Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a sleep disorder characterized by sensorimotor symptoms such as unpleasant sensations before sleep, akathisia, and periodic limb movements during sleep. It is also closely related to hyper- arousal and is often accompanied by insomnia. Although the mechanism is not clear, the understanding of etiology and pathophysiology has greatly expanded through recent advances in genetic and neurobiological research. The most impor- tant pathophysiology of RLS/WED is brain iron deficiency. Such iron deficiency in the brain is caused by complex interac- tions between several genetic factors and various environmental factors, including comorbidities. Iron deficiency in the brain results in dysfunction of several neurotransmitters. A decrease in adenosine activity appears first, followed by an in- crease in the activity of glutamate and dopamine. A decrease in adenosine activity and an increase in glutamate activity stimulate the brain arousal system, resulting in hyperarousal. In addition, overproduction of dopamine and glutamate leads to dysfunction of the cortical-striatal-thalamic circuit, resulting in symptoms such as akathisia and periodic limb movements during sleep.
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