• before birth, the atrial septum is formed by two leaves. After birth, the pressure rises in the left atrium, and the two leaves fuse together
  • in 1/3 of people, the leaves do not fuse, and a different-sized opening called a patent foramen ovale (PFO) or foramen ovale apertum (FOA) persist
  • PFO causes a right-to-left shunt – blood can flow from the right atrium directly into the left atrium, bypassing the pulmonary circulation
  • various particles in the blood can bypass the pulmonary circulation and enter the systemic circulation along with the blood (paradoxical embolism)
    • small blood clots released from the veins of the lower limbs and pelvis
    • gas bubbles (formed during rapid decompression in scuba divers or can be administered by IV injections)
    • certain hormones (serotonin in migraine with aura?)
  • PFO alone does not cause hemodynamic problems
  • PFO is not the only cause of right-to-left shunting:
Patent Foramen Ovale (PFO)

PFO and cryptogenic stroke

  • patent foramen ovale (PFO) is associated with cryptogenic stroke (CS), though the pathogenicity of discovered PFO in the setting of CS is typically unclear
    • the prevalence of PFO is ~ 25% in the general population and up to 46% in patients with CS
  • PFO is occasionally associated with the following conditions:
    • atrial septal aneurysm (ASA) /  hypermobile atrial septum – defined as excursion ≥ 10-15 mm from the midline Atrial septal aneurysm on TEE Patent Foramen Ovale (PFO) and Atrial Septal Aneurysm (ASA)
    • atrial septal defect
  • PFO-related stroke mechanisms:
    • paradoxical embolization from peripheral veins
    • embolization of a thrombus formed directly within the PFO canal
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Diagnostic evaluation

PFO detection

Contrast-enhanced transesophageal echocardiography (cTEE)

  • 2D or 3D + bubble test – sensitivity and specificity between 89-95%
  • information on PFO shape and size + associated pathologies (ASA, septal hypermobility, LAA thrombus, etc.)
  • disadvantages:
    • invasive nature of the procedure; some patients may not tolerate it
    • lower sensitivity for small PFOs
Patent Foramen Ovale on TEE with positive bubble test

TCD/TCCD bubble test

  • non-invasive screening method → see here
  • detects all right-to-left shunts (cardiac and extracardiac)
  • sensitivity and specificity reported over 90%
TCD/TCCD bubble test with proof of right-to-left shunt (grade II-IV)

Cardiac MRI/CTA

  • can be performed in patients who cannot tolerate TEE
  • provides information about potential thrombi and other pathology
  • may also be useful for monitoring PFO occlusion
Patent foramen ovale on cardiac CTA
Postcontrast MRI with detection of right-to-left shunt after contrast agent administration (left image). Amplatzer occluder on cardiac MRI (right image)

Other methods

Doppler ultrasound / MR venography

  • detection of a possible source of embolism in the veins of the pelvis and lower extremities
Right-sided deep vein thrombosis on the utrasound examiantion
MR venography showing thrombosis of the right femoral vein. Large arrow shows hypointense thrombus, small arrow edema.


  • normal D-dimer levels:  0.068-0.494 mg/L
  • leveles <0.5 mg/L make DVT unlikely but not impossible
  • false-positive results are common


  • primary prevention: PFO closure not indicated
  • secondary prevention:  consider antiplatelet or anticoagulant therapy and PFO closure

AAN 2020 ESC 2018 AHA/ASA 2021
PFO closure in carefully selected patients (thorough evaluation must exclude more plausible etiologies)
  • PFO closure followed by antiplatelet therapy over antiplatelet or anticoagulant therapy alone
  • patients < 60 years old with PFO who have had a cryptogenic ischemic stroke (extensive workup for other etiologies of stroke is negative)
In patients with ESUS and PFO, closure may be considered, taking into account the likelihood of a causal role of the PFO.
This should be a joint decision between the patient, the neurologist, and the cardiologist (I/C-EO)
  • antiplatelet or anticoagulant therapy (warfarin / DOAC)
  • the benefit of PFO closure is unknown when anticoagulation is indicated for another reason (e.g., VTE)
if the closure is not possible/available or is refused, anticoagulation is slightly preferred over antiplatelet therapy
in patients 18-60 years of age with ESUS and high-risk PFO prefer PFO closure followed by antiplatelet therapy (2a/B-R)
    in patients 18-60 years with ESUS and no high-risk PFO, the benefit of PFO occlusion versus antiplatelet therapy is not clearly established (2b/C-LD)
  in patients 18-60 years with ESUS and PFO, there is no known benefit of PFO occlusion versus warfarin (2b/C-LD)
    * different trials had different definitions (see table above)

