Patent Foramen Ovale

A patent foramen ovale (PFO) is a persistent flap like channel across the interatrial septum at the fossa ovalis. It is left when the septum primum fails to fuse with the septum secundum after birth.

It is present in about 25% of adults, with prevalence falling and size rising with age (mean diameter about 5 mm, range 1 to 19 mm). Most carriers never have an event.

A PFO matters in five settings: cryptogenic ischaemic stroke or transient ischaemic attack (TIA) through paradoxical embolism, migraine with aura, decompression illness in divers, platypnoea orthodeoxia, and hypoxaemia when right sided pressures are raised.

It is found in about 40 to 50% of patients under 55 years with cryptogenic stroke.

Pathophysiology. The foramen ovale works as a flap valve. Left atrial pressure normally holds the septum primum against the septum secundum.

When right atrial pressure exceeds left atrial pressure (Valsalva, cough, straining, pulmonary embolism, right ventricular infarction, pulmonary hypertension, sleep apnoea), blood crosses right to left, carrying venous thrombus, gas bubbles or vasoactive substances into the systemic circulation.

Thrombus can also form in situ within the PFO tunnel.

Features that make a PFO more likely to be causal:

• a large shunt
• an atrial septal aneurysm
• a long tunnel
• a prominent Eustachian valve or Chiari network directing inferior caval flow towards the septum
• a cortical embolic infarct pattern in a younger patient with few vascular risk factors

Most PFOs are silent and are found incidentally on echocardiography. Clinical presentations are:

• Cryptogenic ischaemic stroke or TIA, often a sudden cortical deficit, sometimes after straining, prolonged sitting or long haul travel
• Migraine with aura, with or without a history of stroke
• Decompression illness in divers: neurological (spinal, cerebral, vestibular) or cutaneous (cutis marmorata) within hours of surfacing
• Platypnoea orthodeoxia: dyspnoea and desaturation on sitting or standing, relieved supine, with oxygen saturation falling by 5% or more (or PaO2 by over 4 mm Hg) on moving from supine to upright
• Hypoxaemia out of proportion to lung disease in right ventricular infarction, pulmonary embolism or pulmonary hypertension
• Systemic embolism: acute limb ischaemia, renal or splenic infarction, myocardial infarction with unobstructed coronary arteries

Examination is usually normal and no murmur is expected. Examine the legs for deep vein thrombosis and look for signs of right sided pressure overload.

Red flags.

• Stroke or TIA under 60 years with no other cause after full workup
• Recurrent embolic events on antiplatelet therapy
• Acute pulmonary embolism or proximal deep vein thrombosis with a known PFO
• Thrombus straddling the PFO on echocardiography (thrombus in transit)
• Resting hypoxaemia that worsens upright
• Neurological symptoms soon after diving

• Agitated saline contrast transthoracic echocardiography. Mix 9 mL saline with 1 mL air between two syringes via a three way tap and inject through an antecubital vein. Image at rest and with a Valsalva manoeuvre released just after injection.
• Bubbles in the left atrium within 3 cardiac cycles indicate an intracardiac shunt. Arrival after 5 or more cycles points to an intrapulmonary shunt. Shunt size is graded by bubble count (small under 10, moderate 10 to 30, large over 30; grading schemes vary).
• Transoesophageal echocardiography. Defines the tunnel length, septal aneurysm, Eustachian valve, left atrial appendage thrombus and aortic arch atheroma.
• Transcranial Doppler with bubbles. Sensitive for right-to-left shunt but cannot localise its level.
• Stroke workup. Brain MRI, vascular imaging of cervical and intracranial arteries, ECG, and ambulatory rhythm monitoring for at least 4 weeks (or an implantable loop recorder) to exclude atrial fibrillation.
• Venous source. Leg vein duplex, with MR venography of the pelvic veins when suspicion is high. Antiphospholipid antibodies are checked in younger patients, and a wider thrombophilia screen when there is recurrent venous thrombosis or a family history.

Attribution of the stroke to the PFO. The Risk of Paradoxical Embolism (RoPE) score gives 1 point each for no hypertension, no diabetes, no prior stroke or TIA, non-smoker, and cortical infarct on imaging.

Age points are added: 18 to 29 years 5, 30 to 39 years 4, 40 to 49 years 3, 50 to 59 years 2, 60 to 69 years 1, 70 years or over 0 (maximum 10).

The estimated PFO-attributable fraction is 0% for scores 0 to 3, 38% for 4, 34% for 5, 62% for 6, 72% for 7, 84% for 8 and 88% for 9 to 10.

Combining the score with high risk anatomy (atrial septal aneurysm or large shunt) classifies the PFO as:

• Unlikely causal: RoPE under 7 and no high risk feature
• Possibly causal: RoPE under 7 with a high risk feature, or RoPE 7 or over without one
• Probably causal: RoPE 7 or over with a high risk feature

Differential diagnosis.

