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Restless legs syndrome in stroke patients
Sleep Medicine 16 (2015) 1006–1010
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Sleep Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s l e e p
Original Article
Restless legs syndrome in stroke patients I. Schlesinger a,b,*, I. Erikh a, M. Nassar a, E. Sprecher a a b
Department of Neurology, Rambam Health Care Campus, Haifa, Israel Technion Faculty of Medicine, Haifa, Israel
A R T I C L E
I N F O
Article history: Received 15 September 2014 Received in revised form 20 November 2014 Accepted 19 December 2014 Available online 23 April 2015
A B S T R A C T
Background: Restless legs syndrome (RLS) is associated with cerebrovascular risk factors, but its possible association with cerebrovascular disease has yielded conflicting results. Objective: This was a case–control, in-hospital study to evaluate the association between RLS and acute stroke or transient ischemic attack (TIA). Methods: We evaluated patients hospitalized with acute stroke/TIA and an age and gender 2:1 frequencymatched control group, for the presence of RLS. Results: Twenty-two of 149 patients (15%) and 10 of 298 controls (3%) suffered from RLS (p < 0.0001). A multivariate logistic regression model employing cerebrovascular risk factors as predictors, that is, hypertension, hyperlipidemia, diabetes, and body mass index (BMI), determined that stroke/TIA was significantly associated with RLS with odds ratio for RLS among patients with stroke/TIA versus controls of 7.60 (95% confidence interval (CI): 2.07–27.87; p = 0.002). Another multivariate logistic regression model adjusting for possible RLS risk factors, that is, hypertension, hyperlipidemia, diabetes, BMI, anemia, and reduced renal function, determined that stroke/TIA was significantly associated with RLS with odds ratio of 6.85 (95% CI: 6.85–1.79; p = 0.005). Stepwise logistic regression with hypertension, hyperlipidemia, diabetes, BMI, anemia, and reduced renal function as potential predictors revealed that only stroke/TIA predicted RLS with similar odds ratio to the RLS-based multivariate model of 6.54 (95% CI: 2.63–16.27; p < 0.0001). Conclusions: Examining stroke patients while in hospital allowed us to conclude that RLS and acute stroke/ TIA are significantly associated. However, the cross-sectional design did not allow for the determination of a causative relationship between the two. © 2014 Elsevier B.V. All rights reserved.
Restless legs syndrome (RLS) is a common sensory-motor disorder of unknown etiology [1]. It is characterized by a desire to move the legs usually accompanied by abnormal leg sensations. Symptoms typically worsen at rest and later on in the day, and they are relieved by movement. Estimates of RLS prevalence in different parts of the world range between 6% and 12% [2], but the persistence of RLS over time is low [3]. RLS has been linked to numerous cerebrovascular risk factors including hypertension, hypercholesterolemia, diabetes, and obesity [4–12], but its association with cerebrovascular disease has been debated. Case reports have suggested the emergence of RLS symptoms within days following stroke [13,14], but given the high prevalence of
The study was performed at the Department of Neurology, Rambam Health Care Campus, Haifa, Israel. Author contributions Dr. Schlesinger I and Erikh I helped in the study concept and design. Dr. Schlesinger I, Dr. Nassar M, and Erikh I helped in the acquisition of data. Dr. Schlesinger I and Dr. Sprecher E carried out analysis and interpretation. All authors carried out critical revision of the manuscript for important intellectual content. Dr. Schlesinger I helped in study supervision. * Corresponding author. Department of Neurology, Rambam Health Care Campus, P.O. Box 9602, Haifa 31096, Israel. Tel.: +972 4 8543558; fax: +972 4 8542944. E-mail address: [email protected] (I. Schlesinger). http://dx.doi.org/10.1016/j.sleep.2014.12.027 1389-9457/© 2014 Elsevier B.V. All rights reserved.
RLS in the general population, this may be a chance occurrence. A few large longitudinal studies examined the possible association between RLS and cerebrovascular disease, but RLS diagnosis was based on baseline questionnaires without the verification of RLS by a face-to-face interview, thus precluding the elimination of subjects with RLS mimics. Furthermore, RLS status was recorded at baseline, sometimes years before the cerebrovascular event; thus, RLS symptoms may have abated or appeared during the elapsed time. Our study aimed to examine a possible association between RLS and cerebrovascular disease, by examining patients during hospitalization for acute stroke or transient ischemic attack (TIA), in a matched case–control design.
