Etiology and pathophysiology of restless legs syndrome

Abstract

Restless legs syndrome (RLS) is a sensorimotor disorder characterized by a strong, nearly irresistible urge to move limbs. The symptoms worsen at rest and follow a circadian pattern, i.e., worsen during evening or at night. Furthermore, patients with RLS also frequently have insomnia. RLS is a complex condition in which predisposing genetic factors (e.g., MEIS1 and BTBD9), environmental factors, and comorbidities contribute to disease expression. RLS can occur alone or with comorbidities, for example, iron deficiency, end–stage renal disease requiring hemodialysis, pregnancy, drug or substance use, neurological disorders, such as migraine, Parkinson disease, multiple sclerosis, and polyneuropathy, cardiovascular diseases, diabetes mellitus, rheumatological disorders, and respiratory disorders, such as chronic obstructive pulmonary disease. The primary pathophysiological mechanism of RLS is related to brain iron deficiency, which might induce dopaminergic dysfunction and changes in the adenosinergic and glutamatergic pathways. Such interplay between brain iron concentration and neurotransmitters may affect the arousal systems, leading to insomnia, and alter the functioning of the cortico–striatal–thalamic–cortical circuits, leading to the sensorimotor symptoms of RLS and periodic leg movements. Other factors involved in the pathophysiology of RLS remain to be identified.