Cryptogenic stroke and embolic stroke of undertermined source (ESUS)

One-third of strokes represent intracerebral or subarachnoid hemorrhage while two-thirds represent cerebral ischaemia (1)

Ischaemic stroke can result from a variety of causes such as atherosclerosis of the cerebral circulation, occlusion of cerebral small vessels, and cardiac embolism (1,2)

• one-third of ischaemic strokes are of unclear cause
  • increasingly accepted that many of these cryptogenic strokes arise from a distant embolism rather than in-situ cerebrovascular disease, leading to the formulation of "Embolic Stroke of Undetermined Source" (ESUS) as a distinct target for investigation

Cryptogenic stroke:

• most frequently used definition of cryptogenic stroke (CS) to date is based on the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria (3)
  • TOAST criteria classify an ischaemic stroke as cryptogenic when no cause can be identified after baseline diagnostic work-up
    • however, ischaemic stroke with incomplete work-up or cerebral infarctions with two or more possible underlying causes are also characterized as cryptogenic.
    • lack of specified mandatory diagnostic testing and work-up algorithm implementation of TOAST criteria results in huge variations in the reported prevalence of CS
      • as a consequence of poor agreement between physicians to classify a cerebral ischaemic event as cryptogenic

"Embolic Stroke of Undetermined Source" (ESUS) (4)

• in 2014, the definition of embolic strokes of undetermined source (ESUS) emerged as a new clinical construct to characterize nonlacunar (>1.5 cm on CT or >2cm on MRI), nonatherosclerotic (absence of significant ipsilateral vessel stenosis >= 50%) strokes of an undetermined embolic source, in the absence of a high-risk for embolism cardiac disease or any other specific cause
  • ESUS working group investigators further proposed that the minimal stroke work-up should include brain neuroimaging with CT or MRI, 12-lead ECG, transthoracic echocardiography (TTE), 24 h Holter-ECG and imaging of both extracranial and intracranial vessels with any available imaging modality (DSA, MRA, CTA, or US)
  • possible aetiologies of ESUS:
    • evidence has indicated that ESUS may often stem from subclinical atrial fibrillation (AF) which can be diagnosed with prolonged heart-rhythm monitoring (5)
    • emerging evidence indicates that a thrombogenic atrial substrate can lead to atrial thromboembolism even in the absence of AF
      • such an atrial cardiopathy may explain many cases of ESUS, and oral anticoagulant drugs may prove to reduce stroke risk from atrial cardiopathy given its parallels to AF
      • improved imaging of ventricular thrombus plus the availability of NOAC drugs may lead to better prevention of stroke from acute myocardial infarction and heart failure

Reference:

• Schulz UG and Rothwell PM. Differences in vascular risk factors between etiological subtypes of ischemic stroke: importance of populationbased studies. Stroke 2003; 34: 2050-2059.
• Tsivgoulis G et al. Stroke incidence and outcomes in Northeastern Greece: the Evros stroke registry. Stroke 2018; 49: 288-295.
• Adams HP Jr et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24: 35-41.
• Hart RG et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol. 2014 Apr; 13(4):429-38.
• Kamel H, Healey JS. Cardioembolic Stroke. Circ Res. 2017 Feb 3;120(3):514-526.