2.1

Migraine headache

Migraines have been associated with PFO. There is a higher prevalence of PFO in patients with migraines with aura (50 %) than patients with migraines without aura (27 %) or the general population [ ]. Observational data suggested some improvement of migraine symptoms with PFO closure. However, a randomized clinical trial with a septal repair implant did not demonstrate efficacy of PFO closure in reducing migraine frequency. Rather, it showed a significant reduction in median total migraine headache days in the implant group compared to the placebo group [ ]. The complication rate for PFO closure is 0.2 to 1.5 % and may include hemorrhage requiring transfusion, cardiac tamponade, fatal pulmonary embolus, and death. Minor complication risks include atrial arrhythmias, device arm fracture, device embolization and thrombosis, and femoral hematoma. Atrial fibrillation may occur more frequently in patients with larger devices [ ].

In a retrospective cohort study of 153 patients with PFO (age 7–19 years), septal device occlusion was performed for migraine or nonmigraine headache, visual, transient ischemic attack, or stroke symptoms [ ]. The symptoms were completely resolved in 112 patients (72 %), decreased in 31 patients (20 %), and worsened or not improved in 10 patients (7 %). In 29 patients (19 %), there was complete resolution or improvement of symptoms despite a residual atrial shunt on echocardiography [ ]. In these patients, it is possible that the device may have reduced or closed the shunting. Alternatively, the improvement may have been due to psychosocial factors and a placebo effect [ ]. Patients with no improvement in symptoms were less likely to recommend PFO closure to family and friends. None of the demographic, preprocedural, procedural, and postprocedural factors were associated with improvement of symptoms after PFO closure with a septal device [ ]. In this study, PFO device closure was safe in most pediatric patients, similar to adult studies, but expenses were high, with cumulative procedure cost of $4.2 million in the 153 pediatric patients and additional follow-up costs [ ]. In this study, 92 % of pediatric patients had symptomatic relief; specifically, 68 % of patients with migraines reporteed none or fewer symptoms, even though the study did not address underlying mechanisms or exclude a placebo effect [ ].

2.2

Cryptogenic ischemic stroke and transient ischemic attack

Ischemic cerebrovascular events are rare in young adults, with an annual incidence of 6 to 26 per 100,000 persons [ ]. The incidence of childhood arterial ischemic stroke is an even more rare event and occurs in 1 to 7 per 100,000 persons per year [ ]. Despite thorough evaluation, a clear cause of stroke is not identified in 30 % of young stroke survivors. Cardiac anomalies such as PFO are found in a significant proportion of children with stroke, as the PFO allows paradoxical shunting of emboli into arterial circulation and into the brain [ ]. In the International Pediatric Stroke Study, which was a multicenter, international observational cohort study about the prevalence of medical conditions in 676 children who had arterial ischemic stroke, an isolated PFO was observed in 5 % of children [ ].

Pediatric cardiologists may vary in how they communicate with patients who have a PFO discovered as an incidental finding on an echocardiogram that was performed for other cardiac complaints. The PFO may be described as a normal variant, considering 25 % of the general adult population may have a PFO [ ]. In contrast, the patient may be told that the PFO may be an abnormality that may increase the risk of developing a stroke, given that 35 % of adults with a cryptogenic stroke have a PFO detected by echocardiography [ ]. It is reasonable to recommend a follow-up echocardiogram in one year to evaluate the PFO, to look for spontaneous closure of the PFO, and to screen for associated risks [ ].

Stroke caused by paradoxical embolus in otherwise healthy infants and children is uncommon despite the high prevalence of PFO [ ]. Transcranial Doppler ultrasonography with agitated saline contrast is a sensitive screening tool for right-to-left shunt, but echocardiography is still needed to confirm intracardiac shunting. The ROPE score (validated risk of paradoxical embolism score) helps predict the likelihood of stroke caused by PFO [ ]. Paradoxical emboli in children may be associated with hypercoagulable conditions, such as hospitalized children with central catheters. Due to the higher tendency of thrombus to form on the catheter, it is advisable to minimize the catheter size and maximize the distance between the catheter tip and PFO to prevent stroke and TIA [ ].

Medical treatment with warfarin and antiplatelet agents is controversial for patients with atrial shunting and a thromboembolic event. Although potentially effective, the feasibility of lifelong treatment in children and young adults is challenging because of poor compliance, the necessity of monitoring anticoagulation levels, and restrictions from competitive sports activity [ ].

