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Research Article
Originally Published 6 March 2017
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Embolic Stroke of Undetermined Source: A Systematic Review and Clinical Update

Robert G. Hart, MD, Luciana Catanese, MD, Kanjana S. Perera, MBBS, George Ntaios, MD, PhD, and Stuart J. Connolly, MDAuthor Info & Affiliations
Stroke
Volume 48, Number 4
https://doi.org/10.1161/STROKEAHA.116.016414
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Abstract

Background and Purpose—

Embolic stroke of undetermined source (ESUS) designates patients with nonlacunar cryptogenic ischemic strokes in whom embolism is the likely stroke mechanism. It has been hypothesized that anticoagulation is more efficacious than antiplatelet therapy for secondary stroke prevention in ESUS patients. We review available information about ESUS.

Methods—

Systematic literature review to assess the frequency of ESUS, patient features, and prognosis using PubMed from 2014 to present, unrestricted by language.

Results—

On the basis of 9 studies, the reported frequency of ESUS ranged from 9% to 25% of ischemic strokes, averaging 17%. From 8 studies involving 2045 ESUS patients, the mean age was 65 years and 42% were women; the mean NIH stroke score was 5 at stroke onset (4 studies, 1772 ESUS patients). Most (86%) ESUS patients were treated with antiplatelet therapy during follow-up, with the annualized recurrent stroke rate averaging 4.5% per year during a mean follow-up of 2.7 years (5 studies, 1605 ESUS patients).

Conclusions—

ESUS comprises about 1 ischemic stroke in 6. Patients with ischemic stroke meeting criteria for ESUS were relatively young compared with other ischemic stroke subtypes and had, on average, minor strokes, consistent with small emboli. Retrospective methods of available studies limit confidence in stroke recurrence rates but support a substantial (>4% per year) rate of stroke recurrence during (mostly) antiplatelet therapy. There is an important need to define better antithrombotic prophylaxis for this frequently occurring subtype of ischemic stroke.

Introduction

In 2014, the clinical construct of “embolic stroke of undetermined source” (ESUS) was introduced to identify patients with nonlacunar cryptogenic ischemic strokes in whom embolism was the likely stroke mechanism.1 It was hypothesized that anticoagulants might be more efficacious than antiplatelet agents for secondary stroke prevention in ESUS patients. At the time of the original publication, little information was available to estimate the frequency of ESUS, patient features, or prognosis. Interest in ESUS has been fueled, in part, by 3 ongoing randomized trials comparing nonvitamin K antagonist direct-acting oral anticoagulants with aspirin for secondary stroke prevention.2–4
Here, we report the results of a systematic review of published studies about ESUS and summarize additional recent information relevant to the ESUS construct.

Methods

A PRISMA-guided systematic PubMed search strategy was initiated to identify the studies of interest (the last searched on December 6, 2016; Figure).5 We also performed a hand searching of bibliographies and citations of included studies. For the online search strategy, the terms (embolic stroke of unknown source OR ESUS) were combined with (embolic stroke OR cryptogenic stroke OR embolism), and results were restricted to those published since 2014. Two coauthors (R.G.H. and L.C.) independently reviewed articles that emerged from the searches for potential inclusion in review. Studies published in abstract only were not included. Discrepancies between the reviewers were resolved by consensus. Publications in any language were included if reporting new information based on the ESUS criteria proposed by the Cryptogenic Stroke/ESUS International Working Group (Table 1). One study reporting a highly selected ESUS cohort was not included,6 nor were 5 published case reports.7–11 Investigators of included studies were selectively contacted seeking additional data.12
Table 1. Criteria for Diagnosis of Embolic Stroke of Undetermined Source (ESUS)*
1. Ischemic stroke detected by CT or MRI that is not lacunar†
2. Absence of extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the area of ischemia
3. No major risk cardioembolic source of embolism‡
4. No other specific cause of stroke identified (eg, arteritis, dissection, migraine/vasospasm, and drug abuse)
CT indicates computed tomography; and MRI, indicates magnetic resonance imaging.
*
Requires minimum diagnostic evaluation that includes cardiac rhythm monitoring for >24 hours with automated rhythm detection.1
†
Lacunar defined as a subcortical infarct ≤1.5 cm (≤2.0 cm on MRI diffusion images) in largest dimension, including on MRI diffusion-weighted images, and in the distribution of the small, penetrating cerebral arteries of the cerebral hemispheres and pons.
‡
Permanent or paroxysmal atrial fibrillation, sustained atrial flutter, intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or other cardiac tumors, mitral stenosis, recent (<4 weeks) myocardial infarction, left ventricular ejection fraction <30%, valvular vegetations, or infective endocarditis.
Figure. Diagram of search strategy. Hand-search refers to review of reference lists from articles identified by the PubMed search. ESUS indicates embolic stroke of undetermined source.
Because ascertainment bias between different studies could potentially be more misleading than random error related to sample sizes, the pooled results are presented both as weighted (by numbers of patients) and unweighted (averaging values for each study) means.

