Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Review and update of the concept of embolic stroke of undetermined source

Abstract

Ischaemic strokes have traditionally been classified according to the TOAST criteria, in which strokes with unclear aetiology are classified as cryptogenic strokes. However, the definition of cryptogenic stroke did not meet the operational criteria necessary to define patient populations for randomized treatment trials. To address this problem, the concept of embolic stroke of undetermined source (ESUS) was developed and published in 2014. A hypothesis that underpinned this concept was that most strokes in patients with ESUS are caused by embolic events, perhaps many cardioembolic, and that anticoagulation would prevent secondary ischaemic events. On this basis, two large randomized trials were conducted to compare the non-vitamin K antagonist oral anticoagulants (NOACs) dabigatran and rivaroxaban with aspirin. Neither NOAC was superior to aspirin in these trials, although subgroups of patients with ESUS seemed to benefit specifically from anticoagulation or antiplatelet therapy. The neutral results of the trials of anticoagulation and insights into ESUS from research conducted since the concept was introduced warrant reassessment of the ESUS construct as a research concept and a treatment target. In this Review, we discuss the evidence produced since the concept of ESUS was introduced, and propose updates to the criteria and diagnostic algorithm in light of the latest knowledge.

Key points

  • Embolic stroke of undetermined source (ESUS) is a subtype of cryptogenic ischaemic stroke and accounts for ~20% of all ischaemic strokes; its diagnosis requires a specified evaluation.

  • Non-stenotic atherosclerotic plaques are a major contributor to ESUS.

  • Neutral results in randomized trials that compared dabigatran and rivaroxaban (non-vitamin K oral anticoagulants) with aspirin mean that anticoagulation cannot be recommended for secondary prevention of ischaemic stroke in unselected patients with ESUS.

  • Patients aged <60 years with an otherwise unexplained ischaemic stroke and a patent foramen ovale (PFO) with high-risk clinical and/or anatomical features should be diagnosed with PFO-associated stroke rather than ESUS.

  • Studies to identify subgroups of patients with ESUS who could benefit from anticoagulation (for example, patients with atrial cardiopathy) are underway.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

References

  1. Hart, R. G. et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol. 13, 429–438 (2014). This article is the original description and definition of the concept of ESUS.

    PubMed  Article  Google Scholar 

  2. Sacco, R. L. et al. Infarcts of undetermined cause: the NINCDS Stroke Data Bank. Ann. Neurol. 25, 382–390 (1989).

    CAS  PubMed  Article  Google Scholar 

  3. Adams, H. P. Jr et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24, 35–41 (1993).

    PubMed  Article  Google Scholar 

  4. Adams, H. P. Jr & Biller, J. Classification of subtypes of ischemic stroke: history of the trial of org 10172 in acute stroke treatment classification. Stroke 46, e114–e117 (2015).

    PubMed  Article  Google Scholar 

  5. Kunitz, S. C. et al. The pilot Stroke Data Bank: definition, design, and data. Stroke 15, 740–746 (1984).

    CAS  PubMed  Article  Google Scholar 

  6. Foulkes, M. A., Wolf, P. A., Price, T. R., Mohr, J. P. & Hier, D. B. The Stroke Data Bank: design, methods, and baseline characteristics. Stroke 19, 547–554 (1988).

    CAS  PubMed  Article  Google Scholar 

  7. Mohr, J. P. et al. The Harvard Cooperative Stroke Registry: a prospective registry. Neurology 28, 754–762 (1978).

    CAS  PubMed  Article  Google Scholar 

  8. Michel, P. et al. The Acute STroke Registry and Analysis of Lausanne (ASTRAL): design and baseline analysis of an ischemic stroke registry including acute multimodal imaging. Stroke 41, 2491–2498 (2010).

    PubMed  Article  Google Scholar 

  9. Ntaios, G. Embolic stroke of undetermined source: JACC review topic of the week. J. Am. Coll. Cardiol. 75, 333–340 (2020).

    CAS  PubMed  Article  Google Scholar 

  10. Hart, R. G., Catanese, L., Perera, K. S., Ntaios, G. & Connolly, S. J. Embolic stroke of undetermined source: a systematic review and clinical update. Stroke 48, 867–872 (2017).

    PubMed  Article  Google Scholar 

  11. Ntaios, G. et al. Embolic strokes of undetermined source in the Athens Stroke Registry: an outcome analysis. Stroke 46, 2087–2093 (2015).

    PubMed  Article  Google Scholar 

  12. Ntaios, G. et al. Embolic strokes of undetermined source in the Athens Stroke Registry: a descriptive analysis. Stroke 46, 176–181 (2015).

