METHODS
For this observational single-center study, approval was obtained from the Local Ethics Committee before data collection began. Images of a total of 720 ESUS and migraine patients who complied with the study protocol between 2020 and 2022 were analyzed. For imaging purposes, two TTE devices and one TEE probe were used in the same center.
The study included patients presenting with migraine and ESUS, along with suspected PFO detection in color Doppler imaging within the interatrial region using at least one transthoracic echocardiographic window. We recorded parameters such as the basal right ventricular (RV) and mediolateral right atrial (RA) diameters, as well as estimated pulmonary artery (PA) systolic pressure for all patients. Additionally, detailed examinations were conducted to assess the presence of interatrial septal aneurysm, Chiari network, and Eustachian valve.
Transthoracic echocardiography was performed using various imaging windows, including parasternal long axis (PLAX), parasternal short axis (PSAX), apical four-chamber (A4C), apical three-chamber (A3C), apical two-chamber (A2C), and subcostal four-chamber (SC4C) views. PSAX, A4C, and SC4C windows were specifically used to detect Doppler blood flow in the IAS. To rule out abnormal pulmonary venous return, we visualized the entry of pulmonary veins into the left atrium using 2D and color Doppler imaging in one or more transthoracic echocardiographic windows. Identical color Doppler gain settings were applied to all patients. Estimated pulmonary artery systolic pressures (PASP) were calculated using the modified Bernoulli equation, considering the peak Doppler velocity of the tricuspid regurgitation jet and the end-diastolic velocity of the pulmonary regurgitation jet (PASP = 4V2 + right atrial pressure [mmHg]). Contrast echocardiography was performed via the transthoracic A4C window following 2D and Doppler TTE. Agitated saline was prepared by adding 9cc of saline to a 10cc syringe. A positive finding was defined as the presence of three or more microbubble transitions from the right atrium to the left atrium during the first five beats of the cardiac cycle following the Valsalva maneuver. TEE involved evaluating 2D and color Doppler images of the IAS at 30-50 degrees mid-esophageal and in the bicaval window. Defects in the fossa ovalis region were diagnosed clefts were identified as PFO.
In this study, the TEE parameters used by Nakayama et al. to define the anatomical and functional high-risk features associated with PFO were used (13). A ’large’ PFO is characterized by a height of ≥ 2 mm, measured as the maximum separation between the septum primum and septum secundum in the end-systolic frame. Furthermore, a ’long’ PFO tunnel is defined as having a length of ≥ 10 mm, measured by the maximum overlap between the septum primum and septum secundum. High-risk PFO is further defined by the presence of an atrial septal aneurysm (ASA), which involves a septal excursion of ≥ 10 mm from the midline into either the right or left atrium or a total excursion of ≥ 15 mm between the right and left atrium. Another characteristic of high-risk PFO is a hypermobile IAS, described as a septum with an excursion of ≥ 5 mm in every heartbeat. Additional determinants associated with an increased risk of cerebrovascular events through PFO include the presence of a large right-to-left (RL) shunt, identified by the presence of ≥20 microbubbles in the left atrium during rest and the Valsalva maneuver. Moreover, high-risk PFO is linked to anatomical factors such as the presence of a prominent Eustachian valve or a Chiari’s network measuring ≥ 10 mm in the right atrium. Additionally, a sharp (≤10°) angle between the inferior vena cava and the PFO flap is associated with a high-risk PFO.
Using the noted anatomical and functional features of PFO determined by TEE, Nakayama and colleagues developed a simple scoring system for identifying high-risk PFO (14) (Table 1). When ESUS-related factors were each scored as 1 point, a total score ≥ 2 points was strongly associated with ESUS. A score of ≥2 points showed 91% sensitivity and 80% specificity for association with ESUS.
Risk criteria for stroke in patients with PFO can be categorized as clinical, anatomical, and functional criteria. The Risk of Paradoxical Embolism (RoPE) score is based on 12 data and is used to distinguish incidental PFO from clinically significant PFO in ESUS patients (15) (Table 2).
We excluded patients with interatrial septal defects outside the fossa ovalis region, and patients under 18 years and above 60 years of age from the study. The primary endpoints of the study are the comparison of atrial septum, PFO and accompanying anatomical variant of right atrial structures in migraine and ESUS patients. Secondary endpoints were comparison of RoPe and High-risk PFO scores in migraine and ESUS patients.