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; Stuart J. Connolly, MD

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.   (Stroke. 2017;48:867-872.
DOI: 10.1161/STROKEAHA.116.016414.)
Key Words: diagnosis ◼ embolism ◼ prognosis ◼ secondary prevention ◼ stroke
Downloaded from http://ahajournals.org by on March 21, 2021

I n 2014, the clinical construct of “embolic stroke of undeter-

mined source” (ESUS) was introduced to identify patients
with nonlacunar cryptogenic ischemic strokes in whom embo-
lism was the likely stroke mechanism.1 It was hypothesized
that anticoagulants might be more efficacious than antiplate-
let 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 antago-
nist direct-acting oral anticoagulants with aspirin for second-
ary stroke prevention.2–4
Here, we report the results of a systematic review of pub-
lished studies about ESUS and summarize additional recent
information relevant to the ESUS construct.
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 arti-
cles 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 con-
tacted seeking additional data.12
Because ascertainment bias between different studies could poten-
tially 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.

Methods Results
A PRISMA-guided systematic PubMed search strategy was ini- Overall, the quality of the included studies was only fair.
tiated to identify the studies of interest (the last searched on Most studies were retrospective analyses of existing databases
December 6, 2016; Figure).5 We also performed a hand searching (extending as far as 1992) and did not report the specific details

Received December 21, 2016; final revision received January 13, 2017; accepted January 20, 2017.
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.).
Correspondence to Robert G. Hart, MD, Population Health Research Institute, DBCVSRI C4-105, 237 Barton St E, Hamilton, Ontario L8L 2X2,
Canada. E-mail robert.hart@phri.ca
© 2017 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.116.016414

867
 868  Stroke  April 2017
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.
of ESUS diagnosis, completeness of the diagnostic evaluation
of patients with cryptogenic stroke required for ESUS diagno-
sis, 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
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from 7% to 42% (Table 2).
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 fre-
quencies of 17%. In 1 study involving 19 different countries,
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.
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 stud-
ies reported that patent foramen ovale was present in 25%,19
28%,25 and 58%22 of ESUS patients who underwent trans-
esophageal echocardiography. The NIH Stroke Scale score
near ESUS onset averaged 5 based on 4 studies involving
1772 ESUS patients (Table 3).
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-fol-
low-up and unspecified selection for oral anticoagulant ther-
apy 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
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 unrec-
ognized 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
 Hart et al   Embolic Stroke of Undetermined Source    869

Table 2.  Frequency of ESUS*

Cardiac Rhythm
Study Design Population Monitoring % ESUS* (n) Comments
Ntaios et al13 Retrospective, single- 2731 Greek pts with first 71% inpt telemetry for 7 10 (275) 29% of ESUS pts had AF
center, inpt stroke ischemic stroke; mean d or discharge; 52% 24 h detected during f/up
registry, 1992–2011 age 71 y Holter ECG
Mahagne et al14 No details 1074 French pts, no Holter ECG as inpt (mean 23 (243) 28% ESUS if only a 24 h
details published 7 d) Holter ECG done
Li et al15 Population-based, 1607 strokes and 948 Ambulatory home 7 (189) Nonlacunar TIAs could be
ischemic stroke or TIA, TIAs in the UK; mean monitoring in 20% first 8 ESUS; most cryptogenic pts
2002–2014 age 74 y y, 80% thereafter did not have the required
cardiac rhythm monitoring
Putaala et al16 Retrospective, single 540 Finnish pts, mean 44% continuous ECG 9 (46) NAVIGATE ESUS trial criteria
center, inpts, 2010–2012 age 69 y monitoring used.2 Most cryptogenic pts
did not have the required
cardiac rhythm monitoring
Ladeira et al17 Retrospective, single 100 young Portuguese NR 42 (42) Minor risk potential
center, ages 18-55 y, pts with ischemic stroke, cardioembolic sources not
2010–2014 mean age 46 y more frequent in young
stroke patients with ESUS
Takasugi et al18 Retrospective, single 623 Japanese acute Continuous ECG 13 (81)
center, 2012–2014 ischemic stroke pts; monitoring for ≥3 days
mean age NR in all
Perera et al19 Retrospective, 19 2144 pts with ischemic 33% only inpt telemetry 16 (351) Excluding pts with
international stroke units, stroke; mean age 67 y for ≥24 h, 59% 24 h incomplete diagnostic
2014–2015 Holter ECG, 8% >24 h testing required for ESUS,
monitoring 19% were ESUS
Montero et al20 Retrospective, single- 318 Spanish pts with No details 19 (60) Support for a cardioembolic
center stroke unit pts ischemic stroke; mean mechanisms for most ESUS
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during 2010 age NR

