Download Embolic Strokes of Undetermined Source in the Athens Stroke

Embolic Strokes of Undetermined Source in the
Athens Stroke Registry
A Descriptive Analysis
George Ntaios, MD; Vasileios Papavasileiou, MD; Haralambos Milionis, MD;
Konstantinos Makaritsis, MD; Efstathios Manios, MD; Konstantinos Spengos, MD;
Patrik Michel, MD; Konstantinos Vemmos, MD
Downloaded from http://stroke.ahajournals.org/ by guest on June 17, 2017
Background and Purpose—A new clinical construct termed embolic stroke of undetermined source (ESUS) was recently
introduced, but no such population has been described yet. Our aim is to provide a detailed descriptive analysis of an
ESUS population derived from a large prospective ischemic stroke registry using the proposed diagnostic criteria.
Methods—The criteria proposed by the Cryptogenic Stroke/ESUS International Working Group were applied to the Athens
Stroke Registry to identify all ESUS patients. ESUS was defined as a radiologically confirmed nonlacunar brain infarct
in the absence of (a) extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the
ischemic area, (b) major-risk cardioembolic source, and (c) any other specific cause of stroke.
Results—Among 2735 patients admitted between 1992 and 2011, 275 (10.0%) were classified as ESUS. In the majority of
ESUS (74.2%), symptoms were maximal at onset. ESUS were of moderate severity (median National Institute Health
Stroke Scale score, 5). The most prevalent risk factor was arterial hypertension (64.7%), and 50.9% of patients were
dyslipidemic. Among potential causes of the ESUS, covert atrial fibrillation (AF) was the most prevalent: in 30 (10.9%)
patients, AF was diagnosed during hospitalization for stroke recurrence, whereas in 50 (18.2%) patients AF was detected
after repeated ECG monitoring during follow-up. Also, covert AF was strongly suggested in 38 patients (13.8%) but never
recorded.
Conclusions—About 10% of patients with first-ever ischemic stroke met criteria for ESUS; covert paroxysmal AF seems to
be a frequent cause of ESUS. (Stroke. 2015;46:176-181. DOI: 10.1161/STROKEAHA.114.007240.)
Key Words: covert atrial fibrillation ◼ cryptogenic ◼ embolic stroke of undetermined cause ◼ embolism ◼ ESUS
T
diagnosis of ESUS in contrast to the absence of standard diagnostic criteria for the definition of cryptogenic stroke.3
No ESUS population has been described yet using the
diagnostic criteria proposed by the Cryptogenic Stroke/ESUS
International Working Group. The aim of the present study is
to provide a detailed descriptive analysis of an ESUS population derived from a large prospective stroke registry using the
proposed diagnostic criteria.
here is accumulating evidence that most strokes of
undetermined origin are thromboembolic: recently,
the Cryptogenic Stroke and Underlying Atrial Fibrillation
(CRYSTAL-AF) and the 30-Day Cardiac Event Monitor Belt
for Recording Atrial Fibrillation after a Cerebral Ischemic
Event (EMBRACE) trials showed that paroxysmal atrial
fibrillation (AF) can be detected in a significant proportion
of cryptogenic strokes.1,2 Other potential sources of embolism
in cryptogenic stroke include the mitral and aortic valves, the
left cardiac chambers, proximal cerebral arteries of the aortic arch, and the venous system via paradoxical embolism.3
Accordingly, a new clinical construct termed embolic stroke
of undetermined source (ESUS) was recently introduced by
the Cryptogenic Stroke/ESUS International Working Group
as a potential therapeutic relevant entity with an indication
for anticoagulation.3 Specific criteria were proposed for the
Methods
Study Population and Definitions
The study population was derived from the Athens Stroke Registry,
which includes all consecutive patients with an acute first-ever ischemic stroke admitted in Alexandra University Hospital, Athens,
Greece, between June 1992 and December 2011.4 Patients with
transient ischemic attack or recurrent stroke are not included in the
Received August 26, 2014; final revision received October 12, 2014; accepted October 16, 2014.
