Emerging Concepts of the Pathophysiology and Adverse Outcomes of Restless Legs Syndrome

Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is a common neurological disorder affecting up to 5% to 10% of the population, but it remains an underdiagnosed condition. RLS/WED is characterized by uncomfortable sensations, mainly in the legs, which appear during inactivity and worsen in the evening or at night. The prevalence of RLS/WED and periodic leg movements (PLMs) is increased in patients with sleep-disordered breathing, particularly in those with OSA, the most common sleep disorder encountered in sleep centers. New advances in the pathophysiology of RLS/WED have shown important implications for various genetic markers, neurotransmitter dysfunction, and iron deficiency. A practical approach to RLS/WED management includes an accurate diagnosis, the identification of reversible contributing factors, and the use of nonpharmacological therapies, including iron substitution (oral or IV) therapy. Many pharmacological agents are effective for the treatment of RLS/WED. Until recently, the first-line treatment of RLS/WED consisted of low-dose dopamine agonists (DA). However, given the fact that DAs cause high rates of augmentation of symptoms, international guidelines recommend that whenever possible the initial treatment of choice should be an α2δ ligand, and avoidance of dopaminergic agents unless absolutely necessary. If necessary, the lowest effective dose should be used for only the shortest possible time. The symptoms of RLS/WED can disrupt the quality of sleep as well as the quality of life. IV iron therapy may be considered in patients with refractory RLS. A better understanding of RLS/WED pathophysiology will allow patients to receive tailored therapy, resulting in an improved quality of life.