LAUSR

We read with interest the recent article by Alushi et al. [1]. In a meta-analysis of five cryptogenic stroke trials, the authors compared the efficacy and safety of percutaneous patent foramen ovale (PFO) closure versus medical therapy for prevention of recurrent stroke, in patients with an index ischemic stroke of unknown etiology. The authors reported that PFO closure reduced the risk of stroke [HR 0.39, (0.19–0.83); p < 0.01], and increased the risk of atrial fibrillation [OR 3.75, (2.44–5.78); p < 0.01] compared to medical therapy. We commend the authors for their work and discuss the challenge of determining PFO-mediated paradoxical embolism as the culprit of stroke, and the potential role of PFO closure in some patients who were not included in the randomized trials. When PFO closure is considered for a patient with ischemic stroke of undetermined source, the question arises whether the PFO was the conduit for a paradoxical embolus originating from the venous circulation, or if the PFO was an incidental finding [2]. In an attempt to help the clinician make this differentiation, the RoPE study separated identified PFOs in cryptogenic stroke patients into those likely to be the offender (and thus requiring device closure) from those more likely to be an incidental finding (and thus to be left untreated) [3]. Using the RoPE score, patients could be given a probability that their PFO was or was not the culprit of their stroke by accounting for their age, cerebral infarct pattern, smoking status, and other comorbidities. However, the RoPE score does not account for additional clinical factors, the presence of which may also increase the likelihood of stroke from paradoxical embolism. These factors include prior venous thromboembolism, occurrence of stroke after straining, and echocardiographic features of the atrial septal anatomy (i.e., atrial septal aneurysm or large PFO/shunt). Although Alushi et al. did not find the presence of an atrial septal aneurysm or shunt size to modify the treatment effect in their meta-analysis [1], the RESPECT, DEFENSE-PFO, and CLOSE trials showed that ischemic stroke patients who have these echocardiographic features benefit the most from PFO closure, having the lowest number needed to treat [4–6]. In fact, the DEFENSE-PFO and CLOSE trials (studies enrolling only patients with an atrial septal aneurysm or large PFO/shunt) observed a remarkable finding of zero recurrent strokes in 2 and 5 years, respectively, in those randomized to a device [5, 6]. Methods such as the RoPE score may lead to the conjecture that a PFO cannot be the culprit for the index stroke in the presence of another known cause of stroke; this assumption is counterintuitive. For instance, a 50-year-old ischemic stroke patient who is found to have a large PFO with an atrial septal aneurysm will likely benefit from PFO closure, even in the presence of a short duration of atrial fibrillation. There are also patients in their 60s or 70s who present with cryptogenic stroke associated with a PFO with no evidence of atherosclerosis, occult atrial fibrillation, or other stroke etiologies. Although these patients were not included in the randomized trials, neurologists often refer them for PFO closure. To help clinicians make the difficult determination of whether an ischemic stroke was or was not a result of PFOmediated paradoxical embolism, we recently published an evidence-based algorithm for patients that will have the highest clinical yield from device closure, based on the results of randomized trials [7]. However, there are scenarios where it is impossible to prove the exact cause of the stroke, or where paradoxical embolism is suspected as the culprit * Mohammad K. Mojadidi [email protected]