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.