Risk of Parkinson Disease Among Patients With Restless Leg Syndrome.

Importance: The association between restless leg syndrome (RLS) and Parkinson disease (PD) remains unclear. Clarifying this association and the role of the dopaminergic pathway may improve understanding of the pathophysiology between these 2 diseases.

Objectives: To assess whether RLS is a risk factor for developing PD and whether the dopamine pathway is meaningfully associated with RLS and PD.

Design, setting, and participants: This retrospective cohort study used data from the Korean National Health Insurance Service Sample Cohort from 2002 to 2019. Statistical analyses were performed between September 2024 and March 2025. Patients with RLS and PD were identified based on codes from the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision and matched to individuals without RLS. For the secondary analysis, the dopamine agonist (DA)-treated group was operationally defined as patients with RLS who received DA during 2 or more distinct clinical visits, while those who did not meet this criterion were classified as the DA-nontreated group.

Exposures: Diagnosis of RLS and treatment with DAs.

Main outcomes and measures: Development of PD. To compare the time to PD diagnosis across groups, a restricted mean survival time (RMST) analysis was conducted.

Results: A total of 9919 patients with RLS and 9919 matched controls were included. The mean (SD) age at enrollment was 50.1 (16.3) years in the control group (6225 women [62.8%]) and 50.3 (16.0) years in the RLS group (6225 women [62.8%]). The incidence of PD was 1.0% (99 of 9919) in the control group and 1.6% (158 of 9919) in the RLS group. At the prespecified time horizon of 15 years (τ = 15), the RMST to PD diagnosis was 14.93 years in the control group and 14.88 years in the RLS group, resulting in a difference of -0.05 years (95% CI, -0.07 to -0.03 years). Compared with the control group, the DA-nontreated RLS group (n = 6842) showed a significantly shorter RMST to PD diagnosis (difference, -0.09 years [95% CI, -0.12 to -0.06 years]) and a higher incidence rate (143 of 6842 [2.1%]). The DA-treated RLS group (n = 3077) showed a significantly longer RMST to PD diagnosis (difference, 0.03 years [95% CI, 0.01-0.06 years]) and a lower incidence rate (15 of 3077 [0.5%]).

Conclusions and relevance: In this cohort study, RLS was associated with an increased risk of developing PD. Furthermore, patients with RLS who were not treated with DAs tended to be at increased risk of developing PD, whereas those who were treated with DAs tended to be at decreased risk compared with the control group. These findings suggest that the pathophysiological connection between RLS and PD may involve mechanisms beyond the dopaminergic pathway.