Aetiopathogenesis of restless legs syndrome

The pathogenesis of restless legs syndrome (RLS) is not yet completely understood. However, recent research addressed the hypothesis that dopaminergic pathways are involved in the mechanisms responsible for the syndrome both for sensory and motor symptoms. Different aspects of RLS physiopathogenesis are discussed: the genetic components indicating different chromosomes are responsible for the heterogeneity in the phenotypic expression of the familial forms of RLS; the neurophysiologic data showing the hyperexcitability of the cortico-motor efferents at supraspinal level, with spinal cord involvement leading to a definition of RLS as a syndrome of somatosensory misperception, disturbed gain regulation and/or a shifted threshold; the paucity of neuroimaging data, which do not definitively clarify the eventual dopaminergic dysfunction in RLS patients, at least at the basal ganglia level; an illustration of the iposideremic hypothesis starting from the therapeutic effect of iron, although not for all patients, and based on some neurophysiologic and neuropathologic results both in humans and animal models; and finally the role of the opioid system, suggesting an imbalance of dopamine-opiate system inputs to brain regions involved in motor responses and pain perception, and representing an aberrant behavioural response to sensory inputs. All these theories may have a final common pathway in the dopaminergic system, reinforcing the empirical results of benefit with dopamine or dopamine-agonist treatments in RLS.