Overview and Future Direction of Embolic Stroke of Undetermined Source from the Insights of CHALLENGE ESUS/CS Registry

Overview

Journal J Atheroscler Thromb

Date 2024 Sep 29

PMID 39343604

Authors

Muneaki Kikuno

Yuji Ueno

Affiliations

Soon will be listed here.

Abstract

Cryptogenic stroke (CS) accounts for approximately one-fourth of acute ischemic strokes, with most cases derived from embolic etiologies. In 2014, embolic stroke of undetermined source (ESUS) was advocated and the efficacy of anticoagulant therapy was anticipated. However, 3 large-scale clinical trials failed to demonstrate the superiority of direct oral anticoagulants (DOACs) over aspirin, potentially due to the heterogeneous and diverse pathologies of ESUS, including paroxysmal atrial fibrillation (AF), arteriogenic sources such as nonstenotic carotid plaque and aortic complicated lesion (ACL), patent foramen oval (PFO), and nonbacterial thrombotic endocarditis (NBTE) related to active cancer.Transesophageal echocardiography (TEE) is one of the most effective imaging modalities for assessing embolic sources in ESUS and CS. The Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke (CHALLENGE ESUS/CS) registry is a multicenter registry that enrolled consecutive patients with CS who underwent TEE at 8 hospitals in Japan between April 2014 and December 2016. Their mean age was 68.7±12.8 years, and 455 patients (67.2%) were male. The median National Institutes of Health Stroke Scale (NIHSS) score was 2. Since 7 analyses have been conducted from each institution to date, novel and significant insights regarding embolic origins and pathophysiologies of ESUS and CS were elucidated from this multicenter registry. This review discusses the diagnosis and treatment of ESUS and CS, tracing their past and future directions. Meaningful insights from the CHALLENGE ESUS/CS registry are also referenced and analyzed.

References

Bansal R, Pauls G, Shankel S . Blue digit syndrome: transesophageal echocardiographic identification of thoracic aortic plaque-related thrombi and successful outcome with warfarin. J Am Soc Echocardiogr. 1993; 6(3 Pt 1):319-23. DOI: 10.1016/s0894-7317(14)80070-9. View

Janion M, Kurzawski J, Sielski J, Ciuraszkiewicz K, Sadowski M, Radomska E . Dispersion of P wave duration and P wave vector in patients with atrial septal aneurysm. Europace. 2007; 9(7):471-4. DOI: 10.1093/europace/eum089. View

. Special report from the National Institute of Neurological Disorders and Stroke. Classification of cerebrovascular diseases III. Stroke. 1990; 21(4):637-76. DOI: 10.1161/01.str.21.4.637. View

Kikuno M, Ueno Y, Shimizu T, Kuriki A, Tateishi Y, Doijiri R . Underlying embolic and pathologic differentiation by cerebral microbleeds in cryptogenic stroke. J Neurol. 2020; 267(5):1482-1490. DOI: 10.1007/s00415-020-09732-4. View

Eikelboom J, Connolly S, Bosch J, Dagenais G, Hart R, Shestakovska O . Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017; 377(14):1319-1330. DOI: 10.1056/NEJMoa1709118. View

Shoamanesh A, Hart R, Connolly S, Kasner S, Smith E, Marti-Fabregas J . Microbleeds and the Effect of Anticoagulation in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Randomized Clinical Trial. JAMA Neurol. 2020; 78(1):11-20. PMC: 7573796. DOI: 10.1001/jamaneurol.2020.3836. View

McGrath E, Paikin J, Motlagh B, Salehian O, Kapral M, ODonnell M . Transesophageal echocardiography in patients with cryptogenic ischemic stroke: a systematic review. Am Heart J. 2014; 168(5):706-12. DOI: 10.1016/j.ahj.2014.07.025. View

Kim S, Hong J, Kim H, Lee J, Chung P, Park K . Ischemic stroke in cancer patients with and without conventional mechanisms: a multicenter study in Korea. Stroke. 2010; 41(4):798-801. DOI: 10.1161/STROKEAHA.109.571356. View

Rogers L . Cerebrovascular complications in patients with cancer. Semin Neurol. 2010; 30(3):311-9. DOI: 10.1055/s-0030-1255224. View

10.

