Altered iron metabolism and iron therapy in restless legs syndrome

Restless legs syndrome (RLS) is a common neurological disorder that impairs sleep and reduces quality of life. The pathogenesis of RLS is incompletely understood. However, two mechanisms in its pathogenesis have been well accepted: iron deficiency, particularly brain iron deficiency, and subsequent dopamine dysregulation, which contribute to sensorimotor symptoms in RLS. In this review, we aim to provide a balanced synthesis of the literature on peripheral and brain iron dysregulation and iron therapy in RLS. We conclude that brain iron deficiency is central to the pathogenesis of RLS, whereas peripheral iron deficiency, although closely linked to RLS, poorly reflects brain iron status. Brain iron deficiency in RLS likely arises from altered iron metabolism at multiple levels, including impaired iron transport at the blood-brain interface and in subcortical neuronal structures such as the dopaminergic and thalamic systems, and potentially altered iron export, with or without systemic iron deficiency. These processes are further modulated by circadian-related changes, genetic susceptibility, and sex differences, adding complexity to iron dysregulation in RLS. Iron therapy, both oral and IV formulations, has become a standard of care in the treatment of RLS. Further research is needed to deepen our understanding of brain iron deficiency, improve the prediction of treatment response, and optimize the selection of iron therapies for RLS.