Localization Of Infratentorial Lesion Could Predict Patent ForamenOvale As An Etiology in Embolic Stroke Of Undetermined Source

Aim

Embolic stroke of undetermined source (ESUS) is a clinical construct introduced to describe cryptogenic stroke cases with ambiguous diagnoses, Cardiac causes are recognized as a major cause of ESUS, and Patent foram erovale (PFO) is among them. We aimed to investigate the relationship between infarct patterns and PFO inpatients with ESUS.

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Methods: We evaluated 190 consecutive patients with ESUS registered in the Tokyo Women's MedicaUniversity Stroke Registry, Among them, 94 patients who underwent magnetic resonance imaging and giography, as well as transthoracic and transesophageal echocardiography, were included in this study. The infarct patterns were classified according to location (infratentorial or non-infratentorial lesions), size (small and large infarcts), and number (single or multiple lesions).

Results: Prevalence of PFO was significantly higher in patients in the infratentorial than those in the non. infratentorial lesion group (40.7% versus 14.9%, respectively; P-0.007). However, neither lesion size nor number was associated with PFO, In multivariate logistic regression analysis, the presence of infratentorial lesions was independently associated with PFO in ESUS patients (odds ratio: 2.18; 95% confidence interval1.24-3.95; P< 0.007). In 21 patients with PFO, large PFOs were more prevalent in the infratentorial than in the non-infratentorial lesion group.

Conclusions: Infratentorial lesions may be independently associated with PFO in patients with ESUS. The presence of infratentorial lesions could predict the presence of PFO in ESUS cases.

Keywords: Patent foramen ovale, Transesophageal echocardiography, Embolic stroke of undetermined source, Acute ischemic stroke, Infratentorial lesion

Introduction

The definition of embolic stroke of unknown (ESUS) has recently emerged as a clinical term that presumably designates cryptogenic strokes to embolism with no evidence of lacunar stroke ipsilateral stenosis in intracranial and extracranial arteries, major cardioembolic sources, or any other definite rate causet, ESUS is a heterogeneous group with multiple potential pathologies as mechanisms of stroke (e.g., several potential embolic sources include minor-risk or covert cardiac sources, veins via paradoxical embolism, and non-occlusive atherosclerotic plaques in the aortic arch, cervical, or cerebral arteries)

1)Patent foramen ovale (PFO)-associated stroke is widely known as one of the most important causes ofESUS2. Previous studies have suggested that large shunts and the presence of concomitant atrial septum aneurysm were associated more with the onset of oPFO-related stroke3, 4, The detection of usually confirmed by transesophageal echocardiography(TEE). However, this examination is invasive and may cause discomfort in patients; in other words, TEE cannot necessarily be performed in all patients. Several studies have reported the relationship between radiological patterns of cerebral infarction; more specifically, studies have demonstrated vertebrobasilar artery territory infarction and PFO in patients with cryptogenic stroke. However, the results have been controversial because cryptogenic stroke includes not only stroke of undetermined cause after comprehensive workup but also stroke with incomplete investigation or due to two or more possible underlying causes. In cases of ESUS, few studies have reported the relationship between radiological patterns of cerebral infarction and PFO-related stroke.

Aim

This study aimed to identify the association between infarct patterns and PFO inpatients with ESUS.

Materials and Methods

Ethics

The present study conforms to the ethical! guidelines of the 1975 Declaration of Helsinki in line with the Ethical Guidelines for Epidemiological Research by the Japanese government and was approved by the ethics committee of Tokyo Medical University Hospital (approval number: 2955-R2).

Study ProtocolTokyo Women's Medical University Stroke Registry (https://upload.umin.ac.jp,UMIN000031913)is an ongoing, prospective cohort for acute ischemic stroke and transient ischemic attack. All patients gave written informed consent for the inclusion of their data in our study and underwent brain magnetic resonance imaging(MRI) or computed tomography scanning. The present cross-sectional study included 190 consecutive patients with ESUS registered between November 2013 and March 2019. The following patients were, then, excluded: 3 patients who could not undergo MRI and 90 patients who did not receive TEE during hospitalization. In total, 94ESUS patients who had a complete poststroke workup, including brain imaging, vessel imaging, and extensive cardiac assessments(12-lead electrocardiography, Holter electrocardiography, transthoracic echocardiography, and TEE), were included in the current analysis (Fig.1). ESUS was defined according to the Cryptogenic Stroke/ESUSInternational Working Group criteria (i.e., stroke detected by computed tomography or MRI that is notacunar; absence of extracranial or intracranial atherosclerosis causing >50% luminal stenosis in arteries supplying the area of ischemia; no major-risk cardioembolic source of embolism or any other specific cause of stroke identified [e.g., arteritis, dissection, migraine or vasospasm, drug misuse,etc.)1. The severity of the event was assessed using the National Institutes of Health Scale(NIHSS)score; NIHSS scores range from 0 to 42, with higher values reflecting more severe neurologic deficits)