1. Subjects and methods 1.1. Subjects 1.1.1. Patient selection and determination of stroke diagnosis We prospectively identified adults hospitalized with a diagnosis of stroke or TIA during weekdays, in the Neurology Department, at the Rambam Health Care Campus in Haifa, Israel, between January and December 2008. Subjects with stroke (International Classification
I. Schlesinger et al./Sleep Medicine 16 (2015) 1006–1010
of Diseases, Ninth Revision (codes 431 and 436) and TIA (code 435) were identified according to their coding on admission. Controls: Controls were 2:1 frequency-matched to the patient group by gender and age (within 3-year intervals), randomly selected from adults attending their annual checkup at the Rambam Center for Preventive Medicine, Rambam Health Care Campus. Controls had no history of stroke or TIA. The study was approved by the institutional review board. All patients gave oral consent, while all controls signed written informed consent. The trial was registered at the Clinical Trials.gov, number NCT01967303. 1.1.2. RLS screening Patients were interviewed by a movement disorders nurse practitioner (I.E.). The interview started with a questionnaire based on the standard questions developed by the International RLS Study Group as previously described as follows: (i) Have you had unpleasant sensations in your legs (such as paresthesias, numbness, and ache) accompanied by a need or urge to move your legs? (ii) Did these sensations occur at rest, and were they improved by movement? (iii) Were these symptoms worse in the evening and at night? (iv) How often did you experience these sensations? Were the sensations less than once a month, two to four times a month, twice a week, two to three times a week, four to five times a week, or six to seven times a week? The questionnaire was translated to Hebrew by two senior neurologists and a professional translator. It was then back-translated to English to ensure the accuracy of the translation. Patients who were screened negative for RLS continued with a face-to-face interview by the nurse, to verify that they did not suffer from RLS. Patients who were screened positive by the questionnaire, and patients whose interview with the nurse was not conclusive, were then interviewed by a senior neurologist with a special interest in RLS (I.S.). If there was a discrepancy between the questionnaire and the interviewer, the final diagnosis was based on the neurologist’s assessment. Patients underwent the same diagnostic procedure, and they were all interviewed face to face by the senior neurologist (I.S.). 1.2. Medical information Information regarding medical history, use of medications, and body mass index (BMI) calculation was gathered from the medical records for all participants. Laboratory results consisted of blood samples that were drawn in the morning after a 12-h fast, and they included a complete blood count, chemistry, and kidney function tests (Hitachi 911, Tokyo, Japan). Medical records of each patient were reviewed to confirm the diagnosis of stroke/TIA.
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sample size would be reached, we interviewed all potential patients within a period of one year. Preliminary analyses involved simple statistics and univariate comparisons between the stroke/TIA patients and control subjects on a number of demographic and clinical parameters. Twotailed t-tests, median tests, or Fisher exact tests were employed for comparisons as appropriate. In order to simultaneously control for potentially correlated statistical predictors, the relationship of RLS with prevalent cerebrovascular risk factors was also examined by multivariate logistic regression analysis using 1:2 case:control stratification. We performed two multivariate logistic regression analyses. The first regression model used the known cerebrovascular risk factors that included hypertension, hyperlipidemia, diabetes, and BMI. The second regression model used possible RLS risk factors that included hypertension, hyperlipidemia, diabetes, BMI, anemia, and reduced renal function. This was followed by stepwise logistic regression analysis (using stepwise selection with default options) starting from the same basic model to develop the most efficient predictive model for RLS. For all analyses, p-values <0.05 were considered to be significant. JMP and SAS (both SAS Institute, Cary, NC, USA) were used for univariate analyses and logistic regression analysis (specifically SAS PROC LOGISTIC), respectively. 2. Results Of the patients with stroke/TIA who were hospitalized during the study period, 426 were screened by the study team. In 19 patients, the diagnosis was changed during the hospitalization. One hundred and sixty-five patients were excluded because their medical condition precluded an interview (coma, dementia, aphasia, etc.). None refused to participate. Among the remaining 261, one patient was admitted three times and 28 patients were admitted twice; only the first hospitalization was included in the analysis. Patients were then matched by age and gender to those attending the Preventive Medicine Department. As subjects in the Preventive Medicine Department are mostly referred for their annual checkup from their workplace, the pool of subjects is mostly below the age of 67 (the official Israeli retirement age) with few elderly subjects. This limited the matching of older patients and excluded all patients above the age of 84. Thus, another 84 patients were randomly excluded for lack of matched controls. Therefore, the total number of subjects participating in the study was 447 (149 patients with stroke/TIA and 298 controls). Among the stroke/TIA group, 30 suffered from TIA, 110 from ischemic stroke, and nine from hemorrhagic stroke. Demographic characteristics are presented in Table 1. The mean age of the study sample was 59.5 years (standard deviation (SD) 9.4, range 32–83); 74% (330/447)
1.3. Cerebrovascular risk factors We defined subjects as suffering from diabetes mellitus, hypercholesterolemia, or hypertension when subjects reported that their physician had diagnosed the disorder and was treating them for it or when fasting glucose was ≥126 mg/dl, cholesterol was >230 mg/dl, or blood pressure was above 140/90 mm Hg. Reduced renal function was defined as serum creatinine ≥1.3 mg/dl and anemia as hemoglobin <13.5 g/dl in men and <11.5 g/dl in women. 1.4. Outcome measures and analysis The primary outcome measure was the prevalence of RLS in patients with acute stroke/TIA versus controls. Prospective power analyses suggested that a 1:2 case–control study would require at least 120 stroke cases and 240 controls to achieve statistical significance at power 0.8 in the worst case. In order to ensure that this
Table 1 Characteristics of the stroke/TIA subjects and controls.
RLS, No. (%) Age, years (mean ± SD) Gender, male % Hypertension, No. (%) Hyperlipidemia, No. (%) Diabetes, No. (%) BMI, kg/m2, median (range) Anemia, No. (%) Reduced renal function, No. (%)
Controls
Stroke/TIA
N = 298
N = 149
10 (3%) 59.4 ± 9.4 220 (74%) 106 (36%) 108 (36%) 57 (19%) 27 (18–42) 17 (6%) 28 (9%)
22 (15%) 59.5 ± 9.4 110 (74%) 114 (77%) 100 (67%) 70 (47%) 27 (19–44) 27 (18%) 27 (18%)
p
<0.0001 CCM CCM <0.0001 <0.0001 <0.0001 0.73 <0.0001 0.01
Abbreviations: TIA, transient ischemic attack; RLS, restless legs syndrome; CCM, Case– control matched; BMI, body mass index. Statistical tests employed for group comparisons were t-tests, median tests, or Fisher exact tests for these summary statistics as appropriate.