A study over 6 years at 3 centers identified 45 patients with paradoxical embolus due to the presence of PFO and atrial septal defect causing stroke, transient ischemic attack, myocardial infarction, and renal infarction. At median follow-up of 5.3 months after closure of the right-to-left shunt, 44 patients (98 %) had no recurrent neurologic events or residual atrial shunt. This study showed that cryptogenic ischemic events may occur in young patients with serious sequelae, and device closure may be a safe therapeutic option for children and young adults [ ]. Rare complications of device closure may include venous access challenges, air embolus, device embolization, thrombosis, and erosion through the free wall of the atria or aortic root [ ].

A study by Caputi et al. (2013) of 1035 patients aged five to 75 years with history of cryptogenic ischemic stroke or transient ischemic attack suggested that percutaneous PFO closure is a safe procedure, and residual right-left shunt is not uncommon, but large residual right-left shunt is a rare occurrence. There were no neurological events at 2-year follow-up post-PFO closure, although non-neurological complications, including cardiac arrhythmias, were seen in very few subjects. This finding can be used to inform treatment decisions for patients with cryptogenic ischemic stroke or transient ischemic attack [ ].

An analysis of the REDUCE Trial by Messe et al. (2021) found that combined treatment with PFO closure with Septal Occluder plus antiplatelet therapy reduces the risk of new brain infarct by half, with no difference in the number of patients with subclinical infarcts compared to those who only received antiplatelet medication [ ]. However, there is a higher occurrence of atrial fibrillation and device complications among patients who underwent PFO closure [ , ]. A meta-analysis by Pan et al. (2021) also concluded that PFO closure significantly reduced the risk of composite outcome of recurrent ischemic neurological events compared with antiplatelet therapy, but the finding is not significant when compared with anticoagulant therapy [ ]. Moreover, in terms of bleeding events, PFO closure reduced the risk of bleeding events compared to both antiplatelet therapy and anticoagulant therapy [ ].

A multi-center randomized controlled trial by Mas et al. (2017) found that PFO closure combined with antiplatelet therapy was superior to antiplatelet therapy alone in preventing stroke recurrence. The rate of recurrent stroke was significantly lower in the PFO closure group than in the antiplatelet-only group, with a hazard ratio of 0.03 (95 % CI, 0 to 0.26; P < 0.001) [ ]. The secondary composite outcome of stroke, transient ischemic attack, or systemic embolism occurred in significantly fewer patients in the PFO closure group than in the antiplatelet-only group (3.4 % vs. 8.9 %; hazard ratio, 0.39; 95 % CI, 0.16 to 0.82; P = 0.01) [ ]. Similarly, the study by Lee et al. (2018), DEFENSE-PFO (Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk Patent Foramen Ovale), suggests that PFO closure may be a beneficial treatment option for patients with cryptogenic stroke and high-risk PFO characteristics, such as PFO with atrial septal aneurysm, hypermobility (phasic septal excursion into either atrium greater than or equal to 10 mm), or PFO size larger than or equal to 2 mm [ ]. PFO closure in patients with high-risk PFO characteristics resulted in a lower rate of stroke, vascular death, thrombolysis in myocardial infarction-defined major bleeding, as well as stroke recurrence [ ].

The result of a meta-analysis by Sitwala et al. (2019) suggests that transcatheter closure of PFO plus medical therapy is superior to medical therapy alone for the prevention of recurrent cryptogenic stroke [ ]. Although patients undergoing PFO closure were more likely to develop transient atrial fibrillation than medical therapy alone (OR: 5.85; CI: 3.06–11.18, p ≤ 0.0001), the risk of bleeding was similar between the two groups (OR: 0.93; CI: 0.55–1.57, p = 0.78) [ ]. However, PFO closure has not been shown to reduce the risk of recurrent TIA or all-cause mortality [ ].

A retrospective study in France found that PFO closure in children is safe and effective with few complications, with postoperative treatment involving aspirin and anticoagulants [ ]. In 2020, the American Academy of Neurology recommended PFO closure for secondary stroke prevention in patients under 60 with embolic strokes and no other clear cause after considering the risks and benefits of the procedure [ ]. An Analysis of the REDUCE Trial by Messé et al. (2021) also suggested that PFO closure in patients with cryptogenic embolic-appearing stroke may be an effective strategy for reducing recurrent stroke risk [ ].

