Cryptogenic Stroke: A Challenge in Diagnosis and Management

Keywords: cryptogenic stroke, diagnostic workup, management strategy, mechanism


Ischemic stroke is responsible for 85% of all stroke globally. However, the etiology of around a quarter of ischemic stroke are undetermined, this is called cryptogenic stroke. This kind of stroke affects younger population. Several mechanism are associated with the incidence of cryptogenic stroke such as paroxysmal atrial fibrillation, patent foramen ovale, atherosclerosis, and atrial cardiopathy. Despite many advanced knowledge on stroke generally, cryptogenic stroke is still a challenge in clinical settings. To understand more about cryptogenic stroke, a new term of embolic strokes of undetermined source (ESUS) is proposed and may need a specific workup. Specific workup aims to detect any silent risk factors and also to evaluate the cardiac structure. The term of ESUS also leads to the understanding that cryptogenic stroke is highly related to embolic mechanism and anticoagulation administration might benefit the patients. However, the result of several recent studies showed that anticoagulant was not superior to antiplatelet, and antiplatelet is still the preferred treatment. Studies on PFO closure also shows different result, but the majority of the trials showed benefit of PFO closure in reducing the risk of stroke recurrence.


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1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016;133(4):e38-360.
2. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, 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. 1993;24(1):35-41
3. Arsava EM, Ballabio E, Benner T, Cole JW, Delgado-Martinez MP, Dichgans M, et al. The Causative Classification of Stroke system: an international reliability and optimization study. Neurology. 2010;75(14):1277-84.
4. Ay H, Benner T, Arsava EM, Furie KL, Singhal AB, Jensen MB, et al. A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. Stroke. 2007;38(11):2979-84.
5. Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Wolf ME, Hennerici MG. The ASCOD phenotyping of ischemic stroke (Updated ASCO Phenotyping). Cerebrovasc Dis. 2013;36(1):1-5.
6. Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O'Donnell MJ, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol. 2014;13(4):429-38.
7. Hart RG, Sharma M, Mundl H, Kasner SE, Bangdiwala SI, Berkowitz SD, et al. Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source. N Engl J Med. 2018;378(23):2191-2201.
8. Diener HC, Sacco RL, Easton JD, Granger CB, Bernstein RA, Uchiyama S, et al. Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source. N Engl J Med. 2019;380(20):1906-1917.
9. Li L, Yiin GS, Geraghty OC, Schulz UG, Kuker W, Mehta Z, et al. Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study. Lancet Neurol. 2015;14(9):903-913.
10. Ji R, Schwamm LH, Pervez MA, Singhal AB. Ischemic stroke and transient ischemic attack in young adults: risk factors, diagnostic yield, neuroimaging, and thrombolysis. JAMA Neurol. 2013;70(1):51-7.
11. Wolf ME, Grittner U, Böttcher T, Norrving B, Rolfs A, Hennerici MG. Phenotypic ASCO Characterisation of Young Patients with Ischemic Stroke in the Prospective Multicentre Observational sifap1 Study. Cerebrovasc Dis. 2015;40(3-4):129-35.
12. Putaala J, Metso AJ, Metso TM, Konkola N, Kraemer Y, Haapaniemi E, et al. Analysis of 1008 consecutive patients aged 15 to 49 with first-ever ischemic stroke: the Helsinki young stroke registry. Stroke. 2009;40(4):1195-203.
13. Gladstone DJ, Spring M, Dorian P, Panzov V, Thorpe KE, Hall J, et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med. 2014;370(26):2467-77.
14. Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370(26):2478-86.
15. Jorfida M, Antolini M, Cerrato E, Caprioli MG, Castagno D, Garrone P, et al. Cryptogenic ischemic stroke and prevalence of asymptomatic atrial fibrillation: a prospective study. J Cardiovasc Med (Hagerstown). 2016;17(12):863-869.
16. Kottoor SJ, Arora RR. Cryptogenic Stroke: To Close a Patent Foramen Ovale or Not to Close?. J Cent Nerv Syst Dis. 2018;10:1179573518819476.
17. Farb A, Ibrahim NG, Zuckerman BD. Patent Foramen Ovale after Cryptogenic Stroke - Assessing the Evidence for Closure. N Engl J Med. 2017 Sep 14;377(11):1006-1009.
18. Alsheikh-Ali AA, Thaler DE, Kent DM. Patent foramen ovale in cryptogenic stroke: incidental or pathogenic? Stroke. 2009;40(7):2349-55.
