title: Restless Legs Syndrome: Current Concepts about Disease Pathophysiology.
abstract: BACKGROUND
  In the past few decades, much has been learned about the pathophysiology of restless legs syndrome (RLS). Investigators have studied neuropathology, imaging, electrophysiology, and genetics of RLS, identifying brain regions and biological systems affected in RLS. This manuscript will review RLS pathophysiology literature, examining the RLS state through consideration of the neuroanatomy, then the biological, organ, and genetic systems.
  
  
  METHODS
  Pubmed (1966 to April 2016) was searched for the term "restless legs syndrome" cross-referenced with "pathophysiology," "pathogenesis," "pathology," or "imaging." English language papers were reviewed. Studies that focused on RLS in relation to another disease were not reviewed.
  
  
  RESULTS
  Although there are no gross structural brain abnormalities in RLS, widespread brain areas are activated, including the pre- and post-central gyri, cingulate cortex, thalamus, and cerebellum. Pathologically, the most consistent finding is striatal iron deficiency in RLS patients. A host of other biological systems are also altered in RLS, including the dopaminergic, oxygen-sensing, opioid, glutamatergic, and serotonergic systems. Polymorphisms in genes including BTBD9 and MEIS1 are associated with RLS.
  
  
  CONCLUSIONS
  RLS is a neurologic sensorimotor disorder that involves pathology, most notably iron deficiency, in motor and sensory brain areas. Brain areas not subserving movement or sensation such as the cingulate cortex and cerebellum are also involved. Other biological systems including the dopaminergic, oxygen-sensing, opioid, glutamatergic, and serotonergic systems are involved. Further research is needed to determine which of these anatomic locations or biological systems are affected primarily, and which are affected in a secondary response.
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT, USA; Department of Neurology, Connecticut Veterans Affairs Health System, West Haven, CT, USA; Yale Center for Neuroepidemiology & Clinical Neurological Research, New Haven, CT, USA.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Koo
authors.affiliation: Department of Neurology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Kanika
authors.initials: K
authors.lastname: Bagai
authors.affiliation: Department of Neurology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Walters
keywords: Restless legs syndrome; neuroanatomy; pathophysiology