• Secundum atrial septal defect (fixed defect with a deficient septum secundum, not a flap)
• Sinus venosus defect
• Pulmonary arteriovenous malformation (late bubbles; consider hereditary haemorrhagic telangiectasia)
• Other causes of embolic stroke: atrial fibrillation, left atrial appendage thrombus, aortic arch atheroma, infective endocarditis, carotid or vertebral dissection, antiphospholipid syndrome, cancer associated hypercoagulability
• Small vessel disease and large artery atherosclerosis

Asymptomatic or incidental PFO. No treatment, no antithrombotic therapy and no closure.

Cryptogenic stroke or TIA with PFO. Acute stroke treatment is unchanged by the PFO.

• Secondary prevention: aspirin 75 to 100 mg orally once daily, or clopidogrel 75 mg orally once daily if aspirin is not tolerated. Long term. Usual maximum 325 mg daily for aspirin and 75 mg daily for clopidogrel. Avoid omeprazole and esomeprazole with clopidogrel (reduced activation); use pantoprazole 40 mg daily when gastric protection is needed.
• Transcatheter closure with a double disc nitinol occluder is considered when all of these hold:
  • age 18 to 60 years
  • ischaemic stroke with an infarct on imaging
  • no alternative cause after full workup including rhythm monitoring
  • a PFO classed as probably or possibly causal, or with an atrial septal aneurysm or large shunt
  • agreement between cardiologist and neurologist
• Randomised studies show fewer recurrent strokes after closure than with antiplatelet therapy alone, with the greater benefit in patients with an atrial septal aneurysm or large shunt. Benefit above 60 years is not established.
• Contraindications to closure: active infection, intracardiac thrombus, inability to take antiplatelet therapy, severe pulmonary hypertension in which the PFO decompresses the right heart, and nickel allergy (nitinol devices).
• After closure: aspirin 75 to 100 mg plus clopidogrel 75 mg orally once daily for 1 to 3 months, then aspirin 75 to 100 mg once daily for at least 5 years. Antibiotic prophylaxis for dental procedures is usual for the first 6 months, until the device is endothelialised.
• Closure complications: new atrial fibrillation in about 4 to 6%, mostly early and often self-limiting; residual shunt in a minority; device thrombus; erosion or embolisation (rare); pericardial effusion; vascular access injury.
• New atrial fibrillation after closure: oral anticoagulation, because the prior stroke carries 2 points on the CHA2DS2-VASc score.
• Apixaban 5 mg orally twice daily, reduced to 2.5 mg twice daily when at least two of age 80 years or over, weight 60 kg or under and serum creatinine 133 micromol/L or over are present. Also 2.5 mg twice daily at creatinine clearance 15 to 29 mL/min, and avoided under 15 mL/min.
• Maximum 10 mg daily. Long term. Reduce the dose or avoid with strong dual CYP3A4 and P-glycoprotein inhibitors such as ketoconazole and ritonavir.

Thrombus in transit across the PFO. Emergency. Start intravenous unfractionated heparin 80 units/kg bolus, then 18 units/kg/h, adjusted to anti-Xa 0.3 to 0.7 IU/mL or an aPTT ratio of 1.5 to 2.5, with no fixed maximum. Check platelets on days 5 to 14 for heparin induced thrombocytopenia. Reduce or withhold in active bleeding. Surgical embolectomy or thrombolysis is decided by the heart team on the basis of haemodynamics and bleeding risk.

Platypnoea orthodeoxia. Closure is effective once pulmonary hypertension and raised right atrial pressure have been excluded. A balloon test occlusion at catheterisation with pressure and saturation measurement confirms that closure is safe.

Migraine and decompression illness. Closure is not advised for migraine alone, because randomised studies did not show consistent benefit. In divers with prior neurological or cutaneous decompression illness who continue to dive, closure or a more conservative dive profile is considered.

Special groups.

• Pregnancy: closure is not performed. After a paradoxical embolic event use aspirin 75 to 150 mg orally once daily. Treat venous thrombosis with enoxaparin 1 mg/kg subcutaneously every 12 hours with anti-Xa monitoring, using 1 mg/kg once daily at creatinine clearance under 30 mL/min. Avoid warfarin in the first trimester.
• Older adults: closure benefit is unproven, so prioritise atrial fibrillation detection and vascular risk control.

Monitoring. Echocardiography with saturated bubble study at about 6 months after closure for residual shunt and device position. Ambulatory ECG at 1 to 3 months after closure and with any palpitations. Bleeding surveillance on dual antiplatelet therapy. For apixaban, check creatinine and haemoglobin at least annually.

Referral and escalation. Refer to stroke and cardiology teams for closure assessment. Escalation is urgent for thrombus in transit, recurrent events on treatment, or hypoxaemia with right heart strain.