Restless legs syndrome (RLS) has been linked to an increased risk for Parkinson’s disease (PD), in new findings that suggest the association may go beyond the dopaminergic pathway.

In a retrospective study of nearly 20,000 people, 1.6% of those with RLS developed PD compared with 1.0% of those without RLS. Among patients with RLS, treatment with dopamine agonists (DAs) was associated with a lower risk of developing PD (0.5%) vs untreated individuals (2.1%), suggesting a potential protective effect.

“Based on these findings, it may be more reasonable to interpret RLS as a potential risk factor for PD rather than an early manifestation,” lead investigator Myeonghwan Bang, MD, of the Department of Physical Medicine and Rehabilitation at the National Health Insurance Service Ilsan Hospital in Goyang, South Korea, and colleagues from South Korea wrote.

The study was published online on October 6 in JAMA Network Open.

First Study of Its Kind

RLS shares dopaminergic mechanisms with PD, and both respond to DAs, raising questions about whether RLS might be an early marker of PD.

Two previous longitudinal studies explored this potential link, but their predominantly male populations limited the broader applicability of the findings.

The current nationwide cohort study is the first to assess the association in a general RLS population — 63% women — and to examine whether treatment with DAs, such as pramipexole or ropinirole, influences PD risk.

The investigators analyzed data from the Korean National Health Insurance Service Sample Cohort (2002-2019), a stratified 2% random sample of the Korean population, encompassing 1 million individuals.

RLS cases were identified using International Classification of Diseases, 10th Revision (ICD-10) code G25.8, requiring at least two outpatient diagnoses to ensure validity; single-visit cases were excluded. Patients with preexisting PD, PD diagnosed before RLS onset, missing socioeconomic data, or unmatched control individuals were also excluded.

The final cohort included 9919 patients with RLS, each matched 1:1 with a control individual based on age, sex, income, region, Charlson Comorbidity Index (CCI) score, and index date. PD was identified using ICD-10 code G20 or rare disease registration code V124, and covariates included CCI score, sleep disorders, and iron deficiency anemia.

Patients with RLS were divided by DA treatment: the DA-treated group included those with at least two outpatient visits or hospitalizations for pramipexole or ropinirole, representing presumed primary RLS responsive to DA therapy, while the DA-untreated group included patients who did not meet these criteria, representing presumed secondary RLS.

The study compared the risk and timing of PD development across RLS subgroups and matched control individuals.

Participants had a mean age of 50 years. At baseline, the only statistically significant difference between the groups was alcohol consumption, reported in 32.7% of the RLS group vs 36.2% of the control group.

Among the RLS cohort, 3077 patients were treated with DAs, while 6842 were not. During follow-up, 15 treated patients developed PD, representing an incidence of 0.5% compared with 143 cases among untreated patients, for an incidence of 2.1%.

Compared with control individuals, patients with RLS who were treated with DA had a lower 15-year cumulative incidence of PD, while untreated patients had a higher incidence over the same period.

Treated patients also experienced a significantly longer time to PD diagnosis (difference, 0.03 years; 95% CI, 0.01-0.06; P = .003), whereas the untreated group had a significantly shorter time to diagnosis (difference, -0.09 years; 95% CI, -0.12 to -0.06; P < .001).

The study’s limitations include the fact that diagnoses of RLS and/or PD were based on ICD-10 codes, raising the possibility of underdiagnosis or overdiagnosis, the researchers noted. The investigators also noted that it is possible that in some cases rapid eye movement sleep disorder could have been misdiagnosed as RLS.

Limitations, Concerns

In an accompanying commentary, Mark S. Baron, MD, a retired researcher from the Southeast Parkinson’s Disease Research, Education and Clinical Center at the Richmond Veterans Administration Medical Center, Richmond, Virginia, noted several concerns.

He emphasized that while the study may support previous suggestions that RLS is linked to a higher risk for PD, possibly as an early or prodromal sign, other explanations for the findings — both in this and prior studies — should be carefully considered.

For instance, he noted that the researchers did not specify the specialty of the physician making the diagnoses of PD or RLS which he characterized as a “a major limitation,” as it is unclear whether a neurologist or sleep medicine specialist confirmed any of the cases.

He noted that there is “no doubt” that “an appreciable portion of these diagnoses were inaccurate.” Furthermore, Baron noted that rapid eye movement sleep behavior disorder is often misdiagnosed as periodic leg movements of sleep, which can in turn lead to RLS misdiagnoses. A diagnosis of RLS may also prompt neurology referrals, increasing the likelihood of a subsequent PD diagnosis.

Baron added that genomic studies primarily support a nondopaminergic pathway for RLS. Also, “these genomic studies failed to support an association between RLS and Parkinson disease.”

This research was supported by a grant from the National Health Insurance Service Ilsan Hospital Research Fund. Bang and Baron reported no relevant financial relationships.