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Restless Legs Syndrome: Contemporary Diagnosis and Treatment


Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs while at rest, relief upon movement or getting up to walk, and worsened symptom severity at night. RLS may be primary (idiopathic) or secondary to pregnancy or a variety of systemic disorders, especially iron deficiency, and chronic renal insufficiency. Genetic predisposition with a family history is common. The pathogenesis of RLS remains unclear but is likely to involve central nervous system dopaminergic dysfunction, as well as other, undefined contributing mechanisms. Evaluation begins with a thorough history and examination, and iron measures, including ferritin and transferrin saturation, should be checked at presentation and with worsened symptoms, especially when augmentation develops. Augmentation is characterized by more intense symptom severity, earlier symptom occurrence, and often, symptom spread from the legs to the arms or other body regions. Some people with RLS have adequate symptom control with non-pharmacological measures such as massage or temperate baths. First-line management options include iron-replacement therapy in those with evidence for reduced body-iron stores or, alternatively, with prescribed gabapentin or pregabalin, and dopamine agonists such as pramipexole, ropinirole, and rotigotine. Second-line therapies include intravenous iron infusion in those who are intolerant of oral iron and/or those having augmentation with intense, severe RLS symptoms, and opioids including tramadol, oxycodone, and methadone. RLS significantly impacts patients’ quality of life and remains a therapeutic area sorely in need of innovation and a further pipeline of new, biologically informed therapies.

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We gratefully acknowledge the contributions of Lea Dacy, Mayo Clinic Department of Neurology, for secretarial support with manuscript formatting and submission.

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This publication was supported by NIH/NCRR/NCATS CCaTS Grant Number UL1 TR002377 and by NIH/NIA R34AG056639 (NAPS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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Gossard, T.R., Trotti, L.M., Videnovic, A. et al. Restless Legs Syndrome: Contemporary Diagnosis and Treatment. Neurotherapeutics 18, 140–155 (2021).

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  • Restless legs syndrome
  • Periodic limb movement disorder
  • Periodic leg movements
  • Cardiovascular risk
  • Treatment
  • Dopamine agonist
  • Alpha-2-delta ligand
  • Opiate
  • Iron deficiency.