Saurav Das, MD

Elgendy AY, Saver JL, Amin Z, Boudoulas KD, Carroll JD, Elgendy I, Grunwald IQ, Gertz ZM, Hijazi ZM, Horlick EM, et al. Proposal for Updated Nomenclature and Classification of Potential Causative Mechanism in Patent Foramen Ovale–Associated Stroke. JAMA Neurol. 2020;77:878-886.

We saw a 59-year-old patient with diabetes, hypertension, hyperlipidemia, coronary artery disease with multiple bypass surgeries but no known history of atrial fibrillation (AFib), and extensive smoking history in office. The patient was admitted to the ICU with recurrent episodes of hemorrhagic shock from gastro-intestinal bleeds requiring embolization of gastric artery and subsequently exploratory laparotomy within a 1-month period. He developed wedge-shaped strokes involving bilateral middle cerebral artery territories during one of these hospitalizations. Subsequently, stroke work-up revealed mild atherosclerosis in the head and neck vessels, and a transthoracic echocardiogram showed a significant large patent foramen ovale (PFO) with right to left shunt without any evidence of straddling thrombus, atrial septal aneurysm, or left atrial enlargement. He was found to have deep vein thrombosis in bilateral lower extremities and had an inferior vena cava filter placed. The question then arises how strongly we attribute the strokes to PFO and if this patient will benefit from PFO closure. In this context, I read the recent update on nomenclature and classification of PFO-associated strokes published in JAMA Neurology by the PFO-Associated Stroke International Working Group, and I will discuss the salient points in this blog post.

The article begins by discussing different classification systems for causative mechanisms of stroke, most notably, Trial of Org 10172 in Acute Stroke Treatment (TOAST), Causative Classification of Stroke (CCS), and Atherosclerosis, small vessel, cardio-embolism and other dissection (ASCOD). The authors then take us on a ride through the history of these classification systems including introduction of terms: “strokes of undetermined cause” in the 1980s, “cryptogenic stroke” in 1989, cerebral autosomal dominant arteriopathy with subacute infarcts and leukoencephalopathy (CADASIL), and reversible cerebral vasoconstriction syndrome (RCVS) in 1993, further refinement of the umbrella term cardio-embolic stroke, use of the term embolic stroke of undetermined significance (ESUS), etc. The “tipping point in PFO closure” trials was in 2017 when three positive trials, REDUCE, CLOSE and long-term follow up results of the RESPECT trial, were published in the New England Journal of Medicine with an enthusiastic editorial by the same title. In light of these trials, the authors argue that old classification systems and nomenclature should be revised. The salient points are discussed here.

Firstly, it is no longer tenable to classify patients with a present PFO as cryptogenic. They propose the use of the term “PFO-associated stroke” as a distinctive mechanism of ischemic stroke. Secondly, in the above-mentioned classification systems, TOAST, CCS, and ASCOD, there is: (a) scope for likelihood rating for causative mechanism of stroke, e.g., possible, probable, and present but unrelated; and (b) rules to attribute the causal likelihood ratings to PFO. However, these rules reflected the perspective in the era they were developed. The authors propose revision to these likelihood ratings by inclusion of now identified PFO-related risk factors: cortical/cerebellar infarcts >1.5 cm, presence of concomitant deep vein thrombosis (DVT) or pulmonary embolism (PE), a large right to left shunt or a small shunt with a coexisting atrial septal aneurysm, presence of a straddling thrombus. Thirdly, it is proposed that terms like “unlikely related” be replaced by terms like “potentially causal” or “uncertainly causal.” Fourthly, the authors discussed if it is appropriate to classify PFO-associated stroke under the “cardio-embolic” category as paradoxical emboli are not cardiac in origin. They recommend continuing to classify them under the same category that can be more broadly called “cardioembolic/trans-cardioembolic.” Last but not the least, the authors propose a clinical practice approach in PFO-associated strokes. This approach takes into account risk score rating for PFO as the causal mechanism juxtaposed against likelihood of a competing causal mechanism. The authors propose the latter be calculated using risk of paradoxical embolism (ROPE) score. Interestingly, the authors reserve “very high” risk score for PFO-associated strokes only if a straddling thrombus was seen along with the PFO. The presence of concomitant DVT or PE was classified separately as a “high” risk score.

Following the proposed clinical approach for the patient discussed in the introduction to this blog post, the risk for PFO being the causal mechanism of stroke is “high” in the presence of a large PFO with bilateral lower extremity DVT. However, his ROPE score was low (4 points) due to presence of several comorbidities, including diabetes, hypertension, and history of smoking. The only points were for the absence of a history of previous stroke or transient ischemic attack (1 point), cortical infarct on imaging (1 point), and an age just below the cut-off value of 60 years (2 points). This combination of high causal likelihood of stroke related to PFO and a low ROPE score (<7 points) makes this patient fall under the “highly probable” PFO causal association. This is a fair proposition, but the exercise never considered the likelihood of paroxysmal AFib, which is important to consider for this patient in the setting of recent hemorrhagic shock. Would this patient at the cusp of age cut-off benefit from PFO closure, or should he rather get an implantable cardiac monitor? Anticoagulation is, anyway, challenging in the setting of recent severe GI bleeds.

As evident in the above example, there are several unanswered questions at the end of reading this historical account on the classification of causal mechanisms of stroke. Additionally, in a pointed response to the article, it has been stated that the clinical clues like waking up with stroke, prolonged sitting, history of migraine, history of dyspnea at onset of stroke, sleep apnea, etc., have been ignored in the risk assessment rubric. The fact that transcranial doppler saline study is more sensitive than transesophageal echocardiogram (TEE) in detecting PFO is not mentioned. Also, a historical flaw is highlighted that the diagnosis of paradoxical embolism well preceded the use of echocardiography. In summary, the name “PFO-associated stroke” and the rubric of competing causal risk of PFO vs ROPE score, even though intuitive, provides an objective template for clinicians to operate on.