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Table 4 Characteristics of the subjects with and without RLS.
Table 2 Relationship between cerebrovascular risk factors and prevalent RLS.
Stroke/TIA Hypertension Hyperlipidemia Diabetes BMI
OR
95% CI
p
RLS
Non-RLS
7.60 1.11 3.08 0.76 0.99
2.07–27.87 0.28–4.39 0.79–11.97 0.14–4.06 0.86–1.13
0.002 0.89 0.10 0.75 0.84
N = 32
N = 415
22 (69%) 61.0 ± 7.8 17 (47%) 23 (72%) 22 (69%) 13 (41%) 26 (20–40) 7 (22%) 7 (22%)
127 (31%) 59.3 ± 9.5 313 (25%) 197 (47%) 186 (45%) 114 (27%) 27 (18–44) 37 (9%) 48 (12%)
Abbreviations: RLS, restless legs syndrome; TIA, transient ischemic attack; BMI, body mass index; OR, odds ratio; CI, confidence interval. Multivaried logistic regression analysis including known cerebrovascular risk factors. The overall model test for statistical regression was significant on likelihood ratio (0.0003), score (0.0003), and Wald test (0.01).
were male. Hypertension, hyperlipidemia, and diabetes were significantly more prevalent among stroke patients (p < 0.0001 for each risk factor, Table 1). The median BMI was 27.1 kg/m2, and it was not significantly different in stroke patients as compared with controls. Anemia was three times more prevalent in stroke patients (18%) as compared with controls (6%) (p < 0.0001). Reduced renal function was twice as likely in patients (18%) as in controls (9%) (p = 0.01). Among patients with stroke/TIA, the diagnosis of RLS was significantly more prevalent than in controls (15% vs. 3%, p < 0.0001). In all 22 stroke/TIA patients with RLS, RLS preceded the stroke/ TIA as follows: new-onset RLS appeared approximately a month before ischemic stroke in six patients. Two of these patients were hospitalized 1 month previously because of TIA appearing together with new-onset RLS symptoms. Five patients reported RLS appearing with a previous stroke 2–5 years earlier. Chronic RLS was reported in 11 patients (five with ischemic stroke, one with hemorrhagic stroke, and five with TIA). The multivariate logistic regression model adjusting for cerebrovascular risk factors, that is, hypertension, hyperlipidemia, diabetes, and BMI, determined that stroke/TIA was significantly associated with RLS with odds ratio (OR) for RLS among patients with stroke/TIA versus controls of 7.60 (95% CI: 2.07–27.87; p = 0.002), Table 2. In this multivariate logistic regression model, no other variable approached statistical significance (hypertension, p = 0.89; hyperlipidemia, p = 0.10; diabetes, p = 0.75; and BMI, p = 0.84). The multivariate logistic regression model adjusting for possible RLS risk factors, that is, hypertension, hyperlipidemia, diabetes, BMI, anemia, and reduced renal function, determined that stroke/TIA was significantly associated with RLS with OR of 6.85 (95% CI: 6.85–1.79; p = 0.005), Table 3. The stepwise logistic regression with hypertension, hyperlipidemia, diabetes, BMI, anemia, and reduced renal function as potential predictors yielded a single predictor model, indicating that only stroke/TIA predicted RLS with similar OR to the multivariate model l of 6.54 (95% CI: 2.63–16.27; p < 0.0001).
Table 3 Relationship between possible RLS risk factors and prevalent RLS.
Stroke/TIA Hypertension Hyperlipidemia Diabetes BMI Anemia Reduced renal function
OR
95% CI
p
6.85 0.95 3.31 0.75 0.99 1.94 1.33
1.79–6.85 0.21–0.95 0.85–3.31 0.13–0.75 0.86–0.99 0.18–1.94 0.22–1.33
0.005 0.94 0.09 0.74 0.89 0.58 0.76
Abbreviations: RLS, restless legs syndrome; TIA, transient ischemic attack; BMI, body mass index; OR, odds ratio; CI, confidence interval. Multivaried logistic regression analysis including possible RLS risk factors. The overall model test for statistical regression was significant on likelihood ratio (0.001), score (0.001), and Wald test (0.04).
Stroke or TIA, No. (%) Age, years (mean ± SD) Gender, male No. (%) Hypertension, No. (%) Hyperlipidemia, No. (%) Diabetes, No. (%) BMI, kg/m2, median (range) Anemia, No. (%) Reduced renal function, No. (%)
p
<0.0001 0.25 0.010 0.01 0.01 0.15 0.14 0.03 0.10
Abbreviations: RLS, restless legs syndrome; TIA, transient ischemic attack; BMI, body mass index; OR, odds ratio; CI, confidence interval. Statistical tests employed for group comparisons were t-tests, median tests, or Fisher exact tests for these summary statistics as appropriate.
