Preliminary study on the application of percutaneous patent foramen ovale (PFO) closure in the treatment of children with PFO and severe migraine

Introduction

Pediatric migraine is a significant clinical problem with a prevalence of about 8–12% in children and adolescents, which seriously affects the quality of life and social interactions (1). However, due to the particularity of children, the overall treatment effect is worse. Transcatheter patent foramen ovale (PFO) closure has been proposed to be a new approach to treat migraine in adults. Although three large randomized controlled trials (RCTs), MIST, PRIMA, and PREMIUM, did not achieve the expected positive results, subgroup analyses found that, compared with the control group, PFO closure can better improve migraine symptoms in patients with aura and comorbid cerebrovascular diseases (2). Numerous studies in adults have shown a significant reduction in migraine symptoms after closure of PFO (3-5), although some studies did not show any benefit (6,7).

The foramen ovale is a physiological passage in the interatrial septum of the fetal heart. If the foramen ovale remains open beyond the age of three, it is diagnosed as PFO (8). Under normal conditions, left atrial pressure is higher than right atrial pressure, keeping the foramen ovale closed without causing blood shunting. When right atrial pressure rises above left atrial pressure, the weaker septum primum is pushed open, leading to right-to-left shunt (RLS). The exact mechanism of PFO-related migraine is unclear, but it is primarily thought to be associated with RLS. It may involve microemboli from the right heart system or vasoactive substances that should normally be filtered by the pulmonary circulation, directly entering the blood-brain barrier and causing cerebral vasospasm (9).

Although the association between PFO and migraine remains controversial and the International Headache Society and the Neurological Society also do not advocate percutaneous closure of PFO as a standard treatment modality for migraine patients, we have witnessed an increasing number of children with migraine referred for device closure of their PFO. However, in contrast to adults, there is a paucity of research about the potential benefits of PFO closure in children. Thus the objective of this study is to evaluate the efficacy of percutaneous PFO closure in the treatment of children with PFO and severe migraine, thereby providing a theoretical foundation for clinical management strategies. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-95/rc).

Methods

Patients

This study adhered to the guidelines of the Declaration of Helsinki and its subsequent amendments. The ethics and plan review committee at the Nanjing Medical University approved this study (No. 202408053-1). Written informed consent to participate in this study was provided by the participants’ legal guardians/next of kin. Forty-six pediatric patients with PFO and severe migraine were admitted between September 2021 and October 2023. The children were aged 12–17 years, with 20 boys (43.48%) and 26 girls (56.52%). Inclusion criteria were as follows: (I) history of migraine lasting >1 year, with monthly headaches that significantly affect quality of life; (II) underwent multiple consultations with neurology and otolaryngology specialists, and brain magnetic resonance imaging (MRI) and neurological assessments showed no significant abnormalities; (III) persistent migraine symptoms despite trials of oral medications, including nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen) and topiramate (an antiepileptic drug); (IV) PFO diagnosis by transthoracic echocardiography (TTE) with no other structural cardiac abnormalities; (V) significant RLS confirmed by right heart contrast echocardiography. Exclusion criteria included: (I) pulmonary arterial hypertension or PFO with right-to-left shunting; (II) recent severe bleeding; (III) active infection; (IV) thrombus in the catheterization pathway or cardiac cavity; (V) presence of other cardiac malformations requiring cardiac surgical procedures. The percutaneous PFO closure methodology has been well-documented across multiple studies (10,11). The Cardi-O-fix PFO Occluder (Starway Medical Technology, Beijing, China) was used to perform the procedure in all children.

Right heart contrast echocardiography

All children underwent right heart contrast echocardiography before the percutaneous closure. The methodology was outlined in prior studies (11). The RLS of PFO was classified into four grades based on the number of microbubbles seen in the left heart chamber on a single still-frame image: (I) grade 0, no microbubbles indicating no RLS; (II) grade I, >0 and <10 microbubbles indicating mild RLS; (III) grade II, 10–30 microbubbles indicating moderate RLS; (IV) grade III, >30 microbubbles indicating severe RLS (11).

