Comparison of Cognitive Function between Patients with Restless Legs Syndrome and Healthy Controls

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1 online ML Comm ORIGINAL ARTICLE pissn / eissn Sleep Med Res 2014;5(1):20-24 Comparison of Cognitive Function between Patients with Restless Legs Syndrome and Healthy Controls Ye Ji Moon, BS 1, Jin-Young Song, MS 2, Byeong Uk Lee, BS, RPSGT 1, Yong Seo Koo, MD, PhD 2, Sang Kun Lee, MD, PhD 1, Ki-Young Jung, MD, PhD 1 1 Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea 2 Department of Neurology, Korea University Medical Center Anam Hospital, Korea University College of Medicine, Seoul, Korea Background and ObjectiveaaStudies regarding cognitive function in patients with restless legs syndrome (RLS) show inconsistent results, although comorbid psychiatric conditions including depression and anxiety are common in these patients. We compared cognitive performance and depression symptoms between drug-naïve RLS patients and healthy controls, in order to determine whether the depression symptoms that result from RLS affect cognitive function. MethodsaaDrug-naïve RLS patients (n = 15) and age-matched controls (n = 17) were enrolled in the study. They completed clinical interviews, sleep questionnaires, and a neuropsychological assessment battery that measured multiple cognitive domains including attention, language ability, memory, and executive function. Depression was measured using the Beck Depression Inventory-II. Statistical analyses included chi-square and non-parametric Mann-Whitney U tests, and Spearman correlations. ResultsaaRestless legs syndrome patients performed better than controls on tests of verbal memory and category word fluency (animal) (p < 0.05). The RLS group had significantly higher depression scores than controls (p = 0.005). Depression scores for the RLS patients showed significant correlations with restless legs symptoms and several measures of sleep quality. There were no significant differences in cognitive function between patients with moderate to severe depression (n = 6) and those without depression (n = 6). ConclusionsaaOur study did not confirm that symptoms of RLS were associated with cognitive dysfunction. In addition, depression symptoms had little impact on cognitive function, but were independently associated with symptoms of RLS regardless of cognitive function. Sleep Med Res 2014;5(1):20-24 Key WordsaaRestless legs syndrome, Depression, Cognition, Neuropsychological tests. INTRODUCTION Received: November 22, 2014 Revised: December 10, 2014 Accepted: December 15, 2014 Correspondence Ki-Young Jung, MD, PhD Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul , Korea Tel Fax jungky10@gmail.com Recent studies have reported that moderate to severe restless legs syndrome (RLS) patients may have significant cognitive deficits, primarily in executive functioning, compared with healthy control subjects. 1-4 Electrophysiological studies also support the existence of cognitive dysfunction in RLS patients. For example, a recent event-related potential (ERP) study showed that underlying cognitive dysfunction, associated with a working memory deficit characterized by increased reaction time and lower amplitude of the P300 component, was evident in patients with severe RLS. 5,6 In contrast, other studies found no difference in cognitive function between RLS patients and controls. RLS subjects performed better than sleep-restricted controls on a test of verbal fluency. 7 In middle-aged and elderly subjects, individuals with mild RLS were found to have no differences in multiple domains of cognitive functioning when compared to those without RLS. 8,9 This discrepancy may be attributable to several factors, such as differences in study samples, the use of different age groups (patients of middle vs. older age), the types of neuropsychological tests administered (full batteries vs. selected tests of frontal function), and medication effects (unmedicated vs. medicated). It has been reported that comorbid psychiatric conditions such as depression and anxiety are common in patients with RLS Epidemiological studies report a 2- to 4-fold risk of a de- 20 Copyright 2014 The Korean Society of Sleep Medicine

