A 15-year national health analysis reveals that people with restless legs syndrome are more likely to develop Parkinson’s. Treatment choices may play a surprising role in how soon symptoms appear.
Study: Risk of Parkinson Disease Among Patients With Restless Leg Syndrome. Image credit: Andrey_Popov/Shutterstock.com
RLS and Parkinson’s share dopaminergic treatment pathways
In a recent study published in JAMA Network Open, researchers investigated the risk of Parkinson’s disease (PD) among individuals with restless legs syndrome (RLS).
RLS is characterized by an irresistible urge to move the legs, often accompanied by uncomfortable sensations. The symptoms tend to increase during rest and mitigate during movement. Various drugs are used to treat RLS, with dopamine agonists (DAs) being the first-line treatment. Although RLS pathophysiology remains incompletely understood, dopaminergic mechanisms are speculated to play a role.
PD is a neurodegenerative disorder with a growing incidence and social burden worldwide. Both PD and RLS are treated with dopaminergic agents, with multiple studies conducted to clarify the associations between the two disorders. Nevertheless, it remains unclear whether RLS is a secondary condition or a prodromal symptom of PD and how the dopaminergic pathway is connected to the two conditions.
National health insurance cohort tracks RLS patients
In the present study, researchers investigated whether RLS is associated with a higher risk of PD. The Korean National Health Insurance (NHIS) Service Sample Cohort was used for analysis, which included de-identified records of one million Koreans from 2002 to 2019. The 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. Individuals with preexisting PD, PD diagnosis before 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 PD development was assessed in RLS patients compared to controls.
RLS patients were further stratified by DA treatment, and PD risk was compared across groups. DA-treated patients (RLS group 1) received DAs, such as ropinirole and pramipexole, during at least two distinct clinical visits; this group was considered to have primary RLS responsive to DAs. RLS group 2 was considered to have secondary RLS, wherein DA treatment was not considered. The CCI was used to adjust for comorbidities.
Additionally, sleep disorder history and iron deficiency anemia (IDA) were used as covariates. Baseline characteristics were assessed using the Mann-Whitney U-test and the chi-squared test. Standardized mean differences and 95 % confidence intervals were calculated. Kaplan-Meier survival curves were used to analyze cumulative PD incidence. The restricted mean survival time (RMST) analysis was performed to compare the time to PD diagnosis across groups.
RLS patients show higher Parkinson’s incidence overall
In total, the study included 9,919 RLS patients and 9,919 controls. The two groups did not significantly differ in age, sex, CCI, income, region, or IDA prevalence. However, the history of sleep disorders and alcohol intake was significantly different. PD incidence 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. The RMST to PD diagnosis was 14.88 years for RLS patients and 14.93 years for controls.
RLS group 1 included 3,077 (DA-treated) patients, and RLS group 2 included 6,842 (DA-nontreated) patients. Fifteen DA-treated patients 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. Notably, RLS group 1 and RLS group 2 had significantly longer and shorter RMST to PD diagnosis than controls, respectively.
Association observed, but causality remains unproven
In sum, RLS was associated with a higher risk of PD development in this cohort. RLS patients were more likely to have a PD diagnosis earlier than controls. RLS patients who were not treated with DAs had a higher PD incidence and shorter time to PD diagnosis, while those treated with DAs had 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 notes that RLS may act as a potential risk factor for PD, though ongoing debate remains as to whether it might instead represent a prodromal feature.
These findings suggest that the pathophysiological links between PD and RLS may involve mechanisms beyond the dopaminergic pathway.
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