Why use it

Not all PFOs are created equal — the PASCAL classification quantifies causal likelihood to guide the most consequential decision in cryptogenic stroke management: whether to close the PFO. Closure in Probable/high-risk cases significantly reduces stroke recurrence (NNT 20–40 over 5 years). Using PASCAL avoids closure in patients with incidental PFOs and alternative stroke etiologies, and helps identify Possible cases who warrant additional workup before deciding on intervention.

About

The PASCAL (PFO-Associated Stroke Causal Likelihood) classification is a validated clinical framework developed by Wessler and colleagues, published in JACC: Cardiovascular Interventions in 2022, to systematically estimate the probability that a patent foramen ovale (PFO) is causally responsible for an ischemic stroke. PFOs are found in approximately 25–27% of the general population, and their presence alone does not confirm causality — the challenge in cryptogenic stroke evaluation is distinguishing a causal PFO from an incidental finding. PASCAL integrates two independent domains: (1) Anatomical risk features of the PFO itself, and (2) Clinical features of the patient and stroke that raise or lower the prior probability of PFO-mediated embolism. Based on these two domains, strokes are classified as Probable PFO-related, Possible PFO-related, or Unlikely PFO-related. This classification directly informs the decision for PFO closure, anticoagulation, or antiplatelet therapy. Multiple randomized controlled trials (CLOSE, REDUCE, DEFENSE-PFO, RESPECT long-term) have demonstrated that PFO closure is superior to antiplatelet therapy in reducing recurrent stroke in appropriately selected patients with high-risk PFO anatomy and favorable clinical profile.

When to use

Ischemic stroke or TIA in a patient found to have a PFO on echocardiography (bubble study or TEE/TTE)
Cryptogenic stroke workup — after completing the standard evaluation (cardiac monitoring ≥30 days, hypercoagulable panel, vascular imaging, advanced cardiac imaging)
Shared decision-making discussions about PFO closure vs. medical therapy in stroke survivors
Guiding referral to interventional cardiology for PFO closure in high-probability cases
NOT for primary stroke prevention or asymptomatic PFO incidentally found

Formula

PASCAL CLASSIFICATION: STEP 1 — ANATOMICAL DOMAIN (PFO features): High-Risk Anatomy: • Moderate/Large PFO (probe-patent gap ≥2 mm OR right-to-left shunt grade ≥2) AND • Atrial Septal Aneurysm (ASA, excursion ≥10 mm or base >15 mm) or Hypermobile Septum Intermediate-Risk Anatomy: • Large PFO alone (without ASA/hypermobility) • Small PFO (<2 mm) with ASA • Prominent Eustachian valve or Chiari network Low-Risk Anatomy: • Small PFO (<2 mm) without ASA or hypermobile septum STEP 2 — CLINICAL DOMAIN (patient and stroke features): High Clinical Probability Features: • Age ≤45 at stroke onset • Cryptogenic stroke (no alternative etiology identified after complete workup) • Embolic infarct pattern on MRI (cortical or juxtacortical, or multiple territories) • Valsalva-associated stroke onset • DVT, PE, or hypercoagulable state • Absence of vascular risk factors (no HTN, DM, AF, smoking, hyperlipidemia) STEP 3 — COMBINED PASCAL CLASSIFICATION: PROBABLE: High-risk anatomy + ≥3 high clinical features + no alternative etiology POSSIBLE: High-risk anatomy + 1–2 clinical features; OR Intermediate anatomy + high clinical UNLIKELY: Low-risk anatomy; OR alternative etiology identified; OR low clinical probability