Results

Overall, the quality of the included studies was only fair. Most studies were retrospective analyses of existing databases (extending as far as 1992) and did not report the specific details of ESUS diagnosis, completeness of the diagnostic evaluation of patients with cryptogenic stroke required for ESUS diagnosis, treatment cross-overs, or numbers lost-to-follow-up.

Frequency of ESUS

We identified 12 studies that reported the frequency of ESUS as a fraction of all ischemic strokes, with prevalences ranging from 7% to 42% (Table 2).
Table 2. Frequency of ESUS*
StudyDesignPopulationCardiac Rhythm Monitoring% ESUS* (n)Comments
Ntaios et al13Retrospective, single-center, inpt stroke registry, 1992–20112731 Greek pts with first ischemic stroke; mean age 71 y71% inpt telemetry for 7 d or discharge; 52% 24 h Holter ECG10 (275)29% of ESUS pts had AF detected during f/up
Mahagne et al14No details1074 French pts, no details publishedHolter ECG as inpt (mean 7 d)23 (243)28% ESUS if only a 24 h Holter ECG done
Li et al15Population-based, ischemic stroke or TIA, 2002–20141607 strokes and 948 TIAs in the UK; mean age 74 yAmbulatory home monitoring in 20% first 8 y, 80% thereafter7 (189)Nonlacunar TIAs could be ESUS; most cryptogenic pts did not have the required cardiac rhythm monitoring
Putaala et al16Retrospective, single center, inpts, 2010–2012540 Finnish pts, mean age 69 y44% continuous ECG monitoring9 (46)NAVIGATE ESUS trial criteria used.2 Most cryptogenic pts did not have the required cardiac rhythm monitoring
Ladeira et al17Retrospective, single center, ages 18-55 y, 2010–2014100 young Portuguese pts with ischemic stroke, mean age 46 yNR42 (42)Minor risk potential cardioembolic sources not more frequent in young stroke patients with ESUS
Takasugi et al18Retrospective, single center, 2012–2014623 Japanese acute ischemic stroke pts; mean age NRContinuous ECG monitoring for ≥3 days in all13 (81) 
Perera et al19Retrospective, 19 international stroke units, 2014–20152144 pts with ischemic stroke; mean age 67 y33% only inpt telemetry for ≥24 h, 59% 24 h Holter ECG, 8% >24 h monitoring16 (351)Excluding pts with incomplete diagnostic testing required for ESUS, 19% were ESUS
Montero et al20Retrospective, single-center stroke unit pts during 2010318 Spanish pts with ischemic stroke; mean age NRNo details19 (60)Support for a cardioembolic mechanisms for most ESUS
Coutinho et al21Retrospective, single-center stroke registry, 2012–20151038 Canadian pts with ischemic stroke, mean age NRMinimum of 24 h of automated rhythm monitoring12 (128)Support for nonstenotic carotid plaques as causing ESUS
Ueno et al22Retrospective, single-center inpt stroke registry, 2008–20141158 Japanese pts with acute ischemic stroke, mean age NRCardiac telemetry ≥24 h25 (292) 
Masina et al12Retrospective, single-center stroke unit, 2010–2012337 Italian ischemic stroke pts, mean age 78 y†72 h continuous inpt telemetry without automated rhythm detection25 (84)41 (49%) ESUS pts had minor risk cardioembolic sources identified by echocardiography
Arauz et al23Retrospective, single-center stroke registry, 2003–20151673 Mexican ischemic stroke pts, mean age NRAt least 24 h of Holter monitor9 (149)60 additional patients with cryptogenic stroke were not ESUS due to incomplete evaluation
AF indicates atrial fibrillation; ESUS, embolic stroke of undetermined source; f/up, follow-up; inpt, inpatient (ie, during hospitalization); NAVIGATE, New Approach Rivaroxaban Inhibition of Factor Xa in a Global trial vs ASA to Prevent Embolism in ESUS; NR, not reported; pts, patients; and TIAs, transient ischemic attacks.
*
ESUS criteria per Cryptogenic Stroke/ESUS International Working Group (Table 1)1 unless otherwise noted in the comments column.
†
Additional unpublished information from Prof M. Masina (personal communication).
In the 2 studies15,16 reporting the lowest frequencies, most patients with ischemic stroke did not undergo cardiac rhythm monitoring required for the diagnosis of ESUS; the study reporting the highest ESUS frequency17 was restricted to young patients with stroke (18–55 years). In the remaining 9 studies, the reported frequency of ESUS ranged from 9% to 25%,12–14,18–23 with both weighted and unweighted average frequencies of 17%. In 1 study involving 19 different countries, there was no observed difference in the frequency of ESUS across global regions.19

