INTRODUCTION
Restless legs syndrome (RLS) is a sensory-motor neurological disorder characterized by an irresistible urge to move the legs, often accompanied by an unpleasant sensation in the legs. Symptoms typically occur at rest, are relieved by movement, and worsen at night [1]. RLS is believed to result from dopaminergic dysfunction caused by iron deficiency in the central nervous system. In the central nervous system, iron serves as an essential enzymatic cofactor for dopamine production by tyrosine hydroxylase. Iron deficiency impairs dopamine production, contributing to RLS symptoms [2-4]. The prevalence of RLS in the general population is estimated to be around 5%–15% [1,4,5]. Previous studies have reported that 50%–85% of RLS patients experience insomnia along with daytime fatigue and sleepiness [6,7], with one study indicating that over 90% of patients experience insomnia [8]. Another study found that RLS patients have an average total sleep time (TST) of 5.5 hours or less [9]. This insomnia is believed to result from difficulty initiating sleep due to nocturnal leg discomfort and/or from hyperarousal associated with the pathophysiology of RLS itself [10,11]. Consequently, RLS patients generally exhibit poorer sleep quality compared to healthy individuals.
Dopamine agonists, a common treatment for RLS, have been shown to improve sleep quality by increasing sleep efficiency (SE) [12]. Another common treatment for RLS, alpha-2-delta ligands, is known to increase slow-wave sleep [13]. However, some patients continue to experience insomnia even after their leg discomforts improve [14-16]. A study found that 53% of treated RLS patients still reported sleep disturbances at least four times per week [17]. These findings suggest that attributing insomnia solely to nocturnal leg discomforts may be an oversimplification.
Understanding the factors contributing to insomnia in patients who continue to experience insomnia even after their leg discomfort has improved is crucial for developing a treatment plan to improve overall sleep quality. Simply maintaining RLS treatment is unlikely to sufficiently improve a patient’s sleep quality unless the underlying factors contributing to insomnia are identified and addressed.
Therefore, this study aims to explore potential factors associated with persistent insomnia in RLS patients who experience significant improvement in leg discomfort following medication.
METHODS
Study Population
We retrospectively reviewed the medical records of patients with RLS who first visited the Sleep Clinic at the Department of Neurology, Seoul National University Hospital, between March 1, 2022 and June 30, 2024. Only patients who received medication and were followed up for at least 6 months after diagnosis were included in the analysis.
The study included individuals diagnosed with RLS based on the 2014 revised criteria of the International Restless Legs Syndrome Study Group [1], who remained on medication and were followed up for at least 6 months. Participants were excluded if they were under 18 years of age, had secondary RLS due to conditions such as severe anemia or chronic kidney disease requiring dialysis, or if their IRLS scores did not decrease by at least 6 points from baseline after 6 months of medication treatment.
This study was approved by the Institutional Review Board of Seoul National University Hospital (IRB no. 2412-061-1594), with patient consent waived due to its retrospective nature.
Investigation Methods
We analyzed the patients’ clinical characteristics, sleep questionnaire results, and polysomnographic findings from their medical records. Patients were initiated on treatment with dopamine agonists or alpha-2-delta ligands. The dose of medication was adjusted during follow-up visits according to the patient’s level of leg discomfort control. Baseline International Restless Legs Syndrome Study Group Rating Scale (IRLS) scores were used as indicators of the initial severity of RLS and follow-up IRLS scores taken after starting medication, were used to assess changes in the severity of RLS. RLS symptoms were considered improved if the follow-up IRLS score decreased by at least 6 points from the initial score [18]. In addition to checking IRLS scores at follow-up visits, patients were assessed for the percentage reduction in the Visual Analogue Scale (VAS) for insomnia severity from baseline, with a reduction of 50% or more considered an improvement. Based on this definition, among patients with improved RLS symptoms, we distinguished those with improved insomnia symptoms from those without. Hereafter, we will refer to these two groups as the “improved insomnia group” and the “persistent insomnia group.”