Pearls & pitfalls

High-risk PFO anatomy (large PFO + atrial septal aneurysm) confers the greatest absolute risk reduction with closure — the CLOSE trial (2017) showed 97% relative risk reduction in this subgroup.
The key anatomical risk marker is the COMBINATION of large PFO (≥2 mm probe-patent gap or right-to-left shunt grade ≥2) with ASA (septal excursion >10 mm) — neither alone carries the same risk as the combination.
Clinical high-risk features (young patient, cryptogenic stroke, embolic pattern on MRI, Valsalva-associated onset, absence of vascular risk factors) substantially strengthen causal attribution.
Prolonged cardiac monitoring (ideally ≥30 days via implantable loop recorder) is MANDATORY before PFO closure to exclude atrial fibrillation — AF changes management entirely (anticoagulation, not closure).
A Valsalva-associated stroke onset (during straining, coughing, defecation, heavy lifting) is a highly specific feature of paradoxical embolism through the PFO.
The presence of DVT, pulmonary embolism, or a hypercoagulable state (Factor V Leiden, protein C/S deficiency, antiphospholipid syndrome) supports a paradoxical embolism mechanism.
Age >60 with multiple vascular risk factors shifts the prior probability toward a competing etiology (small vessel disease, large artery atherosclerosis) even if PFO anatomy is high-risk.
The RoPE (Risk of Paradoxical Embolism) score, while predating PASCAL, provides complementary information and assigns a pre-test probability to PFO causality.
TEE is preferred over TTE for anatomical characterization of PFO — it provides better visualization of ASA, septum mobility, and can measure PFO diameter accurately.
After transcatheter PFO closure, dual antiplatelet therapy (aspirin + clopidogrel) for 1–6 months is standard to prevent device thrombosis, followed by aspirin monotherapy indefinitely.

Next steps

Probable PFO-Related Stroke: PFO closure should be strongly considered in appropriate candidates (age typically ≤60, no major contraindications to closure, completed embolism workup excluding alternative etiology). Class I or IIa recommendation in major guidelines (ESC 2021, AHA/ASA 2021). Add antiplatelet therapy until closure is confirmed complete. Possible PFO-Related Stroke: Further workup to exclude alternative etiology (extended cardiac monitoring, hypercoagulable testing, vasculitis screen). Individualize closure decision based on patient age, anatomy, and preferences. Antiplatelet therapy as default unless hypercoagulable state identified. Unlikely PFO-Related Stroke: Treat the identified etiology. No indication for PFO closure. PFO is considered incidental. Optimize secondary stroke prevention per underlying etiology (anticoagulation for AF, statin/antihypertensive for small vessel disease, etc.).

Evidence

Wessler BS et al. PFO-Associated Stroke Causal Likelihood (PASCAL) Classification System: A Framework for Clinical Decision-Making. JACC Cardiovasc Interv. 2022;15(17):1711-1727. PMID:36055663. Key RCTs supporting PFO closure: CLOSE (N Engl J Med 2017;377:1011-1021, PMID:28902593); REDUCE (N Engl J Med 2017;377:1022-1032, PMID:28902585); DEFENSE-PFO (Circulation 2018;137:209-217, PMID:29030346); RESPECT long-term (N Engl J Med 2017;377:1022-1032). Meta-analysis: Turc G et al. Stroke 2018 — closure reduces recurrence by ~50–60% vs antiplatelet in selected patients. ESC 2021 Guidelines on PFO management.

References

Wessler BS et al. PFO-Associated Stroke Causal Likelihood (PASCAL) Classification System. JACC Cardiovasc Interv. 2022;15(17):1711-1727. — link
Mas JL et al. (CLOSE Trial). Patent Foramen Ovale Closure or Anticoagulants versus Antiplatelet Therapy after Stroke. N Engl J Med. 2017;377:1011-1021. — link
Søndergaard L et al. (REDUCE Trial). Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Engl J Med. 2017;377:1033-1042. — link
Lee PH et al. (DEFENSE-PFO Trial). Cryptogenic Stroke and High-Risk Patent Foramen Ovale. Circulation. 2018;137:209-217. — link
Pristipino C et al. (ESC). European position paper on the management of patients with patent foramen ovale. Eur Heart J. 2019;40(38):3182-3195. — link

PFO-Associated Stroke Causal Likelihood (PASCAL)

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