Patient Features of ESUS

Eight studies reported patient features of 2045 ESUS patients (Table 3). Pooling these studies, the mean age of ESUS patients was 65 years and 42% were women. ESUS patients were younger and with lower frequencies of conventional vascular risk factors than non-ESUS patients with ischemic stroke13,15,16; in 1 study, ESUS patients were significantly younger than other patients with ischemic stroke even after patients with atrial fibrillation were excluded.19 Three studies reported that patent foramen ovale was present in 25%,19 28%,25 and 58%22 of ESUS patients who underwent transesophageal echocardiography. The NIH Stroke Scale score near ESUS onset averaged 5 based on 4 studies involving 1772 ESUS patients (Table 3).
Table 3. Features of ESUS Patients*
StudynMean age, yWomen, %Median NIHSS ScoreHistory of Hypertension, %Diabetes Mellitus, %PFO, %†
Ntaios et al13275683656524NR
Li et al151896547NR4712NR
Putaala et al16466243<6447NR
Ntaios et al24‡1095684156020NR
Perera et al1935162434642525§
Ueno et al22‖17764283663258
Masina et al12847352NR7417NR
Arauz et al23#14944497259NR
Pooled – unweighted average‡2045634355619…
Pooled – weighted average‡2045654255820…
ESUS indicates embolic stroke of undetermined source; NIHSS, National Institutes of Health Stroke Scale; NR, not reported; and PFO, patent foramen ovale.
*
ESUS criteria per Cryptogenic Stroke/ESUS International Working Group (Table 1)1 if not otherwise specified under comments in Table 2. Ladeira et al17 involving young ESUS patients not included.
‡
Patients from Ntaios et al13 and Putaala et al16 were included in Ntaios et al.24
§
Of 123 ESUS patients undergoing transesophageal echocardiography.19
†
Katsanos et al25 reported PFO in 28% of 61 young ESUS patients who underwent transesophageal echocardiography.
‖
Subgroup of 292 ESUS patients who underwent transesophageal echocardiography and had follow-up.
Additional unpublished information from Prof M. Masina (personal communication).
#
Eighty-nine of the 149 ESUS patients included in Ntaios et al24 (A. Arauz, personal communication) and hence are double-counted.

Prognosis of ESUS Patients

Five studies that included1605 ESUS patients provided data on the rate of recurrent stroke during follow-up of ESUS patients (Table 4). Most (86%) ESUS patients were treated with antiplatelet therapy during follow-up, and 13% were given oral anticoagulants. Incomplete reporting of lost-to-follow-up and unspecified selection for oral anticoagulant therapy confound available data; annualized recurrent stroke rates averaged 4.5% per year during a mean follow-up of 2.7 years (Table 4). ESUS patients had higher rates of stroke recurrence compared with non-ESUS patients in 2 studies.16,26 One study reported that atrial fibrillation was subsequently diagnosed in 29% of ESUS patients during 3.2 years of follow-up;13 in this study, for the diagnosis of ESUS, Holter ECG monitoring was used in 52% of ESUS patients and cardiac telemetry in most of the remainder.26,27
Table 4. Prognosis of ESUS Patients*
Studyn/Mean Follow-Up (y)Mean Age, yAntithrombotic TherapyAF During Follow-Up†Stroke (Est Annualized Rate)†Stroke, MI, Vascular Death (Est Annualized Rate)Total Mortality (Est Annualized Rate)
Ntaios et al13,26‡275 (3.2)6874% APT only, 22% OAC80 (29%)6.8%/y9.0%/y§8.2%/y
Li et al15189 (1)65NRNR≈5%/yNRNR
Putaala et al16‡46 (1.8)6285% APT, 11% OACNR5.1%/yNR1.3%/y
Ntaios et al24‡1095 (3.0)6887% APT only, 12% OACNR4.8%/y‖NR4.5%/y
Masina et al1284 (2.1)7399% APTNR2.3%/yNRNR
Ueno et al22#177 (3.5)6472% APT, 29% OACNR3.9%/y5.0%/y**1.3%/y
Arauz et al23††149 (2.3)4491% APT, 5% OACNR2.3%/yNR0%/y
Pooled – unweighted average‡,††1545 (2.4)6887% APT, 12% OAC…4.0%/y…2.9%/y
Pooled – weighted average‡,††1605 (2.7)6586% APT, 13% OAC…4.5%/y…3.9%/y
AF indicates atrial fibrillation; APT, antiplatelet; Est, estimated; ESUS, embolic stroke of undetermined source; MI, myocardial infarction; NR, not reported; and OAC, oral anticoagulant.
*
ESUS criteria per Cryptogenic Stroke/ESUS International Working Group (Table 1).1 See Table 2 for description of studies.
†
Additionally, Mahagne et al14 reported AF identification in 2.1% and ischemia recurrence rate of 1.2% among 243 ESUS patients during a mean follow-up of 2.4 years, but no details about the study have been published.
‡
Patients from Ntaios et al13 and Putaala et al16 were included in Ntaios et al.24
§
Recurrent stroke, MI, systemic embolism, ruptured aortic aneurysm, or sudden cardiac death.
‖
Included ischemic stroke or transient ischemic attack.
Additional unpublished information from Prof M. Masina (personal communication).
#
Subgroup of 292 ESUS patients who underwent transesophageal echocardiography and had follow-up.
**
Included incident peripheral artery disease.
††
Eighty-nine (60%) of the 149 ESUS patients included in Ntaios et al24 (A. Arauz, personal communication) and not included in unweighted analysis and adjusted for the weighted analysis.

