This section details key aspects of ESUS, including its definition, potential causes and prognosis for ESUS patients

In this section:

Definition of ESUS

Cerebral infarcts account for the vast majority of strokes and are of diverse subtypes ranging from cardioembolic, large artery extracranial and intracranial atherosclerosis, small vessel lacunar, to other determined aetiologies

  • ESUS, previously known as cryptogenic stroke, is a clinical entity that refers to patients with embolic stroke for which the aetiology of embolism remains unidentified despite thorough investigations ruling out established cardiac and vascular sources
  • ESUS is defined as a radiologically confirmed non-lacunar brain infarct without:
    • Extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the ischaemic area
    • Major-risk cardioembolic source
    • Any other specific cause of stroke

Epidemiology of ESUS

  • Globally, 15 million people per year have a stroke
    • Nearly 6 million of these die, and another 5 million are left permanently disabled
  • Ischaemic stroke accounts for up to 90% of all strokes
    • In over half of strokes in patients aged <55 years the cause is unknown
  • ESUS is now thought to comprise approximately 25% of all ischaemic strokes
    • Around 300,000 people experience ESUS each year in North America and Europe
    • Data from a cross-sectional global sample of patients with recent ischaemic stroke found the mean age of ESUS patients (62 years) to be significantly lower than non-ESUS ischaemic stroke patients (68 years; p≤0.001)
  • It is important to note that some patients, particularly younger patients, may have been classified as having ESUS based on incomplete diagnostic evaluations or competing identified mechanisms, or where cases were not reliably classified into the other known infarct subtypes despite an adequate work-up
ESUS comprises around 25% of all ischaemic strokes [Adapted from Hart <em>et al</em>. 2014]
ESUS comprises around 25% of all ischaemic strokes
Adapted from Hart et al. 2014

Burden of ESUS

ESUS is a major health issue because of its high frequency and clinical relevance. Despite advances in the understanding of ischaemic stroke, ESUS remains a diagnostic and therapeutic challenge.

  • The Athens Stroke Registry showed that although the long-term mortality in ESUS was lower compared with cardioembolic strokes, rates of recurrence and the composite cardiovascular endpoint were similar

ESUS and stroke recurrence risk

  • Patients who experience an ESUS are at high risk of having another stroke. Patients in the ‘stroke with no determined cause’ group showed a significantly higher rate (30%) of recurrent stroke than those of other subtypes (large artery disease 16%; cardioembolism 14%; small artery disease 2%)
Patients with ESUS show a significantly higher rate of recurrent stroke than those of other subtypes [Adapted from Bang et al. 2003]
Patients with ESUS show a significantly higher rate of recurrent stroke than those of other subtypes
Adapted from Bang et al. 2003
  • Recent data from the Athens Stroke Registry confirmed that recurrent stroke risk was higher in ESUS than in non-cardioembolic strokes

Potential causes of ESUS

Atrial fibrillation
Paroxysmal AF carries the same risk of ischaemic stroke as persistent AF and has increasingly gained attention as a potential source of ESUS. Several studies have shown that paroxysmal AF is present in a significant proportion of patients experiencing cryptogenic stroke.

Potential causes of ESUS [Adapted from Hart et al 2014]
Potential causes of ESUS
Adapted from Hart et al. 2014

Patent foramen ovale
Several studies have shown a significant association between ESUS and the presence of a PFO, suggesting that paradoxical emboli (i.e. emboli crossing from the venous to arterial circulation through a PFO) may be an important cause of ESUS.

The prevalence of PFO was high among patients with ESUS.

  • Of note, approximately one-third of PFOs discovered in patients with ESUS were deemed likely to be incidental and unrelated to the stroke

Vascular substenotic atherosclerosis
Substenotic atherosclerotic plaques may cause ischaemic stroke by plaque rupture and artery-to-artery embolization. Complicated atherosclerotic plaques with evidence of intraplaque haemorrhage on imaging have been suggested as a potential mechanism in ESUS.

  • Aortic arch atherosclerosis is considered to be a risk factor for ESUS

Hypercoagulable states

  • Hypercoagulable states are a recognized, albeit uncommon, aetiology of ischaemic stroke
  • Hypercoagulable states have a reported prevalence of 3–21% in ischaemic stroke

Ischaemic stroke incidence can be as high as 15% in patients with malignancy, of which only 50% are identified. Occult cancer as a cause of ESUS should be considered once traditional risk factors have been considered in patients with suggestive clinical history, advanced age or familial cancers.

Increased visceral adipose tissue has been identified in over half of patients with ESUS suggesting it may have a role in the pathogenesis of thromboembolism.

  • Other potential causes include migraine, Fabry disease and hyperhomocysteinemia

Defining ESUS based on established criteria

A new clinical construct for ESUS was introduced by the Cryptogenic Stroke/ESUS International Working Group as a potential therapeutic relevant entity with an indication for anticoagulation. In contrast to the absence of standard diagnostic criteria for cryptogenic stroke, the working group proposed specific criteria for the diagnosis of ESUS.

  • This construct provides the means to define ESUS based on established criteria, rather than a diagnosis of exclusion
Diagnostic criteria for ESUS
Brain CT or MRI to demonstrate non-lacunar stroke
Extracranial and intracranial imaging to exclude ≥50% proximal stenosis
ECG, echocardiogram, and cardiac rhythm monitoring for ≥24 hours to exclude cardioembolic sources
No other specific cause of stroke identified (e.g. autoimmune arteritis, arterial dissection, migraine with aura, vasospasm, drug abuse)

The ESUS definition provides a useful construct for clinical and research purposes, and is highly heterogeneous by including:

  • Cardiac abnormalities of uncertain risk (e.g. covert paroxysmal AF, mitral annular calcification, aortic valve disease or atrial pathology)
  • Arteriogenic embolism (e.g. from a non-stenotic ulcerated plaque)
  • Paradoxical embolism (e.g. PFO or pulmonary arteriovenous malformation)
  • Unknown prothrombotic disorders (e.g. occult malignancy)

Of note, ESUS has the fewest atherosclerotic markers and no excess of cardioembolic markers.

Unmet medical need in patients with ESUS

The recurrence rate of ischaemic stroke remains substantial despite antiplatelet therapy with recurrence rates with ASA (325 mg per day) of approximately 8%.

  • Adverse events associated with antiplatelet use, such as major gastrointestinal bleeding, may lead to discontinuation and potentially increase risk of stroke recurrence
  • A higher proportion of older patients (aged ≥55 years) who have an ESUS may have underlying paroxysmal AF
    • Detection of AF in patients who might benefit from treatment with anticoagulants over antiplatelet therapy remains crucial


The prognosis of ESUS varies, which likely reflects the heterogeneity of the definition as well as the shortage of studies. Long-term outcomes of ESUS patients in the Athens Stroke Registry have been reported.

  • Cumulative probability of stroke recurrence in ESUS was similar to cardioembolic strokes (29% vs 27%) but higher than all other types of non-cardioembolic stroke, including large artery atherosclerosis (13%) and lacunar strokes (13%)
  • Notably, there was a higher percentage of ESUS patients with a favourable functional outcome, defined as modified Rankin scale ≤2 (62.5%), compared with patients with cardioembolic strokes (32.2%)

Next section: Treatment

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