    PubMed  Article  Google Scholar 

  13. de la Riva, P. et al. Nontraditional lipid variables predict recurrent brain ischemia in embolic stroke of undetermined source. J. Stroke Cerebrovasc. Dis. 26, 1670–1677 (2017).

    PubMed  Article  Google Scholar 

  14. Iwata, T. et al. Features of patients aged 80 years or older with embolic stroke of undetermined source. J. Stroke Cerebrovasc. Dis. 28, 251–255 (2019).

    PubMed  Article  Google Scholar 

  15. Jalini, S. et al. Atrial cardiopathy in patients with embolic strokes of unknown source and other stroke etiologies. Neurology 92, e288–e294 (2019).

    CAS  PubMed  Article  Google Scholar 

  16. Piffer, S. et al. Different clinical phenotypes of embolic stroke of undetermined source: a subgroup analysis of 86 patients. J. Stroke Cerebrovasc. Dis. 27, 3578–3586 (2018).

    PubMed  Article  Google Scholar 

  17. Siegler, J. E. et al. Prevalence of nonstenotic carotid plaque in stroke due to atrial fibrillation compared to embolic stroke of undetermined source. J. Stroke Cerebrovasc. Dis. https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.07.005 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Takasugi, J. et al. Detection of left ventricular thrombus by cardiac magnetic resonance in embolic stroke of undetermined source. Stroke 48, 2434–2440 (2017).

    PubMed  Article  Google Scholar 

  19. Umemura, T. et al. Importance of finding embolic sources for patients with embolic stroke of undetermined source. J. Stroke Cerebrovasc. Dis. 28, 1810–1815 (2019).

    PubMed  Article  Google Scholar 

  20. Lattanzi, S. et al. The P-wave terminal force in embolic strokes of undetermined source. J. Neurol. Sci. 375, 175–178 (2017).

    PubMed  Article  Google Scholar 

  21. Bembenek, J. P., Karlinski, M. A., Kurkowska-Jastrzebska, I. & Czlonkowska, A. Embolic strokes of undetermined source in a cohort of Polish stroke patients. Neurol. Sci. 39, 1041–1047 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  22. Chua, S.-K. et al. Prognostic impact of renal dysfunction on embolic stroke of undetermined source–role beyond CHA2DS2-VASc score: results from Taiwan Stroke Registry. Eur. J. Neurol. 28, 1253–1264 (2021).

    PubMed  Article  Google Scholar 

  23. Chen, J., Gao, F. & Liu, W. Atrial cardiopathy in embolic stroke of undetermined source. Brain Behav. 11, e02160 (2021).

    PubMed  PubMed Central  Google Scholar 

  24. Kamran, S. et al. Left heart factors in embolic stroke of undetermined source in a multiethnic Asian and North African cohort. J. Am. Heart Assoc. 9, e016534 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  25. Grifoni, E. et al. Age-related burden and characteristics of embolic stroke of undetermined source in the real world clinical practice. J. Thromb. Thrombolysis 49, 75–85 (2020).

    CAS  PubMed  Article  Google Scholar 

  26. Kiyuna, F. et al. Association of embolic sources with cause-specific functional outcomes among adults with cryptogenic stroke. JAMA Netw. Open 1, e182953 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  27. Lee, Y. K., Gwak, B. C., Yoon, B. A., Kim, D. H. & Cha, J. K. Atrial cardiopathy biomarkers and MRI-based infarct patterns in patients with embolic strokes of undetermined source. J. Stroke Cerebrovasc. Dis. 30, 105933 (2021).

    PubMed  Article  Google Scholar 

  28. Tsivgoulis, G. et al. Incidence, characteristics and outcomes in patients with embolic stroke of undetermined source: a population-based study. J. Neurol. Sci. 401, 5–11 (2019).

    PubMed  Article  Google Scholar 

  29. Li, L. et al. Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study. Lancet Neurol. 14, 903–913 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  30. Merkler, A. E. et al. Association between troponin levels and embolic stroke of undetermined source. J. Am. Heart Assoc. https://doi.org/10.1161/jaha.117.005905 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kasner, S. E. et al. Characterization of patients with embolic strokes of undetermined source in the NAVIGATE ESUS randomized trial. J. Stroke Cerebrovasc. Dis. 27, 1673–1682 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  32. Perera, K. S. et al. Embolic strokes of undetermined source: prevalence and patient features in the ESUS Global Registry. Int. J. Stroke 11, 526–533 (2016). This is a registry study in which the features of patients with ESUS are described.

    PubMed  Article  Google Scholar 

  33. Martinez-Majander, N. et al. Embolic strokes of undetermined source in young adults: baseline characteristics and long-term outcome. Eur. J. Neurol. 25, 535–541 (2018).

