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\begin{document}

\title{Patent foramen oval and ESUS in cryptogenic stroke: still a complex
puzzle}



\author[1]{Diana-Elena Iov}%
\author[1]{Mariana Floria}%
\author[1]{Daniela Maria Tanase}%
\affil[1]{Universitatea de Medicina si Farmacie Grigore T Popa lasi Facultatea de Medicina}%


\vspace{-1em}



  
  \date{May 25, 2024}


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Patent foramen oval and ESUS in cryptogenic stroke: still a complex
puzzle

Diana-Elena Iov\textsuperscript{1,2}, MD, Mariana
Floria\textsuperscript{1,3*}, MD, PhD, Daniela Maria
Tanase\textsuperscript{1,3}, MD, PhD

\textsuperscript{1}Faculty of Medicine, Department of Internal Medicine,
University of Medicine and Pharmacy ''Grigore T. Popa'', 700111 Iasi,
Romania.

\textsuperscript{2}Emergency Clinical Hospital ''Saint Spiridon'',
Institute of Gastroenterology and Hepatology, 700111 Iasi, Romania.

\textsuperscript{3}Emergency Clinical Hospital ''Saint Spiridon'',
Internal Medicine Clinic, 700111 Iasi, Romania.

\textbf{Running title:} Patent foramen oval related stroke

\textbf{ORCID and e-mail of all authors}

Diana-Elena Iov diana-elena.iov@d.umfiasi.ro;
https://orcid.org/0000-0003-2727-9913

Mariana Floria floria.mariana@umfiasi.ro;
https://orcid.org/0000-0002-9465-1503

Daniela Maria Tanase daniela.tanase@umfiasi.ro;
https://0000-0002-7144-2506

\textbf{Correspondence} : Floria Mariana, Internal Medicine Department,
Grigore T. Popa'' University of Medicine and Pharmacy,
16\textsuperscript{th} University Ia\selectlanguage{romanian}și, 700115, Romania. E-mail:
floria.mariana@umfiasi.ro; floria\_mariana@yahoo.com

\textbf{Conflict of interest}

The authors declare no potential conflict of interest.

Patent foramen oval (PFO) is an anatomical variant of the interatrial
septum. The two anatomical components of PFO, septum secundum and septum
primum, can act as a flap valve in almost 25\% of adult general
population, allowing a transient or continuous right-to-left shunt
(after a Valsalva maneuver or when the right atrial pressure exceeds the
left atrial pressure during a short interval of cardiac
cycle)\textsuperscript{1}. In these patients, PFO can act as a conduit
for paradoxical embolization (reported to be between 3.4\% and
11\%\textsuperscript{1}) and ischemic left circulation embolism. Patent
foramen oval has highly variable anatomical morphology with respect to
size, tunnel length, redundancy of septum, lipomatous hypertrophy,
thickness of septum secundum and relationship to neighboring
structures\textsuperscript{1}. The morphology of the interatrial septum
can be more complicated when PFO associates defects such as atrial
septal aneurysm and atrial septal defects. It can be associated with
embolic strokes of undetermined source (ESUS) - a subcategory of
ischemic cryptogenic stroke ranging from 9 to 25\% of all stroke
patients, migraine, peripheral embolism, platypnea-orthodeoxia syndrome
or Alzheimer's dementia\textsuperscript{2}. ESUS type of cryptogenic
strokes (without an identifiable etiology) is a clinical entity, which
requires an extensive and accurate diagnostic work-up. It was defined as
ischemic stroke that is not lacunar, detected by specific imaging
modality (computer-tomography or magnetic resonance imaging). In
addition, it comprise excluding the extracranial or intracranial
atherosclerosis causing \selectlanguage{english}[?]50\% luminal stenosis in arteries supplying the
area of ischemia, major risk cardio-embolic source of embolism or other
specific cause of stroke identified (e.g., arteritis, dissection,
migraine/vasospasm, or drug abuse).

The study of Polat F et al.\textsuperscript{3} analyzed atrial septum,
PFO and accompanying anatomical variant of right atrial structures in
migraine and ESUS patients. In addition, they compared RoPe and
High-risk PFO scores (two scores based on clinical and anatomical
criteria to identify high-risk PFO) in migraine and ESUS patients. In
this study, the patients with ESUS were older, with a higher prevalence
of diabetes and hypertension and exhibited notable echocardiographic
differences (higher pulmonary artery systolic pressure, increased
microbubble crossings through the interatrial septum, and longer PFOs).
They have also a slightly elevated High-risk PFO score. In this study,
both scores were not different between ESUS and migraine group, which
means that, practically, the presence of high-risk criteria alone may
not be sufficient to differentiate between ESUS and migraine patients
with PFO. This is underlie by another result of this study: ESUS
patients have had a slightly elevated High-risk PFO score. The patients
with migraine and PFO exhibit a higher prevalence of active smoking,
which means that tobacco use can affect migraine
patterns\textsuperscript{3}. The study of Polat F et al identified
distinctive features in patients with PFO, ESUS, and migraine, putting
other pieces in the puzzle of cryptogenic stroke/transient ischemic
attack. It is essential because it could help to stratify PFO with ESUS
patients (which seems to be a very inhomogeneous population) who are
most likely to benefit from an aggressive therapeutic approach. Symptoms
are important arguments in every pathology that impose treatment.\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

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Permeable foramen oval was incriminated in 40-56\% of cryptogenic stroke
patients younger than 55 years\textsuperscript{1}. 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
hypertrophy\textsuperscript{1}. When the patient with ESUS has a PFO
(\textbf{Figure 1} ), the stroke can be reclassified as
PFO-related\textsuperscript{4}. 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
parameters\textsuperscript{5} 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.

\textbf{Figure 1} . Patent foramen oval and embolic strokes of
undetermined source in cryptogenic stroke. \emph{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 (\textbf{R} isk \textbf{o} f \textbf{P} aradoxical\textbf{E}
mbolism) score can identify patients with PFO-mediated cryptogenic
stroke\textsuperscript{2}. 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
certainty\textsuperscript{2}. 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 low\textsuperscript{2}. 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 attack\textsuperscript{2}. 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
shunt\textsuperscript{5}. 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.\textsuperscript{3}reinforce 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 (\textless{}30 seconds) and this type of
stroke\textsuperscript{6}. 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
anticoagulation\textsuperscript{7}. 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 AF\textsuperscript{7}.

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 PFO\textsuperscript{8}.
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
recurrence\textsuperscript{9}.

ESUS has the highest rate of stroke recurrence compared to other
ischemic stroke subtypes (annual recurrence risk of
4.5--5\%)\textsuperscript{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 patients\textsuperscript{11}.

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 stroke\textsuperscript{12}. 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 added\textsuperscript{13}. Sometimes this shunt
work in association with the Chiari network. However, Chiari network is
detected in 83\% of patients with PFO\textsuperscript{12}. Recently, a
simple scoring system for the identification of high-risk PFO was
developed\textsuperscript{14}. A score value [?]2 points is associated
with 91\% sensitivity and 80\% specificity with cryptogenic
stroke\textsuperscript{14}. Older patients, with coagulation disorders,
a value of D--dimer \textgreater{}1000 ng/mL at admission, and
acetylsalicylic acid treatment (versus anticoagulation) have a higher
PFO-related stroke recurrence rate\textsuperscript{14}.

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
ESUS\textsuperscript{15}. 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.

\textbf{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.

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\end{enumerate}\selectlanguage{english}
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