Additional Recent Information Relevant to the ESUS Construct or to Cryptogenic Stroke

On the basis of histopathologic analysis of specimens extracted by the endovascular treatment of acute stroke in ESUS patients, most thrombi were erythrocyte-rich (13%) or of mixed composition (80%), with platelet-rich thrombi in only 8%.28 In another study, thrombi extracted from ESUS patients more closely resembled cardioembolic clots versus noncardioembolic thrombi.29
In mid-2014, 2 high-quality studies reported that episodes (usually brief, lasting several minutes) of previously unrecognized atrial fibrillation could be detected in 10% to 20% of patients with cryptogenic ischemic stroke if the duration of cardiac monitoring was prolonged beyond 24 hours of Holter ECG monitoring.30,31 This has been confirmed by others,14,32,33 with the frequency of detection of atrial fibrillation directly related to the duration of cardiac rhythm monitoring. Stroke severity of ESUS patients who are later diagnosed with atrial fibrillation is similar to strokes in ESUS patients without atrial fibrillation.34
Left atrial myopathy/dysfunction unassociated with atrial fibrillation may be a cause of ESUS.35,36 Other studies have emphasized a relationship of nonstenotic cervical carotid artery plaques with cryptogenic stroke37 and with ESUS.21 Wider availability of computed tomography imaging of the aortic arch allows assessment of aortic plaque without transesophageal echocardiography.38 There has been additional emphasis on occult cancer in patients with cryptogenic stroke.39,40

Discussion

Methodological limitations in existing studies likely contributed to relatively wide ranges in the estimated frequencies of ESUS patients, their features, and prognosis. About 17% of patients with ischemic stroke met criteria for ESUS based on studies published to date, but this may be an underestimate because several diagnostic tests are required to make a diagnosis of ESUS, and there has been incomplete diagnostic evaluation in all studies reported to date. The different types and duration of cardiac rhythm monitoring undertaken in the available studies influenced the frequency of detection of covert paroxysmal atrial fibrillation (that excludes ESUS) and likely contributed further to the range of reported prevalences of ESUS14 (Table 2).
It remains uncertain what fraction of ESUS patients will have atrial fibrillation detected during long-term follow-up, nor is the pathophysiological relationship between late detection of brief episodes of atrial fibrillation and ESUS adequately understood. It is unclear whether brief episodes of atrial fibrillation detected weeks or months after ESUS are relevant to stroke cause or identify patients who benefit from anticoagulation.
The mean age of ESUS patients (averaging 65 years) may reflect incomplete diagnostic investigation of older patients with stroke that permit the diagnosis of ESUS.41 With this caveat, the picture of ESUS patients that emerged is of relatively young (compared with atrial fibrillation-associated stroke) patients with mild strokes and with lower frequencies of conventional vascular risk factors compared with non-ESUS patients with ischemic stroke. We speculate that ESUS is usually caused by relatively smaller emboli from valvular and arterial sources rather than larger emboli originating in the cardiac chambers, notably left atrial appendage thrombi in patients with atrial fibrillation that embolize to cause large, devastating strokes.42 Most minor risk emboli sources hypothesized to underlie most ESUS typically produce small emboli.1
Recurrent stroke during follow-up averaged 4.5% per year (Table 4), but this estimate is based on patient cohorts dating back to 199213 and limited by the retrospective design of available studies. Concomitant therapies have evolved, and stroke rates in secondary prevention trials have consistently declined during the past 25 years. Consequently, this estimate of stroke recurrence rate in ESUS patients may be an overestimate. However, ESUS patient features as characterized in this analysis resemble those of participants in 2 clinical trials who had recurrent stroke rates of 7% to 11% within 3 months after an index minor ischemic stroke when treated with aspirin.43,44 It is likely that absolute rates of recurrent stroke will differ among subgroups of ESUS patients according to patient age and comorbidities. Furthermore, it is currently unknown whether the stroke recurrence risk is particularly high in the initial weeks after an ESUS, and this, too, may vary with the presumed ESUS source (ie, PFO-associated ESUS versus aortic arch plaque-associated ESUS).
That most cryptogenic ischemic strokes are embolic is not a new concept.45,46 However, there has been little progress in the secondary prevention for most patients with cryptogenic ischemic stroke in recent decades. The ESUS construct, a repackaging of nonlacunar cryptogenic stroke, was developed to identify patients with cryptogenic stroke in whom the underlying mechanism is likely thromboembolic and to facilitate the design of randomized trials.
Available evidence supports that ESUS comprises about 1 ischemic stroke in 6, and that these relatively young patients with stroke have a substantial risk of recurrent stroke during antiplatelet therapy. Doubts have been expressed about the value of the ESUS as a therapeutic target, particularly because of the heterogeneity of the occult embolic sources.25,47,48 Clinical trials comparing oral anticoagulants with aspirin in ESUS patients are ongoing with results anticipated in 2018.

