Abstract
Background
Patent foramen ovale (PFO) transcatheter closure is recommended for carefully selected patients with cryptogenic stroke and transient ischemic attack (TIA). It has also been associated with significant improvement in the severity of refractory migraine headaches.
Objective
To report long-term outcome after PFO closure for patients with stroke, TIA, and refractory migraine.
Methods
This retrospective study represents a single-center experience including patients undergoing PFO transcatheter closure for stroke, TIA, or refractory migraine. Patients were followed at 1 and 6 months, one year, and then annually for at least 5 years after closure. After that, patients either attended annually or were followed by telephone interviews. Holter monitoring was done 1–3 months after closure, then selectively according to patient symptoms.
Results
We enrolled 480 patients undergoing PFO transcatheter closure between March 2001 and July 2020. 432 patients completed follow-up through August 2024. The follow-up duration ranged from (4–23) years. PFO closure was successful in all patients without complications. New onset atrial fibrillation (AF) occurred in 6 patients (1.39 %), typically later during follow-up (14.0 ± 4.1 years), all with cardiovascular risk factors. Cerebrovascular events recurred 0.31 events/100 person/years. Using the Log-rank test, event recurrence was more observed in patients >40 years in the presence of other cardiovascular risk factors and AF. Regarding Migraine, (82.4 %) of patients experienced complete resolution of symptoms, and (17.6 %) reported mild symptoms (Migraine Disability Assessment Questionnaire (MIDAS) grade I). The mean MIDAS score significantly improved; the mean before closure was 28.3 ± 7.23 and 0.83 ± 1.82 after closure ( P = 0.001). The migraine persistence rate was 1.9 events per 100 person-years.
Conclusions
Percutaneous PFO closure is a safe and effective long-term intervention for preventing recurrent cerebrovascular events and significantly improves migraine symptoms.
Graphical abstract
Highlights
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Percutaneous PFO closure is a safe and effective long-term intervention for preventing recurrent cerebrovascular events.
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Stroke and TIA recurrence is more observed with increasing age, in the presence of other cardiovascular risk factors and AF
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Improvement of refractory migraine headache severity after PFO closure.
1
Introduction
The management of patent foramen ovale (PFO) has been a topic of significant interest and debate within the medical community, particularly regarding its association with cryptogenic stroke, transient ischemic attack (TIA), and migraine [ , ]. One of the earlier studies was the CLOSURE I trial, published in 2012. Over 900 PFO patients with cryptogenic stroke or TIA were enrolled. There was no significant reduction in stroke recurrence compared to medical management [ ].
Subsequent large, randomized trials comparing PFO device closure to medical therapy yielded more promising outcomes about the decrease of recurrent stroke or TIA risk in individuals who had the PFO closure, especially in the presence of an atrial septal aneurysm (ASA) and in people younger than 60 years [ ]. PFO transcatheter closure is presently advised for carefully chosen patients aged 18 to 65 years who have experienced cryptogenic stroke, TIA, or systemic embolism, with a high likelihood of the PFO being causally implicated, as assessed both clinically and morphologically, alongside a significant right-to-left shunt [ ].
Potential complications of PFO closure include risk of device embolization, development of atrial fibrillation (AF) following the procedure, and vascular access complications [ ]. Limited data is available regarding the long-term (up to 15–20 years) outcomes after PFO closure; thus, it is essential to gather extended follow-up data from individuals who have undergone PFO closure. This data will help assess the incidence of recurrent ischemic events, development of atrial fibrillation, and migraine improvement over an extended period [ ].
Our study aimed to report our experience of PFO closure involving a very long-term follow-up, giving insights into this intervention’s relative safety and efficacy.
2
Patients and methods
This retrospective study involved 480 participants and was done at a single center from March 2001 to July 2020. The research obtained approval from the ethical committee of Tanta University’s Medical Science (Approval code: 36264PR262/7/23) and adheres to the standards of the 1975 Declaration of Helsinki. Consent was waived as the study is retrospective.
2.1
Patient selection
Patients were considered for PFO closure if they had a PFO with complex morphology as an etiology of ischemic stroke, transient ischemic attack (TIA), or severe disabling migraine as diagnosed by a neurologist. Migraine severity and disability were evaluated using the Migraine Disability Assessment Questionnaire (MIDAS), which also reflects the quality of life in such patients.