Abe A, Harada-Abe M, Ueda M, Katano T, Nakajima M, Muraga K . Aortic arch atherosclerosis in ischaemic stroke of unknown origin affects prognosis. Cerebrovasc Dis Extra. 2014; 4(2):92-101. PMC: 4035681. DOI: 10.1159/000362434. View

11.

Ntaios G, Pearce L, Meseguer E, Endres M, Amarenco P, Ozturk S . Aortic Arch Atherosclerosis in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Trial. Stroke. 2019; 50(11):3184-3190. DOI: 10.1161/STROKEAHA.119.025813. View

12.

Kikuno M, Ueno Y, Takekawa H, Kanemaru K, Shimizu T, Kuriki A . Distinction in Prevalence of Atherosclerotic Embolic Sources in Cryptogenic Stroke With Cancer Status. J Am Heart Assoc. 2021; 10(21):e021375. PMC: 8751843. DOI: 10.1161/JAHA.120.021375. View

13.

Hasegawa Y, Setoguchi T, Sakaida T, Iuchi T . Utility of a scoring system for differentiating cancer-associated stroke from cryptogenic stroke in patients with cancer. Neurol Sci. 2020; 41(5):1245-1250. DOI: 10.1007/s10072-019-04231-5. View

14.

Iguchi Y, Kimura K, Kobayashi K, Ueno Y, Inoue T . Ischaemic stroke with malignancy may often be caused by paradoxical embolism. J Neurol Neurosurg Psychiatry. 2006; 77(12):1336-9. PMC: 2077399. DOI: 10.1136/jnnp.2006.092940. View

15.

Kopczak A, Schindler A, Bayer-Karpinska A, Koch M, Sepp D, Zeller J . Complicated Carotid Artery Plaques as a Cause of Cryptogenic Stroke. J Am Coll Cardiol. 2020; 76(19):2212-2222. DOI: 10.1016/j.jacc.2020.09.532. View

16.

Maheshwari A, Norby F, Inciardi R, Wang W, Zhang M, Soliman E . Left Atrial Mechanical Dysfunction and the Risk for Ischemic Stroke in People Without Prevalent Atrial Fibrillation or Stroke : A Prospective Cohort Study. Ann Intern Med. 2022; 176(1):39-48. PMC: 11793084. DOI: 10.7326/M22-1638. View

17.

Sakai Y, Cao Q, Rubin J, Witsch J, Cohen-Addad D, de Macedo Rodrigues K . Imaging Biomarkers and Prevalence of Complex Aortic Plaque in Cryptogenic Stroke: A Systematic Review. J Am Heart Assoc. 2023; 12(23):e031797. PMC: 10727354. DOI: 10.1161/JAHA.123.031797. View

18.

Diener H, Sacco R, Easton J, Granger C, Bernstein R, Uchiyama S . Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source. N Engl J Med. 2019; 380(20):1906-1917. DOI: 10.1056/NEJMoa1813959. View

19.

Tateishi Y, Ueno Y, Tsujino A, Kuriki A, Kamiya Y, Shimizu T . Cardiac and Echocardiographic Markers in Cryptogenic Stroke with Incidental Patent Foramen Ovale. J Stroke Cerebrovasc Dis. 2021; 30(8):105892. DOI: 10.1016/j.jstrokecerebrovasdis.2021.105892. View

20.

Nedeltchev K, Wiedmer S, Schwerzmann M, Windecker S, Haefeli T, Meier B . Sex differences in cryptogenic stroke with patent foramen ovale. Am Heart J. 2008; 156(3):461-5. DOI: 10.1016/j.ahj.2008.04.018. View