Beyond the Legs: A Systematic Review on Multisystem Autonomic Dysfunction in Primary Restless Legs Syndrome

Restless legs syndrome (RLS), traditionally considered a sensorimotor sleep disorder, is increasingly recognised as a condition with broader autonomic nervous system (ANS) involvement. Such dysfunction, often underdiagnosed, may affect cardiovascular, gastrointestinal, genitourinary, thermoregulatory, and sexual domains, contributing to impaired quality of life. This systematic review examines evidence for organ-specific autonomic disturbances in primary RLS, explores underlying mechanisms, and outlines clinical and research implications. PubMed (MEDLINE) was searched from inception to August 2, 2025, for studies comparing adults with primary RLS and healthy controls using validated autonomic, endothelial, or blood-flow measures. Study quality was assessed with the modified Newcastle-Ottawa Scale and domain-specific checklists for heart rate variability (HRV), flow-mediated dilatation (FMD), dynamic cerebral autoregulation (DCA), and muscle sympathetic nerve activity (MSNA). Forty-one studies (1895 RLS patients; 1934 controls) met criteria. Findings showed heterogeneous but convergent evidence of multidomain ANS dysfunction. Cardiovascular alterations included abnormal HRV, impaired baroreflex sensitivity, non-dipping nocturnal blood pressure, and sympathetic overactivation during periodic limb movements. Endothelial dysfunction, elevated vascular resistance, and impaired cerebral and peripheral vasoreactivity were frequent. Thermoregulatory changes involved reduced heat-induced vasodilation and temperature intolerance. Non-cardiovascular disturbances included gastrointestinal dysmotility, bladder symptoms, sexual dysfunction, and light sensitivity. Dopaminergic therapy improved several indices, but evidence for other interventions remains scarce. Primary RLS is linked to widespread autonomic impairment involving dopaminergic/serotonergic dysregulation, central autonomic network changes, endothelial dysfunction, and nocturnal sympathetic overactivity. Recognition of ANS involvement is essential for comprehensive care, risk assessment, and future therapeutic development.