PFO complex morphology included: long tunnel (≥8 mm), thick secondary septum (≥ 10 mm), ASA (Exceeding 10 mm of tissue displacement in each direction from the septal plane or surpassing 15 mm of total displacement between the right and left atrium), and long redundant Eustachian valve (EV) [ ]. The right to left shunt was confirmed by transcranial Doppler (TCD), and a shunt grade III or higher was considered significant. Right-to-left shunt (RLS) grading on TCD followed the Spencer grading Scale [ , ]. RLS quantification by transesophageal echocardiography (TEE) utilized color flow mapping and agitated saline injection. Shunting significant bubbles within the first three cardiac cycles after agitated saline injection was considered significant. We excluded other causes of stroke (e.g., atherosclerotic cerebrovascular disease through imaging of carotid arteries, thrombophilia screening, and other cardio-embolic etiologies such as atrial fibrillation by 48-h Holter monitoring). The Risk of Paradoxical Embolism (RoPE) score was calculated for cases >18 years [ ]. A RoPE score > 6 suggested PFO-related stroke [ ].
2.2
Procedure
The procedure was done under general anesthesia under two-dimensional [2D TEE], when possible, three-dimensional [3D TEE], and fluoroscopic guidance using the standard technique of PFO closure [12] . The residual shunt was immediately assessed after closure using agitated saline injection and right atrial angiography. The procedure was successful if complete closure was achieved with no significant residual shunt or complications, e.g., embolization and arrhythmia. Patients were discharged on aspirin and clopidogrel for six months [ ].
Device selection was determined according to PFO morphology; a Cribriform device was used in the presence of ASA with multiple fenestrations. Larger PFO devices were used in patients with long PFO tunnels and the presence of aneurysmal/floppy primary septum. In patients exhibiting long redundant Eustachian valves, the valve was positioned against the right atrial free wall, distanced from the inter-atrial septum, utilizing a steerable ablation catheter (Boston Scientific/Vascular, Quincy, MA) introduced via an alternative venous access on the contralateral side, maintaining separation from the inter-atrial septum [ ].
2.3
Follow-up
Patients were followed at 1 and 6 months, one year, and then annually for at least 5 years after closure. After that, patients either attended annual clinical visits or were followed by telephone interviews. Holter monitoring to detect new-onset arrhythmias (e.g., AF) was done 1–3 months after closure and then selectively prescribed according to clinical judgment.
3
Statistical analysis
Statistical analysis was done using SPSS version 25 (IBM©, Armonk, NY, USA). The Shapiro-Wilk test and histograms assessed data normality. Mean and SD were used to evaluate parametric quantitative data using Student’s t -test. Qualitative data were presented in frequency (%) and assessed using Chi-square or Fisher’s exact tests. Event-free times from outcomes were reported using Kaplan-Meier survival analysis. Comparison of survival in both groups was done using the Long Rank test, A P < 0.05, using a two-tailed method, indicated statistical significance.
4
Results
Four hundred eighty patients who underwent PFO device closure from March 2001 to July 2020 in Tanta University Hospital were enrolled, and follow-up was completed in August 2024. 48 patients were excluded as they were missed during follow-up; 432 patients completed the whole follow-up period.
4.1
Included patients
The indications for PFO closure were cryptogenic stroke in 205 (47.45 %) patients, TIA in 119 (27.55 %) patients, and disabling migraine in 108 (25 %) patients. The mean age of the study population was 29.537 ± 8.55 years, and 167 (38.66 %) patients were males.
A- Stroke and TIA group ( N = 324): ( Table 1 ) 15 pediatric patients (<18 years) with stroke were included, mean age 9.3 ± 1.35, and 309 adult patients (>18 years), mean age 30.4 ± 7.57. For adult patients, the mean RoPE score was 8.82 ± 0.75. 301 (92.9 %) patients had no cardiovascular risk factors. 10 (3.1 %) patients were smokers, 6 (1.85 %) patients were hypertensive, 4 (1.23 %) patients were dyslipidemic, and 3 (0.93 %) patients had diabetes. Migraine headache with aura coexisted with stroke/ TIA patients in 172 (53.1 %) patients.