    CAS  PubMed  Article  Google Scholar 

  34. Perera, K. S. et al. Frequency and features of embolic stroke of undetermined source in young adults. Eur. Stroke J. 3, 110–116 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  35. Diener, H. C. et al. Design of randomized, double-blind, evaluation in secondary stroke prevention comparing the efficacy and safety of the oral thrombin inhibitor dabigatran etexilate vs. acetylsalicylic acid in patients with embolic stroke of undetermined source (RE-SPECT ESUS). Int. J. Stroke 10, 1309–1312 (2015).

    PubMed  Article  Google Scholar 

  36. Hart, R. G. et al. Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: design of the NAVIGATE ESUS randomized trial. Eur. Stroke J. 1, 146–154 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  37. Diener, H. C. et al. Dabigatran for prevention of stroke after embolic stroke of undetermined source. N. Engl. J. Med. 380, 1906–1917 (2019). This randomized trial compared dabigatran with aspirin for secondary stroke prevention in patients with ESUS.

    CAS  PubMed  Article  Google Scholar 

  38. Hart, R. G. et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N. Engl. J. Med. 378, 2191–2201 (2018). This randomized trial compared rivaroxaban with aspirin for secondary stroke prevention in patients with ESUS.

    CAS  PubMed  Article  Google Scholar 

  39. Ntaios, G. et al. Age- and sex-specific analysis of patients with embolic stroke of undetermined source. Neurology 89, 532–539 (2017). This article is an analysis of the role of age and sex in patients with ESUS.

    PubMed  PubMed Central  Article  Google Scholar 

  40. Handke, M., Harloff, A., Bode, C. & Geibel, A. Patent foramen ovale and cryptogenic stroke: a matter of age? Semin. Thromb. Hemost. 35, 505–514 (2009).

    PubMed  Article  Google Scholar 

  41. Mikulík, R. et al. Frequency and predictors of major bleeding in patients with embolic strokes of undetermined source: NAVIGATE-ESUS trial. Stroke 51, 2139–2147 (2020).

    PubMed  Article  CAS  Google Scholar 

  42. Geisler, T. et al. Apixaban for treatment of embolic stroke of undetermined source (ATTICUS randomized trial): rationale and study design. Int. J. Stroke 12, 985–990 (2017). This randomized trial compared apixaban with aspirin in patients with ESUS.

    PubMed  Article  Google Scholar 

  43. Hagen, P. T., Scholz, D. G. & Edwards, W. D. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin. Proc. 59, 17–20 (1984).

    CAS  PubMed  Article  Google Scholar 

  44. Ma, B. et al. Risk of stroke in patients with patent foramen ovale: an updated meta-analysis of observational studies. J. Stroke Cerebrovasc. Dis. 23, 1207–1215 (2014).

    PubMed  Article  Google Scholar 

  45. Furlan, A. J. et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N. Engl. J. Med. 366, 991–999 (2012).

    CAS  PubMed  Article  Google Scholar 

  46. Carroll, J. D. et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N. Engl. J. Med. 368, 1092–1100 (2013).

    CAS  PubMed  Article  Google Scholar 

  47. Meier, B. et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N. Engl. J. Med. 368, 1083–1091 (2013).

    CAS  PubMed  Article  Google Scholar 

  48. Mas, J. L. et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N. Engl. J. Med. 377, 1011–1021 (2017).

    CAS  PubMed  Article  Google Scholar 

  49. Sondergaard, L. et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N. Engl. J. Med. 377, 1033–1042 (2017).

    PubMed  Article  Google Scholar 

  50. Saver, J. L. et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N. Engl. J. Med. 377, 1022–1032 (2017).

    PubMed  Article  Google Scholar 

  51. Lee, P. H. et al. Cryptogenic stroke and high-risk patent foramen ovale: The DEFENSE-PFO trial. J. Am. Coll. Cardiol. 71, 2335–2342 (2018).

    PubMed  Article  Google Scholar 

  52. Mir, H. et al. Patent foramen ovale closure, antiplatelet therapy or anticoagulation in patients with patent foramen ovale and cryptogenic stroke: a systematic review and network meta-analysis incorporating complementary external evidence. BMJ Open 8, e023761 (2018). This article is a meta-analysis of the randomized trials in which PFO closure plus antithrombotic treatment was compared with antithrombotic therapy alone in patients with cryptogenic stroke.

    PubMed  PubMed Central  Article  Google Scholar 

  53. Elgendy, A. Y. et al. Proposal for updated nomenclature and classification of potential causative mechanism in patent foramen ovale-associated stroke. JAMA Neurol. 77, 878–886 (2020).