From the Department of Medicine, Larissa University Hospital, School of Medicine, University of Thessaly, Larissa, Greece (G.N., V.P., K.M.);
Department of Medicine, Ioannina University Hospital, School of Medicine, University of Ioannina, Ioannina, Greece (H.M.); Department of Clinical
Therapeutics, Medical School of Athens, Alexandra Hospital, Athens, Greece (E.M., K.V.); Department of Neurology, Eginition Hospital, University of
Athens Medical School, Athens, Greece (K.S.); and Stroke Center, Neurology Service, CHUV, University of Lausanne, Lausanne, Switzerland (P.M.).
Correspondence to George Ntaios, MD, MSc (ESO Stroke Medicine), PhD, FESO, Assistant Professor of Internal Medicine, Department of Medicine,
Larissa University Hospital, School of Medicine, University of Thessaly, Biopolis 41110, Larissa, Greece. E-mail [email protected]
© 2014 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.114.007240
176
Ntaios et al ESUS in Athens Stroke Registry 177
Downloaded from http://stroke.ahajournals.org/ by guest on June 17, 2017
registry. The scientific use of the data collected in the Athens Stroke
Registry was approved by the local Ethics Committee.
Detailed data were prospectively recorded, including demographics, medical history and associated cardiovascular risk factors,
current medication, time of stroke onset and hospital admission,
duration of hospitalization, stroke characteristics, clinical findings
and vital signs on admission, laboratory investigations, and treatment. Stroke severity was assessed by means of the National Institute
Health Stroke Scale score (NIHSS) at admission.5 For the study
period between 1993 and 1998, NIHSS score was calculated from
the Scandinavian Stroke Scale using the following formula: NIHSS
score=25.68−(0.43×Scandinavian Stroke Scale score).6
All patients had a 12-lead ECG at admission. In patients on sinus rhythm, paroxysms of AF were sought by means of (a) repeated
ECGs during hospital stay, (b) continuous ECG monitoring for 1
week or until discharge for patients treated in the acute stroke unit,
and (c) 24-hour Holter ambulatory ECG monitoring in cases that AF
was strongly suspected from the clinical presentation and brain imaging findings (eg, multiterritorial infarcts, strokes presenting with
maximum severity at onset, largely dilated left atrium) and a and b
were negative.
ESUS was defined according to the criteria proposed by the
Cryptogenic Stroke/ESUS International Working Group as a visualized nonlacunar brain infarct in the absence of (a) extracranial or
intracranial atherosclerosis causing ≥50% luminal stenosis in arteries
supplying the area of ischemia, (b) major-risk cardioembolic source,
and (c) any other specific cause of stroke (eg, arteritis, dissection,
migraine/vasospasm, drug misuse).3 Major risk sources of cardioembolism included permanent or paroxysmal AF, sustained atrial flutter,
intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or other cardiac tumours, mitral stenosis, recent (<4 weeks) myocardial infarction, left ventricular ejection fraction <30%, valvular vegetations,
or infective endocarditis.3 Lacunar stroke was defined as a subcortical
brain infarct ≤1.5 cm in largest dimension in the distribution of the
small, penetrating cerebral arteries.3 Patients without identification of
the underlying etiopathophysiologic cause as a result of incomplete
evaluation were classified as undetermined other than ESUS.
Hypertension was defined as systolic blood pressure >140 mm Hg
or diastolic blood pressure >90 mm Hg diagnosed at least twice before stroke or if patient was already on antihypertensives.7 Diabetes
mellitus was defined if patient was already on antidiabetic drugs or
insulin or if fasting blood glucose level was >6.0 mmol/L before
stroke.8 Dyslipidemia was defined as total cholesterol concentration
>6.5 mmol/L the day after admission or if patient had a previous diagnosis of dyslipidemia.9 Coronary heart disease was assessed by
questionnaire and relevant medical confirmation. Heart failure was
defined according to the criteria recommended by the working group
on heart failure of the European Society of Cardiology.10 Transient
ischemic attack was defined as complete disappearance of signs and
symptoms within 24 hours, regardless of infarction being shown on
neuroimaging.11 Stroke was defined according to the World Health
Organization criteria.12
Statistical Analysis
Continuous data are summarized as median value and interquartile range and categorical data as absolute number and percentage.
