (ng/ml) 13.4 (7.70–21.5) 12.0 (7.95–19.6) 0.63 12.6 (7.95–19.8) – –

Folic acid (ng/ml) 10.1 ± 3.36 10.0 ± 3.64 0.83 10.0 ± 3.52 – –

ESR (mm/h) 19.0 (7.0–36.0) 13.0 (7.0–27.0) 0.32 7.0 (15.0–30.0) – –

CRP (mg/dl) 6.40 (3.40–13.7) 5.0 (3.40–13.7) 0.82 5.60 (3.40–13.5) – –

BASDAI 4.21 ± 1.89 2.88 ± 2.34 0.003 3.36 ± 2.27 – –

BASFI 3.10 (1.40–5.10) 0.60 (0.0–2.05) \\0.001 1.2 (0.02–3.60) – –

VAS patient’s global assessment 4.97 ± 2.00 3.60 ± 2.71 0.004 4.10 ± 2.56 – –

Subjective sleep quality 2.0 (1.0–2.0) 0.0 (0.0–1.0) \\0.001 1.0 (0.0–2.0) 0.5 (0–1.0) 0.009

Sleep latency 2.0 (1.0–2.0) 1.0 (0.0–2.0) 0.001 2.0 (1.0–2.0) 1.0 (0–1.0) \\0.001

Sleep duration 2.0 (1.0–2.0) 1.0 (0.0–1.0) \\0.001 1.0 (0.0–2.0) 1.0 (0–1.0) 0.03

Habitual sleep efficiency 1.0 (0.0–2.0) 0.0 (0.0–1.0) \\0.001 0.0 (0.0–1.0) 0 (0–0) \\0.001

Sleep disturbances 2.0 (2.0–2.0) 1.0 (1.0–2.0) \\0.001 2.0 (1.0–2.0) 1.0 (1.0–1.0) \\0.001

Use of sleep medication 2.0 (1.0–2.0) 1.0 (1.0–2.0) 0.001 1.0 (1.0–2.0) 1.0 (0–1.0) \\0.001

Daytime dysfunction 1.0 (0.0–2.0) 0.0 (0.0–1.0) 0.003 0.0 (0.0–1.0) 0 (0–1.0) 0.74

Total PSQI 11.0 (8.0–13.0) 6.0 (3.0–9.0) \\0.001 8.0 (5.0–11.0) 4.0 (3.0–6.75) \\0.001

ISI 12.0 (8.0–15.0) 5.0 (2.0–10.0) \\0.001 8.0 (3.0–13.0) 5.0 (3.0–7.0) 0.009

ASQoL 10.5 (5.0–14.2) 2.0 (0.0–8.0) \\0.001 5.0 (1.0–11.0) – –

p for Student’s t test and Mann–Whitney U test Mean ± SD, median (25–75 interquartile ranges)

AS ankylosing spondylitis, RLS restless legs syndrome, TNF tumor necrosis factor, ESR erythrocyte sedimentation rate, CRP C reactive protein, BASDAI Bath Ankylosing Spondylitis Disease Activity Index, BASFI Bath Ankylosing Spondylitis Functional Index, VAS visual analog scale, PSQI Pittsburgh sleep quality index, ISI insomnia severity index, ASQoL ankylosing spondylitis quality of life questionnaire

RLS severity were observed to be independently associated with ASQoL when controlling for gender and BASDAI (p \\ 0.05).

Discussion

There are four major findings in this study. First, the fre- quency of RLS and mean RLS severity score was signifi- cantly higher in patients with AS than in controls. Second, sleep quality was disturbed in AS patients in comparison with the healthy controls. 64.8 % of the AS patients had poor sleep quality. Third, RLS severity was positively

correlated with the scores of disease activity, functional status, sleep quality, and quality of life. Finally, RLS severity was independently associated with sleep quality and quality of life. Namely RLS severity seemed to be an independent predictor of the quality of sleep and life in AS patients. According to the best of our knowledge, this is the first study assessing the relationships between RLS and clinical status, sleep quality and quality of life in patients with AS.

Several studies showed that RLS occurred more fre- quently in patients with rheumatologic conditions such as rheumatoid arthritis, scleroderma, Sjo¨gren’s syndrome, and fibromyalgia [23–26]. Recently, Tekatas and Pamuk [11]

Table 2 Comparison of

AS (n = 39) Controls (n = 9) p

patients with RLS in terms of

sleep parameters in groups

Mean ± SD, median (25–75 interquartile ranges)

AS ankylosing spondylitis, RLS restless legs syndrome, PSQI Pittsburgh sleep quality index, ISI insomnia severity index

Table 3 Correlation between the scores of RLS severity and disease activity, quality of sleep and life parameters in patient with AS (n = 108)

