ARCADIA: atrial cardiopathy and antithrombotic drugs in prevention after cryptogenic stroke

CI: confidence interval

COMPASS: cardiovascular outcomes for people using anticoagulation strategies

CT scan: computed tomography scan

ECG: electrocardiogram

EF: ejection fraction

ESUS: embolic stroke of undetermined source

HR: hazard ratios

LV: left ventricle

MRI: magnetic resonance imaging

mRS: modified Rankin scale

NAVIGATE ESUS: rivaroxaban versus aspirin in secondary prevention of stroke and prevention of systemic embolism in patients with recent embolic stroke of undetermined source

NIHSS: National Institute of Health Stroke score

NT Pro-BNP: N-terminal pro-B-type natriuretic peptide

PES: potential embolic source

PFO: patent foramen ovale

RE-SPECT ESUS: dabigatran etexilate for secondary stroke prevention in patients with ESUS

SD: standard deviation

TEE: trans-oesophageal echography

TOAST: trial of ORG 10172 in acute stroke treatment

TTE: transthoracic echography

About 10–30% of ischemic strokes have no identifiable cause despite a thorough diagnostic evaluation (cryptogenic stroke) [1,2]. In 2014, researchers proposed the concept of “embolic stroke of undetermined source” (ESUS) [2], which is defined as a non-lacunar brain infarct without a significant (≥50%) stenosis of extracranial or intracranial arteries, major cardio-embolic sources or any other specific cause of stroke such as arteritis, dissection, and vasospasm [3].

As its diagnosis is based on an exclusive process, ESUS represents an etiologically heterogeneous group and may be caused by various potential sources of thromboembolism, which may respond better to anticoagulation or antiplatelet therapy [4,5]. Despite the increased number of published studies focusing on the aetiologies of the ESUS, little is known about the prevalence and overlap of potential embolic sources (PES) in north African patients with ESUS [6].

In this study, we, therefore, aimed to assess the prevalence and degree of overlap of different PES, and to evaluate the stroke recurrence rate by identifying PES among Tunisian patients with ESUS.

We assessed all consecutive ischemic stroke patients admitted to our department of neurology in Fattouma Bourguiba hospital (Monastir, Tunisia), between January 2017 and December 2020.

The scientific use of the data collected was approved by the local Ethics Committee. Data were prospectively obtained from digital hospital records including demographics, medical history and associated vascular risk factors, prior medications, time of stroke onset and hospital admission, duration of hospitalisation, stroke severity assessed by the National Institute of Health Stroke scale score (NIHSS), results of routine laboratory and imaging investigations, and initial and discharge treatments.

Stroke was defined according to the World Health Organisation criteria as an episode of acute neurological dysfunction based on a new infarct visualised in brain imaging or symptoms persisting over 24 hours [7]. For ischemic stroke diagnosis, work up included cerebral CT and/or MRI if available. In search of potential cardio-embolic aetiologies, in addition to the electrocardiogram, we performed a first 24-hour rhythmic holter, in the acute phase of the ischemic stroke, then we performed a second holter, during follow-up, to identify heart rhythm disorders such as atrial fibrillation, atrial flutter, atrial hyperexcitability. We also performed a transthoracic echocardiography supplemented by a trans-oesophageal echocardiography in search of major or minor cardio-embolic causes (valvular heart disease, atrial cardiopathy, etc.). The assay of the NT- pro-BNP was carried out.

In search of stenotic or non-stenotic (<50%) carotid, vertebrobasilar and aortic arch atheromatous plaques, all patients initially had an ultrasound of the supra-aortic trunks, supplemented by angio-CT scan and/or angio-MRI if available.

The aetiologies of ischemic strokes were classified using the modified trial of ORG 10172 in acute stroke treatment (TOAST) and ESUS criteria [3,8].

Between January 2017 and December 2020, 330 patients with acute first-ever ischemic stroke were included in our study. Nine patients were excluded from this analysis because of missing data (cardiac explorations (n = 5) and supra-aortic vascular imaging (n = 4). Of the remaining 321 patients, 66 (20.6%) were classified as ESUS (Figure 1).

This is the first description of a Tunisian ESUS cohort using the criteria proposed by the Cryptogenic Stroke/ESUS International Working Group in 2014. In our study, we found that approximately 20% of all included ischemic strokes (n = 330) were classified as ESUS type and they were more prevalent among young adults. Our data are consistent with a systematic review of published studies and trials evaluating ESUS patients, where frequency of ESUS ranged from 7% to 42% of all ischemic strokes with an average of 17% and the mean age ranged from 53 to 69 years [9,11,12]. Some discrepancies between studies may result from differences in methods and frequency in providing diagnostic workup in various countries, as well as the heterogeneity of the characteristics of the patients included in these studies [5,13].

The present study of 66 consecutive patients with ESUS shows that the most common potential causes of ESUS were atrial cardiopathy (71.2%), arterial atherosclerosis (69.7%) and left ventricular disease (39.4%). Added to that, there was a major overlap of PES in patients with ESUS: most patients (84.8%) had ≥ 2 PES, whereas one third of patients had at least 3 PES. The identification of many PES in our study likely relies on the practice of a panel of investigations that are not routinely used in most of our patients with ESUS. Added to basic explorations proposed by the Cryptogenic Stroke/ESUS International Working Group [3] (standard 12-lead ECG, transthoracic echocardiogram, extracranial vascular imaging, and automated cardiac rhythm monitoring), most patients with ESUS were investigated with contrast trans-oesophageal echocardiogram for PFO detection, serum NT-pro-BNP [10,14] and P-wave indices in ECG for the assessment of atrial cardiopathy [15,16], intracranial and aortic imaging for the assessment of arterial atherosclerosis disease [17-19].