Outcomes and follow-up

The clinical outcomes were mainly evaluated by the following four indicators. (I) Frequency of migraine: average number of headaches per month in the last 3 months. (II) Duration of migraine: given the unique characteristics of children, who are often unable to clearly describe the exact duration of migraines, we defined four categorical options: “headache for a while” (<1 hour), “headache for all morning/afternoon” (1–6 hours), “headache for half a day” (>6–12 hours), and “headache for more than half a day” (>12 hours). (III) Visual Analogue Scale (VAS) score: presented as a 10-cm horizontal line, where 0 indicates no pain and 10 indicates the most intense pain (12). Children marked points on the line according to their pain intensity during migraine attacks. (IV) Headache Impact Test-6 (HIT-6) score: used to assess the negative impact of migraine on daily life, with scores categorized as follows: <50, no impact; 50–55, mild impact; 56–60, significant impact; and >60, severe impact (13). We assessed postoperative headache occurrence to determine the effectiveness of the treatment.

Statistical analysis

The statistical analysis in this study was performed using SPSS version 29.0 and GraphPad Prism version 10.2. Continuous data were presented as mean ± standard deviation (x¯±s) and compared using Student’s t-test or Mann-Whitney U test. Probability (P) values ≤0.05 were considered statistically significant.

Results

Demographic and clinical characteristics

All 46 children with PFO had severe migraine preoperatively. They were followed up for more than 12 months, and 15 of them exceeded 24 months. The percutaneous PFO closure was successful in all 46 children without complications such as infection, cardiac perforation, occluder dislodgement, or embolism. The demographic and clinical characteristics were summarized in Table 1.

Improvement of headache

Follow-up data for all patients were obtained by telephone, WeChat, or outpatient visits at 1, 6, 12, and 24 months after PFO closure. The migraine was significantly alleviated in 43 children, while three others experienced no change. There was a significant reduction in the frequency, duration, VAS score, and HIT-6 score after PFO closure (Table 2, Figure 1).

Figure 1 Comparison of headache frequency, VAS score, HIT-6 score and duration before and after PFO closure at different follow-up time points. (*, P<0.05 vs. 0 M; ^, P<0.05 vs. 1 M; +, P<0.05 vs. 6 M). HIT-6, Headache Impact Test-6; M, month; VAS, Visual Analogue Scale.

We found that the frequency and duration of headache, the VAS score almost decreased in parallel in effective children in our study, so we used the reduction of headache frequency to represent the effective rate of the closure. The frequency of migraine decreased ≥90% and the clinical symptoms basically disappeared, which was defined as cure. It was defined as remission that the frequency of migraine decreased more than 50% and the clinical symptoms significantly improved. After 1 month, the remission rate was 47.83% and cure rate was 17.40% which respectively increased to 93.48% and 76.09% by 12 months (Figure 2). The effect of percutaneous PFO closure was good.

Figure 2 Migraine effective rate over time. M, month; PFO, patent foramen ovale.

The special cases

There were a total of 31 children who underwent repeated right heart contrast echocardiography one month after intervention and all the results were negative. Some cases require attention. The first case involved a 12-year-old girl with no RLS after intervention whose migraine significantly improved postoperatively but developed new symptoms of abdominal pain and chest tightness during follow-up (Figure 3). Relevant examination revealed no abnormalities. We inquired about her family situation again and learned that her parents were divorced. She was later diagnosed with depression at psychological clinic, and her symptoms improved with treatment. We believe that the postoperative headache relief of the girl may have been due to the placebo effect. In addition, the three children whose headaches continued unabated also deserve attention. Before the operation, they all have obvious RLS of grade III but the results of repeated right heart contrast echocardiography were negative after intervention. This suggests that PFO-associated migraine is more than just with RLS and should not be extended to indications for PFO closure.

Figure 3 A 12-year-old girl with severe migraine and PFO. (A) Preoperative grade III RLS, with the left heart chamber filled with microbubbles. (B) One-month postoperative grade 0 RLS. PFO, patent foramen ovale; RSL, right-to-left shunt.

Association of RLS grade with headache frequency and HIT-6 score

Spearman rank correlation analysis was performed to examine the relationship between the RLS grade and preoperative migraine frequency as well as the HIT-6 score. The correlation coefficients were r=0.280 (P=0.06, not significant) and r=0.122 (P=0.42, not significant) for migraine frequency and HIT-6 score, respectively. The results indicated no significant correlation between the RLS grade and either migraine frequency or the HIT-6 score. This suggests that the RLS grade was not positively correlated with migraine frequency or the impact on children as assessed by the HIT-6 score.