    PubMed  Article  Google Scholar 

  54. Kent, D. M. et al. Heterogeneity of treatment effects in an analysis of pooled individual patient data from randomized trials of device closure of patent foramen ovale after stroke. JAMA 326, 2277–2286 (2021). This article introduces a new classification system to assign possible causality in patients with cryptogenic stroke and PFO.

    PubMed  Article  Google Scholar 

  55. Diener, H.-C. et al. Dabigatran or aspirin after embolic stroke of undetermined source in patients with patent foramen ovale. Stroke 52, 1065–1068 (2021).

    CAS  PubMed  Article  Google Scholar 

  56. Kasner, S. E. et al. Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial. Lancet Neurol. 17, 1053–1060 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Sagris, D. et al. Antithrombotic treatment in cryptogenic stroke patients with patent foramen ovale: systematic review and meta-analysis. Stroke 50, 3135–3140 (2019).

    CAS  PubMed  Article  Google Scholar 

  58. Ntaios, G., Wintermark, M. & Michel, P. Supracardiac atherosclerosis in embolic stroke of undetermined source: the underestimated source. Eur. Heart J. 42, 1789–1796 (2020).

    Article  CAS  Google Scholar 

  59. Ay, H. et al. A computerized algorithm for etiologic classification of ischemic stroke: the causative classification of stroke system. Stroke 38, 2979–2984 (2007).

    PubMed  Article  Google Scholar 

  60. Ay, H. et al. An evidence-based causative classification system for acute ischemic stroke. Ann. Neurol. 58, 688–697 (2005).

    PubMed  Article  Google Scholar 

  61. Amarenco, P. et al. The ASCOD phenotyping of ischemic stroke (updated ASCO phenotyping). Cerebrovasc. Dis. 36, 1–5 (2013).

    CAS  PubMed  Article  Google Scholar 

  62. Ntaios, G. et al. Data-driven machine-learning analysis of potential embolic sources in embolic stroke of undetermined source. Eur. J. Neurol. 28, 192–201 (2020).

    PubMed  Article  Google Scholar 

  63. Ntaios, G. et al. Aortic arch atherosclerosis in patients with embolic stroke of undetermined source: an exploratory analysis of the NAVIGATE ESUS trial. Stroke 50, 3184–3190 (2019).

    PubMed  Article  Google Scholar 

  64. Bentsen, L. et al. Vascular pathology in the extracranial vertebral arteries in patients with acute ischemic stroke. Cerebrovasc. Dis. Extra 4, 19–27 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Ntaios, G. et al. Efficacy and safety of rivaroxaban versus aspirin in embolic stroke of undetermined source and carotid atherosclerosis. Stroke 50, 2477–2485 (2019).

    CAS  PubMed  Article  Google Scholar 

  66. Sun, P. et al. Intracranial atherosclerosis burden and stroke recurrence for symptomatic intracranial artery stenosis (sICAS). Aging Dis. 9, 1096–1102 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  67. Ntaios, G. et al. Potential embolic sources and outcomes in embolic stroke of undetermined source in the NAVIGATE-ESUS trial. Stroke 51, 1797–1804 (2020).

    PubMed  Article  Google Scholar 

  68. Ntaios, G. et al. Prevalence and overlap of potential embolic sources in patients with embolic stroke of undetermined source. J. Am. Heart Assoc. 8, e012858 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  69. Ntaios, G. & Hart, R. G. Embolic stroke. Circulation 136, 2403–2405 (2017).

    PubMed  Article  Google Scholar 

  70. Saba, L. et al. Imaging biomarkers of vulnerable carotid plaques for stroke risk prediction and their potential clinical implications. Lancet Neurol. 18, 559–572 (2019).

    PubMed  Article  Google Scholar 

  71. Eto, F. et al. Atherosclerotic components in thrombi retrieved by thrombectomy for internal carotid artery occlusion due to large artery atherosclerosis: a case report. Front Neurol. 12, 670610 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  72. Rajalingam, R., Jalini, S. & Pikula, A. Extracranial and intracranial non-stenotic carotid atherosclerotic plaques in ESUS patients [abstract]. Neurology 90 (Suppl. 15), P5.221 (2018).

    Google Scholar 

  73. Kamel, H. et al. Cryptogenic stroke and nonstenosing intracranial calcified atherosclerosis. J. Stroke Cerebrovasc. Dis. 26, 863–870 (2017).

    PubMed  Article  Google Scholar 

  74. Gupta, A. et al. Association between nonstenosing carotid artery plaque on MR angiography and acute ischemic stroke. JACC Cardiovasc. Imaging 9, 1228–1229 (2016).

