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Special Communication
April 13, 2020

Proposal for Updated Nomenclature and Classification of Potential Causative Mechanism in Patent Foramen Ovale–Associated Stroke

Author Affiliations
  • 1Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville
  • 2Comprehensive Stroke Center, David Geffen School of Medicine, Department of Neurology, University of California, Los Angeles, Los Angeles
  • 3Children's Hospital of Georgia, Department of Pediatric Cardiology, Augusta University, Augusta, Georgia
  • 4Division of Cardiovascular Medicine, Department of Medicine, Ohio State University, Columbus
  • 5Division of Cardiology, Department of Medicine, University of Colorado, Denver, Aurora
  • 6Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
  • 7Cardiovascular Center Frankfurt, Frankfurt, Germany
  • 8Anglia Ruskin University, Chelmsford, United Kingdom
  • 9Division of Cardiovascular Medicine, Department of Medicine, Virginia Commonwealth University, Richmond
  • 10Sidra Heart Center, Sidra Medicine, Weill Cornell Medical College, Doha, Qatar
  • 11Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
  • 12Perelman School of Medicine, Department of Neurology, University of Pennsylvania, Philadelphia
  • 13Department of Neurology, Tufts University School of Medicine, Boston, Massachusetts
  • 14David Geffen School of Medicine, Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles
  • 15Division of Cardiology, Rush University Medical Center, Chicago, Illinois
  • 16Department of Neurology, Oregon Health & Science University, Portland
  • 17Sainte-Anne Hospital, Department of Neurology, Département Hospitalo-Universitaire NeuroVasc Sorbonne Paris-Cité, Institut National de la Santé et de la Recherche Médicale 894, Paris, France
  • 18Department of Neurology, University Hospital of Bern, Bern, Switzerland
  • 19Department of Cardiology, University Hospital of Bern, Bern, Switzerland
  • 20Department of Medicine, University of Florida, Gainesville
  • 21Division of Cardiology, Department of Medicine, University of Washington Medical Center, Seattle
  • 22CardioVascular Center Zurich, Hirslanden Klinik Im Park, Zürich, Switzerland
  • 23Medical University of South Carolina, Charleston
  • 24Herbert and Sandi Feinberg Interventional Cardiology and Heart Valve Center, Columbia University Medical Center, New York, New York
  • 25Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
JAMA Neurol. 2020;77(7):878-886. doi:10.1001/jamaneurol.2020.0458

Importance  Recent epidemiologic and therapeutic advances have transformed understanding of the role of and therapeutic approach to patent foramen ovale (PFO) in ischemic stroke. Patent foramen ovale is likely responsible for approximately 5% of all ischemic strokes and 10% of those occurring in young and middle-aged adults.

Observations  Randomized clinical trials have demonstrated that, to prevent recurrent ischemic stroke in patients with PFO and an otherwise-cryptogenic index ischemic stroke, PFO closure is superior to antiplatelet medical therapy alone; these trials have provided some evidence that, among medical therapy options, anticoagulants may be more effective than antiplatelet agents.

Conclusions and Relevance  These new data indicate a need to update classification schemes of causative mechanisms in stroke, developed in an era in which an association between PFO and stroke was viewed as uncertain. We propose a revised general nomenclature and classification framework for PFO-associated stroke and detailed revisions for the 3 major stroke subtyping algorithms in wide use.

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    1 Comment for this article
    More Clinical Clues to Paradoxical Embolism, and the Importance of Transcranial Doppler
    J David Spence, M.D. | Robarts Research Institute, Western University, London, ON, Canada
    A recent paper discussing assessment of causality of patent foramen ovale (PFO) in paradoxical embolism [1] focused on anatomical issues: the size of the PFO and association of atrial septal aneurysm. Three clinical clues were mentioned (a Valsalva maneuver at the onset of stroke, the presence of a pulmonary embolus, and deep vein thrombosis). However, additional clinical clues should be taken into consideration: waking up with stroke, prolonged sitting, and a history of migraine are all significantly more common in patients with stroke and PFO than in those without a PFO [2]. A history of sleep apnea [3] and dyspnea at the onset of stroke should also be considered clinical clues to paradoxical embolism.

    The authors failed to mention that a transcranial Doppler (TCD) saline study is more sensitive than trans-esophageal echocardiography (TEE) for detecting a PFO, and for predicting recurrent stroke. Among patients with suspected paradoxical embolism, 15% of PFOs were missed by TEE, and of those 41.7% were large shunts (shunt grade III or higher, which predicted recurrent stroke [4].

    The authors estimated that 5% of strokes are due to paradoxical embolism, and stated that only 128 cases of paradoxical emboli had been reported prior to the advent of contrast echocardiography in 1972. However, Hutchinson and Acheson reported in 1975 [5] that they had diagnosed PFO clinically in 4% of stroke patients, and confirmed it in 4% of 600 autopsied cases, among 2000 consecutive patients with stroke seen over a 20-year period. So the diagnosis of paradoxical embolism preceded the advent of echocardiography. It seems that echocardiography has added ~1% to the cases. The estimate of 5% of cases of stroke being due to paradoxical embolism accords with our previously published report of 5.5% [2].


    1. Elgendy AY, Saver JL, Amin Z, Boudoulas KD, Carroll JD, Elgendy IY, et al. Proposal for Updated Nomenclature and Classification of Potential Causative Mechanism in Patent Foramen Ovale-Associated Stroke. JAMA Neurol. 2020.
    2. Ozdemir AO, Tamayo A, Munoz C, Dias B, Spence JD. Cryptogenic stroke and patent foramen ovale: clinical clues to paradoxical embolism. J Neurol Sci. 2008;275(1-2):121-7.
    3. Ozdemir O, Beletsky V, Hachinski V, Spence JD. Cerebrovascular events on awakening, patent foramen ovale and obstructive sleep apnea syndrome. J Neurol Sci. 2008;268(1-2):193-4.
    4. Tobe J, Bogiatzi C, Munoz C, Tamayo A, Spence JD. Transcranial Doppler is Complementary to Echocardiography for Detection and Risk Stratification of Patent Foramen Ovale. Can J Cardiol. 2016;32(8):986 e9- e16.
    5. Hutchinson EC, Acheson, E.J. Strokes: natural history, pathology and surgical treatment. Walton J, editor. Philadelphia: W.B. Saunders; 1975.