Restless Legs Syndrome

Demographic (age, gender, height, weight), CSI-J, and four pain-related outcomes [pain duration, health-related quality of life (QOL), pain intensity, and pain interference] were assessed in all participants. A test-retest reliability of the CSI-J was determined with a time interval of 1 week. These domains were selected because patients whose presenting symptoms may be related to a CSS (e.g. chronic whiplash-associated disorders, fibromyalgia, and PTSD) showed significant relationships between CS outcome and QOL, pain intensity, and disability [33 (link), 40 (link)–42 (link)].
The CSI-J consists of two parts: A and B. Part A is a 25-item self-report questionnaire designed to assess health-related symptoms that are common to CSSs. Each item is rated on a 5-point Likert-type scale (0 = never and 4 = always), with total scores of 0–100. Part B (which is not scored) is designed to determine whether one or more specific disorders, including seven separate CSSs, have been previously diagnosed [restless leg syndrome, chronic fatigue syndrome, fibromyalgia, temporomandibular joint disorder, migraine or tension headaches, irritable bowel syndrome, multiple chemical sensitivities, neck injuries (including whiplash), anxiety or panic attacks, and depression].
Health-related QOL was measured using EuroQol 5-dimension (EQ-5D) [43 (link)]. EQ-5D was developed as an instrument that is not specific to disease, but standardized, and can be used as a complement to existing health-related QOL measures [44 (link)]. It comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has three grades (no problems, some problems, and extreme problems), which can generate a single index value for each health state. These values are numbers on a scale with 1 for full health and 0 for being dead. Tsuchiya et al. showed the Japanese value set [45 (link)].
Pain intensity and pain interference were measured using the Brief Pain Inventory (BPI) [46 (link),47 (link)]. It consists of four pain intensity and seven pain interference items. These items were presented with 0–10 scales, with 0 = no and 10 = worst (completely). From these, individual pain intensity and pain interference scores are calculated by averaging. The validation and clinical utility of BPI has been evaluated for several disorders [48 (link)–50 (link)]. To investigate the prevalence rates of CS severity levels, we referred to the five categories with increasing severity [33 (link)]. The authors reviewed the score distributions of previously published CSI study samples, including those with no CSS diagnosis, those with a single CSS diagnosis, those with multiple CSS diagnoses, and a group of nonpatient comparison subjects. Through empirical reasoning and deduction, using these score distributions as a guide, the CSI was divided into five categories with increasing severity: subclinical (0–29), mild (30–39), moderate (40–49), severe (50–59), and extreme (60–100).

All participants were assessed for demographic data (age, gendar, height, and weight), pain duration, CSI, health-related quality of life (QOL), pain intensity, and pain interference. CSI-J consists of Parts A and B. Part A consists of a 25-item self-report questionnaire designed to assess health-related symptoms that are common to CSS. Each item is rated on a 5-point Likert-type scale, with total scores ranging from 0 to 100. Part B (which is not scored) asks the participants whether one or more specific disorders, including seven separate CSSs, have been diagnosed previously (restless leg syndrome, chronic fatigue syndrome, fibromyalgia, temporomandibular joint disorder, migraine or tension headaches, irritable bowel syndrome, multiple chemical sensitivities, neck injury (including whiplash], anxiety or panic attacks, and depression).
Health-related QOL was measured using the EuroQol 5-dimension (EQ-5D) instrument [39 (link)]. EQ-5D was developed as a non-disease specific standardized instrument, which could be used to complement existing health-related QOL measure [40 (link), 41 (link)]. It comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has three grades (no problems, some problems, and extreme problems), which generates a single index value for each health state. These values are numbers on a scale where 1 refers to full health and 0 refers to death.
Pain intensity and interference were measured using the Brief Pain Inventory (BPI) [42 (link), 43 (link)]. BPI comprises four pain intensity and seven pain interference items. These items are rated using a scale of 0–10, where 0 = no pain and 10 = worst possible pain. Based on the values obtained, individual pain intensity and interference scores were evaluated by calculating the mean. The validation and clinical utility of BPI has been evaluated for several disorders [44 (link)–46 (link)].

The population selection flowchart is presented in Fig. 1. Since NHIS-EC was an administrative claim data, we could not apply formal diagnostic criteria of the International RLS Study Group [5 (link)] to identify patients with RLS. Instead, the presence of RLS was defined using the ICD-10 code G25.8. For diagnostic accuracy, patients with RLS were defined as those who had been diagnosed at least twice with this code (n = 5940). Meanwhile, RLS-free controls were defined as those who were never diagnosed with this code (n = 538,046). Among the 5940 patients with RLS, we excluded those diagnosed with dementia before the first diagnosis of RLS (n = 586) and the second diagnosis of RLS (n = 4). Considering the gradual onset of dementia, the minimal gap between the onset of RLS and any type of dementia was set at 2 years to minimize detection bias. Therefore, patients with RLS who were first diagnosed between 2012 and 2013 (n = 2361) or diagnosed with dementia within 2 years after RLS diagnosis (n = 329) were excluded. Additionally, patients with RLS in 2002, the first observation year of the NHIS-EC, were excluded due to the possibility that their first diagnosis was made before the observation period (n = 22). The patients were matched to controls in a maximum 1:4 ratio based on age, sex, and index date. Finally, 2501 patients with RLS and 9977 matched controls were included in the analysis.Fig. 1

Flowchart of study population selection

Abbreviations: NHIS-EC, National Health Insurance Service-Elderly Cohort; RLS, restless leg syndrome

All-cause dementia was defined as AD (ICD-10 F00 or G30), VaD (ICD-10 F01), and other types of dementia (ICD-10 F02, F03, F10.7, G23.1, G31.0, G31.1, G31.2, or G31.8). Dementia patients were defined as those diagnosed at least twice with the relevant ICD code(s) to minimize the possibility of over-classification of cases due to using ICD codes instead of formal diagnostic criteria. If patients had ICD codes of both AD and VaD, we classified these patients into VaD as a primary diagnosis following a previous study using the same database [27 (link)]. Among all-cause dementia cases (n = 874), 54.4% (n = 475) was AD, and 22.2% (n = 194) was VaD, which was consistent with the general epidemiology of dementia in South Korea [28 ]. Patients with other types of dementia were not analyzed separately because of heterogeneous disease entities and small sample sizes.