Discussion

In recent years, with the intensive study of the pathogenesis of migraine, more and more evidence shows that PFO incidence is higher in patients with migraine than in the general population and closing the PFO can significantly relieve migraine (14,15). Most of these reports involve adult age groups. The relationship between severe migraine and PFO in children has drawn increasing attention from clinicians. Some studies suggest that children with migraine with aura have a higher prevalence of PFO, indicating that PFO may promote the onset of migraine with aura in pediatric patients (16,17). As early as 2014, Menon et al. reported the percutaneous closure of PFO in 104 children aged 7–19 years with migraine, and after an average follow-up of 1 year, 97 children showed significant headache relief (18). Similarly, Sel et al. successfully performed PFO closure in three children who all showed significant improvement in headache symptoms respectively with 2.5, 5.5, and 6 years of follow-up (19).

In this study, the time, frequency, location, intensity and nature of migraine varied among the 46 children, and no consistent pattern was observed. We hypothesize that it may be related to the small sample size or the particularities of childhood migraines. After percutaneous PFO closure, migraines were significantly alleviated in 43 children including 35 children (76.09%) completely cured. Some studies have shown that oral aspirin can alleviate migraine, but in this study, the children did not experience migraine recurrence after stopping aspirin which had been taken orally for 6 months. This suggests that the relief of migraine is primarily related to the PFO closure rather than the analgesic effect of aspirin. All children underwent a brain MRI, and only one child showed a small infarct lesion. It is possible that the pathogenesis of PFO-associated migraine in children has unique characteristics. In children, the cause of PFO-related migraine may lie not in microemboli but in vasoactive substances. This warrants larger-sample and more in-depth studies. Once PFO closure is performed, migraine is relieved in most children. With longer follow-up time, especially within 1 year after the intervention, their symptoms have further improved. We speculate that this might be related to the occluder gradually undergoing endothelialization.

It is worth noting that Spearman rank correlation analysis between RLS grade and either the migraine frequency or the HIT-6 score showed no significant correlation. Currently, the relationship between headache symptoms and the severity of RLS is unclear. Qi et al. (11) found no statistically significant difference in preoperative headache frequency or HIT-6 score among different grades of RLS-PFO. However, other studies have found that high-grade RLS-PFO is more strongly associated with migraine than moderate-grade RLS-PFO (20,21). We hypothesize that significant RLS is merely a foundation for PFO-related migraine but not the sole factor. Headache is a subjective symptom, and each child responds differently to pain. Therefore, significant RLS does not necessarily result in migraine, so indications for PFO closure should not be broadened.

We found that the efficacy rate in this study was significantly higher than in other related studies, and the reasons may be as follows: (I) the sample size was small, and the inclusion criteria were strict. (II) Headaches are common somatic symptoms in children and adolescents, and some children may not accurately describe their migraine, which may have affected follow-up results. (III) The placebo effect may have influenced the results.

This study confirms that percutaneous PFO closure is a minimally invasive, safe, and effective method. It is worth noting that in some children, migraine is merely the result of emotional stress. Family relationships, academic pressure, and peer relationships need to be repeatedly assessed. To rule out these factors, it is necessary to observe the duration of migraines for being sufficiently long and to prove that the migraines seriously impact the child’s daily life and studies.

There are some limitations in this study, such as retrospective design, small sample size, absence of a non-surgical control group, recall bias, and short follow-up duration. We should acknowledge that there is still considerable controversy surrounding PFO closure in children. However, most patients do experience symptom relief or even complete resolution after closure. At the same time, there are also some additional benefits of PFO closure for migraine: mechanical vaccination for life against paradoxical embolism causing deaths, cerebral ischemic events, myocardial infarctions, and systemic ischemic events. Currently, there is limited research on PFO closure in children, and the criteria for PFO closure are not uniform. Future multicenter, RCTs are needed.