Coutinho et al21 Retrospective, single- 1038 Canadian pts with Minimum of 24 h of 12 (128) Support for nonstenotic
center stroke registry, ischemic stroke, mean automated rhythm carotid plaques as causing
2012–2015 age NR monitoring ESUS
Ueno et al22 Retrospective, single- 1158 Japanese pts with Cardiac telemetry ≥24 h 25 (292)
center inpt stroke acute ischemic stroke,
registry, 2008–2014 mean age NR
Masina et al12 Retrospective, single- 337 Italian ischemic 72 h continuous inpt 25 (84) 41 (49%) ESUS pts had
center stroke unit, stroke pts, mean age telemetry without minor risk cardioembolic
2010–2012 78 y† automated rhythm sources identified by
detection echocardiography
Arauz et al23 Retrospective, single- 1673 Mexican ischemic At least 24 h of Holter 9 (149) 60 additional patients with
center stroke registry, stroke pts, mean age NR monitor cryptogenic stroke were
2003–2015 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).

plaques with cryptogenic stroke37 and with ESUS.21 Wider
availability of computed tomography imaging of the aortic
arch allows assessment of aortic plaque without transesopha-
geal echocardiography.38 There has been additional emphasis
on occult cancer in patients with cryptogenic stroke.39,40
Discussion
Methodological limitations in existing studies likely contrib-
uted 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 underesti-
mate 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
 870  Stroke  April 2017

Table 3.  Features of ESUS Patients*

Median NIHSS History of Diabetes
Study n Mean age, y Women, % Score Hypertension, % Mellitus, % PFO, %†
Ntaios et al13 275 68 36 5 65 24 NR
Li et al 15
189 65 47 NR 47 12 NR
Putaala et al 16
46 62 43 <6 44 7 NR
Ntaios et al24‡ 1095 68 41 5 60 20 NR
Perera et al19 351 62 43 4 64 25 25§
Ueno et al ‖ 22
177 64 28 3 66 32 58
Masina et al ¶ 12
84 73 52 NR 74 17 NR
Arauz et al23# 149 44 49 7 25 9 NR
Pooled – unweighted average‡ 2045 63 43 5 56 19 …
Pooled – weighted average‡ 2045 65 42 5 58 20 …
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.

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,
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nor is the pathophysiological relationship between late detec-
tion of brief episodes of atrial fibrillation and ESUS ade-
quately understood. It is unclear whether brief episodes of
atrial fibrillation detected weeks or months after ESUS are

Table 4.  Prognosis of ESUS Patients*

Stroke (Est Stroke, MI,
n/Mean Follow- AF During Annualized Vascular Death (Est Total Mortality (Est
Study Up (y) Mean Age, y Antithrombotic Therapy Follow-Up† Rate)† Annualized Rate) Annualized Rate)
Ntaios et al13,26‡ 275 (3.2) 68 74% APT only, 22% OAC 80 (29%) 6.8%/y 9.0%/y§ 8.2%/y
Li et al15
189 (1) 65 NR NR ≈5%/y NR NR
Putaala et al16‡ 46 (1.8) 62 85% APT, 11% OAC NR 5.1%/y NR 1.3%/y
Ntaios et al24‡ 1095 (3.0) 68 87% APT only, 12% OAC NR 4.8%/y‖ NR 4.5%/y
Masina et al ¶ 12
84 (2.1) 73 99% APT NR 2.3%/y NR NR
Ueno et al22# 177 (3.5) 64 72% APT, 29% OAC NR 3.9%/y 5.0%/y** 1.3%/y
Arauz et al23†† 149 (2.3) 44 91% APT, 5% OAC NR 2.3%/y NR 0%/y
Pooled – unweighted
1545 (2.4) 68 87% APT, 12% OAC … 4.0%/y … 2.9%/y
average‡,††
Pooled – weighted
1605 (2.7) 65 86% APT, 13% OAC … 4.5%/y … 3.9%/y
average‡,††
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.
 Hart et al   Embolic Stroke of Undetermined Source    871
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 rela-
tively young (compared with atrial fibrillation-associated
stroke) patients with mild strokes and with lower frequen-
cies 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 hypoth-
esized 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 dat-
ing 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 overes-
timate. 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 aspi-
rin.43,44 It is likely that absolute rates of recurrent stroke will
differ among subgroups of ESUS patients according to patient
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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 aor-
tic 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 isch-
emic stroke in recent decades. The ESUS construct, a repack-
aging of nonlacunar cryptogenic stroke, was developed to
identify patients with cryptogenic stroke in whom the under-
lying 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.
Disclosures
All coauthors except Dr Catanese have received financial remu-
neration 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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