Patent Foramen Ovale Closure in Cryptogenic Stroke

Patent foramen ovale (PFO) is present in approximately 25% of the general population, but is found in 40-50% of patients with cryptogenic stroke — raising the question of whether PFO is the culprit or an incidental finding. The challenge in clinical practice is determining which patients have a causally related PFO that warrants closure versus those in whom the PFO is merely a bystander.

After initial disappointment with the CLOSURE I trial in 2012, three landmark trials in 2017 (RESPECT, CLOSE, REDUCE) established that PFO closure reduces stroke recurrence in appropriately selected patients — those with cryptogenic stroke and high-risk PFO features.

Pathophysiology: Paradoxical Embolism

PFO allows right-to-left shunting during transient elevations in right atrial pressure (Valsalva maneuver, coughing, straining), providing a conduit for venous thrombi to bypass the pulmonary circulation and embolize to the brain. Clinical clues suggesting paradoxical embolism include: wake-up stroke, Valsalva-associated onset, recent DVT or prolonged immobility, and cortical infarct pattern in a young patient without traditional vascular risk factors.

Diagnosis of PFO

Transthoracic Echocardiography (TTE) with Agitated Saline

TTE with bubble study is the first-line screening test. The patient is coached to perform a Valsalva maneuver, and agitated saline is injected intravenously with release of Valsalva during injection.

• Timing matters: Bubbles appearing within 3 cardiac cycles indicate an intracardiac shunt (PFO); later appearance (>3-6 cycles) suggests a pulmonary arteriovenous shunt
• Sensitivity is limited (~50-60%) — a negative TTE does not exclude PFO
• Adequate Valsalva is critical; suboptimal effort is a common cause of false negatives

Transesophageal Echocardiography (TEE)

TEE is the gold standard for PFO visualization and characterization. It allows direct measurement of PFO size, tunnel length, and detection of atrial septal aneurysm (ASA).

• Critical: Bubble study on TEE requires minimal or no sedation to permit an effective Valsalva maneuver — heavy sedation renders the bubble study unreliable
• Indication: If TTE is negative but clinical suspicion is high (young patient with ESUS, negative workup, high RoPE score), TEE should be performed to confirm or exclude PFO

Transcranial Doppler (TCD) with Bubble

TCD with agitated saline has high sensitivity for detecting right-to-left shunt but does not localize the shunt (cardiac vs. pulmonary). It is a useful screening tool when TEE is not feasible or as an adjunct to TTE.

Shunt Grading by Bubble Count

Workup Prior to PFO Closure

Before attributing stroke to PFO and proceeding with closure, a comprehensive workup must confirm truly cryptogenic stroke.

Cardiac Monitoring

• At least 1 month of continuous cardiac monitoring (external loop recorder or patch monitor) to rule out paroxysmal AF
• Longer monitoring with implantable loop recorder may be considered in select cases with high suspicion for occult AF

Hypercoagulability Panel

• Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2 glycoprotein I)
• Consider Factor V Leiden, prothrombin gene mutation, protein C/S, antithrombin III — particularly in younger patients or those with VTE history

Evaluation for Venous Thrombus Source

• Lower extremity venous duplex — screen for DVT
• Pelvic venous imaging (CTV or MRV) — iliac and pelvic DVT are often missed on leg duplex alone

Standard Stroke Workup

• Brain MRI (infarct pattern — cortical suggests embolic)
• Vessel imaging (CTA/MRA head and neck)
• Lipid panel, HbA1c
• Must exclude large artery atherosclerosis, lacunar mechanism, and other cardioembolic sources

Who Should Get Closure?

RoPE Score (Risk of Paradoxical Embolism)

The RoPE score estimates the probability that a PFO found in a cryptogenic stroke patient is causally related to the stroke, rather than incidental.

Interpretation:

• RoPE ≥7: High probability stroke is PFO-attributable (~70-80%); closure likely beneficial
• RoPE 0-6: Lower attributable fraction; benefit of closure less certain

PASCAL Classification

The PASCAL classification combines the RoPE score with PFO anatomical features to better identify closure candidates. It integrates clinical probability (from RoPE) with high-risk PFO characteristics.

PFO features assessed:

• Large shunt (≥20 bubbles or “curtain”)
• Atrial septal aneurysm (ASA)
• Atrial septal hypermobility

Evolution of PFO Closure Evidence

The initial CLOSURE I trial (2012) failed to show benefit, likely due to a broader patient population without requirement for high-risk PFO features and use of an inferior device (STARFlex, now discontinued). In 2017, three landmark trials changed the paradigm. RESPECT showed a 45% relative risk reduction with the Amplatzer device over extended follow-up (HR 0.55). CLOSE demonstrated the most dramatic results — 0% stroke recurrence in the closure arm versus 6% with antiplatelet therapy alone (HR 0.03) — in patients with high-risk PFO features (ASA or large shunt). REDUCE confirmed benefit with GORE devices (HR 0.23, 77% RRR). DEFENSE-PFO (2018) reinforced these findings specifically in patients with high-risk anatomical features, with 0% versus 10.5% stroke recurrence.

PFO Closure Devices

Complications of PFO Closure

• Atrial fibrillation (4-6%) — usually occurs within the first 45 days post-procedure; most episodes are transient and self-resolve without long-term sequelae
• Device thrombosis — rare with contemporary devices; mitigated by post-procedure antithrombotic therapy
• Residual shunt (~5-10% at 1 year) — small residual shunts are often clinically insignificant; larger shunts may warrant repeat closure or continued medical therapy
• Vascular access complications — hematoma, arteriovenous fistula (<2%)
• Device erosion/embolization — very rare with modern devices

Post-Closure Antithrombotic Therapy

Regimens vary by device and institution. A typical approach:

• DAPT (aspirin 81-325 mg + clopidogrel 75 mg) for 1-6 months
• Followed by aspirin monotherapy for 2-5 years (some clinicians continue indefinitely)
• Some centers use anticoagulation for 3-6 months if large ASA or perceived high thrombus risk

Follow-Up

• TTE or TEE with bubble study at 6-12 months to assess device position and residual shunt
• If significant residual shunt persists, consider repeat closure procedure or continued antiplatelet/anticoagulation therapy

Trial Comparison Table

References

1. Furlan AJ, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale (CLOSURE I). N Engl J Med. 2012;366(11):991-999.
2. Saver JL, et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke (RESPECT). N Engl J Med. 2017;377(11):1022-1032.
3. Mas JL, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke (CLOSE). N Engl J Med. 2017;377(11):1011-1021.
4. Søndergaard L, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke (REDUCE). N Engl J Med. 2017;377(11):1033-1042.
5. Lee PH, et al. Cryptogenic stroke and high-risk patent foramen ovale (DEFENSE-PFO). J Am Coll Cardiol. 2018;71(20):2335-2342.
6. Kent DM, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke (RoPE Score). Neurology. 2013;81(7):619-625.
7. Diener HC, et al. Cryptogenic stroke and patent foramen ovale: The PASCAL Scoring System. J Am Coll Cardiol. 2019;73(9):1096-1097.