Statistical analyses were performed with the Statistical Package for
Social Science (SPSS Inc, version 17.0 for Windows, Chicago, IL).
Results
Between June 1992 and December 2011, 2735 patients with
acute first-ever ischemic stroke were included in the Athens
Stroke Registry, of whom 1918 (70.1%) were admitted in a
5-bed comprehensive stroke unit. Four patients were excluded
from this analysis because of missing data. From the remaining 2731 patients, 275 (10.0%) were classified as ESUS
(Figure 1). When the registry was analyzed in 5-years strata,
the proportion of ESUS patients among all patients did not
Figure 1. Flow diagrams of the study. CT indicates computed
tomography.
differ between strata (8.7%, 9.8%, 10.3%, and 13.1% for each
5-years stratum; P=0.36).
In the overall stroke population of eligible patients (n=2731),
all patients had a 12-lead ECG and a noncontrast computed
tomography at admission. Echocardiography was performed
in 1304 (47.8%) patients (transthoracic in 1300 [47.6%] and
transesophageal in 236 [8.6%] patients). Heart rhythm was
continuously monitored during the stay in the stroke unit in
1566 (57.3%) patients, and 24-hour Holter ambulatory ECG
monitoring was performed in 305 (11.2%) patients. Cervical
artery ultrasound was performed in 1866 (68.3%) patients,
whereas 848 (31.1%) patients had an angiography (CTA or
MRA or DSA). The diagnostic approach in ESUS patients is
summarized in Table 1. Transthoracic echocardiography was
performed in 89.8% of ESUS patients and transesophageal in
30.2%, and the vast majority of these patients (86.9%) had an
angiogram.
The baseline characteristics of patients with ESUS and
other types of stroke are summarized in Table 1. There was a
male preponderance (64.0%) among ESUS patients. The age
distribution of ESUS patients is summarized in Figure 2. The
distribution of stroke risk factors in ESUS patients follows the
same pattern as in the general stroke population, with the most
prevalent risk factor being arterial hypertension (64.7%) and
approximately half of patients being dyslipidemic (50.9%;
Table 1).
178 Stroke January 2015
Table 1. Baseline Characteristics of Patients With ESUS and Other Types of Ischemic Stroke
ESUS (n=275)
Large-Artery
Atherosclerotic (n=497)
Cardioembolic
(n=869)
Lacunar
(n=622)
Undetermined Other
Than ESUS* (n=366)
Other Determined
(n=102)
Demographics
Female sex
Age, y
99 (36.0%)
68.0 (58.0–76.0)
114 (22.9%)
461 (53.0%)
173 (27.8%)
166 (45.4%)
67.0 (60.0–73.0)
76.0 (70.0–82.0)
69.0 (60.0–75.0)
74.0 (67.0–81.0)
49 (48.0%)
56.0 (43.0–74.0)
Comorbidities—risk factors
Hypertension
178 (64.7%)
382 (76.9%)
631 (72.6%)
518 (83.3%)
259 (70.8%)
50 (49.0%)
Diabetes mellitus
65 (23.6%)
163 (32.8%)
192 (22.1%)
181 (29.1%)
115 (31.4%)
17 (16.7%)
Smoking
83 (30.2%)
251 (50.5%)
157 (18.1%)
235 (37.8%)
111 (30.3%)
39 (38.2%)
Previous TIA
27 (9.8%)
102 (20.5%)
53 (6.1%)
59 (9.5%)
39 (10.7%)
17 (16.7%)
Heart failure
22 (8.0%)
23 (4.6%)
139 (16.0%)
