Overview

The PFO-Associated Stroke Causal Likelihood (PASCAL) Classification System is a structured framework for estimating whether an index ischemic stroke in a patient with a patent foramen ovale (PFO) is causally related to that PFO. PASCAL was developed to address a common clinical dilemma: after cryptogenic stroke, transthoracic or transesophageal echocardiography often reveals a PFO, yet not every PFO is pathogenic. Incidental PFOs are common in the general population, and many strokes have alternative mechanisms even when a shunt is present.

PASCAL integrates two well-established dimensions of PFO-related stroke risk: the Risk of Paradoxical Embolism (RoPE) score, which captures the clinical phenotype suggestive of paradoxical embolism, and high-risk PFO anatomy, which reflects structural features associated with greater right-to-left shunting and higher event rates in observational and trial data. The result is a simple 2×2 classification that places patients into one of three likelihood strata: unlikely, possible, or probable PFO-attributable stroke.

This tool is intended for education, shared decision-making, and multidisciplinary discussion. It does not replace guideline-directed medical therapy, complete stroke etiology evaluation, or individualized procedural risk assessment for PFO closure.

Clinical background: cryptogenic stroke and the PFO question

Cryptogenic (embolic stroke of undetermined source, ESUS) stroke accounts for a substantial fraction of ischemic strokes, particularly in younger patients without obvious cardioembolic or large-vessel sources. When brain imaging and vascular studies do not identify an alternative mechanism, attention often turns to occult embolism, including paradoxical embolism through a PFO.

A PFO is a persistent interatrial communication that can permit right-to-left passage of venous thrombus under conditions that raise right atrial pressure (Valsalva, pulmonary embolism, obstructive sleep apnea, and others). The biologic plausibility of PFO-mediated stroke is strongest when the clinical and imaging pattern fits paradoxical embolism: younger age, cortical or multifocal infarcts, absence of traditional vascular risk factors, and no competing high-risk source such as atrial fibrillation.

Randomized trials of percutaneous PFO closure versus medical therapy alone have shown benefit in selected populations, but treatment effects are not uniform across all patients with PFO and stroke. PASCAL helps clinicians and patients articulate how strongly the PFO is implicated as the stroke mechanism before pursuing closure, which carries procedural risk and long-term follow-up obligations.

Why PASCAL was developed

Prior to PASCAL, clinicians often relied separately on the RoPE score, shunt size on agitated saline contrast studies, and the presence of an atrial septal aneurysm (ASA). Each measure adds information, but using them in isolation can be ambiguous. A high RoPE score with a small shunt may still warrant discussion; a large shunt in an older patient with hypertension may be less likely to be causal.

PASCAL formalizes a cross-classification aligned with trial populations and outcome analyses from the PFO closure literature. By collapsing RoPE into a binary threshold at 7 points and PFO anatomy into presence or absence of high-risk features, PASCAL yields three actionable strata that map to increasingly strong inference that the index stroke should be attributed to the PFO.

Prerequisites before applying PASCAL

PASCAL should be applied only after a stroke work-up appropriate to the clinical context. Key prerequisites include:

• Confirmed ischemic stroke or TIA as the index event, with imaging consistent with the clinical syndrome.
• PFO documented on echocardiography (transthoracic echo with bubble study and/or transesophageal echo as clinically indicated).
• Competing stroke mechanisms evaluated and addressed, including prolonged cardiac monitoring for atrial fibrillation, cervical and intracranial vascular imaging, hypercoagulability testing when indicated, and assessment for other cardioembolic sources.
• RoPE score calculated from index-event variables (age, vascular risk factors, infarct topography, and related items per the RoPE instrument).
• PFO anatomy characterized for shunt burden and septal morphology per local imaging standards.

If a definite alternative cause is identified (for example, symptomatic carotid stenosis, atrial fibrillation with clear temporal relationship, or intracranial atherosclerosis explaining the infarct territory), PASCAL does not override that attribution. The framework assumes the remaining question is whether the PFO plausibly caused a otherwise cryptogenic event.

