Restless Legs Syndrome: Pathophysiology and Treatment

Restless legs syndrome (RLS) is a complicated sensory-motor syndrome. The pathology is increasingly understood, but a clear physiologic understanding still remains elusive. The most robust findings remain reduced central nervous system (CNS) iron and some perturbation in dopaminergic systems. Other neurotransmitter systems are also like involved, and the phenotype may result from distinct pathophysiologic processes. Treatment of RLS is often very successful, and treatment goals should be high. Dopamine agonists may most robustly improve pure urge to move and certainly periodic limb movements. They do not directly improve sleep, and long-term use is limited by augmentation. Alpha-2-delta ligand drugs such as gabapentin enacarbil and pregabalin improve RLS, presumably in a less specific manner. These drugs increase slow wave sleep and improve pain, but have less impact on leg movements. Mu specific opioids also robustly improve RLS and are probably underutilized in severe cases. Intravenous iron inconsistently but sometimes considerably improves RLS and can be considered in refractory cases.