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A physiological left-to-right shunt through a patent foramen ovale (PFO) can be demonstrated in 32–55% of young adults with unexplained stroke compared with 10–35% of the general population.1 Transoesophageal or transthoracic echocardiographic evidence of a PFO consists of demonstration of a defect in the wall between the atria and ideally the passage of bubble contrast from right to left at this level. Provocative measures may be used to raise right atrial pressure, such as coughing, Valsalva manoeuvre or pressure on the liver, and increase the detection rate of PFO by at least 25%, but are not always performed rigorously or even routinely in children. The characteristics of the PFO, such as the size of the defect and of the shunt, are also important considerations; associated atrial septal aneurysm, larger defects and those with a greater right-to-left shunt may carry a higher risk of recurrence, particularly in patients with cryptogenic stroke. However, prospective population-based studies have failed to confirm the association (even with atrial septal aneurysm), a recent study failed to find any link with recurrent stroke2 and there are very few data in children. Despite this, studies of the effect of closure of PFO detected echocardiographically with devices placed at catheterisation are in progress,3 and such procedures have been advocated in children who have had a stroke.4
Transcranial Doppler (TCD) with bubble contrast and Valsalva appears to be a more sensitive technique than echocardiography for detecting PFO in adults.5 Benidik et al's careful bubble contrast TCD study published in this issue6 (in press) was carried out with a specially designed apparatus to enable children to perform the equivalent of a Valsalva manoeuvre by blowing into a glass tube. The population appears to be different from other recent series, with a much smaller proportion of children with vasculopathy, in whom the recurrence risk is higher. There is some evidence for a causal relationship, in that the excess of PFOs was seen in the children with no aetiology or prothrombotic risk factors only. In addition, the sudden onset of stroke in most of the cases with PFO is compatible with an embolic mechanism, as is the distribution of the infarcts. However, the mechanism of the association of PFO with stroke and the proportion of PFOs which are incidental7 have been controversial.
Mechanisms of the association between patent foramen ovale and stroke
Paradoxical embolism
The most obvious mechanism is paradoxical embolism, from the systemic venous circulation or the right side of the heart to the brain, which relies on the presence of a shunt. This can be a major structural anomaly such as a ventricular or atrial septal defect, or more minor anomalies such as pulmonary arteriovenous fistulae, or PFO, often associated in adults with atrial septal aneurysm. In the resting state when left atrial pressure exceeds right atrial pressure, there may be no inter-atrial shunting; however, increased right atrial pressure may enable right-to-left shunting of blood and therefore transmission of embolic material from the venous circulation to the cerebral arterial system. Although clinically evident or occult venous thrombosis is rarely demonstrated in these patients, up to 30% of deep venous thromboses may be missed with currently available diagnostic techniques. Left atrial pressure is normally higher than right, but although this pressure gradient may transiently reverse in early systole, studies have not found Valsalva-provoking activities to be common at stroke onset. The role of transient atrial arrhythmias, which could predispose to intracardiac thrombus formation, requires further exploration.
Infection and inflammation
At least one third of strokes in childhood occur in the context of infection and many of these patients have evidence of intra- or extracranial vasculopathy. Benedik's data suggest that PFO is less likely in this group, and only one patient with a PFO had a possible stenosis, while the other had an occlusion. However, it is possible that systemic inflammation involves the venous endothelium and that endothelial microparticles break off, possibly behaving like activated platelets and white cells and adhering to the arterial wall of the cerebral circulation if they have access via a PFO. This may be a mechanism in strokes associated with Mycoplasma pneumonia, for example, and any associated prothrombotic disorders or requirement for bed rest may be additional risk factors in promoting venous stasis. Hypoxia might also play a role and the relative importance of these triggers could be examined as part of the Vascular Effects of Infection in Paediatric Stroke study, recently funded by the National Institutes of Health (USA).
Sleep-disordered breathing, pulmonary disease and hypoxia
Bubble microemboli compatible with PFO have been observed using TCD during prolonged obstructive sleep apnoeas in adults, and PFO may be associated with sustained and intermittent hypoxia.8 This could be a mechanism linking overt or covert cerebral infarction in anaemias, such as sickle cell disease (SCD),9 where sleep-disordered breathing is common and also appears to be a risk factor for central nervous system events. A vicious cycle of increased pulmonary artery pressure leading to right-to-left shunting and systemic hypoxia might increase the risk of stroke alongside other factors, such as vasculopathy, because of reduced oxygen supply to cerebral tissue. Reports of paradoxical embolus in cystic fibrosis suggest that the shunt through a PFO may transiently reverse from the usual left-to-right to right-to-left with chest disease. This may be an additional, rather than an alternative mechanism, perhaps in relation to the Valsalva mechanism invoked during coughing as well as increased pulmonary artery pressure in the context of chronic lung disease. The Patent Foramen Ovale and Stroke (PFAST) study is an opportunity to explore these mechanisms in SCD.
Transient reduction in perfusion
In a number of studies, patients who have had closure of shunts at the atrial level have reported improvement in symptoms of migraine and controlled trials of PFO closure using devices are in progress. Data from an animal model suggest that the mechanism of triggering an aura in those predisposed to migraine probably involves a transient reduction in perfusion.10 This could also be important in determining stroke risk, again possibly in the context of other pathologies such as vasculopathy.
Management
At present, there is little evidence that paradoxical embolism is a common mechanism of ischaemic stroke in children, and atrial septal aneurysm, which is associated with a high risk of recurrent stroke, is uncommon. However, well-documented case reports and series of PFO associated with stroke in neonates and children make the case for specifically excluding a PFO in cryptogenic paediatric ischaemic stroke, provided that resources are adequate to also exclude cerebrovascular disease. The most sensitive technique available appears to be TCD with contrast and Valsalva. However, the role of these small right-to-left shunts in the pathophysiology of initial and recurrent cryptogenic stroke requires further exploration in terms of mechanism and natural history before invasive techniques for closure are recommended. This is particularly important as recurrent childhood stroke may have reduced since many paediatric neurologists have been advising aspirin prophylaxis.11 There are cerebrovascular risks associated with PFO closure,3 12 in addition to the possibility of triggering an arrhythmia, such as atrial fibrillation,3 13 also associated with stroke and transient ischaemic events. Superiority for one device for closure of PFO detected by transoesophageal echocardiography has not been demonstrated over 2 years of follow-up.3 Studies in progress to determine who may benefit from PFO closure might consider using bubble TCD to determine whether efficacy is improved when 'the door really is shut'14 by the procedure. In principle, fully informed children should be included as they probably have a lifelong exposure to the risk of recurrent stroke and may find long term compliance with medical therapy onerous. One advantage of Benedik's technique is that it will allow this type of follow-up audit of any PFOs closed in childhood after appropriate consent.
References
Footnotes
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Funding FJK was funded by the Wellcome Trust.
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Competing interests None.
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Provenance and peer review Commissioned; internally peer reviewed.
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