Input 1: RoPE score threshold (≥7 vs <7)

The RoPE score estimates the probability that a discovered PFO is pathogenic (stroke-related) rather than an incidental finding in the setting of cryptogenic stroke. It incorporates clinical features inversely associated with conventional atherothrombotic risk and positively associated with paradoxical embolism, including younger age, absence of hypertension and diabetes, non-smoking status, absence of prior stroke/TIA, cortical infarct on imaging, and clinical evidence of a cortical syndrome.

RoPE scores range from 0 to 10. Higher scores indicate a greater estimated PFO-attributable fraction and, in derivation cohorts, higher recurrence risk among medically treated patients. PASCAL uses a single cut point:

• RoPE ≥7: clinical profile strongly favors a PFO-related mechanism.
• RoPE <7: clinical profile less characteristic of paradoxical embolism; incidental PFO is more plausible.

When using this calculator, compute the full RoPE score first, then enter whether the total is at least 7. Borderline scores should be interpreted in full clinical context, including infarct pattern, embolic-appearing lesions, and the completeness of stroke evaluation.

Input 2: High-risk PFO features

The second PASCAL input is whether the PFO demonstrates high-risk anatomy, typically defined as:

• Large right-to-left shunt on agitated saline contrast study (often graded as substantial or large passage of microbubbles at rest or with provocative maneuver, per institutional protocol), and/or
• Atrial septal aneurysm (ASA), characterized by excessive mobility of the septum primum in the fossa ovalis region.

These features have been associated with higher stroke recurrence in observational studies and enriched many patients enrolled in PFO closure trials. Exact definitions of shunt size vary by laboratory technique (transthoracic vs transesophageal echo, number of bubbles at rest vs Valsalva, timing of appearance). PASCAL should be applied using definitions consistent with your echocardiography report and local guidelines.

Neither a small shunt nor the absence of ASA excludes paradoxical embolism entirely; PASCAL simply reflects that, when RoPE is also low, the combined likelihood of PFO causality is reduced.

The PASCAL classification grid

PASCAL assigns likelihood by crossing the two binary inputs:

RoPE score	High-risk PFO feature	PASCAL likelihood
< 7	Absent	Unlikely
< 7	Present	Possible
≥ 7	Absent	Possible
≥ 7	Present	Probable

Only the cell with both RoPE ≥7 and high-risk anatomy reaches the probable stratum. Discordant combinations (high RoPE without high-risk anatomy, or high-risk anatomy with low RoPE) fall into the possible intermediate category.

Interpretation by likelihood stratum

Unlikely PFO-attributable stroke

This stratum applies when RoPE is below 7 and no high-risk PFO features are present. The clinical and anatomic profile together suggest that the PFO may be incidental relative to the index stroke. Management emphasis typically includes:

• Thorough search for alternative mechanisms not yet excluded.
• Guideline-directed secondary prevention for ischemic stroke (antiplatelet therapy, vascular risk factor control, lifestyle modification).
• Conservative approach to PFO closure unless compelling new information emerges.

Counseling should acknowledge that a PFO is present but that PASCAL does not support strong causal attribution to the index event.

Possible PFO-attributable stroke

The intermediate stratum captures two distinct clinical scenarios:

• RoPE ≥7 without high-risk PFO anatomy: the phenotype fits paradoxical embolism, but structural risk markers are absent.
• RoPE <7 with high-risk PFO anatomy: the shunt or ASA raises concern, but the clinical profile is less typical for PFO-mediated stroke.

These patients often benefit from multidisciplinary review (neurology, cardiology, and sometimes hematology). Decisions regarding closure versus medical therapy alone should incorporate patient age, infarct severity, recurrent event risk, procedural candidacy, device-specific considerations, and patient preferences. PASCAL supports nuanced counseling: causality is plausible but not definitive.

Probable PFO-attributable stroke

When RoPE is at least 7 and high-risk PFO features are present, PASCAL places the case in the highest causality stratum. This combination aligns with patients who experienced the greatest relative benefit from closure in pooled trial analyses compared with medical therapy alone.