Clinical Assessment
We compared the clinical characteristics and polysomnographic findings between the improved insomnia group and the persistent insomnia group. The clinical characteristics compared included age, sex, age of onset, duration of RLS, body mass index (BMI), and family history. Polysomnography was performed to assess comorbid sleep disorders, and the polysomnographic findings compared included time in bed (TIB), TST, the proportion of each sleep stage relative to the TST, sleep latency (SL), wake after sleep onset (WASO), SE, apnea-hypopnea index (AHI), and lowest peripheral oxygen saturation (SpO2).
Within each group, we also compared how sleep questionnaire results changed before and after the control of leg discomfort. The sleep questionnaire results we compared included the IRLS, the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI), the Hospital Anxiety and Depression Scale (HADS), and mid-sleep time on free days corrected for sleep debt (MSFsc), calculated from the Munich ChronoType Questionnaire (MCTQ) [19].
Statistical Analysis
Continuous variables were presented as mean±standard deviation, and categorical variables as number (percentage). Continuous variables were tested for normality using the Shapiro-Wilk test. To compare differences between groups, continuous variables were analyzed using either the independent t-test or the Mann-Whitney U test, while categorical variables were analyzed using either the chi-square test or Fisher’s exact test. To compare within-group differences, continuous variables were analyzed using either the paired t-test or the Wilcoxon signed-rank test. Statistical analysis was performed using SPSS version 29.0 (IBM Corp.), and statistical significance was considered when the p-value was less than 0.05, based on a two-tailed test.
RESULTS
A total of 34 patients were identified during the study period. Of these, 9 patients were excluded from the analysis because their IRLS scores did not decrease by 6 points or more despite 6 months of treatment. Ultimately, 25 patients were selected for analysis, 19 of whom (76%) were in the improved insomnia group, and 6 of whom (24%) were in the persistent insomnia group (Fig. 1).
Clinical Characteristics
No significant differences were found between the improved insomnia group and the persistent insomnia group in age, sex, age of onset, proportion of patients with early onset (onset before age 45), duration of RLS, proportion of patients with RLS lasting 10 years or more, family history of RLS, and BMI (Table 1).
Polysomnographic Findings
None of the polysomnographic findings differed significantly between the improved insomnia group and the persistent insomnia group. The two groups did not differ in SL, WASO, and SE. They also did not differ in terms of comorbid sleep disorders that may contribute to insomnia. For instance, no significant differences were observed in AHI and periodic limb movement index during sleep (PLMSI) (Table 2).
Sleep Questionnaire Outcomes
The improved insomnia group had significantly higher initial and IRLS scores (31.8±3.6 vs. 27.3±3.5, p=0.030) compared to the persistent insomnia group. However, no significant differences were found between the two groups in initial PSQI, ISI, Hospital Anxiety and Depression Scale-Anxiety (HADS-A), Hospital Anxiety and Depression Scale-Depression (HADS-D), and MSFsc (Table 3).
The improved insomnia group showed significant reductions in the IRLS (31.8±3.6 vs. 13.6±5.9, p<0.001), PSQI (14.2±4.3 vs. 8.7±3.3, p<0.001), and ISI (18.3±6.7 vs. 8.1±4.6, p<0.001) after improvement of leg discomfort. There were no significant changes in HADS-A, HADS-D, or MSFsc. However, a significant decrease in the proportion of participants with a HADS-D score of 8 or higher (42.1% vs. 21.1%, p=0.018) after improvement of leg discomfort.
The persistent insomnia group showed a significant decrease in IRLS (27.3±3.5 vs. 15.7±2.1, p=0.027) and ISI (16.0±5.4 vs. 11.2±6.1, p=0.043) after controlling for leg discomfort. There were no significant changes in PSQI, HADS-A, HADS-D, MSFsc, or the proportion of participants with a HADS-D score of 8 or higher (Table 4).
DISCUSSION
Patients with RLS often report insomnia. While comorbid insomnia can be attributed to RLS symptoms, some patients continue to experience insomnia even after their leg discomforts have resolved. Therefore, it is important to identify contributing factors beyond RLS. In this study, we conducted a retrospective analysis of medical records to compare the clinical characteristics of RLS patients who experienced improvements in both their RLS symptoms and insomnia with those who continued to experience insomnia.