15 (2.4%)
31 (8.5%)
10 (9.8%)
Dyslipidemia
140 (50.9%)
273 (55.3%)
266 (30.7%)
306 (49.4%)
159 (43.6%)
40 (39.2%)
65 (23.7%)
132 (26.8%)
169 (19.5%)
84 (13.6%)
86 (23.7%)
16 (15.7%)
0 (0.0%)
21 (4.2%)
774 (89.1%)
36 (5.8%)
41 (11.2%)
0 (0.0%)
Coronary artery disease
Atrial fibrillation
Pattern of presentation
Downloaded from http://stroke.ahajournals.org/ by guest on June 17, 2017
Mode of onset
Maximal at onset
204 (74.2%)
255 (51.3%)
713 (82.1%)
290 (46.6%)
219 (59.8%)
58 (56.9%)
Gradual worsening
37 (13.5%)
112 (22.5%)
82 (9.4%)
99 (16.0%)
62 (16.9%)
15 (14.7%)
Shuttering/stepwise
15 (5.5%)
66 (13.3%)
24 (2.8%)
132 (21.3%)
25 (6.8%)
9 (8.8%)
4 (1.5%)
23 (4.6%)
10 (1.2%)
40 (6.5%)
11 (3.0%)
8 (7.8%)
15 (5.5%)
41 (8.2%)
39 (4.5%)
59 (9.5%)
49 (13.4%)
12 (11.8%)
During sleep
48 (17.5%)
108 (21.7%)
155 (17.8%)
209 (33.6%)
77 (21.0%)
17 (16.7%)
1–2 h after awakening
57 (20.7%)
86 (17.3%)
187 (21.5%)
70 (11.3%)
69 (18.9%)
10 (9.8%)
Fluctuating
Unknown or missing data
Time of onset
During usual activity
141 (51.3%)
249 (50.1%)
420 (48.3%)
281 (45.2%)
167 (45.6%)
48 (47.1%)
During stress
12 (4.4%)
21 (4.2%)
30 (3.5%)
23 (3.7%)
6 (1.6%)
10 (9.8%)
Unknown
14 (5.1%)
29 (5.8%)
57 (6.6%)
38 (6.1%)
38 (10.4%)
8 (7.8%)
3 (1.1%)
4 (0.8%)
20 (2.3%)
1 (0.2%)
9 (2.5%)
9 (8.8%)
Systolic blood pressure, mm Hg
150 (130–160)
150 (140–170)
150 (130–170)
160 (140–180)
150 (135–170)
140 (120–150)
Diastolic blood pressure, mm Hg
85 (80–90)
90 (80–90)
85 (80–90)
90 (80–100)
84 (80–90)
80 (70–90)
109 (93–141)
111 (95–154)
118 (98–153)
105 (92–139)
116 (98–163)
100 (90–125)
5 (2–14)
5 (2–15)
13 (4–22)
2 (1–4)
8 (3–18)
4 (1–12)
Continuous ECG monitoring in the
stroke unit
195 (70.9%)
276 (55.5%)
564 (64.9%)
289 (46.5%)
187 (51.1%)
55 (53.9%)
24-hour Ambulatory Holter
Monitoring
142 (51.6%)
26 (5.2%)
56 (6.4%)
17 (2.7%)
40 (10.9%)
24 (23.5%)
No rhythm monitoring modality
other than admission ECG
0 (0.0%)
206 (41.4%)
296 (34.1%)
322 (51.8%)
156 (42.6%)
30 (29.4%)
Transthoracic echocardiography
247 (89.8%)
221 (44.5%)
365 (42.0%)
277 (44.5%)
123 (33.6%)
67 (65.7%)
83 (30.2%)
22 (4.4%)
83 (9.6%)
20 (3.2%)
16 (4.4%)
12 (11.8%)
Any angiography (CT or MR or
digital)†
239 (86.9%)
323 (65.0%)
53 (6.1%)
150 (24.1%)
33 (9.0%)
50 (49.0%)
Cervical artery ultrasound
252 (91.6%)
465 (93.6%)
376 (43.3%)
516 (83.0%)
177 (48.4%)
80 (78.4%)
No cervical artery imaging
0 (0.0%)
0 (0.0%)
481 (55.4%)
92 (14.8%)
186 (50.8%)
15 (14.7%)
During hospitalization for other
reason
Clinical and laboratory values
Glucose, mg/dL
NIHSS score
Etiologic work-up
Transesophageal
echocardiography
Continuous variables are presented as median±interquartile range. Nominal variables are presented as absolute number and percent (percent refers to recorded
values only; missing values have been excluded). CT indicates computed tomography; ESUS, embolic strokes of undetermined source; MR, magnetic resonance; NIHSS,
National Institutes of Health Stroke Scale; and TIA, transient ischemic attack.
