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Restless legs syndrome

Nature Reviews Disease Primers volume 7, Article number: 80 (2021) Cite this article

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Abstract

Restless legs syndrome (RLS) is a common sensorimotor disorder characterized by an urge to move that appears during rest or is exacerbated by rest, that occurs in the evening or night and that disappears during movement or is improved by movement. Symptoms vary considerably in age at onset, frequency and severity, with severe forms affecting sleep, quality of life and mood. Patients with RLS often display periodic leg movements during sleep or resting wakefulness. RLS is considered to be a complex condition in which predisposing genetic factors, environmental factors and comorbidities contribute to the expression of the disorder. RLS occurs alone or with comorbidities, for example, iron deficiency and kidney disease, but also with cardiovascular diseases, diabetes mellitus and neurological, rheumatological and respiratory disorders. The pathophysiology is still unclear, with the involvement of brain iron deficiency, dysfunction in the dopaminergic and nociceptive systems and altered adenosine and glutamatergic pathways as hypotheses being investigated. RLS is poorly recognized by physicians and it is accordingly often incorrectly diagnosed and managed. Treatment guidelines recommend initiation of therapy with low doses of dopamine agonists or α2δ ligands in severe forms. Although dopaminergic treatment is initially highly effective, its long-term use can result in a serious worsening of symptoms known as augmentation. Other treatments include opioids and iron preparations.

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Fig. 1: Proposed pathogenetic model of RLS.
Fig. 2: Algorithm for management of RLS.
Fig. 3: Periodic leg movements during sleep.
Fig. 4: Quality-of-life effects of RLS.

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Authors and Affiliations

  1. Sleep Medicine Unit, Neurocenter of the Southern Switzerland, Regional Hospital of Lugano, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland

    Mauro Manconi

  2. Department of Neurology, University of Bern, Bern, Switzerland

    Mauro Manconi

  3. Sleep Research Institute, Madrid, Spain

    Diego Garcia-Borreguero

  4. Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany

    Barbara Schormair

  5. Institute of Human Genetics, Technical University of Munich, School of Medicine, Munich, Germany

    Barbara Schormair

  6. Movement Disorders Unit and Division of Sleep Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Aleksandar Videnovic

  7. Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany

    Klaus Berger

  8. Sleep Research Centre, Oasi Research Institute (IRCCS), Troina, Italy

    Raffaele Ferri

  9. Centre National de Référence Narcolepsie Hypersomnies, Unité des Troubles du Sommeil, Département de Neurologie, Hôpital Gui-de-Chauliac, INSERM, Université Montpellier, Montpellier, France

    Yves Dauvilliers

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Contributions

Introduction (M.M. and Y.D.); Epidemiology (K.B.); Mechanisms/pathophysiology (B.S., A.V., Y.D. and M.M.); Diagnosis, screening and prevention (M.M., R.F. and D.G.-B.); Management (D.G.-B., A.V. and Y.D.); Quality of Life (K.B., D.G.B. and Y.D.); Outlook (B.S., M.M. and Y.D.); Overview of Primer (M.M. and Y.D.)

Corresponding authors

Correspondence to Mauro Manconi or Yves Dauvilliers.

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Competing interests

Y.D. participated on the advisory boards for UCB Pharma, Jazz, Theranexus, Avadel, Idorsia, Takeda, and Bioprojet, outside this work. K.B. has received, for a study on the ‘Course of Restless Legs Syndrome’ (2008–2014), unrestricted grants to the University of Muenster from the German Restless Legs Society and a consortium with equal shares formed by Boehringer Ingelheim Pharma, Mundipharma Research, Neurobiotec, UCB Germany and Switzerland, Vifor Pharma and Roche Pharma. M.M. participated on the advisory boards of Jazz and Avadel, and also received an unrestricted grant from Vifor Pharma and Philips Respironics for the “Life-ON Study” to explore sleep disorders during pregnancy. R.F. participated in educational activities for Jazz. B.S. has received research funding from the German Restless Legs Society and has filed a patent application. D.G.-B. has received research grants from MSDS and Roche, and has consulted for Roche, Idorsia, Luye Pharma, Takeda and American Regent. A.V. declares no competing interests.

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Nature Reviews Disease Primers thanks Birgit Högl, who co-reviewed with Melanie Bergmann; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Manconi, M., Garcia-Borreguero, D., Schormair, B. et al. Restless legs syndrome. Nat Rev Dis Primers 7, 80 (2021). https://doi.org/10.1038/s41572-021-00311-z

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