A 15-year national health analysis reveals that people with restless legs syndrome are more likely to develop Parkinson’s disease. Treatment options can play a surprising role in how soon symptoms appear.
Study: Risk of Parkinson’s disease among patients with restless legs syndrome. Image credit: Andrey_Popov/Shutterstock.com
RLS and Parkinson’s share dopaminergic pathways
In a recent study published in JAMA Network Openresearchers investigated the risk of Parkinson’s disease (PD) among people with restless legs syndrome (RLS).
RLS is characterized by an overwhelming urge to move the legs, often accompanied by uncomfortable sensations. Symptoms tend to increase with rest and decrease with movement. Various drugs are used to treat RLS, with dopamine agonists (DAs) being the first-line treatment. Although the pathophysiology of RLS remains poorly understood, dopaminergic mechanisms are speculated to play a role.
PD is a neurodegenerative disorder with increasing incidence and societal burden worldwide. Both PD and RLS are treated with dopaminergic agents, with multiple studies conducted to elucidate the associations between the two disorders. However, it remains unclear whether RLS is a secondary condition or a precursor symptom of PD and how the dopaminergic pathway is linked to the two conditions.
The national health insurance group monitors patients with RLS
In the present study, researchers investigated whether RLS is associated with a higher risk of PD. The Korea National Health Insurance Service Sample Group (NHIS), which included de-identified records of one million Koreans from 2002 to 2019, was used for the analysis. International Classification of Diseases, Tenth Revision (ICD-10) codes were used to identify RLS cases.
At least two documented outpatient RLS diagnoses were required for inclusion. Subjects with pre-existing PD, PD diagnosis prior to RLS onset, and those lacking socioeconomic information were excluded. RLS patients were matched to controls by sex, age, income, index date, region, and Charlson Comorbidity Index (CCI) score. PD was also defined using ICD-10 codes. The risk of developing PD was assessed in patients with RLS compared with controls.
RLS patients were further stratified by DA treatment and PD risk was compared between groups. DA-treated patients (RLS group 1) received DAs, such as ropinirole and pramipexole, during at least two separate clinic visits. This group was considered to have primary DA-responsive RLS. Group 2 RLS was considered to have secondary RLS, where DA treatment was not considered. CCI was used to adjust for comorbidities.
In addition, history of sleep disorders and iron deficiency anemia (IDA) were used as covariates. Baseline characteristics were assessed using the Mann-Whitney U test and the chi-square test. Standardized mean differences and 95 % confidence intervals were calculated. Kaplan-Meier survival curves were used to analyze the cumulative incidence of PD. Restricted median survival time (RMST) analysis was performed to compare time to PD diagnosis between groups.
RLS patients have a higher incidence of Parkinson’s overall
In total, the study included 9,919 RLS patients and 9,919 controls. The two groups did not differ significantly in age, gender, CCI, income, region, or IDA prevalence. However, history of sleep disorders and alcohol intake were significantly different. The incidence of PD was 1.6% among RLS patients and 1% among controls, with incidence rates of 10.1 and 6.3 per 10,000 patient-years, respectively. RMST diagnosis in PD was 14.88 years for RLS patients and 14.93 years for controls.
RLS group 1 included 3,077 patients (treated with DA) and RLS group 2 included 6,842 (non-DA treated) patients. Fifteen patients treated with DA developed PD, with an estimated incidence rate in the RLS group of 1.3 per 10,000 patient-years in the DA-treated subgroup. In contrast, 143 patients in RLS group 2 developed PD, with an incidence rate of 27.3 per 10,000 patient-years. Specifically, RLS group 1 and RLS group 2 had significantly longer and shorter RMST diagnoses in PD than controls, respectively.
An association has been observed, but causation remains unproven
In summary, RLS was associated with a higher risk of developing PD in this cohort. RLS patients were more likely to have an earlier diagnosis of PD than controls. RLS patients not treated with DAs had a higher PD incidence and shorter time to PD diagnosis, whereas those treated with DAs had a lower PD incidence and longer time to PD diagnosis.
However, the authors emphasize that these findings reflect associations rather than proven causal effects, and DA use should not be interpreted as protective without further evidence. The study also points out that RLS may act as a potential risk factor for PD, although debate continues as to whether it may represent a precursor feature.
These findings suggest that the pathophysiological relationships between PD and RLS may involve mechanisms beyond the dopaminergic pathway.