2 Moon YJ, et al. pressive disorder in patients with RLS compared with healthy controls. As depression is well known to compromise cognitive functioning, 13 depression might be a contributing factor to the cognitive deficit observed in patients with RLS. Furthermore, RLS-related sleep loss might cause depressive symptoms, and vice versa. Therefore, depression should be taken into consideration when evaluating cognition in RLS. However, only a few studies have examined whether depression is associated with cognitive dysfunction in RLS patients. These studies have revealed that, in RLS patients, depression does have an impact on cognitive function. 2,3,8,9 The aim of the present study was to investigate cognitive function as measured with a comprehensive neuropsychological test battery in drug-naïve RLS patients, compared to age-matched healthy controls. Depression was also evaluated, and was taken into consideration in the interpretation of cognitive function in RLS patients. METHODS Subjects All subjects signed written informed consents. The experimental protocol was approved by the local ethics committee. The diagnosis of RLS was made based on the diagnostic criteria established by the International RLS Study Group. 14 The inclusion criteria were: 1) age years, 2) RLS symptom duration longer than 1 year, 3) International RLS Severity Scale (IRLS) score > 19, and 4) no prior treatment for RLS. Patients whose symptoms were associated with secondary RLS such as pregnancy, chronic kidney disease or peripheral neuropathy, or who had sleep disorders other than RLS were excluded from the study. An age-matched group of healthy volunteers participated as controls. Subjects were included as healthy controls in the present study only if they were in the normal range in a sleep questionnaire and not identified as having RLS during a faceto-face interview. The structured sleep questionnaire included the Global Sleep Assessment Questionnaire, 15 the Pittsburgh Sleep Quality Index (PSQI), 16 the Epworth Sleepiness Scale (ESS), 17 and the Insomnia Severity Index (ISI). 18 RLS severity was determined using the IRLS. 19 Neuropsychological Assessment The neuropsychological test battery included: 1) Digit span forward and backward to assess attention span, 20 2) Short form of the Korean-Boston Naming Test to evaluate language function using confrontational naming skills, 21 3) Rey-Osterrieth Complex Figure Test to measure visuospatial abilities and visuospatial memory, 22 4) Korean-California Verbal Learning Test (K-CVLT) for verbal memory and learning, 23 5) Controlled Oral Word Association Test (COWAT), 24,25 6) Digit Symbol Coding, 26 7) Trail Making Test, 27,28 and 8) Korean-Color Word Stroop Test to test executive functions. 29 Depression Assessment Subjects completed the 21-item Korean version of the Beck Depression Inventory II (BDI-II) to assess the intensity of depression. 30 The standard cut-offs are as follows: 0 13 indicates minimal depression; indicates mild depression; indicates moderate depression; and indicates severe depression. Higher scores on BDI-II are associated with more intense depression. The Korean version of the BDI-II has good reliability and validity as a measure to assess severity of depressive symptoms in patients and nonclinical populations. 30,31 The BDI-II has been widely applied to identify RLS patients with depression, and is a useful tool in the studies of RLS patients. 32,33 Statistical Analyses Chi-square and Mann-Whitney U tests were used to compare RLS patients with controls. Spearman correlations were conducted to determine the correlation between clinical and sleeprelated variables and depression scores in the RLS group. p < 0.05 was considered to indicate statistical significance. RESULTS Demographic Data and Sleep-Related Variables Fifteen drug-naïve RLS patients [median: 41 years old, interquartile range (IQR): years, F: 12] and 17 age- Table 1. Demographic data Control (n = 17) RLS (n = 15) Age, years * Sex M:1/F:16 M:3/F: Education, years * BMI, kg/m * Ferritin, ng/ml *Mann-Whitney U test. Chi-square test. RLS: restless legs syndrome, BMI: body mass index, IQR: interquartile range, M: male, F: female. 21

3 Cognition in Restless Legs Syndrome matched healthy control subjects (median: 51 years old, IQR: years, F: 16) participated in the study (Table 1). No significant group differences on demographic data or clinical characteristics were observed across the two groups. The median (IQR) IRLS score in the RLS patients was 27 ( ). ESS score and sleep duration were not significantly dif- Table 2. Sleep-related variables Control (n = 17) RLS (n = 15) Sleep duration (h) IRLS ESS ISI < PSQI < RLS: restless legs syndrome, IRLS: International RLS Severity Scale, ESS: Epworth Sleepiness Scale, ISI: Insomnia Severity Index, PSQI: Pittsburgh Sleep Quality Index, IQR: interquartile range. Table 3. Results of the neuropsychological tests Attention Control RLS Digit span: forward Digit span: backward Language S-K-BNT Visuospatial abilities RCFT copy score RCFT copy time* Memory RCFT immediate recall RCFT delayed recall RCFT recognition K-CVLT trial K-CVLT trial 1 5 total K-CVLT short delay free recall K-CVLT long delay free recall K-CVLT recognition Executive function COWAT category word fluency: animal COWAT category word fluency: market COWAT phoneme word fluency total DSC TMT-A* TMT-B* K-CWST word correct response K-CWST color correct response BDI-II *Variable for which lower scores mean better performance. CWST word of control group is a constant. This constant is omitted. RLS: restless legs syndrome, S-K-BNT: Short form of the Korean-Boston Naming Test, RCFT: Rey-Osterrieth Complex Figure Test, K-CVLT: Korean-California Verbal Learning Test, COWAT: Controlled Oral Word Association Test, DSC: Digit Symbol Coding, TMT: Trail Making Test, K-CWST: Korean-Color Word Stroop Test, BDI-II: Beck Depression Inventory II, IQR: interquartile range. 22 Sleep Med Res 2014;5(1):20-24

