Affiliations: The Michael Trimble Neuropsychiatry Research Group,
Department of Neuropsychiatry, BSMHFT and University of Birmingham, Birmingham,
UK | Department of Motor Neuroscience and Movement
Disorders, Institute of Neurology and University College London, London,
UK
Note: [] Corresponding author: Dr. Andrea Eugenio Cavanna MD, Department
of Neuropsychiatry, The Barberry National Centre for Mental Health, Birmingham
B15 2FG, UK. Tel.: +44 121 3012317; Fax: +44 121 3012291; E-mail:
[email protected]
Abstract: Background: Restless legs syndrome (RLS) is a relatively common
neurological disorder affecting sleep and health-related quality of life.
Neuroimaging studies, autopsy investigations and experimental studies using
animal models have been conducted to investigate the potential causes of RLS,
resulting in the generation of multiple pathophysiological hypotheses. Methods: This paper reviews the neurobiology and pharmacotherapy of
RLS, with a critical analysis of the heterogeneity and methodological
limitations of the existing scientific literature. Results: Although several neurotransmitter systems dysfunction and
neuroanatomical abnormalities have been implicated in RLS pathogenesis,
dopamine dysfunction within basal ganglia pathways, iron deficiency and opioid
system abnormalities have consistently been found to be involved. Their
involvement is further strengthened by the therapeutic effectiveness of
dopaminergic agents, iron supplementation and opioid medications. Discussion: Converging evidence from neuroimaging, autoptic and
animal studies points towards dopamine dysregulation and iron metabolism
alterations as the main contributors to RLS pathophysiology. The possible
interactions between different neurotransmitter systems should guide further
neuropharmacological research in order to improve therapeutic efficacy for this
disabling condition.
Keywords: Dopamine, iron, opioids, pathophysiology, pharmacotherapy, restless legs syndrome