There was a higher prevalence of RLS among females in the entire cohort, Table 4. Furthermore, for the entire cohort, hyperlipidemia, hypertension, and anemia were positively associated with the diagnosis of RLS. Diabetes, BMI, and reduced renal function were not associated with RLS. There was a trend toward an increase in the diagnosis of RLS with age. 3. Discussion To the best of our knowledge, this is the first case–control study to assess the association between acute stroke/TIA and RLS. We found that RLS was significantly more prevalent in acute stroke/TIA patients than in the control group. As expected, cerebrovascular risk factors were significantly more prevalent in stroke/TIA patients, and they were significantly more prevalent in subjects with RLS, but the association of stroke/TIA with RLS was independent of these risk factors. Previous studies showed conflicting results regarding a possible association between cerebrovascular disease and RLS. For example, among 30,262 female health professionals participating in the Women’s Health Study, no association was found between RLS and stroke [15]. But the same authors found an increased prevalence of stroke among 22,786 participants of the US Physician’s Health studies I and II with an OR of 1.4 (95% CI: 1.05–1.86) [16]. Szentkiralyi et al. combined data from the Dortmund Health Study (1312 subjects with a median follow-up of 2.1 years) and the Study of Health in Pomerania (4306 subjects with a follow-up of 5.0 years) where RLS was assessed by questionnaires at baseline and a few years later [17]. They found no association between RLS and stroke, but they found that the persistence of RLS over time was low, thus limiting their findings due to possible misclassification of subjects. Longitudinal sleep studies have also tried to assess the association between RLS and cerebrovascular disease. Elwood et al. followed up 1986 men who completed a questionnaire regarding sleep disorders, with one question dedicated to RLS symptoms [18]. Men who responded positively to this single question had OR of an ischemic stroke of 1.67 (95% CI: 1.07–2.6, p = 0.024) when compared to men who reported no sleep disturbance of any kind. But in another longitudinal study, the MEMO study (Memory and Morbidity in Augsburg Elderly) [19,20], Walters et al. found that, in a subset of 24 subjects with RLS and 241 not suffering from RLS, there was no significant difference in the prevalence of stroke in RLS subjects [20]. There are a few drawbacks to the abovementioned studies. The first is that in some older studies, RLS diagnosis was not consistent with current criteria. The second is that in most of these studies, the ascertainment of RLS symptoms was based solely on questionnaires without face-to-face interviews, thus allowing falsepositive results due to RLS mimics. Another drawback is the length
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of time between RLS ascertainment and stroke as RLS symptoms may appear immediately following stroke [21], and they may wax and wane over time. Our study was conducted during hospitalization for an acute cerebrovascular event with the ascertainment of RLS in a face-to-face interview according to the standard criteria of the International Restless Legs Syndrome Study Group. We found a highly significant association between RLS and acute cerebrovascular disease. These differences in study design between previously published studies and the present work may have contributed to the discrepancies in results. In this study, we reconfirmed the association between cerebrovascular risk factors and cerebrovascular events. We also confirmed previous observations that cerebrovascular risk factors, hypertension, hyperlipidemia, and BMI are associated with RLS symptoms. We expected that the association between RLS and stroke and TIA would depend on these cerebrovascular risk factors, but multivariate analysis revealed that RLS was independently associated with cerebrovascular events. This study, being cross-sectional, does not allow drawing conclusions regarding the direction and causality of the association, whether RLS subjects are at an increased risk to develop cerebrovascular events or RLS is a consequence of the cerebrovascular event. Among our hospitalized patients, new-onset RLS patients suffered from stroke, while patients with chronic, long-standing RLS symptoms suffered from TIA as well as from stroke. This observation raises an intriguing possibility that new-onset RLS is in itself a symptom of brain ischemia. Our study was not designed to answer this question, and therefore this observation can only be viewed as anecdotal. There are several possible explanations for the association between RLS and cerebrovascular disease [22]. Lee et al. [21] evaluated 137 patients immediately following stroke, and they documented new-onset RLS symptoms in 12.4%. The patients with RLS had subcortical lesions mainly at the basal ganglia, suggesting that the latter may play a role in the pathogenesis of RLS. In addition, RLS and cerebrovascular events may be associated with the same risk factors, for example, smoking. Similarly, sleep deprivation may be a consequence of RLS symptoms or coexisting periodic leg movement of sleep, and it may increase the risk of cerebrovascular events [22,23]. Changes in blood pressure documented during sleep may underlie the increase in cerebrovascular events, as RLS patients display a non-dipping nocturnal blood pressure [24], and patients with periodic leg movement of sleep show nocturnal blood pressure elevations [25,26]. Alternatively, RLS may share pathophysiologic pathways with cerebrovascular risk factors such as alteration in the central nervous system dopaminergic system, which is thought to play a major role in RLS symptomatology, and to be altered in subjects with obesity [27]. Another possibility is that RLS and cerebrovascular events have a common cause such as shared genetic predisposition [28]. Yet, others have suggested that RLS may be a marker of unfavorable life habits and poor health including a sedentary lifestyle, hypertension, hypercholesterolemia, diabetes, and obesity [4–12,29,30]. Though it was not the aim of the present study, we confirmed previous observations that RLS predominantly affects women [4], and it is associated with anemia [4]. The association between diabetes and RLS has been debated. As in previous studies [4,7,23], we did not find an association between diabetes and RLS. The main strength of our study is the meticulous verification of RLS diagnosis and acute cerebrovascular events. The main limitations of our study are the small number of subjects and the exclusion of elderly patients. Therefore, our findings can only be relevant to the studied age group. In conclusion, we found a highly significant association between RLS and acute cerebrovascular events. Given the prevalence of stroke worldwide, these findings carry a potentially significant impact
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on public health. Further research is warranted to determine the time of onset of RLS relative to the cerebrovascular event, as preventive measures could become relevant if RLS indeed precedes the event.
Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2014.12.027.
Acknowledgments We would like to thank all the participants for their cooperation in the study. We would like to thank Ophir Avizohar, M.D., from the Department of Preventive Medicine for providing medical information for control subjects, David Yarnitsky, M.D., for reviewing the manuscript, and Mrs.Yafa Markiewicz for helping with the data entry.