19. Mojadidi MK, Winoker JS, Roberts SC, Msaouel P, Zaman MO, Gevorgyan R, et al. Accuracy of conventional transthoracic echocardiography for the diagnosis of intracardiac right-to-left shunt: a meta-analysis of prospective studies. Echocardiography. 2014;31(9):1036-48.
20. Singh HS, Katchi F, Naidu SS. PFO Closure for Cryptogenic Stroke: A Review and Clinical Treatment Algorithm. Cardiol Rev. 2017;25(4):147-157.
21. 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.e9-986.e16.
22. Kent DM, Ruthazer R, Weimar C, Mas JL, Serena J, Homma S, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology. 2013;81(7):619-25.
23. Gladstone DJ, Dorian P, Spring M, Panzov V, Mamdani M, Healey JS, et al. Atrial premature beats predict atrial fibrillation in cryptogenic stroke: results from the EMBRACE trial. Stroke. 2015;46(4):936-41.
24. Mac Grory B, Flood SP, Apostolidou E, Yaghi S. Cryptogenic Stroke: Diagnostic Workup and Management. Curr Treat Options Cardiovasc Med. 2019 Dec 3;21(11):77.
25. Fonseca AC, Alves P, Inácio N, Marto JP, Viana-Baptista M, Pinho-E-Melo T, et al. Patients With Undetermined Stroke Have Increased Atrial Fibrosis: A Cardiac Magnetic Resonance Imaging Study. Stroke. 2018;49(3):734-737.
26. Gupta A, Gialdini G, Lerario MP, Baradaran H, Giambrone A, Navi BB, et al. Magnetic resonance angiography detection of abnormal carotid artery plaque in patients with cryptogenic stroke. J Am Heart Assoc. 2015;4(6):e002012.
27. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(7):2160-236.
28. Molina CA, Santamarina E, Alvarez-Sabín J. Cryptogenic stroke, aortic arch atheroma and patent foramen ovale. Cerebrovasc Dis. 2007;24 Suppl 1:84-8.
29. Ito A, Sugioka K, Matsumura Y, Fujita S, Iwata S, Hanatani A, et al. Rapid and accurate assessment of aortic arch atherosclerosis using simultaneous multi-plane imaging by transesophageal echocardiography. Ultrasound Med Biol. 2013;39(8):1337-42.
30. Nouh A, Hussain M, Mehta T, Yaghi S. Embolic Strokes of Unknown Source and Cryptogenic Stroke: Implications in Clinical Practice. Front Neurol. 2016;7:37.
31. Furlan AJ, Reisman M, Massaro J, Mauri L, Adams H, Albers GW, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366(11):991-9.
32. Meier B, Kalesan B, Mattle HP, Khattab AA, Hildick-Smith D, Dudek D, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med. 2013;368(12):1083-91.
33. Søndergaard L, Kasner SE, Rhodes JF, Andersen G, Iversen HK, Nielsen-Kudsk JE, et al. Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Engl J Med. 2017;377(11):1033-1042.
34. Saver JL, Carroll JD, Thaler DE, Smalling RW, MacDonald LA, Marks DS, et al. Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke. N Engl J Med. 2017;377(11):1022-1032.
35. Mas JL, Derumeaux G, Guillon B, Massardier E, Hosseini H, Mechtouff L, et al. Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke. N Engl J Med. 2017;377(11):1011-1021.
36. Lee PH, Song JK, Kim JS, Heo R, Lee S, Kim DH, et al. Cryptogenic stroke and high-risk patent foramen Ovale: the DEFENSE-PFO trial. J Am Coll Cardiol. 2018;71(20):2335–42
37. Albers GW, Bernstein RA, Brachmann J, Camm J, Easton JD, Fromm P, et al. Heart Rhythm Monitoring Strategies for Cryptogenic Stroke: 2015 Diagnostics and Monitoring Stroke Focus Group Report. J Am Heart Assoc. 2016;5(3):e002944.
38. Tsivgoulis G, Katsanos AH, Köhrmann M, Caso V, Perren F, Palaiodimou L, et al. Duration of Implantable Cardiac Monitoring and Detection of Atrial Fibrillation in Ischemic Stroke Patients: A Systematic Review and Meta-Analysis. J Stroke. 2019;21(3):302-311.
39. Kamel H, Longstreth WT Jr, Tirschwell DL, Kronmal RA, Broderick JP, Palesch YY, et al. The AtRial Cardiopathy and Antithrombotic Drugs In prevention After cryptogenic stroke randomized trial: Rationale and methods. Int J Stroke. 2019;14(2):207-214
40. Geisler T, Poli S, Meisner C, Schreieck J, Zuern CS, Nägele T, et al. Apixaban for treatment of embolic stroke of undetermined source (ATTICUS randomized trial): Rationale and study design. Int J Stroke. 2017;12(9):985-990.
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How to Cite
Purwowiyoto, S., Setianto, B., Panindhita, G., Halomoan, R., & Wiryawan, I. N. (2021). Cryptogenic Stroke: A Challenge in Diagnosis and Management. Indonesian Journal of Cardiology, 42(3).

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