Clinical next steps often include:

• Discussion of percutaneous PFO closure versus continued medical therapy, including risks of the procedure and need for post-procedural antiplatelet regimens.
• Confirmation that no alternative stroke source remains untreated.
• Long-term vascular risk reduction regardless of closure decision.

Probable attribution does not mandate closure in every patient; contraindications, anatomical unsuitability, bleeding risk on antithrombotic therapy, and informed refusal remain relevant.

Relationship to PFO closure trials and guidelines

Randomized trials comparing PFO closure plus medical therapy to medical therapy alone (including RESPECT, CLOSE, REDUCE, and DEFENSE-PFO among others) established that closure reduces recurrent stroke in selected patients with cryptogenic stroke and PFO. Benefit has been most consistent among patients with RoPE ≥7 and high-risk PFO characteristics, which corresponds to the PASCAL probable group.

Professional society guidance has evolved to support shared decision-making for closure in patients with clinical and anatomic features similar to trial enrollees, after careful etiologic evaluation. PASCAL does not replace guideline documents or local pathways; it translates trial-enriched characteristics into a bedside-friendly classification for counseling.

Medical therapy alone remains appropriate for many patients, particularly when PASCAL likelihood is unlikely or when procedural risk outweighs expected benefit.

Integration with stroke etiology work-up

PASCAL is most informative when embedded in a complete diagnostic algorithm:

1. Acute stroke management per local protocols, including reperfusion when eligible.
2. Brain and vessel imaging to define infarct pattern and exclude large-artery and small-vessel causes.
3. Cardiac evaluation, with extended rhythm monitoring duration tailored to stroke severity and yield (often 30 days or longer in cryptogenic stroke).
4. Echocardiography with bubble study; transesophageal echo when better septal visualization is needed for closure planning or ASA assessment.
5. RoPE calculation and PASCAL classification.
6. Multidisciplinary decision regarding closure, antithrombotic regimen, and secondary prevention targets.

Reclassification may be warranted if new data appear (for example, atrial fibrillation on implantable loop recorder, or a deep penetrating artery infarct suggesting small-vessel disease).

Special populations and clinical nuances

Young adults commonly have higher RoPE scores; PASCAL should still be paired with evaluation for hypercoagulability, cervical artery dissection, and migraine-related stroke mimics when appropriate.

Pregnancy and postpartum stroke may increase right-to-left shunting; high-risk anatomy may be more consequential, but management must account for obstetric considerations and device timing.

Deep infarcts without cortical involvement lower RoPE and may shift PASCAL toward unlikely or possible strata even when a PFO is present.

Prior closure or device is outside the scope of index-event PASCAL; recurrent events after closure require separate assessment (residual shunt, device thrombus, alternative mechanisms).

Limitations and cautions

• PASCAL is a classification aid, not a diagnostic test with independent sensitivity or specificity reported for every setting.
• Shunt grading and ASA reporting vary across laboratories; inconsistent definitions can misclassify patients.
• RoPE was derived in cryptogenic stroke cohorts; applying it when alternative causes are likely inflates perceived PFO attribution.
• PASCAL does not quantify absolute recurrence risk or procedural benefit; it stratifies causal likelihood.
• Shared decision-making must include bleeding risk, occupational factors, sports restrictions, and patient values.
• Closure candidacy depends on anatomic suitability, venous thromboembolism risk, and access to experienced structural heart programs.

How to use this calculator

On the Calculator tab, answer two questions:

1. Is the RoPE score 7 or higher?
2. Is a high-risk PFO feature present (large shunt and/or atrial septal aneurysm)?

The tool displays the PASCAL likelihood stratum (unlikely, possible, or probable), highlights the corresponding row in the classification grid, and provides brief educational context for counseling. Use the Formula Explained tab for variable definitions and the classification table. For RoPE point assignment, use the dedicated RoPE score calculator on CalcMD.

Disclaimer: This content is for educational purposes only and is not medical advice. All treatment decisions require evaluation by qualified clinicians familiar with the individual patient.