Patients with restless leg syndrome had a higher incidence of Parkinson disease, while those treated with dopamine agonists showed a statistically significant lower risk, according to a recent study published in JAMA Network Open.
The researchers conducted a nationwide retrospective cohort study to examine whether restless leg syndrome is associated with the development of Parkinson disease (PD) and to evaluate the potential role of dopaminergic pathways. During follow-up, 158 patients with restless leg syndrome (RLS; 1.6%) developed PD compared with 99 patients in the control group (1%), representing incidence rates of 10.1 vs 6.3 per 10,000 patient-years. Restricted mean survival time analysis showed that patients with RLS were diagnosed with PD 0.05 years earlier than controls. Specifically, diagnoses occurred 0.09 years earlier among nondopamine agonist (DA) users and 0.03 years later among DA users, which indicated a small but measurable effect.
Among the 6,842 patients with RLS who did not receive DA therapy, 143 developed PD (2%). In contrast, among 3,077 patients treated with DAs, only 15 developed PD (0.5%). “Based on these findings, it may be more reasonable to interpret RLS as a potential risk factor for PD rather than an early manifestation,” noted lead author Myeonghwan Bang, MD, of the Department of Physical Medicine and Rehabilitation at the National Health Insurance Service Ilsan Hospital in Goyang, Republic of Korea, and colleagues. They continued, “These findings suggest that the pathophysiological connection between RLS and PD may involve mechanisms beyond the dopaminergic pathway.” Among nondopaminergic pathways, the noradrenergic system may represent a possible link between RLS and PD, they explained. Evidence from several studies suggests that the locus coeruleus and its projections within the central nervous system are involved in the pathological processes of both disorders. Iron deficiency anemia may also play a role in linking the two disorders because iron is involved in dopamine synthesis and neurotransmission. Patients with RLS frequently experience reduced sleep quality, and such sleep disturbances may increase the risk of developing PD.
Using data from the Korean National Health Insurance Service Sample Cohort from 2002 to 2019, the investigators identified 9,919 patients with RLS and matched them with 9,919 controls by age, sex, income, region, and comorbidity profile. The mean age was 50 years, and about 63% were women. Patients with RLS were defined as having at least two outpatient diagnoses, while PD cases were confirmed using diagnostic and registry codes. The RLS cohort was further stratified by DA treatment, which was defined as two or more recorded prescriptions during separate clinical encounters. To reduce baseline confounding, inverse probability of treatment weighting with stabilized propensity score weights was applied, adjusting for demographic, clinical, and lifestyle factors, including body mass index, smoking, alcohol use, sleep disorder, and iron deficiency anemia.
Patients with RLS and those with PD were identified through ICD-10 diagnostic codes assigned by physicians based on clinical assessment. As a result, diagnostic accuracy may vary, the authors described. For instance, rapid eye movement sleep behavior disorder—a recognized early sign of PD—might have been misclassified as RLS in certain cases. Subgroups were defined operationally as patients who received dopamine agonists at two or more separate clinical visits and those who did not. Differentiating idiopathic RLS from secondary RLS solely by dopamine agonist treatment may be challenging.
Analyses involving large cohorts of patients of European ancestry have identified 164 genetic risk loci associated with RLS. Although the specific pathological roles of these loci remain unclear, many appear to involve nondopaminergic pathways. In contrast, these genomic investigations have not found evidence of an association between RLS and PD.
In an invited commentary published in the same JAMA Network Open issue, Mark S. Baron, MD, of the Department of Engineering at Virginia Commonwealth University in Richmond, cautioned that alternative explanations must be considered, despite the findings that suggest an increased risk of PD among patients with RLS. He agreed that rapid eye movement sleep behavior disorder may be misclassified as RLS and could inflate the observed association. Furthermore, he wrote, DA treatment may mask parkinsonian symptoms and delay recognition of PD, rather than prevent its onset. He emphasized that genome-wide association studies have not demonstrated a genetic dopaminergic link between RLS and PD, and instead implicate nondopaminergic mechanisms.
The research was supported by the National Health Insurance Service Ilsan Hospital Research Fund, and both the study investigators and Dr. Mark S. Baron reported no conflicts of interest.
Sources: