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Willis-Ekbomdisease (Restless Legs Syndrome) Pathophysiology: The Imbalance Between Dopamine and Thyroid Hormone Theory

José Carlos Pereira Jr and Marcia Pradella-Hallinan

Willis-Ekbom disease (WED), also known as restless legs syndrome, is generally accepted as a disease of unknown pathophysiology, though it is believed that dysfunctions in the dopaminergic system and iron metabolism may play a role. However, an increasing body of evidence points to the insufficient modulation of thyrotropin hormone by the neurohormone dopamine (DA) as the underlying mechanism of the disease pathology. Additionally, it has generally been accepted that the annoying symptoms of the disease are generated inside the Blood Brain Barrier (BBB). This assumption, which has little evidence supporting it, has been weakened by the recent observation that domperidone, a DA blocking agent that does not cross the BBB, worsens the severity of WED symptoms. In 1974, it was discovered that levodopa dramatically relieves WED symptoms, thus supporting the hypothesis that insufficient dopaminergic function contributes to WED pathogenesis. Earlier, in 1970, it was observed that venous infusion of DA diminishes thyrotropin levels, and from clinical studies, it is known that WED symptoms are worse in the evening and night, when thyrotropin activity increases. Furthermore, drugs that alleviate WED symptoms increase the DA activity or decrease the Thyroid Hormone (TH) activity, whereas drugs that worsen WED tend to have the opposite effects on DA and TH activity. In this article, we present robust evidence to support the hypothesis that WED is caused by an imbalance between DA and TH and that its symptoms are generated in the periphery of the somatosensory system. We theorize that WED should be considered a functional peripheral neuropathy.