The improved insomnia group experienced enhanced sleep quality, reduced insomnia severity, and improved depression after RLS symptoms improved. In contrast, the persistent insomnia group showed no significant improvement in self-reported insomnia despite the improvement in RLS symptoms.
The relationship between RLS and insomnia is complex and multifactorial. We believe that insomnia in RLS may be a secondary consequence of leg discomfort, or in some cases, an inherent component of the disorder itself. Difficulty initiating sleep may be directly related to nocturnal leg discomfort [11], while difficulty maintaining sleep may result from hyperarousal associated with the pathophysiology of RLS, potentially involving central dopaminergic and glutamatergic dysfunction [10].
There are several possible explanations for these findings. First, differences in comorbid sleep disorders such as obstructive sleep apnea or periodic limb movements during sleep can be considered, as these conditions can cause frequent awakenings and lead to insomnia. However, polysomnographic findings showed no significant differences in AHI or PLMSI between the two groups.
Differences in psychological factors that may contribute to insomnia, such as anxiety or depression, can also be considered. At baseline, there were no significant differences in depression and anxiety scores on the HADS between the two groups, nor were there significant changes in these scores within each group from pre- to post-treatment. However, at follow-up, the persistent insomnia group had significantly higher HADS-D scores and a greater proportion of patients with a HADS-D score of 8 or higher. While it is difficult to determine whether these results reflect persistent insomnia leading to a lack of improvement in depression, or a lack of improvement in pre-existing depression leading to persistent insomnia, the persistent insomnia group may face the added challenge of managing both depression and ongoing insomnia. Winkelman et al. [20] identified poor sleep habits and comorbid psychiatric disorders resulting from chronic RLS as contributing factors in patients who continued to experience insomnia even after their leg discomfort was controlled.
Maladaptive behaviors and/or dysfunctional beliefs can also be considered a contributing factor to insomnia. Patients with RLS who are complaining of severe leg discomfort often inappropriately lie down earlier than their habitual sleeping time. This may lead to worsening their RLS symptoms. Rigid beliefs or unrealistic expectations about sleep may significantly contribute to the persistence of insomnia, and it is well established that individuals with poor sleep quality tend to hold more inappropriate beliefs about sleep [21-24]. These distorted beliefs increase cognitive activity and arousal, both of which interfere with sleep [24]. We anticipated that such beliefs would increase with longer duration of RLS. As expected, the persistent insomnia group had a longer duration of RLS and a higher proportion of individuals with RLS lasting 10 years or more. However, these differences were not statistically significant, likely due to the small sample size. In an analysis of the Dysfunctional Beliefs and Attitudes about Sleep Scale in patients admitted for polysomnography, Crönlein et al. [25] reported that individuals with RLS may experience insomnia not only due to their leg discomforts but also as a result of dysfunctional beliefs and maladaptive behaviors related to sleep. Unfortunately, we did not evaluate directly maladaptive behaviors and dysfunctional belief using structured questionnaires such as DBAS.
Taken together, our findings suggest that patients who continue to report insomnia despite improvement in leg discomfort should be evaluated for comorbid depression and maladaptive behaviors and dysfunctional beliefs. If either is identified, appropriate interventions should be implemented to increase the likelihood of improving the patient’s persistent insomnia.
This study has several limitations. First, the small sample size makes it difficult to generalize the research findings and assess the effects of major covariates. Second, the ≥50% reduction in the VAS for insomnia severity from baseline after RLS treatment is a benchmark arbitrarily established by the research team. Third, objectively verifying the patients’ reported insomnia was challenging, as no objective tests, such as actigraphy, were conducted to confirm it. Finally, medications prescribed for RLS treatment may affect sleep, potentially contributing to the observed improvement. Therefore, the improvement in insomnia may not be solely attributable to the alleviation of leg discomfort. Future prospective studies with larger sample sizes and objective screening tools are warranted. Nevertheless, to our knowledge, this is the first study to characterize the clinical features of RLS patients who continue to report insomnia despite improvement in their RLS symptoms.
In conclusion, patients with RLS may still suffer from insomnia even after their leg discomfort has been successfully relieved through medical treatment. Depression appears to be a potential contributing factor to this persistent insomnia and should be thoroughly evaluated as part of the holistic management of RLS patients.
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