| Groups | ||||
|---|---|---|---|---|
| Stroke | Migraine | Total | ||
| Age | 29.824 ± 8.359 | 29.441 ± 8.623 | 29.537 ± 8.550 | |
| Age group | < 20 Years | 35(10.8 %) | 6(5.56 %) | 41(9.49 %) |
| 20–40 Years | 260(80.25 %) | 91(84.26 %) | 351(81.25 %) | |
| > 40 Years | 29(8.95 %) | 11(10.19 %) | 40(9.26 %) | |
| Gender | Male | 114(35.19 %) | 53(49.07 %) | 167(38.66 %) |
| Female | 210(64.81 %) | 55(50.93 %) | 265(61.34 %) | |
| Cardiovascular risk factors | No | 301(92.9 %) | 106(98.15 %) | 407(94.21 %) |
| Smoking | 10(3.09 %) | 2(1.85 %) | 12(2.78 %) | |
| HTN | 6(1.85 %) | 0 | 6(1.39 %) | |
| Dyslipidemia | 4(1.23 %) | 0 | 4(0.93 %) | |
| Diabetes | 3(0.93 %) | 0 | 3(0.69 %) | |
| RoPE score for Stroke/TIA patients | 8.822 ± 0.754 | – | – | |
| MIDAS Grade for migraine patients | Grade III | – | 23 (21.30 %) | – |
| Grade IV | – | 85 (78.70 %) | – | |
| MIDAS score for migraine patients | – | 28.296 ± 7.23 | – | |
| TCD before closure | Grade III | 114(35.19 %) | 43(39.81 %) | 157(36.34 %) |
| Grade IV | 210(64.81 %) | 65(60.19 %) | 275(63.66 %) | |
B- Migraine group ( N = 108): ( Table 1 ) Patients’ mean age 29.82 ± 8.36. MIDAS grade III (moderate disability) in 23 (21.3 %) patients and grade IV (severe disability) in 85 (78.7 %) patients. Mean MIDAS score before closure 28.3 ± 7.23.
4.2
PFO measurements, morphology, and magnitude of right to left shunt
The average PFO tunnel length was 11.48 ± 4.04 mm, and the average tunnel height was 3.15 ± 0.84 mm. PFO morphologic features were ( Table 2 ): long tunnel (38.7 %), ASA (52.1 %), thick septum secundum (7.6 %), prominent Eustachian valve (16.4 %), aortic root dilatation (2.1 %). All patients showed a large right to left shunt on TEE, and the contrast-enhanced transcranial Doppler grade was III in 157 (36.3 %) and IV in 275 (63.7 %) patients. (See Table 1 .)
| Groups | ||||
|---|---|---|---|---|
| Stroke | Migraine | Total | ||
| PFO Morphology | ASA | 179(55.25 %) | 46(42.59 %) | 225(52.08 %) |
| Long tunnel | 119(36.73 %) | 48(44.44 %) | 167(38.66 %) | |
| Thick secondary septum | 19(5.86 %) | 14(12.96 %) | 33(7.64 %) | |
| Prominent EV | 52(16.05 %) | 19(17.59 %) | 71(16.44 %) | |
| Dilated aortic root | 9(2.78 %) | 0(0 %) | 9(2.08 %) | |
| Tunnel Length (mm) | 11.429 ± 4.12 | 11.625 ± 3.795 | 11.478 ± 4.038 | |
| Tunnel Width (mm) | 3.145 ± 0.86 | 3.148 ± 0.768 | 3.146 ± 0.837 | |
| Occluder device | Amplatzer PFO 18 × 18 | 18(5.56 %) | 11(10.19 %) | 29(6.71 %) |
| Amplatzer PFO 25 × 18 | 63(19.44 %) | 13(12.04 %) | 76(17.59 %) | |
| Cribriform 25 | 61(18.83 %) | 17(15.74 %) | 78(18.06 %) | |
| Amplatzer PFO 30 × 25 | 17(5.25 %) | 8(7.41 %) | 25(5.79 %) | |
| Amplatzer PFO 35 × 25 | 39(12.04 %) | 13(12.04 %) | 52(12.04 %) | |
| Occlutech Figulla Flex II PFO 16 × 18 | 26(8.02 %) | 3(2.78 %) | 29(6.71 %) | |
| Occlutech Figulla Flex II PFO 23 × 25 | 28(8.64 %) | 19(17.59 %) | 47(10.88 %) | |
| Occlutech Figulla Flex II PFO 27 × 30 | 17(5.25 %) | 13(12.04 %) | 30(6.94 %) | |
| Occlutech Figulla Flex II PFO 31 × 35 | 13(4.01 %) | 2(1.85 %) | 15(3.47 %) | |
| Cribriform 30 | 17(5.25 %) | 0(0 %) | 17(3.94 %) | |
| Cribriform 35 | 9(2.78 %) | 5(4.63 %) | 14(3.24 %) | |
| Cera Lifetech PFO 18 × 18 | 2(0.62 %) | 1(0.93 %) | 3(0.69 %) | |
| Cera Lifetech PFO 25 × 18 | 6(1.85 %) | 1(0.93 %) | 7(1.62 %) | |
| Cera Lifetech PFO 35 × 25 | 6(1.85 %) | 0(0 %) | 6(1.39 %) | |
| Cera Lifetech PFO 30 × 25 | 2(0.62 %) | 2(1.85 %) | 4(0.93 %) | |
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