Acknowledgments

We are grateful to Dr M. Masina for kindly providing unpublished data.

Supplemental Material

File (hart_867.pdf)

References

1.
Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell MJ, et al.; Cryptogenic Stroke/ESUS International Working Group. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol. 2014;13:429–438. doi: 10.1016/S1474-4422(13)70310-7.
Crossref
PubMed
Google Scholar
2.
Hart RG, Sharma M, Mundl H, Shoamanesh A, Kasner SE, Berkowitz SD, et al.; for the NAVIGATE ESUS Steering Committee. Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: design of the NAVIGATE ESUS randomized trial. Eur Stroke J. 2016;1:146–154.
Crossref
PubMed
Google Scholar
3.
Diener HC, Easton JD, Granger CB, Cronin L, Duffy C, Cotton D, et al.; RE-SPECT ESUS Investigators. 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. 2015;10:1309–1312. doi: 10.1111/ijs.12630.
Crossref
PubMed
Google Scholar
4.
ATTICUS (Apixaban for Treatment of Embolic Stroke of Undetermined Source). https://clinicaltrials.gov/ct2/show/NCT02427126. Accessed January 20, 2017.
Google Scholar
5.
Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al.; PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;349:g7647.
Crossref
Google Scholar
6.
Muuronen AT, Taina M, Hedman M, Marttila J, Kuusisto J, Onatsu J, et al. Increased visceral adipose tissue as a potential risk factor in patients with embolic stroke of undetermined source (ESUS). PLoS One. 2015;10:e0120598. doi: 10.1371/journal.pone.0120598.
Crossref
PubMed
Google Scholar
7.
Bulwa Z, Kim A, Singh K, Kantorovich A, Suhail F. recurrent embolic strokes of undetermined source in a patient with extreme lipoprotein(a) levels. Front Neurol. 2016;7:144. doi: 10.3389/fneur.2016.00144.
Crossref
PubMed
Google Scholar
8.
Eswaradass PV, Qazi E, Menon BK. Embolic Stroke of Undetermined Source (ESUS) Unraveled: The May-Thurner Syndrome. Can J Neurol Sci. 2016;43:713–714. doi: 10.1017/cjn.2016.267.
Crossref
PubMed
Google Scholar
9.
Katsanos AH, Fiolaki A, Pappas K, Siarava E, Tsivgoulis G, Giannopoulos S. A case contradicting the definition of embolic strokes of undetermined source: the necessity of transesophageal echocardiography. J Clin Neurol. 2016;12:241–242. doi: 10.3988/jcn.2016.12.2.241.
Crossref
PubMed
Google Scholar
10.
Hayduk-Costa G. Embolic stroke of undetermined source in a young female with a history of intravenous drug use. Dalhousie Med J 2016; 42: 15–18.
Crossref
Google Scholar
11.
Kato A, Ikeda T, Kono T, Morishima H, Nagashima G. Systemic thromboembolism presenting as vertebral artery occlusion caused by patent foramen ovale with low D-dimer elevation. J Japan Soc Intens Care Med 2016; 23: 660–665.
Crossref
Google Scholar
12.
Masina M, Cicognani A, Lofiego C, Malservisi, Parlangeli R, Lombardi A. Embolic stroke of undetermined source: a retrospective analysis from an Italian stroke unit. Italian J Med 2016; 10: 202–206.
Crossref
Google Scholar
13.
Ntaios G, Papavasileiou V, Milionis H, Makaritsis K, Manios E, Spengos K, et al. Embolic strokes of undetermined source in the Athens stroke registry: a descriptive analysis. Stroke. 2015;46:176–181. doi: 10.1161/STROKEAHA.114.007240.
Crossref
PubMed
Google Scholar
14.
Mahagne MH, Lachaud S, Suissa L. Letter by Mahagne et al regarding article, “Embolic strokes of undetermined source in the athens stroke registry: a descriptive analysis”. Stroke. 2015;46:e69. doi: 10.1161/STROKEAHA.114.008546.
Crossref
PubMed
Google Scholar
15.
Li L, Yiin GS, Geraghty OC, Schulz UG, Kuker W, Mehta Z, et al.; Oxford Vascular Study. Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study. Lancet Neurol. 2015;14:903–913. doi: 10.1016/S1474-4422(15)00132-5.
Crossref
PubMed
Google Scholar
16.
Putaala J, Nieminen T, Haapaniemi E, Meretoja A, Rantanen K, Heikkinen N, et al. Undetermined stroke with an embolic pattern–a common phenotype with high early recurrence risk. Ann Med. 2015;47:406–413. doi: 10.3109/07853890.2015.1057612.