    PubMed  Article  Google Scholar 

  75. Singh, N., Moody, A. R., Panzov, V. & Gladstone, D. J. Carotid intraplaque hemorrhage in patients with embolic stroke of undetermined source. J. Stroke Cerebrovasc. Dis. 27, 1956–1959 (2018).

    PubMed  Article  Google Scholar 

  76. Hirunagi, T., Miwa, S. & Katsuno, M. Nonstenotic carotid plaque in patients with anterior circulation embolic stroke of undetermined source. Brain Nerve 70, 1295–1299 (2018).

    PubMed  Google Scholar 

  77. Komatsu, T. et al. Large but nonstenotic carotid artery plaque in patients with a history of embolic stroke of undetermined source. Stroke 49, 3054–3056 (2018).

    PubMed  Article  Google Scholar 

  78. Coutinho, J. M. et al. Nonstenotic carotid plaque on CT angiography in patients with cryptogenic stroke. Neurology 87, 665–672 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  79. Freilinger, T. M. et al. Prevalence of nonstenosing, complicated atherosclerotic plaques in cryptogenic stroke. JACC Cardiovasc. Imaging 5, 397–405 (2012).

    PubMed  Article  Google Scholar 

  80. Hyafil, F. et al. High-risk plaque features can be detected in non-stenotic carotid plaques of patients with ischaemic stroke classified as cryptogenic using combined (18)F-FDG PET/MR imaging. Eur. J. Nucl. Med. Mol. Imaging 43, 270–279 (2016).

    PubMed  Article  Google Scholar 

  81. Buon, R. et al. Carotid ultrasound for assessment of nonobstructive carotid atherosclerosis in young adults with cryptogenic stroke. J. Stroke Cerebrovasc. Dis. 27, 1212–1216 (2018).

    PubMed  Article  Google Scholar 

  82. Tao, L. et al. Intracranial atherosclerotic plaque as a potential cause of embolic stroke of undetermined source. J. Am. Coll. Cardiol. 77, 680–691 (2021).

    PubMed  Article  Google Scholar 

  83. Kamtchum-Tatuene, J., Wilman, A., Saqqur, M., Shuaib, A. & Jickling, G. C. Carotid plaque with high-risk features in embolic stroke of undetermined source: systematic review and meta-analysis. Stroke 51, 311–314 (2020).

    PubMed  Article  Google Scholar 

  84. Fitzgerald, S. et al. Platelet-rich emboli in cerebral large vessel occlusion are associated with a large artery atherosclerosis source. Stroke 50, 1907–1910 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  85. Hart, R. G., Pearce, L. A. & Aguilar, M. I. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann. Intern. Med. 146, 857–867 (2007).

    PubMed  Article  Google Scholar 

  86. Diener, H. C. et al. Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial. Lancet Neurol. 11, 225–231 (2012).

    CAS  PubMed  Article  Google Scholar 

  87. Yang, X. M. et al. Atrial fibrillation known before or detected after stroke share similar risk of ischemic stroke recurrence and death. Stroke 50, 1124–1129 (2019).

    PubMed  Article  Google Scholar 

  88. Veltkamp, R. et al. Characteristics of recurrent ischemic stroke after embolic stroke of undetermined source: secondary analysis of a randomized clinical trial. JAMA Neurol. 77, 1233–1240 (2020).

    PubMed  Article  Google Scholar 

  89. Uphaus, T. et al. Development and validation of a score to detect paroxysmal atrial fibrillation after stroke. Neurology 92, e115–e124 (2019).

    PubMed  Article  Google Scholar 

  90. Ntaios, G. et al. Identification of patients with embolic stroke of undetermined source and low risk of new incident atrial fibrillation: the AF-ESUS score. Int. J. Stroke 16, 29–38 (2021).

    PubMed  Article  Google Scholar 

  91. Hsieh, C. Y., Lee, C. H. & Sung, S. F. Development of a novel score to predict newly diagnosed atrial fibrillation after ischemic stroke: the CHASE-LESS score. Atherosclerosis 295, 1–7 (2020).

    CAS  PubMed  Article  Google Scholar 

  92. Hijazi, Z. et al. The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation. Eur. Heart J. 37, 1582–1590 (2016). This article introduces a score based on biomarkers to predict atrial fibrillation.

    PubMed  PubMed Central  Article  Google Scholar 

  93. Wang, T. J. et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N. Engl. J. Med. 350, 655–663 (2004).

    CAS  PubMed  Article  Google Scholar 

  94. Pala, E. et al. B-type natriuretic peptide over N-terminal pro-brain natriuretic peptide to predict incident atrial fibrillation after cryptogenic stroke. Eur. J. Neurol. 28, 540–547 (2021).

