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Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED) is a neurological condition with an overall prevalence in adults of 5-10% in Europe and North America. It is characterised by strong feelings of restlessness and distressing paraesthesia-like sensations in the lower legs, particularly when at rest. The symptoms vary considerably in severity and frequency. RLS/WED has a variable clinical expression influenced by genetic, environmental, and medical factors. Research into the pathophysiology of RLS/WED has found that various genetic markers and existing dysfunctions in dopaminergic mechanisms and iron mechanisms play a central role. Until recently, the first line treatment of RLS/WED was with low dose dopamine agonists, with three drugs having been approved by the US Food and Drug Administration and the European Medicines Agency. However, the occurrence of dopaminergic augmentation and an overall increase in severity of symptoms during long term treatment with dopamine agonists is leading to a shift towards non-dopaminergic alternatives as initial treatments, and particularly to α2δ ligands. Recent international guidelines recommend, whenever possible, to start treatment with these drugs (α2δ ligands) to avoid augmentation from the start. Other (eg, glutamatergic or adenosine) neurotransmitters might also play an important role in causing RLS/WED and might thus lead to new treatments.