Personal ViewEmbolic strokes of undetermined source: the case for a new clinical construct
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
References (143)
- et al.
Arteriographic study of cerebral embolism
Lancet
(1965) - et al.
Cerebral embolism. Angiographic observations on spontaneous clot lysis
Lancet
(1965) - et al.
Significance of aortic atheroma in elderly patients with ischemic stroke. A hospital-based study and literature review
Clin Neurol Neurosurg
(2007) Cardiogenic embolism to the brain
Lancet
(1992)- et al.
Patent foramen ovale: innocent or guilty? Evidence from a prospective population-based study
J Am Coll Cardiol
(2006) - et al.
Comparison of frequencies of patent foramen ovale and thoracic aortic atherosclerosis in patients with cryptogenic ischemic stroke undergoing transesophageal echocardiography
Am J Cardiol
(2011) - et al.
Echocardiographic assessment of the left atrial appendage
J Am Coll Cardiol
(1999) - et al.
Systemic embolism in chronic left ventricular aneurysm: incidence and the role of anticoagulation
J Am Coll Cardiol
(1985) - et al.
Frequency of stroke and embolism in left ventricular hypertrabeculation/noncompaction
Am J Cardiol
(2011) - et al.
Impact of mitral annular calcification on cardiovascular events in a multiethnic community: the Northern Manhattan Study
JACC Cardiovasc Imaging
(2008)
Improved morphologic characterization of atrial septal aneurysm by transesophageal echocardiography: relation to cerebrovascular events
J Am Coll Cardiol
Calcium emboli to the retinal artery in calcific aortic stenosis
Am Heart J
Echocardiography for the detection of cardiac sources of embolism in patients with stroke or transient ischemic attack
J Stroke Cerebrovasc Dis
Pilot study of cardiac magnetic resonance imaging for detection of embolic source after ischemic stroke
J Stroke Cerebrovasc Dis
Transesophageal echocardiography and carotid ultrasound in patients with cerebral ischemia: prevalence of findings and recurrent stroke risk
J Am Coll Cardiol
Transesophageal echocardiography screening in subjects with a first cerebrovascular ischemic event
J Stroke Cerebrovasc Dis
Newly diagnosed atrial fibrillation after acute ischemic stroke and transient ischemic attack: importance of immediate and prolonged continuous cardiac monitoring
J Stroke Cerebrovasc Dis
Outpatient cardiac telemetry detects a high rate of atrial fibrillation in cryptogenic stroke
J Neurol Sci
Paroxysmal atrial fibrillation in cryptogenic stroke: a case-control study
J Stroke Cerebrovas Dis
Risk of stroke in patients with atrial flutter
Am J Cardiol
Prevalence of nonstenosing, complicated atherosclerotic plaques in cryptogenic stroke
JACC Cardiovasc Imaging
Ulcerated carotid plaques with ultrasonic echolucency are causatively associated with thromboembolic cerebrovascular events
J Stroke Cerebrovasc Dis
Atherosclerosis of the aorta: risk factor, risk marker, or innocent bystander? A prospective population-based transesophageal echocardiography study
J Am Coll Cardiol
Aortic atheroma morphology and the risk of ischemic stroke in a multiethnic population
Am Heart J
Atheroma of the aortic arch: an important and poorly recognised factor in the aetiology of stroke
Lancet Neurol
Atherosclerosis of the thoracic aorta and aortic debris as a marker of poor prognosis: benefit of oral anticoagulants
J Am Coll Cardiol
Mobile aortic atheroma and systemic emboli: efficacy of anticoagulation and influence of plaque morphology on recurrent stroke
J Am Coll Cardiol
Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging
Lancet Neurol
Infarcts of undetermined cause: the NINCDS Stroke Data Bank
Ann Neurol
The risk of embolic stroke. Another piece of the puzzle
N Engl J Med
Observations on brain embolism with special reference to the mechanism of hemorrhagic infarction
J Neuropathol Exp Neurol
The moving embolus seed during serial cerebral angiography
Stroke
Clinical and neuroradiological analysis of thrombotic and embolic cerebral infarction
Jpn Circ J
Biomarker level improves the diagnosis of embolic source in ischemic stroke of unknown origin
J Neurol
Watershed infarcts in transient ischemic attack/minor stroke with > or = 50% carotid stenosis: hemodynamic or embolic?
Stroke
Clinical practice. Carotid stenosis
N Engl J Med
Transhemispheric passage of microemboli in patients with unilateral internal carotid artery occlusion
Stroke
Delayed cerebral ischemic episodes distal to occlusion of major cerebral arteries
Neurology
Cause of cerebral infarction in the carotid territory. Its relation to the size and the location of the infarct and to the underlying vascular lesion
Stroke
Images in clinical medicine. Paradoxical embolism–thrombus in transit through a patent foramen ovale
N Engl J Med
Atheromatous disease of the thoracic aorta: pathologic and clinical implications
Ann Intern Med
Embolism in mitral valve prolapse
Annu Rev Med
Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both
N Engl J Med
Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies
Neurology
Current management and risk of recurrent stroke in cerebrovascular patients with right-to-left cardiac shunt
Cerebrovasc Dis
Patent foramen ovale and cryptogenic stroke in older patients
N Engl J Med
An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke
Neurology
Further evidence relating mitral-valve prolapse to cerebral ischemic events
N Engl J Med
Serial cardiac magnetic resonance imaging of a rapidly progressing liquefaction necrosis of mitral annulus calcification associated with embolic stroke
Circulation
Thrombus associated with mitral valve calcification. A possible mechanism for embolic stroke
Stroke
Cited by (1166)
Risk scores for prediction of paroxysmal atrial fibrillation after acute ischemic stroke or transient ischemic attack: A systematic review and meta-analysis
2024, International Journal of Cardiology: Cardiovascular Risk and PreventionEmbolic stroke of undetermined source: Focusing on atrial cardiopathy and patent foramen ovale
2024, International Journal of CardiologyLeft Atrial Septal Pouch (LASP) and cryptogenic stroke risk: An updated systematic review and meta-analysis of observational studies
2024, Current Problems in Cardiology