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Contents lists available at ScienceDirect
Sleep Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s l e e p
Original Article
Restless legs syndrome in stroke patients I. Schlesinger a,b,*, I. Erikh a, M. Nassar a, E. Sprecher a a b
Department of Neurology, Rambam Health Care Campus, Haifa, Israel Technion Faculty of Medicine, Haifa, Israel
A R T I C L E
I N F O
Article history: Received 15 September 2014 Received in revised form 20 November 2014 Accepted 19 December 2014 Available online 23 April 2015
A B S T R A C T
Background: Restless legs syndrome (RLS) is associated with cerebrovascular risk factors, but its possible association with cerebrovascular disease has yielded conflicting results. Objective: This was a case–control, in-hospital study to evaluate the association between RLS and acute stroke or transient ischemic attack (TIA). Methods: We evaluated patients hospitalized with acute stroke/TIA and an age and gender 2:1 frequencymatched control group, for the presence of RLS. Results: Twenty-two of 149 patients (15%) and 10 of 298 controls (3%) suffered from RLS (p < 0.0001). A multivariate logistic regression model employing cerebrovascular risk factors as predictors, that is, hypertension, hyperlipidemia, diabetes, and body mass index (BMI), determined that stroke/TIA was significantly associated with RLS with odds ratio for RLS among patients with stroke/TIA versus controls of 7.60 (95% confidence interval (CI): 2.07–27.87; p = 0.002). Another multivariate logistic regression model adjusting for possible RLS risk factors, that is, hypertension, hyperlipidemia, diabetes, BMI, anemia, and reduced renal function, determined that stroke/TIA was significantly associated with RLS with odds ratio of 6.85 (95% CI: 6.85–1.79; p = 0.005). Stepwise logistic regression with hypertension, hyperlipidemia, diabetes, BMI, anemia, and reduced renal function as potential predictors revealed that only stroke/TIA predicted RLS with similar odds ratio to the RLS-based multivariate model of 6.54 (95% CI: 2.63–16.27; p < 0.0001). Conclusions: Examining stroke patients while in hospital allowed us to conclude that RLS and acute stroke/ TIA are significantly associated. However, the cross-sectional design did not allow for the determination of a causative relationship between the two. © 2014 Elsevier B.V. All rights reserved.
Restless legs syndrome (RLS) is a common sensory-motor disorder of unknown etiology [1]. It is characterized by a desire to move the legs usually accompanied by abnormal leg sensations. Symptoms typically worsen at rest and later on in the day, and they are relieved by movement. Estimates of RLS prevalence in different parts of the world range between 6% and 12% [2], but the persistence of RLS over time is low [3]. RLS has been linked to numerous cerebrovascular risk factors including hypertension, hypercholesterolemia, diabetes, and obesity [4–12], but its association with cerebrovascular disease has been debated. Case reports have suggested the emergence of RLS symptoms within days following stroke [13,14], but given the high prevalence of
The study was performed at the Department of Neurology, Rambam Health Care Campus, Haifa, Israel. Author contributions Dr. Schlesinger I and Erikh I helped in the study concept and design. Dr. Schlesinger I, Dr. Nassar M, and Erikh I helped in the acquisition of data. Dr. Schlesinger I and Dr. Sprecher E carried out analysis and interpretation. All authors carried out critical revision of the manuscript for important intellectual content. Dr. Schlesinger I helped in study supervision. * Corresponding author. Department of Neurology, Rambam Health Care Campus, P.O. Box 9602, Haifa 31096, Israel. Tel.: +972 4 8543558; fax: +972 4 8542944. E-mail address: [email protected] (I. Schlesinger). http://dx.doi.org/10.1016/j.sleep.2014.12.027 1389-9457/© 2014 Elsevier B.V. All rights reserved.
RLS in the general population, this may be a chance occurrence. A few large longitudinal studies examined the possible association between RLS and cerebrovascular disease, but RLS diagnosis was based on baseline questionnaires without the verification of RLS by a face-to-face interview, thus precluding the elimination of subjects with RLS mimics. Furthermore, RLS status was recorded at baseline, sometimes years before the cerebrovascular event; thus, RLS symptoms may have abated or appeared during the elapsed time. Our study aimed to examine a possible association between RLS and cerebrovascular disease, by examining patients during hospitalization for acute stroke or transient ischemic attack (TIA), in a matched case–control design.