*That is, ≥2 causes or incomplete evaluation.
†Refers to both intracranial and extracranial imaging.
Ntaios et al ESUS in Athens Stroke Registry 179
Downloaded from http://stroke.ahajournals.org/ by guest on June 17, 2017
The arterial territories affected in the ESUS patient were
the anterior cerebral artery (n=4; 1.5%), entire middle cerebral
artery (n=77; 28.0%), upper segment of the middle cerebral
artery (n=50; 18.2%), lower segment of the middle cerebral
artery (n=47; 17.1%), deep large subcortical (n=41; 14.9%),
borderzone (n=2; 0.7%), posterior cerebral artery (n=33;
12.0%), cerebellar (n=14; 5.1%), and other posterior circulation (n=4; 1.5%).
Among the potential causes of the ESUS, covert AF was the
most prevalent: in 30 patients, AF was subsequently diagnosed
during hospitalization for a stroke recurrence (mean time of
AF diagnosis was at 6 months after the index stroke; interquartile range, 1–30 months), whereas in 50 patients, AF was
subsequently detected after repeated ECG monitoring during
the follow-up (mean time of AF diagnosis was at 4 months
after the index stroke; interquartile range, 2–9 months). Also,
covert AF was strongly suggested in 38 patients (eg, largely
dilated left atrium plus multiterritorial strokes). Other potential causes of ESUS are summarized in Table 2. The recurrent
stroke rate at 1 year was 11.3%.
Figure 2. Age distribution in embolic stroke of undetermined
source (ESUS) and other types of ischemic stroke.
With regards to the pattern of symptom presentation, in the
majority of ESUS (74.2%), the symptoms were maximal at
onset; the distribution of the time of onset was similar to cardioembolic and large-artery atherosclerotic, with the majority of strokes (51.3%) occurring during usual activity or in
the first morning hours (Table 1). In general, ESUS were of
moderate severity (median NIHSS, 5) similar to large-artery
atherosclerotic but less compared with cardioembolic strokes
(median NIHSS, 13). Figure 3 presents a stratified distribution
of the NIHSS in ESUS and the other stroke types.
Figure 3. Stroke severity in embolic stroke of undetermined
source (ESUS) and other types of ischemic stroke.
Discussion
This is the first description of an ESUS population using the
criteria proposed recently by the Cryptogenic Stroke/ESUS
International Working Group.3 The most common potential
cause of ESUS was covert AF. Stroke severity was moderate
and, in most cases, the intensity of stroke symptoms was maximum at onset, a finding that resembles the clinical picture of
cardioembolic strokes.
In 29.1% of ESUS patients, AF was detected during followup either during a recurrence or during further heart rate monitoring. It cannot be proven whether AF was indeed the cause
of the index stroke event, but the finding that in most ESUS
the intensity of stroke symptoms was maximum at onset raises
strong suspicions in favor of this argument. On the contrary,
the finding that ESUS were not as severe as cardioembolic
strokes (median NIHSS of 5 versus 13, respectively) argues
for the opposite; still, this may be explained by the fact that
strokes caused by paroxysmal AF (like ESUS) are less severe
compared with strokes caused by persistent or permanent
AF.13 In this context, patients with ESUS seem to be appropriate candidates for prolonged ECG recording either in a noninvasive manner or with an implantable loop recorder.
