The impressive relief from
restless legs syndrome (RLS) symptoms provided by
levodopa treatment indicates RLS is caused by a dopaminergic abnormality. But similar and more lasting relief also occurs for
iron treatment in some patients. Thus there are two major putative causes for RLS: CNS dopaminergic abnormality and CNS
iron insufficiency. This article presents the data documenting that both peripheral and CNS
iron insufficiency occur with RLS symptoms. Brain
iron insufficiency is supported by independently replicated cerebrospinal fluid and brain imaging studies for patients without
iron deficiency (ID)
anemia. Autopsy studies and intravenous
iron treatment further link brain
iron insufficiency to RLS. The brain
iron insufficiency in patients with RLS is now well established. In this article the data are reviewed that support the following postulates combining dopaminergic and
iron causes of RLS: (1) All conditions that compromise
iron availability will increase the risk of RLS leading to a higher than expected prevalence of RLS in these conditions. (2) Some patients with RLS have marginal CNS
iron status that can become insufficient when deprived of normal access to adequate peripheral
iron or may be insufficient even with normal access to adequate peripheral
iron. (3) The change or reduced CNS
iron status produces RLS symptoms largely through its effects on the dopaminergic system and the corollary to 3. (4) Dopaminergic system abnormalities producing RLS symptoms will be included in those produced by brain ID. Study of the
iron model of RLS offers hope for developing new treatment approaches and perhaps methods to prevent or cure the disorder.