Permeable foramen oval was incriminated in 40-56% of cryptogenic stroke patients younger than 55 years1. There are two types of PFO: type I or a tunnel morphology without atrial septal defect or atrial septal aneurysm, and type II with a more complicated morphology with atrial septal defect, atrial septal aneurysm or lipomatous hypertrophy1. When the patient with ESUS has a PFO (Figure 1 ), the stroke can be reclassified as PFO-related4. The risk criteria for stroke in patients with a PFO can be categorized into clinical, anatomical, functional, and circumstantial criteria. Anatomical and functional high risk PFO parameters5 are: height at least 2 mm and length at least 10 mm; the presence of atrial septal aneurysm, hypermobile atrial septum or prominent Eustachian valve or Chiari’s network; right-to-left shunt more than 20 microbubbles; less than 10 degrees between inferior vena cava and PFO.
Figure 1 . Patent foramen oval and embolic strokes of undetermined source in cryptogenic stroke. ECG: electrocardiogram; ESUS: embolic strokes of undetermined source; PFO: permeable foramen oval.
In spite of these features, in clinical practice, there is an intricate interplay between demographics, comorbidities, and echocardiographic parameters in the assessment of risk stratification in patients with PFO.
The RoPE (R isk o f P aradoxicalE mbolism) score can identify patients with PFO-mediated cryptogenic stroke2. However, this score is limited in determining risk of anatomical and functional features of PFO (as amount of shunt, multiple openings, length and thickness of tunnel). It seems that a high RoPE score (more than 7) cannot rule out a PFO-related stroke with certainty2. Although patients in the high RoPE score strata are much more likely to have PFO-related strokes, the recurrence rates in these patients are relatively low2. Different morphologic features of PFO may predispose to cerebrovascular events and frequently associated with cryptogenic stroke. Usually, variables associated with a PFO-related strokes in ESUS patients include younger age, the presence of a cortical stroke on neuroimaging, and the absence of these factors: diabetes, hypertension, smoking, and prior stroke or transient ischemic attack2. The specific features PFOs that seems to be associated with stroke/transient ischemic attack are larger septal excursion distance, concomitant atrial septal aneurysm, a greater PFO height during a Valsalva maneuver, and a large right-to-left shunt5. In these patients with cryptogenic stroke and ESUS there are PFO-dependent (in these patients PFO is likely to be stroke-related rather than incidental) and PFO-independent mechanisms. The results obtained in the study of Polat F et al.3reinforce the idea that stroke in patients with PFO and ESUS are sometimes independent of it. This underlie the fact that ESUS associated to PFO is more complex, the necessity of rigorous patient selection for PFO closure and the methodologic challenges facing PFO closure trials. Data about stroke/transient ischemic attack risk related to PFO and their specific treatment strategy are, in sometimes, controversially. However, in these selected patients, device-closure strategy is superior to a medical-therapy strategy.
There are still some questions related to ESUS in patients with newly detected atrial fibrillation (AF), which means without previously diagnosed AF or AF detected after stroke or transient ischemic attack. For example, how many patients with ESUS will be detected with AF during long-term follow-up after stroke or transient ischemic attack or what is the pathophysiological relationship between late detection of very brief episodes of AF (<30 seconds) and this type of stroke6. In addition, it is unclear whether the brief episodes of AF detected weeks or months after ESUS are relevant to stroke cause or identify patients who benefit from anticoagulation7. These patients seems to be older, with lower prevalence of cardiovascular comorbidities, lower degree of cardiac comorbidities than those with known AF, with episodes of very brief AF paroxysms, with more frequently insular brain infarction, which have double risk of recurrences than patients with no-AF, and lower risk of recurrences than those with known AF7.
In the absence of subclinical AF detected by prolonged ECG monitoring, potential causes of ESUS include atrial cardiomyopathy, left ventricular dysfunction or heart failure, aortic plaques and PFO8. However, one in seven young ESUS patients has additional chronic ischemic lesions. These lesions were associated with several vascular risk factors, lower probability of a pathogenic PFO, and lower stroke recurrence9.
ESUS has the highest rate of stroke recurrence compared to other ischemic stroke subtypes (annual recurrence risk of 4.5–5%)10. That why it is important to understand specific ESUS etiology and possible heterogeneous pathways; in addition, patient risk stratification and therapeutic prevention of recurrent stroke is mandatory in these patients11.
In clinical practice, any patient with cryptogenic stroke/transient ischemic attack requires transthoracic and/or transesophageal echocardiography to diagnose a PFO or any communication at the level of the atrial and ventricular septum. PFO was identified by saline contrast injection in 70% of the patients with stroke12. In those with cryptogenic stroke and PFO, a large right-to-left shunt alone was diagnosed in 50% of cases and was increased to 83% when direct right-to-left shunt was added13. Sometimes this shunt work in association with the Chiari network. However, Chiari network is detected in 83% of patients with PFO12. Recently, a simple scoring system for the identification of high-risk PFO was developed14. A score value ≥2 points is associated with 91% sensitivity and 80% specificity with cryptogenic stroke14. Older patients, with coagulation disorders, a value of D–dimer >1000 ng/mL at admission, and acetylsalicylic acid treatment (versus anticoagulation) have a higher PFO-related stroke recurrence rate14.
Treatment options beside risk stratification is more challenging. ESUS is a non-lacunar cryptogenic ischemic stroke with embolism being most likely the stroke mechanism. It seems to be provoked by relatively smaller emboli from valvular and arterial sources rather than larger emboli originating in the cardiac chambers (left atrial appendage, left atrium, left ventricle, etc). The older studies showed that anticoagulation is more efficacious than antiplatelet therapy for secondary stroke prevention in these patients. Until now, direct oral anticoagulants do not provide a net benefit in patients with ESUS15. In patients who experienced a PFO-related stroke, for secondary prevention, a single antiplatelet therapy is recommended now. Obviously, it is still need for more refined risk stratification tools to prevent stroke recurrences by an appropriate management. Probably, ARCADIA (Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke Randomized) study will respond to this dilemma. The need for more refined risk stratification tools in patients with ESUS remains a challenge in view of more tailored treatment in these patients.
CONFLICT OF INTEREST
The authors declare no potential conflict of interest.
DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
Authors’ contributions: M.F., D.E.I. and D.M.T. conceived of the presented idea. D.E.I. developed the theory and write the manuscript. M.F., D.M.T. and D.E.I. verified the analytical methods. M.F. and D.M.T. supervised this work. All authors discussed the results and contributed to the final manuscript.