Crossref
PubMed
Google Scholar
17.
Ladeira F, Barbosa R, Caetano A, Mendonça MD, Calado S, Viana-Baptista M. Embolic stroke of unknown source (ESUS) in young patients. Int J Stroke. 2015;10(Suppl A100):165. doi: 10.1111/ijs.12596.
Crossref
PubMed
Google Scholar
18.
Takasugi J, Yamagami H, Toyoda K, Nagatsuka K. Diagnostic considerations of embolic strokes of undetermined source on admission. Neurosonology 2015; 28:17–20.
Crossref
Google Scholar
19.
Perera KS, Vanassche T, Bosch J, Giruparajah M, Swaminathan B, Mattina KR, et al.; ESUS Global Registry Investigators. Embolic strokes of undetermined source: Prevalence and patient features in the ESUS Global Registry. Int J Stroke. 2016;11:526–533. doi: 10.1177/1747493016641967.
Crossref
PubMed
Google Scholar
20.
Montero MV, Pastor AG, Cano BC, García PS, Mohedano AI, Otero FD, et al. The A-S-C-O classification identifies cardioembolic phenotypes in a high proportion of embolic stroke of undetermined source (ESUS). J Neurol Sci. 2016;367:32–33. doi: 10.1016/j.jns.2016.05.029.
Crossref
PubMed
Google Scholar
21.
Coutinho JM, Derkatch S, Potvin AR, Tomlinson G, Kiehl TR, Silver FL, et al. Nonstenotic carotid plaque on CT angiography in patients with cryptogenic stroke. Neurology. 2016;87:665–672. doi: 10.1212/WNL.0000000000002978.
Crossref
PubMed
Google Scholar
22.
Ueno Y, Yamashiro K, Tanaka R, Kuroki T, Hira K, Kurita N, et al. Emerging risk factors for recurrent vascular events in patients with embolic stroke of undetermined source. Stroke. 2016;47:2714–2721. doi: 10.1161/STROKEAHA.116.013878.
Crossref
PubMed
Google Scholar
23.
Arauz A, Morelos E, Colín J, Roldán J, Barboza MA. Comparison of functional outcome and stroke recurrence in patients with Embolic Stroke of Undetermined Source (ESUS) vs. cardioembolic stroke patients. PLoS One. 2016;11:e0166091. doi: 10.1371/journal.pone.0166091.
Crossref
PubMed
Google Scholar
24.
Ntaios G, Vemmos K, Lip GY, Koroboki E, Manios E, Vemmou A, et al. Risk stratification for recurrence and mortality in embolic stroke of undetermined source. Stroke. 2016;47:2278–2285. doi: 10.1161/STROKEAHA.116.013713.
Crossref
PubMed
Google Scholar
25.
Katsanos AH, Bhole R, Frogoudaki A, Giannopoulos S, Goyal N, Vrettou AR, et al. The value of transesophageal echocardiography for embolic strokes of undetermined source. Neurology. 2016;87:988–995. doi: 10.1212/WNL.0000000000003063.
Crossref
PubMed
Google Scholar
26.
Ntaios G, Papavasileiou V, Milionis H, Makaritsis K, Vemmou A, Koroboki E, et al. Embolic Strokes of Undetermined Source in the Athens Stroke Registry: An Outcome Analysis. Stroke. 2015;46:2087–2093. doi: 10.1161/STROKEAHA.115.009334.
Crossref
PubMed
Google Scholar
27.
Ntaios G, Vemmos K. Response to letter regarding article, “Embolic stroke of undetermined source in the athens stroke registry: a descriptive analysis”. Stroke. 2015;46:e70. doi: 10.1161/STROKEAHA.114.008577.
Crossref
PubMed
Google Scholar
28.
Gratz PP, Gralla J, Mattle HP, Schroth G. Embolic strokes of undetermined source: support for a new clinical construct. Lancet Neurol. 2014;13:967. doi: 10.1016/S1474-4422(14)70196-6.
Crossref
PubMed
Google Scholar
29.
Boeckh-Behrens T, Kleine JF, Zimmer C, Neff F, Scheipl F, Pelisek J, et al. Thrombus histology suggests cardioembolic cause in cryptogenic stroke. Stroke. 2016;47:1864–1871. doi: 10.1161/STROKEAHA.116.013105.
Crossref
PubMed
Google Scholar
30.
Gladstone DJ, Spring M, Dorian P, Panzov V, Thorpe KE, Hall J, et al.; EMBRACE Investigators and Coordinators. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med. 2014;370:2467–2477. doi: 10.1056/NEJMoa1311376.
Crossref
PubMed
Google Scholar
31.
Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA, et al.; CRYSTAL AF Investigators. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370:2478–2486. doi: 10.1056/NEJMoa1313600.
