Key takeaways:
- In a 15-year cohort of 9,919 RLS patients, Parkinson’s disease developed more often than in matched controls (1.6% vs 1.0%).
- Untreated RLS showed the highest Parkinson’s disease incidence (2.1%) and earlier onset.
- Dopamine-agonist–treated patients had lower incidence (0.5%) and later onset than controls.
Both restless legs syndrome (RLS) and Parkinson’s disease are associated with dysfunction in the brain’s dopaminergic system, but their causal relationship has remained unclear.
A joint research team from Korea University Ansan Hospital, Pohang Stroke and Spine Hospital, and National Health Insurance Service Ilsan Hospital, Republic of Korea, has now clarified that untreated RLS may increase the risk of developing Parkinson’s disease, while dopamine-agonist (DA) therapy may significantly reduce that risk. The study was published online in the journal JAMA Network Open.
This retrospective cohort study, led by Jong Hun Kim, a professor in the department of neurology at Korea University Ansan Hospital, analyzed data from the Korean National Health Insurance Service Sample Cohort (2002–2019). The researchers identified 9,919 individuals with RLS and compared them with an equal number of matched controls without the condition.
Over a median follow-up of 15 years, Parkinson’s disease developed in 1.6% of RLS patients compared with 1.0% of controls. When analyzed by treatment status, the results revealed a divergence. Patients with untreated RLS showed the highest Parkinson’s disease incidence (2.1%) and an earlier onset whereas dopamine agonist-treated patients showed a lower Parkinson’s disease incidence (0.5%) and a delayed onset compared with controls.
“These findings indicate the existence of ‘heterogeneity within RLS,’ which allows for multiple interpretations. One of the interpretations is that restless legs syndrome may serve as an early clinical marker for Parkinson’s disease, particularly among untreated individuals. Our results also indicate that [dopamine agonist] therapy, used for symptom control, may confer protective benefits to the brain’s motor pathways,” Kim says in a release.
To strengthen the validity of their conclusions, the team employed target-trial emulation methods, an advanced analytical approach that reduces bias in observational research. This methodological rigor reinforces the biological plausibility of a link between RLS and Parkinson’s disease rather than a mere overlap in symptoms.
The authors propose that beyond dopamine dysfunction, other factors—such as sleep disruption, iron deficiency, and immune or metabolic pathways—may mediate this association.
The protective trend observed with dopamine agonist therapy could reflect neuroprotective mechanisms or improved identification of genuine RLS cases that are distinct from early-stage Parkinson’s disease.
“This dual pattern underscores the importance of recognizing and managing restless legs syndrome early,” Kim says. “Monitoring and treating RLS may not only improve sleep quality but could also influence long-term neurological health.”
In a clinical practice guideline issued last year, the American Academy of Sleep Medicine recommends against the standard use of dopamine agonists in RLS patients after longer-term evidence clarified the risks of augmentation that occur in many patients on these drugs. The Restless Legs Syndrome Foundation also revealed an updated algorithm recently that states dopamine agonists are no longer considered a first-line therapy for RLS.
