Beyond the Obvious: Evaluating Incidence and Causes of False Positive Patent Foramen Ovale Diagnoses in Cryptogenic Ischemic Stroke—A Retrospective Analysis

(1) Background: Transesophageal echocardiography (TEE) is the gold standard for diagnosing patent foramen ovale (PFO) in cryptogenic ischemic stroke. However, false-positive diagnoses remain clinically relevant, exposing patients to unnecessary invasive procedures. (2) Methods: We retrospectively analyzed 346 patients with cryptogenic ischemic stroke who underwent TEE for PFO from 2012-2021. PFO was confirmed in 326 patients (94.2%), whereas 20 patients (5.8%, 95% CI 3.6-8.9%) were adjudicated as false positives during subsequent cardiac catheterization (intracardiac echocardiography, angiography, and inability to cross the interatrial septum). Univariable and multivariable logistic regression identified predictors of diagnostic accuracy. (3) Results: False-positive cases were associated with less frequent use of the mid-esophageal bicaval view (50% vs. 87%, <i>p</i> < 0.001) and absence of early bubble transit. Multivariable analysis confirmed the mid-esophageal bicaval view as an independent predictor of accurate diagnosis (OR 5.23, 95% CI 2.11-12.9, <i>p</i> < 0.001). (4) Conclusion: False-positive PFO diagnoses occur in ~6% of patients referred for closure. Three quality criteria-mid-esophageal aortic valve short axis, bicaval view, and bubble test with x-plane analysis-may improve diagnostic reliability. These hypothesis-generating findings require prospective validation and alignment with ASE/ESC guidelines to reduce unnecessary invasive procedures.