Crossref
PubMed
Google Scholar
32.
Favilla CG, Ingala E, Jara J, Fessler E, Cucchiara B, Messé SR, et al. Predictors of finding occult atrial fibrillation after cryptogenic stroke. Stroke. 2015;46:1210–1215. doi: 10.1161/STROKEAHA.114.007763.
Crossref
PubMed
Google Scholar
33.
Higgins P, MacFarlane PW, Dawson J, McInnes GT, Langhorne P, Lees KR. Noninvasive cardiac event monitoring to detect atrial fibrillation after ischemic stroke: a randomized, controlled trial. Stroke. 2013;44:2525–2531. doi: 10.1161/STROKEAHA.113.001927.
Crossref
PubMed
Google Scholar
34.
Ntaios G, Papavasileiou V, Lip GY, Milionis H, Makaritsis K, Vemmou A, et al. Embolic stroke of undetermined source and detection of atrial fibrillation on follow-up: how much causality is there? J Stroke Cerebrovasc Dis. 2016;25:2975–2980. doi: 10.1016/j.jstrokecerebrovasdis.2016.08.015.
Crossref
PubMed
Google Scholar
35.
Goldberger JJ, Arora R, Green D, Greenland P, Lee DC, Lloyd-Jones DM, et al. Evaluating the atrial myopathy underlying atrial fibrillation: identifying the arrhythmogenic and thrombogenic substrate. Circulation. 2015;132:278–291. doi: 10.1161/CIRCULATIONAHA.115.016795.
Crossref
PubMed
Google Scholar
36.
Yaghi S, Song C, Gray WA, Furie KL, Elkind MS, Kamel H. Left atrial appendage function and stroke risk. Stroke. 2015;46:3554–3559. doi: 10.1161/STROKEAHA.115.011273.
Crossref
PubMed
Google Scholar
37.
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:e002012. doi: 10.1161/JAHA.115.002012.
Crossref
PubMed
Google Scholar
38.
Kawada S, Hamaguchi T, Kitayama M, Imamura T, Ohno M, Kashihara K, et al. Multidetector computed tomography angiography to detect the cause of multiple brain infarctions. J Stroke Cerebrovasc Dis. 2015;24:348–353. doi: 10.1016/j.jstrokecerebrovasdis.2014.08.032.
Crossref
PubMed
Google Scholar
39.
Cocho D, Gendre J, Boltes A, Espinosa J, Ricciardi AC, Pons J, et al. Predictors of occult cancer in acute ischemic stroke patients. J Stroke Cerebrovasc Dis. 2015;24:1324–1328. doi: 10.1016/j.jstrokecerebrovasdis.2015.02.006.
Crossref
PubMed
Google Scholar
40.
Lee EJ, Nah HW, Kwon JY, Kang DW, Kwon SU, Kim JS. Ischemic stroke in patients with cancer: is it different from usual strokes? Int J Stroke. 2014;9:406–412. doi: 10.1111/ijs.12124.
Crossref
PubMed
Google Scholar
41.
Siegler JE, Swaminathan B, Giruparajah M, Bosch J, Perera KS, Hart RG, et al. Age disparity in diagnostic evaluation of stroke patients. ESUS Global Registry Project. Euro Stroke J 2016; 1:130–138.
Crossref
Google Scholar
42.
Bogousslavsky J, Ginsberg M. Cerebrovascular Disease. 1st ed. Cambridge, MA: Blackwell Science; 1998.
Google Scholar
43.
Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, et al.; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11–19. doi: 10.1056/NEJMoa1215340.
Crossref
PubMed
Google Scholar
44.
Johnston SC, Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, et al.; SOCRATES Steering Committee and Investigators. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med. 2016;375:35–43. doi: 10.1056/NEJMoa1603060.
Crossref
PubMed
Google Scholar
45.
Sacco RL, Ellenberg JH, Mohr JP, Tatemichi TK, Hier DB, Price TR, et al. Infarcts of undetermined cause: the NINCDS Stroke Data Bank. Ann Neurol. 1989;25:382–390. doi: 10.1002/ana.410250410.
Crossref
PubMed
Google Scholar
46.
Fisher CM. Concerning strokes. Can Med Assoc J. 1953;69:257–268.
PubMed
Google Scholar
47.
Eckerle B, Massaro A. Lumpers or splitters: evaluation and management of embolic stroke of undetermined source. Neurology. 2016;87:972–973. doi: 10.1212/WNL.0000000000003072.
Crossref
PubMed
Google Scholar
48.
Dennis M. Embolic stroke of undetermined source: a therapeutic target? Lancet Neurol. 2014;13:344–346. doi: 10.1016/S1474-4422(14)70043-2.
Crossref
PubMed
Google Scholar

