Embolic Strokes of Undetermined Source in the Athens Stroke Registry
A Descriptive Analysis
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.
There 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 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.
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 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
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).
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 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).
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.
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%.
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 follow-up 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, double-blind, 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, Event-Driven, 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 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 work-up 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.
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.
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.
- Received August 26, 2014.
- Revision received October 12, 2014.
- Accepted October 16, 2014.
- © 2014 American Heart Association, Inc.
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