Those undergoing percutaneous device closure intracardiac echocardiography can be performed safely and effectively in a large cohort of children and adolescents. Measurements of PFO using intracardiac echocardiography correlate well with preprocedural transesophageal echocardiography. However, intracardiac echocardiography may be more accurate in identifying the absence or deficiency of critical septal rims before device closure [ ].

Although it is plausible that PFO closure could reduce the risk of recurrent stroke, several randomized trials have not shown the superiority of PFO closure over antithrombotic therapy [ ]. The CLOSURE I (Evaluation of the STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism through a Patent Foramen Ovale) trial and the PC Trial (Clinical Trial Comparing Percutaneous Closure of the Patent Foramen Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism) showed no differences in stroke recurrence between PFO closure versus medical therapy, similar to the RESPECT trial. The mean age of patients in these three trials was 45 years, and the CLOSURE I and RESPECT trials excluded children aged <18 years. Hence, these results are difficult to extrapolate to the problem of cryptogenic stroke in children and adolescents [ ].

2.3

Paradoxical embolus

Emboli can migrate in either direction across a PFO, although left to right migration is incredibly rare [ ]. Stroke is usually caused when emboli migrate from the right to the left side of the heart. Paradoxical embolism right-to-left across a PFO may lead to pulmonary septic emboli [ ]. Septic pulmonary emboli may also originate from a left-sided heart vegetation migrating through a PFO, even when right-sided heart valves are normal [ ].

Children and adolescents, ages 2 to 19 years, with sickle cell disease and stroke were identified to have a higher prevalence of PFO (25 %) compared with children and adolescents without sickle cell disease and a stroke (11.7 %) [ ]. Patients with sickle cell disease and PFO with right-to-left shunting may have an increased risk of developing paradoxical embolus due to predisposition to thrombosis, increased right atrial pressures associated with pain during a sickle cell crisis, analogous to a Valsalva maneuver. These patients may be at high risk of having stroke occurrence and recurrence and a hypercoagulable state associated with immobility, neurocognitive dysfunction, and psychological and socioeconomic problems. As these patients may be young and have an increased risk of bleeding while on anticoagulation therapy, transcatheter PFO closure may be preferable to nonoperative treatment [ ]. These patients may benefit from multidisciplinary evaluation and treatment with a pediatric cardiologist, neurologist, hematologist, and radiologist, with consideration of the high-risk features of the PFO, stroke characteristics observed with brain imaging, and risks of ischemia and bleeding [ ].

2.4

Syncope

The association between PFO and syncope in children and adolescents may be unclear because of varied results in published studies that mostly include adults. In a study by Shehata et al. (2024) of patients with CT coronary angiography confirmed PFO, 16.3 % of 1000 patients with a mean age of 52.5 +/− 10.9 years, the frequency of syncope was four-fold higher in patients with PFO (6.7 %) when compared to those without PFO (1.6 %), indicating a significant association between PFO and syncope [ ].

In another study by Wang et al. (2023) of adult patients with PFO and syncope, patients with percutaneous PFO device closure had a lower frequency of recurrent syncope when compared to those who did not have PFO closure [ ]. Among 111 patients, mostly adults with syncope associated with PFO, 91 patients were treated with percutaneous PFO device closure and had a lower frequency of recurrent syncope (10 patients, 11 %) compared to the 20 patients who did not undergo PFO closure (7 patients, 35 %). These conclusions may have been limited by the small sample size [ ]. In contrast, a retrospective, single-center study by Zou et al. (2024) in the pediatric population showed that PFO is not associated with an increased risk of syncope in children, which contradicts the results in adults [ ]. 1001 children and adolescents (age, 4–17 years; 519 boys) were hospitalized due to unexplained syncope, palpitations, headaches, dizziness, and chest pain. Right heart contrast transthoracic echocardiography was performed to evaluate for the presence of right-to-left shunting with similar frequency of PFO between 276 patients who had simple syncope (PFO in 4.7 % patients), 379 patients who had headache or dizziness (4.7 %), 265 patients who had chest pain (4.2 %), and 81 patients who had palpitations (6.2 %; P = 0.90). Multivariable logistic regression showed that PFO was not associated with an increased risk of syncope ( P = 0.081).