Conclusions

Our retrospective study showed that percutaneous PFO closure may be attempted in children with PFO and severe migraine. In some children, percutaneous PFO closure may significantly improve headache symptoms. But we also emphasize that PFO closure should not be used as a first-line treatment for childhood migraines and that significant RLS is not the sole factor in PFO-related migraine.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-95/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-95/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-95/prf

Funding: This study was supported by grants from the National Natural Science Foundation of China (No. 82100779).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-95/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study adhered to the guidelines of the Declaration of Helsinki and its subsequent amendments. The ethics and plan review committee at the Nanjing Medical University approved this study (No. 202408053-1). Written informed consent to participate in this study was provided by the participants’ legal guardians/next of kin.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Greene K, Irwin SL, Gelfand AA. Pediatric Migraine: An Update. Neurol Clin 2019;37:815-33. [Crossref] [PubMed]
2. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38:1-211.
3. Zhang Y, Wang H, Liu L. Patent Foramen Ovale Closure for Treating Migraine: A Meta-Analysis. J Interv Cardiol 2022;2022:6456272. [Crossref] [PubMed]
4. Mojadidi MK, Kumar P, Mahmoud AN, et al. Pooled Analysis of PFO Occluder Device Trials in Patients With PFO and Migraine. J Am Coll Cardiol 2021;77:667-76. [Crossref] [PubMed]
5. He YD, Yan XL, Qin C, et al. Transcatheter Patent Foramen Ovale Closure Is Effective in Alleviating Migraine in a 5-Year Follow-Up. Front Neurol 2019;10:1224. [Crossref] [PubMed]
6. Garg P, Servoss SJ, Wu JC, et al. Lack of association between migraine headache and patent foramen ovale: results of a case-control study. Circulation 2010;121:1406-12. [Crossref] [PubMed]
7. Dowson A, Mullen MJ, Peatfield R, et al. Migraine Intervention With STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation 2008;117:1397-404. [Crossref] [PubMed]
8. Maloku A, Hamadanchi A, Günther A, et al. Patent Foramen Ovale (PFO): History, Diagnosis, and Management. Rev Cardiovasc Med 2024;25:422. [Crossref] [PubMed]
9. Shah AH, Horlick EM, Kass M, et al. The pathophysiology of patent foramen ovale and its related complications. Am Heart J 2024;277:76-92. [Crossref] [PubMed]
10. Wang Y, Lou Y, Chen Y, et al. Construction and validation of a nomogram for predicting remission of migraine patients with patent foramen ovale after closure. Int J Cardiol 2024;407:132026. [Crossref] [PubMed]
11. Qi Y, Zhang Y, Luo X, et al. Efficacy of patent foramen ovale closure for treating migraine: a prospective follow-up study. J Investig Med 2021;69:7-12. [Crossref] [PubMed]
12. Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin Nurs 2005;14:798-804. [Crossref] [PubMed]
13. Houston MN, Bookbinder HA, Roach SP, et al. Reference Values for the Headache Impact Test-6 Questionnaire. Arch Phys Med Rehabil 2021;102:2369-76. [Crossref] [PubMed]
14. Ferrarini G, Malferrari G, Zucco R, et al. High prevalence of patent foramen ovale in migraine with aura. J Headache Pain 2005;6:71-6. [Crossref] [PubMed]
15. Tariq N, Tepper SJ, Kriegler JS. Patent Foramen Ovale and Migraine: Closing the Debate--A Review. Headache 2016;56:462-78. [Crossref] [PubMed]
16. McCandless RT, Arrington CB, Nielsen DC, et al. Patent foramen ovale in children with migraine headaches. J Pediatr 2011;159:243-7.e1. [Crossref] [PubMed]
17. Choi DY, Shin DH, Cho KH, et al. Migraine with aura: a predictor of patent foramen ovale in children and adolescents. Cephalalgia 2013;33:463-8. [Crossref] [PubMed]
18. Menon SC, Grove A, McFadden M, et al. Clinical practice, resource utilization, and outcomes of device closure of patent foramen ovale in pediatrics. Pediatr Neurol 2014;50:213-7. [Crossref] [PubMed]
19. Sel K, Aykan HH, Duman D, et al. Transcatheter closure of the patent foramen ovale in children: intermediate-term follow-up results. Cardiol Young 2017;27:1545-9. [Crossref] [PubMed]
20. He Q, Zhang Y, Wang F, et al. Impact of right-to-left shunt and transcatheter closure on the clinical features of migraine. Int J Neurosci 2020;130:270-5. [Crossref] [PubMed]
21. Tang Y, Peng A, Peng B, et al. Association between patent foramen ovale and migraine without aura: a community-based cross-sectional study in China. BMJ Open 2022;12:e056937. [Crossref] [PubMed]