    CAS  PubMed  Article  Google Scholar 

  95. Wasser, K. et al. Brain natriuretic peptide and discovery of atrial fibrillation after stroke: a subanalysis of the Find-AF(RANDOMISED) trial. Stroke 51, 395–401 (2020).

    PubMed  Article  Google Scholar 

  96. Svennberg, E. et al. NT-proBNP is a powerful predictor for incident atrial fibrillation–validation of a multimarker approach. Int. J. Cardiol. 223, 74–81 (2016).

    PubMed  Article  Google Scholar 

  97. Healey, J. S. et al. Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial. JAMA Neurol. 76, 764–773 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  98. Mohr, J. P. et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N. Engl. J. Med. 345, 1444–1451 (2001).

    CAS  PubMed  Article  Google Scholar 

  99. Longstreth, W. T. Jr et al. Amino terminal pro-B-type natriuretic peptide, secondary stroke prevention, and choice of antithrombotic therapy. Stroke 44, 714–719 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. Kamel, H., Okin, P. M., Elkind, M. S. & Iadecola, C. Atrial fibrillation and mechanisms of stroke: time for a new model. Stroke 47, 895–900 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  101. Kamel, H. et al. The AtRial cardiopathy and antithrombotic drugs in prevention after cryptogenic stroke randomized trial: rationale and methods. Int. J. Stroke 14, 207–214 (2019). This randomized trial compared apixaban and aspirin in patients with ESUS and atrial cardiopathy.

    PubMed  Article  Google Scholar 

  102. Goette, A. et al. EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication. Heart Rhythm. 14, e3–e40 (2017).

    PubMed  Article  Google Scholar 

  103. Sanna, T. et al. Cryptogenic stroke and underlying atrial fibrillation. N. Engl. J. Med. 370, 2478–2486 (2014). The first randomized study of long-term ECG monitoring in patients with cryptogenic stroke.

    CAS  PubMed  Article  Google Scholar 

  104. Gladstone, D. J. et al. Atrial fibrillation in patients with cryptogenic stroke. N. Engl. J. Med. 370, 2467–2477 (2014).

    CAS  PubMed  Article  Google Scholar 

  105. Wachter, R. et al. Holter-electrocardiogram-monitoring in patients with acute ischaemic stroke (Find-AFRANDOMISED): an open-label randomised controlled trial. Lancet Neurol. 16, 282–290 (2017).

    PubMed  Article  Google Scholar 

  106. Sposato, L. A. et al. Diagnosis of atrial fibrillation after stroke and transient ischaemic attack: a systematic review and meta-analysis. Lancet Neurol. 14, 377–387 (2015).

    PubMed  Article  Google Scholar 

  107. Brambatti, M. et al. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation 129, 2094–2099 (2014).

    PubMed  Article  Google Scholar 

  108. Daoud, E. G. et al. Temporal relationship of atrial tachyarrhythmias, cerebrovascular events, and systemic emboli based on stored device data: a subgroup analysis of TRENDS. Heart Rhythm. 8, 1416–1423 (2011).

    PubMed  Article  Google Scholar 

  109. Buck, B. H. et al. Effect of implantable vs prolonged external electrocardiographic monitoring on atrial fibrillation detection in patients with ischemic stroke: the PER DIEM randomized clinical trial. JAMA 325, 2160–2168 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  110. Bernstein, R. A. et al. Effect of long-term continuous cardiac monitoring vs usual care on detection of atrial fibrillation in patients with stroke attributed to large- or small-vessel disease: the STROKE-AF randomized clinical trial. JAMA 325, 2169–2177 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  111. Gladstone, D. J. et al. Screening for atrial fibrillation in the older population: a randomized clinical trial. JAMA Cardiol. 6, 558–567 (2021).

    PubMed  Article  Google Scholar 

  112. Healey, J. S. et al. Subclinical atrial fibrillation in older patients. Circulation 136, 1276–1283 (2017).

    PubMed  Article  Google Scholar 

  113. Connolly, S. J. et al. Apixaban in patients with atrial fibrillation. N. Engl. J. Med. 364, 806–817 (2011).

    CAS  PubMed  Article  Google Scholar 

  114. Rubio Campal, J. M. et al. Detecting atrial fibrillation in patients with an embolic stroke of undetermined source (from the DAF-ESUS registry). Am. J. Cardiol. 125, 409–414 (2020).

    PubMed  Article  Google Scholar 

  115. Svendsen, J. H. et al. Implantable loop recorder detection of atrial fibrillation to prevent stroke (the LOOP study): a randomised controlled trial. Lancet 398, 1507–1516 (2021).