4 Moon YJ, et al. ferent between the two groups. However, RLS patients had worse ISI and PSQI scores than controls, proving that RLS patients had more insomnia and poorer sleep quality (Table 2). Neuropsychological Tests Within the cognitive domain of memory, significant group differences were observed on the K-CVLT word recognition test. Within the executive function domain, significant group differences were seen on the COWAT test of category word fluency: animal. On both tests, RLS patients performed slightly but significantly better than controls (p < 0.05) (Table 3). Depression and Correlation with Cognition The RLS group had a significantly higher BDI-II score compared with the control group (6 vs. 16, p = 0.005) (Table 3). RLS patients had a BDI-II score that was significantly correlated with IRLS (r = 0.619, p = 0.014), ISI (r = 0.757, p = 0.001), and PSQI (r = 0.583, p = 0.022). Nine (52.9%) out of 17 RLS patients had depression, and six patients had no depression. Six patients (35.3%) showed moderate to severe depression. We compared cognitive function between patients with moderate to severe depression (n = 6) and those without depression (n = 6). There was no significant difference in cognitive function between the two groups. DISCUSSION The present study was performed to investigate the differences in cognitive function and depression between drug-naïve RLS patients and healthy controls. The main findings of this study were 1) RLS patients do not exhibit cognitive decline compared to age-matched control subjects, 2) RLS patients experienced more depression than control subjects, and 3) the depression in patients with RLS had little impact on cognitive function, but were independently associated with symptoms of RLS regardless of cognitive function. Inconsistent findings using neuropsychological tests have been reported in patients with RLS. Some studies have reported cognitive dysfunction in the domain of frontal lobe functions. However, other studies revealed no differences in cognition between RLS patients and control subjects. Our study demonstrated higher performance in verbal memory and word fluency in patients with RLS compared to control subjects. There are some explanations for the normal cognitive function in our patients. Self-reported sleep duration was not different between patients and control subjects, although our patients had severe RLS symptomatology as well as significant sleep disturbances. Adaptation to the effects of chronic sleep disturbances in RLS may reduce the contribution of sleep loss to cognitive function in these patients. An alerting mechanism that is associated with an enhanced level of physiologic alertness in RLS 8 may operate to mitigate some effects of sleep disruption on cognitive function. 2 A recent neuroimaging study showed significant regional decreases of gray matter volume in multiple cortical regions including the left hippocampal gyrus, both parietal lobes, medial frontal areas, and cerebellum in patients with RLS. 34 These findings suggest cortical dysfunction in RLS patients. Moreover, ERP studies demonstrated clearly decreased P300 amplitudes in oddball and Sternberg working memory tasks. Therefore, subtle cognitive decline in RLS could be revealed by sophisticated neuroimaging or neurophysiological methods. We found that the RLS patients scored higher on the depression evaluation than the control group. About half of the patients suffered from depression, and one third of the patients showed moderate to severe depression. This figure is comparable to previous studies The depression score showed a significant positive correlation with both sleep disturbance and RLS severity. To identify whether depression had impact on cognitive function, we compared cognitive function between patients with moderate to severe depression and those without depression. We found no significant difference in cognitive function regardless of whether the patients had depression. This result indicates that depression might not be an important factor affecting cognition in patients with RLS. However, our small sample size may have introduced statistical bias and precludes us from drawing a firm conclusion from our results. Further studies with larger sample sizes will be required to corroborate our results. Nevertheless, some points regarding our study are worth mentioning. The present study targeted drug-naïve patients with RLS. Most previous studies have weaned participants off RLSrelated medications before examining the impact of untreated RLS symptoms on cognitive function. Our study recruited only drug-naïve RLS patients so that we could independently examine the effect of RLS symptoms on cognitive performance, excluding any secondary effects caused by the sudden termination of RLS treatment. In addition, cognitive performance was compared with healthy control subjects without RLS in multiple domains, using a comprehensive battery of neuropsychological tests along with an evaluation of depression. In conclusion, patients with RLS may not show cognitive dysfunction when evaluated by comprehensive neuropsychological tests. In addition, depression is likely to have little impact on cognitive function, but may be associated with RLS symptoms. Acknowledgments This research was supported by the National Research Foundation of Korea grant funded by the Korean government (no ). Conflicts of Interest The authors have no financial conflicts of interest. REFERENCES 1. Pearson VE, Allen RP, Dean T, Gamaldo CE, Lesage SR, Earley CJ. Cog- 23

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