Elsevier

The Lancet Neurology

Volume 13, Issue 4, April 2014, Pages 429-438
The Lancet Neurology

Personal View
Embolic strokes of undetermined source: the case for a new clinical construct

https://doi.org/10.1016/S1474-4422(13)70310-7Get rights and content

Summary

Cryptogenic (of unknown cause) ischaemic strokes are now thought to comprise about 25% of all ischaemic strokes. Advances in imaging techniques and improved understanding of stroke pathophysiology have prompted a reassessment of cryptogenic stroke. There is persuasive evidence that most cryptogenic strokes are thromboembolic. The thrombus is thought to originate from any of several well established potential embolic sources, including minor-risk or covert cardiac sources, veins via paradoxical embolism, and non-occlusive atherosclerotic plaques in the aortic arch, cervical, or cerebral arteries. Accordingly, we propose that embolic strokes of undetermined source are a therapeutically relevant entity, which are defined as a non-lacunar brain infarct without proximal arterial stenosis or cardioembolic sources, with a clear indication for anticoagulation. Because emboli consist mainly of thrombus, anticoagulants are likely to reduce recurrent brain ischaemia more effectively than are antiplatelet drugs. Randomised trials testing direct-acting oral anticoagulants for secondary prevention of embolic strokes of undetermined source are warranted.

Introduction

Despite the high incidence of cryptogenic strokes (which comprise about 25% of ischaemic strokes) and their importance (about 300 000 incident cases annually in North America and Europe), there has been little progress in secondary prevention during the past two decades. No randomised trials devoted specifically to cryptogenic stroke have defined optimum antithrombotic prophylaxis. In this Personal View, we develop the construct that most of these strokes are embolic, and propose the pragmatic clinical construct of embolic stroke of undetermined source (ESUS) as the basis for future randomised trials for secondary prevention.

Section snippets

Embolic strokes

Ischaemic stroke has long been recognised to result from several different causes of obstruction of the arteries supplying the brain (figure 1). Most non-lacunar ischaemic strokes are embolic; haemodynamic mechanisms, vasospasm, and in-situ thrombotic occlusion are collectively less common causes than embolism.1, 2 Emboli to the brain can originate from the mitral or aortic valves or the left cardiac chambers (cardiogenic embolism), from proximal cerebral arteries or the aortic arch

Cardiac sources

Many patients with ESUS have common cardiac abnormalities that are associated with embolic stroke but have a sufficiently low inherent risk of embolism that a causal role of stroke at the patient level is unclear (panel 1, figure 2). For example, patent foramen ovale has a population prevalence of about 25% and is not a risk factor for stroke in the general population;19 however, this defect has been well documented in some patients with stroke to be the conduit for paradoxical embolism of a

Diagnosis of ESUS

Investigations to establish a diagnosis of ESUS must be sufficient to exclude major-risk cardioembolic sources, proximal occlusive atherosclerosis, and lacunar strokes due to cerebral small artery disease (panel 2). The proposed approach is informed partly by the response of these excluded stroke causes to specific interventions, such as revascularisation for secondary prevention in patients with ipsilateral occlusive carotid artery stenosis, and anticoagulation for patients with stroke

Cryptogenic stroke versus ESUS

About 25% of ischaemic strokes have been categorised in studies as cryptogenic (figure 1, table).8, 54, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116 This proportion varies according to the patient population (largest in young stroke and transient ischaemic attack cohorts), the criteria for classification as cryptogenic (no generally accepted definition exists), and the extent of diagnostic assessment (not specified and

Antithrombotic therapy for secondary stroke prevention in ESUS

The only randomised assessment of anticoagulation in cryptogenic stroke is the subgroup analysis of the Warfarin-Aspirin Recurrent Stroke Study (WARSS) done between 1993 and 2000.94, 124 Among 2206 patients aged between 30 and 85 years with recent (<30 days) ischaemic stroke who were randomly assigned to aspirin 325 mg per day or adjusted-dose warfarin (target international normalised ratio [INR] 1·4–2·8, median achieved INR 1·9), 576 (26%) strokes were deemed cryptogenic on the basis of the

Net clinical benefit of anticoagulation in patients with ESUS

In randomised trials of secondary prevention of ischaemic stroke that compared warfarin with antiplatelet therapies in patients with a range of ischaemic stroke mechanisms,136, 137 trends toward reduction in ischaemic strokes were offset by increases in major intracranial and extracranial haemorrhages. Patients with ESUS selected because of an embolic stroke mechanism are likely to respond especially well to anticoagulants, as discussed. The novel oral anticoagulants all have greatly reduced

Guideline recommendations for secondary prevention

The 2008 American College of Chest Physicians guideline140 and 2008 American Heart Association guideline specifically recommend antiplatelet therapy for patients with cryptogenic ischaemic stroke.141 The European Stroke Organisation guideline,90 the 2011 American Heart Association revised guideline,142 the 2012 American College of Chest Physicians guideline,143 and the 2010 Canadian Best Practice Recommendations for Stroke Care89 do not comment specifically on cryptogenic stroke, but recommend

Conclusions

Findings from recent monitoring and imaging studies show the many potential sources of embolism present in most patients with ischaemic stroke that potentially cause ESUS. When identified in individual patients, the causal association with stroke is usually not possible to prove. Quite often, more than one potential source is present in the same patient. Yet, an embolic mechanism is common to most of these strokes, with potential implications for secondary prevention.

Randomised clinical trials

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