    CAS  PubMed  Article  Google Scholar 

  116. Hindricks, G. et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur. Heart J. 42, 373–498 (2021). The most recent guidelines for the management of atrial fibrillation.

    PubMed  Article  Google Scholar 

  117. Schnabel, R. B. et al. Searching for atrial fibrillation poststroke: a white paper of the AF-SCREEN international collaboration. Circulation 140, 1834–1850 (2019).

    PubMed  Article  Google Scholar 

  118. Ikenouchi, H. et al. Left ventricular abnormality and covert atrial fibrillation in embolic stroke of undetermined source. J. Atheroscler. Thromb. https://doi.org/10.5551/jat.62994 (2021).

    Article  PubMed  Google Scholar 

  119. Elkind, M. S. V. Atrial cardiopathy and stroke prevention. Curr. Cardiol. Rep. 20, 103 (2018).

    PubMed  Article  Google Scholar 

  120. Kamel, H. et al. Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke 44, 1550–1554 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. Kamel, H. et al. Electrocardiographic left atrial abnormality and risk of stroke: Northern Manhattan Study. Stroke 46, 3208–3212 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  122. Ntaios, G. et al. Supraventricular extrasystoles on standard 12-lead electrocardiogram predict new incident atrial fibrillation after embolic stroke of undetermined source: the AF-ESUS study. J. Stroke Cerebrovasc. Dis. 29, 104626 (2020).

    PubMed  Article  Google Scholar 

  123. Perlepe, K. et al. Left atrial diameter thresholds and new incident atrial fibrillation in embolic stroke of undetermined source. Eur. J. Intern. Med. 75, 30–34 (2020).

    PubMed  Article  Google Scholar 

  124. Kitsiou, A., Sagris, D., Schäbitz, W. R. & Ntaios, G. Validation of the AF-ESUS score to identify patients with embolic stroke of undetermined source and low risk of device-detected atrial fibrillation. Eur. J. Intern. Med. 89, 135–136 (2021).

    PubMed  Article  Google Scholar 

  125. Navi, B. B. et al. Risk of arterial thromboembolism in patients with cancer. J. Am. Coll. Cardiol. 70, 926–938 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  126. Navi, B. B. et al. Cancer and embolic stroke of undetermined source. Stroke 52, 1121–1130 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. Navi, B. B. et al. Recurrent thromboembolic events after ischemic stroke in patients with cancer. Neurology 83, 26–33 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  128. Martinez-Majander, N. et al. Rivaroxaban versus aspirin for secondary prevention of ischaemic stroke in patients with cancer: a subgroup analysis of the NAVIGATE ESUS randomized trial. Eur. J. Neurol. 27, 841–848 (2020).

    CAS  PubMed  Article  Google Scholar 

  129. Nahab, F. et al. Markers of coagulation and hemostatic activation aid in identifying causes of cryptogenic stroke. Neurology 94, e1892–e1899 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. Patel, K. et al. Anticoagulation therapy reduces recurrent stroke in embolic stroke of undetermined source patients with elevated coagulation markers or severe left atrial enlargement. Front. Neurol. 12, 695378 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  131. Choi, K. H. et al. d-dimer level as a predictor of recurrent stroke in patients with embolic stroke of undetermined source. Stroke 52, 2292–2301 (2021).

    CAS  PubMed  Article  Google Scholar 

  132. Liu, M. et al. The utility of the markers of coagulation and hemostatic activation profile in the management of embolic strokes of undetermined source. J. Stroke Cerebrovasc. Dis. 30, 105592 (2021).

    PubMed  Article  Google Scholar 

  133. Algra, A. & van Gijn, J. Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. J. Neurol. Neurosurg. Psychiatry 60, 197–199 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. Baigent, C. et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373, 1849–1860 (2009).

    PubMed  Article  CAS  Google Scholar 

  135. Rothwell, P. M. et al. Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials. Lancet 388, 365–375 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. Ameriso, S. F. et al. Intracranial and systemic atherosclerosis in the NAVIGATE ESUS trial: recurrent stroke risk and response to antithrombotic therapy. J. Stroke Cerebrovasc. Dis. 29, 104936 (2020).

    PubMed  Article  Google Scholar 

  137. Merkler, A. et al. Left ventricular dysfunction among patients with embolic stroke of undetermined source and the effect of rivaroxaban versus aspirin: an exploratory analysis of the NAVIGATE ESUS. JAMA Neurol. 78, 1454–1460 (2021).

