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Restless legs syndrome and periodic limb movements of sleep — the relationship with stroke and other cerebrovascular disease

Nature Reviews Neurology volume 22, pages 37–53 (2026)Cite this article

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Abstract

Restless legs syndrome (RLS) and periodic limb movements (PLMs) are increasingly recognized as risk factors for cerebrovascular and cardiovascular diseases, particularly stroke. Conversely, stroke can precipitate or exacerbate the symptoms of RLS and PLMs. This Review explores the shared pathophysiological mechanisms linking RLS and PLMs to cerebrovascular pathology, highlighting a bidirectional relationship. We discuss mechanisms including neurotransmitter dysregulation, autonomic dysfunction, inflammation, oxidative stress, hypoxia and genomic and proteomic factors. Furthermore, we summarize emerging evidence and provide new insights on the potential clinical relevance of RLS in cerebrovascular risk assessment and management.

Key points

  • Restless legs syndrome (RLS) and periodic limb movements (PLMs) are linked to increased risks of stroke and cardiovascular disease. Stroke might trigger or worsen RLS and/or PLM symptoms, suggesting a bidirectional relationship.

  • Shared pathophysiological mechanisms among RLS, PLMs and stroke include neurotransmitter imbalance, autonomic dysfunction, inflammation, oxidative stress, hypoxia and overlapping proteomic and genetic pathways.

  • RLS and PLMs are linked to nocturnal blood pressure surges and heightened sympathetic activity, which can contribute to long-term vascular injury and elevated stroke risk.

  • A large study found that untreated RLS significantly increases the risk of vascular events, whereas effective RLS treatment might mitigate stroke and cardiovascular complications.

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Fig. 1: Pathophysiological connections among restless legs syndrome, periodic limb movements and stroke.
Fig. 2: Bidirectional pathophysiological links among restless legs syndrome, periodic limb movements and stroke.

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Acknowledgements

No funding was received for the preparation of this Review. A.S.W. reports receiving a ‘Sleep Research in Neurology’ grant from Vanderbilt University Medical Center. K.S. reports funding from the European Union under Grant Agreement No. 101129822 (EOSC TITAN project). M.I.B. reports no conflicts of interest specific to this manuscript. Outside the submitted work, M.I.B. reports funding from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, CanStroke Recovery Trials Network, Restless Legs Syndrome Foundation, Alternative Funding Plan from the Academic Health Sciences Centres of Ontario, the Temerty Centre for AI Research and Education in Medicine (T-CAIREM), the McLaughlin Centre for Molecular Medicine and the Toronto Dementia Research Alliance. He also reports consulting fees and honoraria from Jazz Pharmaceuticals, Paladin Labs, Eisai, Precision AQ and the OntarioMD Peer Leader Program; travel support from McGill University; and receipt of sleep equipment or research support from Braebon Medical Corporation, CGX, The Mahaffy Family Research Fund and Green Mountain. M.I.B. also reports unrestricted educational grants from Jazz Pharmaceuticals and Paladin Labs.

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Authors and Affiliations

  1. Neurology Division, Department of Internal Medicine, Max Rady School of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

    Nahal Farhani

  2. Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada

    Yakdehikandage S. Costa, Marina Rozik & Mark I. Boulos

  3. Department of Medicine, Division of Neurology, University of Toronto, Toronto, Ontario, Canada

    Yakdehikandage S. Costa, Marina Rozik & Mark I. Boulos

  4. Sleep Laboratory, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

    Yakdehikandage S. Costa, Marina Rozik & Mark I. Boulos

  5. INSERM, Université Paris Cité, NeuroDiderot, Paris, France

    Karen Spruyt

  6. Sleep Division, Department of Neurology, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    Arthur S. Walters

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Contributions

Y.S.C. prepared the primary draft of the manuscript under the supervision of M.I.B. N.F. expanded and substantially revised the paper, prepared the figures and created several of the tables. M.R. prepared the remaining tables. K.S., A.S.W. and M.I.B. provided critical input and expert guidance as senior researchers, shaping the intellectual framework and direction of the manuscript.

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Correspondence to Nahal Farhani.

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Farhani, N., Costa, Y.S., Rozik, M. et al. Restless legs syndrome and periodic limb movements of sleep — the relationship with stroke and other cerebrovascular disease. Nat Rev Neurol 22, 37–53 (2026). https://doi.org/10.1038/s41582-025-01161-z

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