1. Subjects and methods 1.1. Subjects 1.1.1. Patient selection and determination of stroke diagnosis We prospectively identified adults hospitalized with a diagnosis of stroke or TIA during weekdays, in the Neurology Department, at the Rambam Health Care Campus in Haifa, Israel, between January and December 2008. Subjects with stroke (International Classification
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of Diseases, Ninth Revision (codes 431 and 436) and TIA (code 435) were identified according to their coding on admission. Controls: Controls were 2:1 frequency-matched to the patient group by gender and age (within 3-year intervals), randomly selected from adults attending their annual checkup at the Rambam Center for Preventive Medicine, Rambam Health Care Campus. Controls had no history of stroke or TIA. The study was approved by the institutional review board. All patients gave oral consent, while all controls signed written informed consent. The trial was registered at the Clinical Trials.gov, number NCT01967303. 1.1.2. RLS screening Patients were interviewed by a movement disorders nurse practitioner (I.E.). The interview started with a questionnaire based on the standard questions developed by the International RLS Study Group as previously described as follows: (i) Have you had unpleasant sensations in your legs (such as paresthesias, numbness, and ache) accompanied by a need or urge to move your legs? (ii) Did these sensations occur at rest, and were they improved by movement? (iii) Were these symptoms worse in the evening and at night? (iv) How often did you experience these sensations? Were the sensations less than once a month, two to four times a month, twice a week, two to three times a week, four to five times a week, or six to seven times a week? The questionnaire was translated to Hebrew by two senior neurologists and a professional translator. It was then back-translated to English to ensure the accuracy of the translation. Patients who were screened negative for RLS continued with a face-to-face interview by the nurse, to verify that they did not suffer from RLS. Patients who were screened positive by the questionnaire, and patients whose interview with the nurse was not conclusive, were then interviewed by a senior neurologist with a special interest in RLS (I.S.). If there was a discrepancy between the questionnaire and the interviewer, the final diagnosis was based on the neurologist’s assessment. Patients underwent the same diagnostic procedure, and they were all interviewed face to face by the senior neurologist (I.S.). 1.2. Medical information Information regarding medical history, use of medications, and body mass index (BMI) calculation was gathered from the medical records for all participants. Laboratory results consisted of blood samples that were drawn in the morning after a 12-h fast, and they included a complete blood count, chemistry, and kidney function tests (Hitachi 911, Tokyo, Japan). Medical records of each patient were reviewed to confirm the diagnosis of stroke/TIA.
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sample size would be reached, we interviewed all potential patients within a period of one year. Preliminary analyses involved simple statistics and univariate comparisons between the stroke/TIA patients and control subjects on a number of demographic and clinical parameters. Twotailed t-tests, median tests, or Fisher exact tests were employed for comparisons as appropriate. In order to simultaneously control for potentially correlated statistical predictors, the relationship of RLS with prevalent cerebrovascular risk factors was also examined by multivariate logistic regression analysis using 1:2 case:control stratification. We performed two multivariate logistic regression analyses. The first regression model used the known cerebrovascular risk factors that included hypertension, hyperlipidemia, diabetes, and BMI. The second regression model used possible RLS risk factors that included hypertension, hyperlipidemia, diabetes, BMI, anemia, and reduced renal function. This was followed by stepwise logistic regression analysis (using stepwise selection with default options) starting from the same basic model to develop the most efficient predictive model for RLS. For all analyses, p-values <0.05 were considered to be significant. JMP and SAS (both SAS Institute, Cary, NC, USA) were used for univariate analyses and logistic regression analysis (specifically SAS PROC LOGISTIC), respectively. 2. Results Of the patients with stroke/TIA who were hospitalized during the study period, 426 were screened by the study team. In 19 patients, the diagnosis was changed during the hospitalization. One hundred and sixty-five patients were excluded because their medical condition precluded an interview (coma, dementia, aphasia, etc.). None refused to participate. Among the remaining 261, one patient was admitted three times and 28 patients were admitted twice; only the first hospitalization was included in the analysis. Patients were then matched by age and gender to those attending the Preventive Medicine Department. As subjects in the Preventive Medicine Department are mostly referred for their annual checkup from their workplace, the pool of subjects is mostly below the age of 67 (the official Israeli retirement age) with few elderly subjects. This limited the matching of older patients and excluded all patients above the age of 84. Thus, another 84 patients were randomly excluded for lack of matched controls. Therefore, the total number of subjects participating in the study was 447 (149 patients with stroke/TIA and 298 controls). Among the stroke/TIA group, 30 suffered from TIA, 110 from ischemic stroke, and nine from hemorrhagic stroke. Demographic characteristics are presented in Table 1. The mean age of the study sample was 59.5 years (standard deviation (SD) 9.4, range 32–83); 74% (330/447)
1.3. Cerebrovascular risk factors We defined subjects as suffering from diabetes mellitus, hypercholesterolemia, or hypertension when subjects reported that their physician had diagnosed the disorder and was treating them for it or when fasting glucose was ≥126 mg/dl, cholesterol was >230 mg/dl, or blood pressure was above 140/90 mm Hg. Reduced renal function was defined as serum creatinine ≥1.3 mg/dl and anemia as hemoglobin <13.5 g/dl in men and <11.5 g/dl in women. 1.4. Outcome measures and analysis The primary outcome measure was the prevalence of RLS in patients with acute stroke/TIA versus controls. Prospective power analyses suggested that a 1:2 case–control study would require at least 120 stroke cases and 240 controls to achieve statistical significance at power 0.8 in the worst case. In order to ensure that this
Table 1 Characteristics of the stroke/TIA subjects and controls.
RLS, No. (%) Age, years (mean ± SD) Gender, male % Hypertension, No. (%) Hyperlipidemia, No. (%) Diabetes, No. (%) BMI, kg/m2, median (range) Anemia, No. (%) Reduced renal function, No. (%)
Controls
Stroke/TIA
N = 298
N = 149
10 (3%) 59.4 ± 9.4 220 (74%) 106 (36%) 108 (36%) 57 (19%) 27 (18–42) 17 (6%) 28 (9%)
22 (15%) 59.5 ± 9.4 110 (74%) 114 (77%) 100 (67%) 70 (47%) 27 (19–44) 27 (18%) 27 (18%)
p
<0.0001 CCM CCM <0.0001 <0.0001 <0.0001 0.73 <0.0001 0.01
Abbreviations: TIA, transient ischemic attack; RLS, restless legs syndrome; CCM, Case– control matched; BMI, body mass index. Statistical tests employed for group comparisons were t-tests, median tests, or Fisher exact tests for these summary statistics as appropriate.