    PubMed  Article  Google Scholar 

  138. Albers, G. W. et al. Reexamination of the embolic stroke of undetermined source concept. Stroke 52, 2715–2722 (2021).

    PubMed  Article  Google Scholar 

  139. Perera, K. S. et al. Association between low-dose rivaroxaban with or without aspirin and ischemic stroke subtypes: a secondary analysis of the COMPASS trial. JAMA Neurol. 77, 43–48 (2020).

    PubMed  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

All authors wrote the manuscript, and reviewed and edited the final version before submission.

Corresponding author

Correspondence to Hans-Christoph Diener.

Ethics declarations

Competing interests

H.-C.D. has received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from Abbott, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Novo-Nordisk, Pfizer, Portola and WebMD Global. He has received financial support for research projects from Boehringer Ingelheim. He has received research grants from the German Research Council (DFG), German Ministry of Education and Research (BMBF), European Union, NIH, Bertelsmann Foundation and Heinz-Nixdorf Foundation. He serves as editor of Neurologie up2date, Info Neurologie & Psychiatrie and Arzneimitteltherapie. J.D.E. has received research grant support from AstraZeneca for the planning and conduct of the SOCRATES trial (NCT01994720), research grant support as a consultant from Boehringer Ingelheim for the planning and conduct of the RE-SPECT ESUS trial (NCT02239120), and research grant support from NIH/NINDS as Co-Principal Investigator on the POINT trial (NCT00991029); POINT received free study drug and placebo from Sanofi. He has also received an honorarium for participating in a consultant/advisory board meeting for Sanofi in May 2019. R.G.H. led the NAVIGATE ESUS trial sponsored by Bayer and received research support and a stipend from Bayer. He currently receives research support and a stipend from Bayer for co-ordination of the PACIFIC-Stroke trial. S.K. has received grant support from Medtronic and WL Gore & Associates; consulting fees from Abbott, Abbvie, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb and Medtronic; and royalties from UpToDate. H.K. serves as a principal investigator for the NIH-funded ARCADIA trial (NINDS U01NS095869), which receives in-kind study drug from the BMS-Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics. He serves as Deputy Editor for JAMA Neurology, serves as a steering committee member of Medtronic’s Stroke AF trial, serves on a trial executive committee for Janssen, and serves on an end point adjudication committee for a trial of empagliflozin for Boehringer Ingelheim. G.N. has received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from Abbott, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Elpen, Pfizer and Sanofi. He has received financial support for research projects from Amgen, the EU and Pfizer.

Peer review

Peer review information

Nature Reviews Neurology thanks N. Akoum; M. Koga; F. Nahab, who co-reviewed with G. Mohamed; and J. Putaala for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

NAVIGATE ESUS

New approach rivaroxaban inhibition of factor Xa in a global trial versus ASA to prevent embolism in embolic stroke of undetermined source.

RE-SPECT ESUS

Randomized, double-blind evaluation in secondary stroke prevention comparing the efficacy and safety of the oral thrombin inhibitor dabigatran etexilate versus acetylsalicylic acid in patients with embolic stroke of undetermined source.

ATTICUS

Apixaban for treatment of embolic stroke of undetermined source.

CLOSURE

Evaluation of the STARFlex Septal Closure System in patients with a stroke and/or transient ischemic attack due to presumed paradoxical embolism through a patent foramen ovale.

RESPECT

Randomized evaluation of recurrent stroke comparing PFO closure to established current standard of care treatment.

PC

Percutaneous closure of patent foramen ovale in cryptogenic embolism.

CLOSE

Patent foramen ovale closure or anticoagulants versus antiplatelet therapy to prevent stroke recurrence.

REDUCE

GORE HELEX Septal Occluder/GORE CARDIOFORM Septal Occluder and antiplatelet medical management for reduction of recurrent stroke or imaging-confirmed TIA in patients with patent foramen ovale (PFO).

DEFENSE-PFO

Device closure versus medical therapy for cryptogenic stroke patients with high-risk patent foramen ovale.

PICSS

Patent foramen ovale in cryptogenic stroke study.

ARCADIA

Atrial cardiopathy and antithrombotic drugs in prevention after cryptogenic stroke.

MOSES

Midregional proatrial natriuretic peptide to guide secondary stroke prevention.

AVERROES

Apixaban versus acetylsalicylic acid (ASA) to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment.

TEACH2

Trial of apixaban versus aspirin in cancer patients with cryptogenic ischemic stroke.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Diener, HC., Easton, J.D., Hart, R.G. et al. Review and update of the concept of embolic stroke of undetermined source. Nat Rev Neurol (2022). https://doi.org/10.1038/s41582-022-00663-4

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41582-022-00663-4

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing