Embolic strokes of undetermined source: a clinical consensus statement of the ESC Council on Stroke, the European Association of Cardiovascular Imaging and the European Heart Rhythm Association of the ESC

Abstract

One in six ischaemic stroke patients has an embolic stroke of undetermined source (ESUS), defined as a stroke with unclear aetiology despite recommended diagnostic evaluation. The overall cardiovascular risk of ESUS is high and it is important to optimize strategies to prevent recurrent stroke and other cardiovascular events. The aim of clinicians when confronted with a patient not only with ESUS but also with any other medical condition of unclear aetiology is to identify the actual cause amongst a list of potential differential diagnoses, in order to optimize secondary prevention. However, specifically in ESUS, this may be challenging as multiple potential thromboembolic sources frequently coexist. Also, it can be delusively reassuring because despite the implementation of specific treatments for the individual pathology presumed to be the actual thromboembolic source, patients can still be vulnerable to stroke and other cardiovascular events caused by other pathologies already identified during the index diagnostic evaluation but whose thromboembolic potential was underestimated. Therefore, rather than trying to presume which particular mechanism is the actual embolic source in an ESUS patient, it is important to assess the overall thromboembolic risk of the patient through synthesis of the individual risks linked to all pathologies present, regardless if presumed causally associated or not. In this paper, a multi-disciplinary panel of clinicians/researchers from various backgrounds of expertise and specialties (cardiology, internal medicine, neurology, radiology and vascular surgery) proposes a comprehensive multi-dimensional assessment of the overall thromboembolic risk in ESUS patients through the composition of individual risks associated with all prevalent pathologies.

Keywords: Aetiology; Atherosclerosis; Cancer; Embolic stroke of undetermined source; Left atrial disease; Left ventricular disease; Patent foramen ovale; Valvular heart disease.

Graphical Abstract

AHRE, atrial high-rate episode; DIC, disseminated intravascular coagulation; ISHT, International Society on Thrombosis and Haemostasis; LV, left ventricular; RoPE, Risk of Paradoxical Embolism; SCAF, subclinical atrial fibrillation; VTE, venous thromboembolism.

Figure 1

Distinction between the terms cryptogenic stroke and embolic stroke of undetermined source. ESUS, embolic stroke of undetermined source

Figure 2

Examples of graphical illustration of the overall thromboembolic risk in embolic stroke of undetermined source patients. (Left upper panel) Patient with embolic stroke of undetermined source and metastatic lung cancer and vegetations at the aortic valve with sterile cultures and an ipsilateral-to-the-infarct atherosclerotic plaque in the common carotid artery causing 40% stenosis with smooth plaque surface and thick fibrous cap. (Right upper panel) A 68-year-old patient with embolic stroke of undetermined source and an ipsilateral-to-the-infarct atherosclerotic plaque in the internal carotid artery causing 40% stenosis with acute intra-plaque haemorrhage on magnetic resonance imaging; aortic valve calcification; and a patent foramen ovale with small shunt and no atrial septal aneurysm. (Left middle panel) Patient with embolic stroke of undetermined source and coronary artery disease with a large dyskinetic scar tissue in the left ventricular wall due to previous myocardial infarction and aortic valve stenosis with thin leaflets and no calcification. (Right middle panel) Patient with embolic stroke of undetermined source and an ipsilateral-to-the-infarct atherosclerotic plaque in the carotid bulb causing 40% stenosis with thick fibrous cap and irregular plaque morphology, but without intra-plaque haemorrhage or superimposed thrombus; heart failure with left ventricular ejection fraction 40%; and a large redundant Barlow mitral valve disease. (Left lower panel) patient with embolic stroke of undetermined source and spontaneous echocardiographic contrast in the left atrium; an ipsilateral-to-the-infarct non-ulcerated atherosclerotic plaque in the common carotid artery with thick plaque, lipid-rich necrotic core > 40% of the wall area without intra-plaque haemorrhage, or superimposed thrombus; and a calcified aortic valve. (Right lower panel) A 56-year-old patient with embolic stroke of undetermined source and a patent foramen ovale with atrial septal aneurysm and Risk of Paradoxical Embolism score 7 and an ipsilateral-to-the-infarct atherosclerotic plaque in the internal carotid artery causing 30% stenosis with significant calcification

Figure 3

Features associated with thromboembolic risk in embolic stroke of undetermined source patients. (Panel 1) Computed tomography angiography axial scan of the right internal carotid artery in a 73-year-old symptomatic male patient with a 45% stenosis according to the NASCET criteria. A hypodense plaque is visible (arrow) with very low attenuation (<30 Hounsfield units). (Panel 2) MR shows intra-plaque haemorrhage at the bifurcation of the right carotid artery in a 75-year-old symptomatic male patient. (Panel 3) Computed tomography angiography axial scan of the right common carotid artery with a floating thrombus in a 69-year-old female patient. (Panel 4) Patent foramen ovale. (Left) Aneurysm of inter-atrial septum with small inter-atrial shunt in colour Doppler (transthoracic echocardiography, parasternal short-axis view). (Right) Massive right-to-left interatrial shunt during contrast echo with Valsalva manoeuvre. (Panel 5) A mitral inflow Doppler in a restrictive cardiomyopathy (amyloid) showing restrictive physiology, E/A > 3, Deceleration time < 120 ms and a short isovolumetric relaxation time. (Panel 6) Brain infarcts in all three cerebral arterial territories (three-territory sign) in a patient with advanced ceacal adenocarcinoma. (Panel 7) Pacemaker recording of an episode of atrial flutter with ventricular pacing. From top to bottom, tracings show atrial electrogram, ventricular electrogram, surface electrocardiogram (ECG), and pacemaker marker channels. (Panel 8) Surface electrocardiographic recording of a short run of non-sustained atrial tachycardia. (Panel 9) Pacemaker atrial electrogram showing an irregular atrial high-rate episode. (Panel 10) Spontaneous echo contrast in the left ventricle (arrows) of a patient with known dilated cardiomyopathy and left ventricular ejection fraction of 12%. (Panel 11) Thrombus (arrow) of the left atrial appendage in a patient with rheumatic mitral stenosis in transoesophageal echocardiography. (Panel 12) Echocardiography demonstrating a severely dilated left atrium in an ESUS patient without known atrial fibrillation. Reprinted from Kamel et al. with permission. (Panel 13) Extensive parietal thrombus of left atrium (arrow) in a patient with rheumatic mitral stenosis at 2D transoesophageal echocardiography (left) and 3D transoesophageal echocardiography (right). (Panel 14) Left ventricular non compaction at four-channel late gadolinium enhancement, T1 mapping, and short-axis view in cardiac magnetic resonance imaging

Figure 4

Assessment of thromboembolic risk related to patent foramen ovale in embolic stroke of undetermined source patients based on the morphological features of the patent foramen ovale, the Risk of Paradoxical Embolism score, patient age, and history of recent venous thromboembolism. The right lower part of the figure is blank because the maximum Risk of Paradoxical Embolism score that a patient > 60 years can have is 6. ASA, atrial septal aneurysm; VTE, venous thromboembolism