Investigated with such an exhaustive diagnostic work-up, which is unrealistic in terms of availability of resources, patients with ESUS would have much identified PES and most included patients would rarely have a single PES [5,20].

In our ESUS cohort, increasing numbers of PES was not statistically associated with increased risk of recurrent stroke.

Similar to our results, The NAVIGATE ESUS (rivaroxaban versus aspirin in secondary prevention of stroke and prevention of systemic embolism in patients with recent embolic stroke of undetermined source) [9,21] and the RE-SPECT ESUS (dabigatran etexilate for secondary stroke prevention in patients with ESUS) trials [22] as well as several observational studies [4,11], reported that two-thirds of all patients with ESUS had at least 2 potential embolic sources, and the most common ones were non-stenotic large artery disease, left ventricular disease, and atrial cardiopathy. Moreover, one-third of the patients had at least 3 such sources (each was present in nearly half of the study population) [5,9].

It was also reported that most patients with ESUS have multiple PES, which could explain the neutral results of therapeutic trials: The NAVIGATE ESUS and the RE-SPECT ESUS trials [9,21,22] showed that anticoagulation is not superior to aspirin to prevent stroke recurrence in patients with ESUS, showing that the lumping therapeutic approach of oral anticoagulation for the unselected population with ESUS was not the optimal strategy and indirectly validating the ESUS concept as an etiologically heterogeneous entity [5,12].

The heterogeneity of embolic sources and their remarkable degree of overlap, as reported in the present study, could explain these negative results. Over 40% of patients with ESUS have multiple PES, some of which may be associated with low-blood flow which predisposes to formation of red thrombi that may respond better to anticoagulation, whereas other embolic sources may be associated with atherosclerotic plaque ulceration which triggers the formation of white thrombi that may have responded better to antiplatelet therapy [20].

In this context, treating patients with ESUS with anticoagulants rather than antiplatelets may cause simply exchanging the type of thrombus, with the overall burden of thrombi remaining unchanged and hence, no change in the rate of stroke recurrence.

If this hypothesis is correct, it would be rational to expect that a combination of anticoagulant and antiplatelet in patients with ESUS would be associated with a substantial reduction of stroke recurrences in patients with ESUS. These thoughts are supported by the results of the COMPASS (cardiovascular outcomes for people using anticoagulation strategies) trial which showed that a combination of low-dose rivaroxaban and aspirin was associated with a large reduction of stroke risk compared with aspirin as monotherapy [23,24].

Furthermore, the strategy of combining anticoagulant and antiplatelet therapy may not apply to patients with atrial cardiopathy. Meanwhile, the ARCADIA (atrial cardiopathy and antithrombotic drugs in prevention after cryptogenic stroke) trial [10], which is currently investigating whether oral anticoagulation with apixaban is a better strategy compared with aspirin in patients with atrial cardiopathy, reports positive results.

We found that the risk of stroke recurrence was similar across different PES, which suggest that the thromboembolic risk across these PES is similar. This is in line with the concept of ESUS, which considers all these PES as minor-risk embolic sources [5,9].

We also found that the risk of stroke recurrence in patients with multiple PES was not further increased. Similar studies with longer follow-up and adequately powered cohort studies are needed to show whether these risk differences would be larger in the long-term.

This is the first description of a Tunisian ESUS population providing detailed data on potential etiologic causes of ESUS and the degree of PES overlap. Another strength of this study is that the definition of ESUS was based on the criteria proposed by the Cryptogenic Stroke/ESUS International Working Group. This may allow future studies to compare other ESUS populations to the current one using standardised criteria. Another strength of the present study is that the estimated degree of PES overlap might be the actual overlap because of the extensive panel of diagnostic work-up investigations that had been performed for most patients, regardless of their ages. Moreover, we used several measurements to define each PES, especially the atrial cardiopathy [9,10]. In this context, our estimates of the prevalence of each PES and of prevalence of multiple PES are likely reasonable. Nevertheless, our study has certain limitations. It is a single-center character rather than a population-based setting, which may have introduced selection bias. In addition, a type II error due to moderate sample size and limited number of events cannot be excluded. Additionally, it is a retrospective analysis of prospectively collected data, which may have introduced collection and registration bias.

In the present study, we conclude that most ESUS patients had multiple PES with a major degree of overlap. Rather, prospective data with advanced diagnostic methods are warranted to identify the true distribution of the underlying stroke aetiology in patients with ESUS. Currently, ESUS may be considered as a developing diagnostic concept that triggers increased diagnostic studies presumably leads to increased detection rates of the underlying stroke cause and subsequently reduces the overall rate of undefined or cryptogenic strokes.

Declaration of interest. The authors declare that they have no conflict of interest.

Funding. The study was approved by the local ethics committee.

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The study was approved by the local ethics committee.