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Table 4 Characteristics of the subjects with and without RLS.
Table 2 Relationship between cerebrovascular risk factors and prevalent RLS.
Stroke/TIA Hypertension Hyperlipidemia Diabetes BMI
OR
95% CI
p
RLS
Non-RLS
7.60 1.11 3.08 0.76 0.99
2.07–27.87 0.28–4.39 0.79–11.97 0.14–4.06 0.86–1.13
0.002 0.89 0.10 0.75 0.84
N = 32
N = 415
22 (69%) 61.0 ± 7.8 17 (47%) 23 (72%) 22 (69%) 13 (41%) 26 (20–40) 7 (22%) 7 (22%)
127 (31%) 59.3 ± 9.5 313 (25%) 197 (47%) 186 (45%) 114 (27%) 27 (18–44) 37 (9%) 48 (12%)
Abbreviations: RLS, restless legs syndrome; TIA, transient ischemic attack; BMI, body mass index; OR, odds ratio; CI, confidence interval. Multivaried logistic regression analysis including known cerebrovascular risk factors. The overall model test for statistical regression was significant on likelihood ratio (0.0003), score (0.0003), and Wald test (0.01).
were male. Hypertension, hyperlipidemia, and diabetes were significantly more prevalent among stroke patients (p < 0.0001 for each risk factor, Table 1). The median BMI was 27.1 kg/m2, and it was not significantly different in stroke patients as compared with controls. Anemia was three times more prevalent in stroke patients (18%) as compared with controls (6%) (p < 0.0001). Reduced renal function was twice as likely in patients (18%) as in controls (9%) (p = 0.01). Among patients with stroke/TIA, the diagnosis of RLS was significantly more prevalent than in controls (15% vs. 3%, p < 0.0001). In all 22 stroke/TIA patients with RLS, RLS preceded the stroke/ TIA as follows: new-onset RLS appeared approximately a month before ischemic stroke in six patients. Two of these patients were hospitalized 1 month previously because of TIA appearing together with new-onset RLS symptoms. Five patients reported RLS appearing with a previous stroke 2–5 years earlier. Chronic RLS was reported in 11 patients (five with ischemic stroke, one with hemorrhagic stroke, and five with TIA). The multivariate logistic regression model adjusting for cerebrovascular risk factors, that is, hypertension, hyperlipidemia, diabetes, and BMI, determined that stroke/TIA was significantly associated with RLS with odds ratio (OR) for RLS among patients with stroke/TIA versus controls of 7.60 (95% CI: 2.07–27.87; p = 0.002), Table 2. In this multivariate logistic regression model, no other variable approached statistical significance (hypertension, p = 0.89; hyperlipidemia, p = 0.10; diabetes, p = 0.75; and BMI, p = 0.84). The multivariate logistic regression model adjusting for possible RLS risk factors, that is, hypertension, hyperlipidemia, diabetes, BMI, anemia, and reduced renal function, determined that stroke/TIA was significantly associated with RLS with OR of 6.85 (95% CI: 6.85–1.79; p = 0.005), Table 3. The stepwise logistic regression with hypertension, hyperlipidemia, diabetes, BMI, anemia, and reduced renal function as potential predictors yielded a single predictor model, indicating that only stroke/TIA predicted RLS with similar OR to the multivariate model l of 6.54 (95% CI: 2.63–16.27; p < 0.0001).
Table 3 Relationship between possible RLS risk factors and prevalent RLS.
Stroke/TIA Hypertension Hyperlipidemia Diabetes BMI Anemia Reduced renal function
OR
95% CI
p
6.85 0.95 3.31 0.75 0.99 1.94 1.33
1.79–6.85 0.21–0.95 0.85–3.31 0.13–0.75 0.86–0.99 0.18–1.94 0.22–1.33
0.005 0.94 0.09 0.74 0.89 0.58 0.76
Abbreviations: RLS, restless legs syndrome; TIA, transient ischemic attack; BMI, body mass index; OR, odds ratio; CI, confidence interval. Multivaried logistic regression analysis including possible RLS risk factors. The overall model test for statistical regression was significant on likelihood ratio (0.001), score (0.001), and Wald test (0.04).
Stroke or TIA, No. (%) Age, years (mean ± SD) Gender, male No. (%) Hypertension, No. (%) Hyperlipidemia, No. (%) Diabetes, No. (%) BMI, kg/m2, median (range) Anemia, No. (%) Reduced renal function, No. (%)
p
<0.0001 0.25 0.010 0.01 0.01 0.15 0.14 0.03 0.10
Abbreviations: RLS, restless legs syndrome; TIA, transient ischemic attack; BMI, body mass index; OR, odds ratio; CI, confidence interval. Statistical tests employed for group comparisons were t-tests, median tests, or Fisher exact tests for these summary statistics as appropriate.