RLS severity

r p

the patients with AS and it may develop gastrointestinal blood loss. There may be a higher subclinical iron defi- ciency in AS patients [27]. In this study, although there was no difference between the patients with RLS and without RLS in terms of hemoglobin, ferritin, and iron, there was a

r Pearson and Spearman’s correlation coefficient

AS ankylosing spondylitis, RLS restless legs syndrome, VAS visual analog scale, BASDAI Bath Ankylosing Spondylitis Disease Activity Index, BASFI Bath Ankylosing Spondylitis Functional Index, PSQI Pittsburgh sleep quality index, ISI insomnia severity index, ASQoL ankylosing spondylitis quality of life questionnaire

found that the frequency of RLS in patients with AS was

30.8 %. Consistent with the result of Tekatas et al.’s study, the frequency of RLS was 36.4 % in AS patients in our study. The frequency of RLS in our control group was

14.0 %, which is similar to the range of 2–15 % observed in the general population [3–5, 11]. The severity of RLS was also significantly higher in AS patients than controls in this study. The association between AS and RLS may be due to several reasons. Long-term non-steroidal anti-in- flammatory drug use for chronic pain states is common in

Similarly, the scores of the disease activity and functional status were higher in the AS patients with RLS than those without RLS in our study. The RLS severity was also correlated with the disease activity and functional status. Given this, we speculate that there is a probable relation- ship between the occurrence of RLS and activity and severity of the disease in patients with AS.

RLS can lead to significantly reduced quality of life, especially through sleep deprivation, resulting in daytime impairment. Sleep disturbance, which includes problems associated with getting to and maintaining sleep, relates to the severity of RLS [6]. Several studies evaluated sleep quality in AS patients [33–36] but none of them investi- gated the relationship with RLS. Hultgren et al. [33] reported that the pain was the main reason of sleep dis- turbances in patients with AS. Another study showed that dissolving the pains at night in patients with AS was the

Table 4 Multivariate linear regression analysis when global scores of PSQI and ISI were taken as dependent and age, gender, BASDAI, and RLS severity score were as independent variables in AS patients

AS ankylosing spondylitis, RLS restless legs syndrome, BASDAI Bath Ankylosing Spondylitis Disease Activity Index, PSQI Pittsburgh sleep quality index, ISI insomnia severity index, ASQoL ankylosing spondylitis quality of life questionnaire

most important predictor of improved sleep [35]. A study of 171 AS patients reported that sleep problems were related to the disease activity and anti-TNF agents improved significantly sleep problems [34]. Batmaz et al.

[36] found that the lower quality of sleep was greatly associated with the pain, disease activity, depression, quality of life, and decreased mobility in AS patients. Recently, a study evaluating the relationship between BASDAI and sleep quality showed that 37.3 % of the patients had poor sleep quality and approximately all the components of PSQI were related to disease activity [37]. Similar to the previous studies [9, 34, 38], in our study the sleep quality in AS patients was observed to be disturbed in comparison with the healthy controls. RLS severity was an independent contributor to the total PSQI and ISI when controlling for age, gender, and disease activity. Therefore, the disturbed sleep commonly observed in AS may be due to RLS. On the other hand, severe RLS may induce sleep deprivation, which may lead to an increase in markers of inflammation and decline in pain thresholds probably by precipitating AS [39].

RLS is frequently associated with reduced quality of life due to discomfort, pain, fatigue, inability to rest, and sleep disturbances [6]. Svetel et al. [40] found that RLS severity, especially frequency of symptoms, negatively affected majority of the domains of 36-Item Short-Form Health Survey. AS also affects the quality of life negatively. Disease activity is one of the most powerful predictors of quality of life in AS [41]. It was shown that the quality of life was closely associated with sleep disorders in patients with AS

[33, 36]. AS patients with RLS had worse quality of life compared to those without RLS. Moreover, RLS severity and poor sleep quality were positively correlated with decreased quality of life in our study. Moreover, by the multivariate regression analysis, RLS severity was found to be an inde- pendent predictor of the quality of life in the patient with AS. This study has a number of limitations which must be con- sidered in interpreting the present results. The cross-sec- tional design is one of the limitations in this study. A longitudinal study may reflect the fluctuations in related parameters and may be able to show associations definitely. The AS patients attended from a tertiary hospital. This may be a selection bias and our study group includes relatively well-treated AS patients; however, the means or medians of BASDAI and BASFI scores were similar to those in previous studies [34, 37]. Additionally, we evaluated the sleep quality with a questionnaire, but polysomnographic recordings could have provided more precise results. Besides these limitations, for the first time we showed associations between RLS and clinical status, quality of sleep and life of AS patients in this study.

In conclusion, our study suggests that RLS may be frequent and associated with poor sleep and life quality in AS patients. Although RLS is comparatively common in the general population, it mostly remains undiagnosed [42]. Since the sleep problems are widespread in the patients with AS, the specific symptoms of RLS might be over- looked. As RLS may negatively affect the sleep and quality of life in these patients, the early diagnosis of RLS is important.

Compliance with ethical standards

Conflict of interest The authors declare that they have no conflict of interest.

Ethical approval All procedures performed in this study were in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent Informed consent was obtained from all indi- vidual participants included in the study. References

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