Conservative approach

  • see table above – typically in patients with low-risk PFO, older age, and associated vascular risk factors in whom the causality of the PFO is highly uncertain
  • antiplatelet therapy or anticoagulation (warfarin/DOAC) may be used as a conservative treatment (AAN 2020, Level C)
    • the CLOSE trial was underpowered to demonstrate the superiority of anticoagulation over antiplatelet therapy
    • a subanalysis of the NAVIGATE-ESUS trial showed a lower risk of stroke recurrence in PFO patients with rivaroxaban compared with aspirin  [Kassner, 2018]
  • according to the ESC guidelines 2018, anticoagulation may be considered in high-risk PFOs (large shunt or PFO with atrial septal aneurysm)   Studie CLOSE
    • in secondary prevention, a meta-analysis of randomized trials found that PFO closure had better outcome compared to medical therapy in large shunts  Metaanalýza randomizovaných studií    [Ahmed, 2018]
    • AHA/ASA guidelines 2021 favor PFO closure in this setting  (2a/B-R)
  • if anticoagulation is indicated for another reason (e.g., VTE), the benefit of PFO closure is unknown ( AAN 2020, level  B)

Endovascular procedure

  • consider in carefully selected patients < 60 years of age with a high probability of paradoxical embolization (large shunt, embolic appearance of ischemia, high ROPE score)
    • the benefit of closure is similar in the age groups < 45 years and 45-60 years
    • closure may also be considered in patients aged 60-65 years without significant risk factors (AAN 2020, Level C)
  • a multidisciplinary approach is advised (neurologist in collaboration with cardiologist + patient) (AHA/ASA 2021  1/C-EO)
    • the vascular neurologist must assess the stroke mechanism and rule out other more likely etiologies!
  • the size of the R-L shunt seems to be crucial for the indication; the presence of ASA is probably less important
  • the patient must be informed about the benefits (absolute risk reduction 4.9%, NNT 20-29/5 years) and risks of the procedure (see below)
  • there are different types of occluders (e.g., Amplatzer Amplatzer occluder , STARflex Starflex occluder , Cardioform)
    • Amplatzer was approved by the FDA in the fall of 2016 based on 10 years of data from the RESPECT trial
    • Cardioform was approved by the FDA in 2018 based on data from the REDUCE trial  → see here
  • occluders are delivered percutaneously through the femoral vein into the right atrium and through the PFO into the left atrium
PFO closure
  • occlusion is associated with the following risks:
    • atrial fibrillation (even permanent!) – REDUCE 6.6%, CLOSE 4.6%!   [Chen, 2021]
    • thromboembolism
    • perforation of the heart with hemopericardium
    • air embolism
    • device-related thrombosis (DRT)
    • septal erosion
    • residual shunt
  • an interesting alternative with a minimum of complications offers NobleStitch EL

Post-procedural management

  • DAPT (ASA + clopidogrel) for 1-6 months, then monotherapy for ≥ 5 years   [Pristipino, 2018]
    • it is not clear whether antiplatelet drugs should be prescribed permanently or only temporarily (and for how long)
    • even after successful occlusion, the incidence of stroke is not zero  ⇒  other etiologies must be considered
  • prevention of bacterial endocarditis for 6 months
  • avoid activities with risk of large shocks or chest impact for 3 months
  • TTE controls – no standard protocol: usually 3 – (6) – 12 months after the procedure
  • a follow-up TCCD bubble test at 3 months is suggested after the procedure

PFO and migraine

  • a higher prevalence of PFO has been reported in patients with migraine with aura than in patients with migraine without aura or patients without migraine (48% vs. 23% and 20%, respectively).
  • the causal relationship remains unclear
  • some small non-randomized trials have reported a reduced incidence of migraine after PFO closure
  • randomized MIST  (Starfix, 2016) and PREMIUM (Amplatzer, 2017) trials did not show a preventive effect
    • MIST –  primary outcome: migraine regression in 3 of 74 (occlusion) vs. 3 of 74 (control), significant complications (SAEs) in 16 of 74 patients
    • PREMIUM – primary outcome: 45/117 (Amplatzer) vs. 33/103 (control)
  • in conclusion, it is less likely that PFO plays a role in the development of migraine headache
  • the role of PFO in the development of ischemic stroke in migraineurs has not been determined yet
    • patients with both migraine and stroke had larger shunts than patients with migraine without stroke, patients without migraine with stroke, and controls 
    • concerning the white matter hyperintensities (WMH), overall WMH did not differ by PFO presence; however, juxtacortical WMHs are more frequently found in patients with migraine and right-to-left shunting
    • these findings suggest that incidental PFO may increase the risk of ischemic stroke in migraineurs

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Patent foramen ovale (PFO)
link: https://www.stroke-manual.com/patent-foramen-ovale-pfo/