There was a higher prevalence of RLS among females in the entire cohort, Table 4. Furthermore, for the entire cohort, hyperlipidemia, hypertension, and anemia were positively associated with the diagnosis of RLS. Diabetes, BMI, and reduced renal function were not associated with RLS. There was a trend toward an increase in the diagnosis of RLS with age. 3. Discussion To the best of our knowledge, this is the first case–control study to assess the association between acute stroke/TIA and RLS. We found that RLS was significantly more prevalent in acute stroke/TIA patients than in the control group. As expected, cerebrovascular risk factors were significantly more prevalent in stroke/TIA patients, and they were significantly more prevalent in subjects with RLS, but the association of stroke/TIA with RLS was independent of these risk factors. Previous studies showed conflicting results regarding a possible association between cerebrovascular disease and RLS. For example, among 30,262 female health professionals participating in the Women’s Health Study, no association was found between RLS and stroke [15]. But the same authors found an increased prevalence of stroke among 22,786 participants of the US Physician’s Health studies I and II with an OR of 1.4 (95% CI: 1.05–1.86) [16]. Szentkiralyi et al. combined data from the Dortmund Health Study (1312 subjects with a median follow-up of 2.1 years) and the Study of Health in Pomerania (4306 subjects with a follow-up of 5.0 years) where RLS was assessed by questionnaires at baseline and a few years later [17]. They found no association between RLS and stroke, but they found that the persistence of RLS over time was low, thus limiting their findings due to possible misclassification of subjects. Longitudinal sleep studies have also tried to assess the association between RLS and cerebrovascular disease. Elwood et al. followed up 1986 men who completed a questionnaire regarding sleep disorders, with one question dedicated to RLS symptoms [18]. Men who responded positively to this single question had OR of an ischemic stroke of 1.67 (95% CI: 1.07–2.6, p = 0.024) when compared to men who reported no sleep disturbance of any kind. But in another longitudinal study, the MEMO study (Memory and Morbidity in Augsburg Elderly) [19,20], Walters et al. found that, in a subset of 24 subjects with RLS and 241 not suffering from RLS, there was no significant difference in the prevalence of stroke in RLS subjects [20]. There are a few drawbacks to the abovementioned studies. The first is that in some older studies, RLS diagnosis was not consistent with current criteria. The second is that in most of these studies, the ascertainment of RLS symptoms was based solely on questionnaires without face-to-face interviews, thus allowing falsepositive results due to RLS mimics. Another drawback is the length
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of time between RLS ascertainment and stroke as RLS symptoms may appear immediately following stroke [21], and they may wax and wane over time. Our study was conducted during hospitalization for an acute cerebrovascular event with the ascertainment of RLS in a face-to-face interview according to the standard criteria of the International Restless Legs Syndrome Study Group. We found a highly significant association between RLS and acute cerebrovascular disease. These differences in study design between previously published studies and the present work may have contributed to the discrepancies in results. In this study, we reconfirmed the association between cerebrovascular risk factors and cerebrovascular events. We also confirmed previous observations that cerebrovascular risk factors, hypertension, hyperlipidemia, and BMI are associated with RLS symptoms. We expected that the association between RLS and stroke and TIA would depend on these cerebrovascular risk factors, but multivariate analysis revealed that RLS was independently associated with cerebrovascular events. This study, being cross-sectional, does not allow drawing conclusions regarding the direction and causality of the association, whether RLS subjects are at an increased risk to develop cerebrovascular events or RLS is a consequence of the cerebrovascular event. Among our hospitalized patients, new-onset RLS patients suffered from stroke, while patients with chronic, long-standing RLS symptoms suffered from TIA as well as from stroke. This observation raises an intriguing possibility that new-onset RLS is in itself a symptom of brain ischemia. Our study was not designed to answer this question, and therefore this observation can only be viewed as anecdotal. There are several possible explanations for the association between RLS and cerebrovascular disease [22]. Lee et al. [21] evaluated 137 patients immediately following stroke, and they documented new-onset RLS symptoms in 12.4%. The patients with RLS had subcortical lesions mainly at the basal ganglia, suggesting that the latter may play a role in the pathogenesis of RLS. In addition, RLS and cerebrovascular events may be associated with the same risk factors, for example, smoking. Similarly, sleep deprivation may be a consequence of RLS symptoms or coexisting periodic leg movement of sleep, and it may increase the risk of cerebrovascular events [22,23]. Changes in blood pressure documented during sleep may underlie the increase in cerebrovascular events, as RLS patients display a non-dipping nocturnal blood pressure [24], and patients with periodic leg movement of sleep show nocturnal blood pressure elevations [25,26]. Alternatively, RLS may share pathophysiologic pathways with cerebrovascular risk factors such as alteration in the central nervous system dopaminergic system, which is thought to play a major role in RLS symptomatology, and to be altered in subjects with obesity [27]. Another possibility is that RLS and cerebrovascular events have a common cause such as shared genetic predisposition [28]. Yet, others have suggested that RLS may be a marker of unfavorable life habits and poor health including a sedentary lifestyle, hypertension, hypercholesterolemia, diabetes, and obesity [4–12,29,30]. Though it was not the aim of the present study, we confirmed previous observations that RLS predominantly affects women [4], and it is associated with anemia [4]. The association between diabetes and RLS has been debated. As in previous studies [4,7,23], we did not find an association between diabetes and RLS. The main strength of our study is the meticulous verification of RLS diagnosis and acute cerebrovascular events. The main limitations of our study are the small number of subjects and the exclusion of elderly patients. Therefore, our findings can only be relevant to the studied age group. In conclusion, we found a highly significant association between RLS and acute cerebrovascular events. Given the prevalence of stroke worldwide, these findings carry a potentially significant impact
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on public health. Further research is warranted to determine the time of onset of RLS relative to the cerebrovascular event, as preventive measures could become relevant if RLS indeed precedes the event.
Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2014.12.027.
Acknowledgments We would like to thank all the participants for their cooperation in the study. We would like to thank Ophir Avizohar, M.D., from the Department of Preventive Medicine for providing medical information for control subjects, David Yarnitsky, M.D., for reviewing the manuscript, and Mrs.Yafa Markiewicz for helping with the data entry.
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