There was great heterogeneity among the potential causes of
ESUS, including atherosclerotic plaque ulceration, valvulopathies, paradoxical embolism, and others. It is not clear whether
antiplatelets or anticoagulants are the ideal antithrombotic
strategy in ESUS.3 Recently, 2 international, phase III, doubleblind, randomized, controlled clinical trial were launched.14,15
The Randomized Evaluation in Secondary stroke Prevention
Comparing the Thrombin inhibitor dabigatran etexilate versus aspirin in Embolic Stroke of Undetermined Source
(RE-SPECT ESUS) trial and the Multicenter, Randomized,
Double-Blind, Double-Dummy, Active-Comparator, EventDriven, Superiority Phase III Study of Secondary Prevention
of Stroke and Prevention of Systemic Embolism in Patients
With a Recent Embolic Stroke of Undetermined Source,
Comparing Rivaroxaban 15 mg Once Daily With Aspirin
180 Stroke January 2015
Table 2. Potential Causes of ESUS
Minor-Risk Potential Cardioembolic Sources
Mitral valve
Myxomatous valvulopathy with prolapse
5 (1.8%)
Mitral annular calcification
8 (2.9%)
Aortic valve
Aortic valve stenosis
3 (1.1%)
Calcific aortic valve
12 (4.4%)
Non-atrial fibrillation atrial dysrhythmias and stasis
Atrial asystole and sick-sinus syndrome
3 (1.1%)
Atrial high-rate episodes
7 (2.6%)
Atrial appendage stasis with reduced flow velocities or
spontaneous echodensities
6 (2.2%)
Atrial structural abnormalities
Atrial septal aneurysm
Chiari network
10 (3.6%)
0
Downloaded from http://stroke.ahajournals.org/ by guest on June 17, 2017
Left ventricle
Moderate systolic or diastolic dysfunction (global or regional)
42 15.4%)
Ventricular noncompaction
12 (4.4%)
Endomyocardial fibrosis
1 (0.4%)
Covert paroxysmal atrial fibrillation (detected during follow-up)
Atrial fibrillation detected on stroke recurrence
30 (11.0%)
Atrial fibrillation detected on monitoring during follow-up
50 (18.3%)
Atrial fibrillation not confirmed but strongly suspected
38 (13.9%)
Cancer-associated
Covert nonbacterial thrombotic endocarditis
1 (0.4%)
Tumor emboli from occult cancer
2 (0.8%)
Arteriogenic emboli
Aortic arch atherosclerotic plaques
Cerebral artery nonstenotic plaques with ulceration
9 (3.3%)
29 (10.6%)
Paradoxical embolism
Patent foramen ovale
Atrial septal defect
11 (4.0%)
3 (1.1%)
100 mg (NAVIGATE) trial will compare dabigatran etexilate
and rivaroxaban, respectively, to aspirin in ESUS patients.14,15
ESUS is a recent clinical construct,3 and obviously further
research is needed to better understand how this entity can be
best implemented in clinical practice: retrospective observational data from stroke registries as well as prospective studies could inform us about the outcome of ESUS patients in
terms of functional outcome, stroke recurrence, cardiovascular events, and overall and cardiovascular mortality, as well as
compare them with the outcome of other stroke types. Also,
the RE-SPECT ESUS and NAVIGATE trials aim to identify
the optimal antithrombotic treatment in this population.14,15
Also, it would be of interest to identify which are the predictors of AF-associated ESUS among the general ESUS population because this could perhaps play a role in the decision
of the proper antithrombotic treatment until the aforementioned ongoing trials are completed. In addition, there is a
need to assess the prognostic validity of stroke prognostication scores like the age, severity of stroke measured by admission NIH Stroke Scale score, stroke onset to admission time,
range of visual fields, acute glucose, and level of consciousness (ASTRAL) score,16 the congestive heart failure, hypertension, age, diabetes, prior stroke/transient ischemic attack
(CHADS2) score,17,18 and the congestive heart failure, hypertension, age ≥75: 2, diabetes, stroke: 2, vascular disease, sex
female (CHA2DS2-VASc) score19,20 in the ESUS population.
This is the first description of an ESUS population providing
detailed data on demographics, stroke risk factors, and patient
and stroke characteristics. Another strength of this study is
that the definition of ESUS was based on the criteria which
were proposed by the Cryptogenic Stroke/ESUS International
Working Group in the paper which introduced the term3; this
may allow future studies to compare other ESUS populations
to the current one using standardized criteria, in contrary to
the inaccurately defined criteria used to delineate the term
stroke of undetermined etiology of the Trial of Org 10 172 in
Acute Stroke Treatment (TOAST) categorization or the cryptogenic stroke term. Also, we provide a detailed report of the
etiologic work-up performed in the ESUS and the other stroke
types, as well as a list with the potential etiologic cause of
ESUS. On the contrary, a limitation of the present study is its
single-center character rather than a population-based setting,
which may have introduced selection bias. Also, it is a retrospective analysis of prospectively collected data, which may
have introduced collection and registration bias. Moreover, a
proportion of patient did not have a complete diagnostic workup and were classified as undetermined other than ESUS. This
limitation reflects the real-world nature of this registry: among
other patients, this term includes patients with severe stroke
who died early before the complete diagnostic evaluation
was performed, and patients with poor functional outcome or
elderly patients for whom a complete diagnostic evaluation
was deemed unnecessary by the family or the treating physician. Finally, the present analysis did not include patients with
transient ischemic attack and a diffusion-weighted imaging
lesion because transient ischemic attack patients are not registered in our registry.
In conclusion, this is the first description of an ESUS population using the criteria proposed recently by the Cryptogenic
Stroke/ESUS International Working Group.3 About 10% of
patients with first-ever ischemic stroke met criteria for ESUS;
covert paroxysmal AF seems to be a frequent cause of ESUS.
These results may be useful in the clinical and research setting.
Acknowledgments
Dr Ntaios was responsible for the study concept, statistical analysis and interpretation, preparation of manuscript, and study supervision; Dr Papavasileiou for statistical analysis and interpretation and
preparation of manuscript; Dr Milionis, Dr Makaritsis, Dr Manios, Dr
Spengos, and Dr Michel for critical revision of the manuscript; and
Dr Vemmos for acquisition of data, statistical analysis and interpretation, critical revision of manuscript, and study supervision.
Disclosures
Dr Michel discloses research grants from the Swiss National Science
Foundation, the Swiss Heart Foundation, and Cardiomet-CHUV;
speakers’ bureau from Bayer, Boehringer-Ingelheim, Covidien and
St. Jude Medical; Consultant or advisory board from Pierre-Fabre;
travel support from Bayer and Boehringer-Ingelheim. The other authors report no conflicts.
Ntaios et al ESUS in Athens Stroke Registry 181
References
Downloaded from http://stroke.ahajournals.org/ by guest on June 17, 2017
1. 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.
2. 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.
3. 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.
4.Vemmos KN, Takis CE, Georgilis K, Zakopoulos NA, Lekakis JP,
Papamichael CM, et al. The Athens stroke registry: results of a five-year
hospital-based study. Cerebrovasc Dis. 2000;10:133–141.
5. Brott T, Adams HP Jr, Olinger CP, Marler JR, Barsan WG, Biller J, et al.
Measurements of acute cerebral infarction: a clinical examination scale.
Stroke. 1989;20:864–870.
6. Gray LJ, Ali M, Lyden PD, Bath PM; Virtual International Stroke Trials
Archive Collaboration. Interconversion of the National Institutes of
Health Stroke Scale and Scandinavian Stroke Scale in acute stroke. J
Stroke Cerebrovasc Dis. 2009;18:466–468.
7. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo
JL Jr, et al; National Heart, Lung, and Blood Institute Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure; National High Blood Pressure Education Program
Coordinating Committee. The Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560–2572.
8. Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R, et al;
Expert Committee on the Diagnosis and Classification of Diabetes
Mellitus. Follow-up report on the diagnosis of diabetes mellitus.
Diabetes Care. 2003;26:3160–3167.
9. National Cholesterol Education Program Expert Panel on Detection E,
Treatment of High Blood Cholesterol in A. Third report of the national
cholesterol education program (ncep) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment
panel III) final report. Circulation. 2002;106:3143–3421.
10. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P,
Poole-Wilson PA, et al; ESC Committee for Practice Guidelines (CPG).
ESC guidelines for the diagnosis and treatment of acute and chronic heart
failure 2008: the Task Force for the diagnosis and treatment of acute
and chronic heart failure 2008 of the European Society of Cardiology.
Developed in collaboration with the Heart Failure Association of the
ESC (HFA) and endorsed by the European Society of Intensive Care
Medicine (ESICM). Eur J Heart Fail. 2008;10:933–989.
11.Advisory Council for the National Institute of Neurological and
Communicative Disorders and Stroke NIoH. A classification and outline
of cerebrovascular diseases. II. Stroke. 1975;6:564–616.
12. Hatano S. Experience from a multicentre stroke register: a preliminary
report. Bull World Health Organ. 1976;54:541–553.
13. Ntaios G, Vemmou A, Koroboki E, Savvari P, Makaritsis K, Saliaris M, et
al. The type of atrial fibrillation is associated with long-term outcome in
patients with acute ischemic stroke. Int J Cardiol. 2013;167:1519–1523.
14. Diener HC, Connolly S, Easton J, Smith J, Duffy C, Bruckmann M.
Rationale, objectives and design of a secondary stroke prevention study
of dabigatran etexilate versus acetylsalicylic acid in patients with embolic
stroke of undetermined source (RE-SPECT-ESUS). Cerebrovasc Dis.
2014; 37(suppl 1):261.
15. The NAVIGATE ESUS trial. Population Health Research Institute. http://
www.phri.ca/research/stroke-cognition/navigate-esus-111/. Accessed
October 12, 2014.
16. Ntaios G, Faouzi M, Ferrari J, Lang W, Vemmos K, Michel P. An integerbased score to predict functional outcome in acute ischemic stroke: the
ASTRAL score. Neurology. 2012;78:1916–1922.
17. Gage BF, van Walraven C, Pearce L, Hart RG, Koudstaal PJ, Boode
BS, et al. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation.
2004;110:2287–2292.
18. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford
MJ. Validation of clinical classification schemes for predicting stroke:
results from the National Registry of Atrial Fibrillation. JAMA.
2001;285:2864–2870.
19. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical
risk stratification for predicting stroke and thromboembolism in atrial
fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137:263–272.
20. Ntaios G, Lip GY, Makaritsis K, Papavasileiou V, Vemmou A, Koroboki
E, et al. CHADS2, CHA2S2DS2-VASc, and long-term stroke outcome in
patients without atrial fibrillation. Neurology. 2013;80:1009–1017.
Embolic Strokes of Undetermined Source in the Athens Stroke Registry: A Descriptive
Analysis
George Ntaios, Vasileios Papavasileiou, Haralambos Milionis, Konstantinos Makaritsis,
Efstathios Manios, Konstantinos Spengos, Patrik Michel and Konstantinos Vemmos
Downloaded from http://stroke.ahajournals.org/ by guest on June 17, 2017
Stroke. 2015;46:176-181; originally published online November 6, 2014;
doi: 10.1161/STROKEAHA.114.007240
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2014 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/46/1/176
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
Once the online version of the published article for which permission is being requested is located, click
Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Stroke is online at:
http://stroke.ahajournals.org//subscriptions/