Emerging Mechanisms in Restless Legs Syndrome: Revisiting the Pathophysiology Over the Past 10 Years to Summarize Current Evidence on the Pathophysiology of Restless Legs Syndrome (RLS) Published Over the Past Decade (2015–2025)
Tanya Baker1, Jia Tian1, Kalli Kremer1, Jenny Zhang1
1Rocky Vista University of Osteopathic Medicine
Objective:
To Summarize Current Evidence On The Pathophysiology of Restless Legs Syndrome (RLS) Published Over The Past Decade (2015–2025)
Background:
RLS affects up to 15% of the population and approximately 3 million individuals annually in the United States. The disorder significantly impairs sleep and quality of life. Despite available pharmacologic options, many patients experience suboptimal long-term control, likely reflecting an incomplete understanding of RLS mechanisms.
Design/Methods:
A structured literature review was performed using PubMed and Google Scholar. Publications from 2015 to 2025 were screened, prioritizing landmark clinical trials, neuroimaging studies, and mechanistic investigations. Data were synthesized to identify consistent and emerging themes in RLS pathophysiology.
Results:
Thirty-five relevant studies were included. The most consistently supported mechanisms involve dopaminergic dysfunction, altered striatal dopamine receptor activity, and abnormalities in brain iron metabolism. Genetic predispositions and circadian influences were also implicated. Recent evidence suggests a novel role for hypoadenosinergic signaling, potentially linking dopaminergic and iron pathways through adenosine modulation.
Conclusions:
Over the past decade, neuroimaging and molecular research advances have expanded understanding of RLS pathophysiology beyond traditional dopamine and iron models. The emerging hypoadenosine hypothesis offers an unique framework that may explain variability in treatment response and disease progression. Future research integrating these pathways could guide the development of more targeted and durable therapies.
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