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The image is taken from an article in this issue, “Cerebral Aneurysm Morphology Before and After Rupture: Nationwide Case Series of 29 Aneurysms” by Skodvin et al (Stroke. 2017;48:880�886. doi: 10.1161/STROKEAHA.116.015288). The image is Figure 2.

Stroke
Volume 48 • Number 4 • April 2017
Pages: 867 - 872
PubMed: 28265016

Copyright

© 2017 American Heart Association, Inc.

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History

Received: 21 December 2016
Revision received: 13 January 2017
Accepted: 20 January 2017
Published online: 6 March 2017
Published in print: April 2017

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Keywords

  1. diagnosis
  2. embolism
  3. prognosis
  4. secondary prevention
  5. stroke

Subjects

  1. Cerebrovascular Disease/Stroke
  2. Ischemic Stroke

Authors

Affiliations

Robert G. Hart, MD
From the Department of Medicine (Neurology) (R.G.H., L.C., K.S.P.), Population Health Research Institute and Department of Medicine (Cardiology) (S.J.C.), McMaster University, Hamilton Health Sciences, Ontario, Canada; Department of Medicine, Larissa University Hospital, University of Thessaly, Larissa, Greece (G.N.).
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Luciana Catanese, MD
From the Department of Medicine (Neurology) (R.G.H., L.C., K.S.P.), Population Health Research Institute and Department of Medicine (Cardiology) (S.J.C.), McMaster University, Hamilton Health Sciences, Ontario, Canada; Department of Medicine, Larissa University Hospital, University of Thessaly, Larissa, Greece (G.N.).
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Kanjana S. Perera, MBBS
From the Department of Medicine (Neurology) (R.G.H., L.C., K.S.P.), Population Health Research Institute and Department of Medicine (Cardiology) (S.J.C.), McMaster University, Hamilton Health Sciences, Ontario, Canada; Department of Medicine, Larissa University Hospital, University of Thessaly, Larissa, Greece (G.N.).
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George Ntaios, MD, PhD
From the Department of Medicine (Neurology) (R.G.H., L.C., K.S.P.), Population Health Research Institute and Department of Medicine (Cardiology) (S.J.C.), McMaster University, Hamilton Health Sciences, Ontario, Canada; Department of Medicine, Larissa University Hospital, University of Thessaly, Larissa, Greece (G.N.).
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Stuart J. Connolly, MD
From the Department of Medicine (Neurology) (R.G.H., L.C., K.S.P.), Population Health Research Institute and Department of Medicine (Cardiology) (S.J.C.), McMaster University, Hamilton Health Sciences, Ontario, Canada; Department of Medicine, Larissa University Hospital, University of Thessaly, Larissa, Greece (G.N.).
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Notes

Correspondence to Robert G. Hart, MD, Population Health Research Institute, DBCVSRI C4-105, 237 Barton St E, Hamilton, Ontario L8L 2X2, Canada. E-mail [email protected]

Disclosures

All coauthors except Dr Catanese have received financial remuneration from Bayer AG for their participation in the NAVIGATE ESUS trial; In addition, Dr Ntaios has received speaker fees from Boehringer-Ingelheim, Bayer AG, and BMS/Pfizer and a research grant from Pfizer, and he is an advisory board member for Boehringer-Ingelheim. The other authors report no conflicts.

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    • Michael Farbaniec,
    • Faye L. Norby,
    • Megan Mann,
    • Mario D. Gonzalez,
    • Gerald V. Naccarelli,
    • Ankit Maheshwari,
    Left Atrial Mechanical Dysfunction Is Associated With Atrial Fibrillation and Recurrent Stroke After Cryptogenic Stroke, Journal of Stroke, 26, 2, (335-338), (2024).https://doi.org/10.5853/jos.2024.00584
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    • Hoyoun Lee,
    • Keon-Joo Lee,
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    • Jae-Kwan Cha,
    • Leonard Sunwoo,
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    • Hee-Joon Bae,
    • Dong-Eog Kim,
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    • Leonard LL Yeo,
    • William KF Kong,
    • Tony YW Li,
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    • Vijay K Sharma,
    • Kian-Keong Poh,
    • Ching-Hui Sia,
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