Risk Factors

Patients diagnosed with hypertension had evidence of systolic blood pressure > 140theymm Hg, diastolic blood pressure > 90 mm Hg, or if they had received any antihypertensive medication. Diabetes mellitus was specified as having a fasting serum glucose level > 126 mg/dL, serum glucose level!> 200 mg/dL on 2 random measurements, glycated hemoglobin level > 6.5%, or use of antidiabetic therapy (oral hypoglycemic agents or insulin)Dyslipidemia was diagnosed if the patient had low-density lipoprotein cholesterol > 140 mg/dL, total cholesterol> 220 mg/dL, or if the patient had been treated with lipid-lowering agents. The estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease formula with the Japanese coefficient. Chronic kidney disease was defined as an estimated glomerular filtration rate <60mL/min per 1.73 m. Smoking status was defined based on current use. Intracranial arterial stenosis >50% on magnetic resonance angiography(MRA),3-dimensional computed tomography angiography, or digital subtraction angiography was considered a significant finding. Findings of carotid artery ultrasonography were evaluated by trained neurologists, and stenosis >50% was defined as significant extracranial arterial stenosis.

Blood and Echocardiography Examination

B-type natriuretic peptide (BNP)levels were assessed for all patients on admission. Transthoracic 2-dimensional and Doppler echocardiography were performed using the iE 33ultrasound system (Philips Healthcare, Bothell, WA)with an S5 transducer, Left atrial dimension was measured at end-systole when the left atrial chambers at its greatest dimension. Left atrial enlargement was defined as a left atrial diameter exceeding 4.0 cm in men and 3.8 cm in women, E/e'ratio, which is a key parameter for left ventricular diastolic function, was defined as having a cutoff point of 14. The left ventricular ejection fraction was calculated using the biplane Simpson formula. Mitral annulus calcification was defined as an intense echocardiographic-producing structure that was located at the junction of the atrioventricular groove and posterior mitral leaflet on the parasternal long axis, apical 4-chamber, or parasternal short-axis view8)TEE was performed using the Affinity 30ultrasound system (Philips Healthcare) using a multiplane probe. Before performing TEE, intraoral xylocaine spray was administered to all patients. The heart rhythm was monitored by electrocardiography during the examination. Patients were placed in the left lateral decubitus position during probe insertion. The probe was advanced to the distal esophagus and withdrawn slowly to a location 40cm from the incisors, The multiplane probe was manipulated to provide appropriate views, including axial and sagittal images, throughout the aorta. the presence of a right. to-left shunt, such as PFO or pulmonary arteriovenous fistula, was examined by a microbubble study%Briefly, tiny bubbles were formed by shaking sterile salt solution and injecting it into the right antecubital vein, PFO, and pulmonary arteriovenous fistula were defined as the appearance of microbubbles in the left atrium within three cardiac cycles or after four cardiac cycles, respectively, The classification of shunt size was based on the number of microbubbles that appeared in the left atrium during the first three cardiac cycles after opacification in the right atrium; the presence of 1 to 5 microbubbles was classified as small PFO, 6 to 25 microbubbles as moderate PFOand more than 25 microbubbles as large PFO1Atrial septal aneurysm (ASA)is defined as an excursion of the septal tissue (typically the fossa ovalis)of greater than 10 mm from the plane of the atrial septum into the RA or LA or a combined total excursion RA and LA of 15 mm. The aortic arch was observed at 0 and 90 degrees. Mobile plaques were diagnosed as mobile components seen swinging on their peduncles. An ulcerative plaque was diagnosed as a discrete indentation of the luminal surface of the plaque with a base width and a maximum depth of at least 2 mm each. complex aortic atheroma was defined as any large plaque greater than or equal to 4mm in thickness or a plaque with ulceration or mobile components!2, The examinations were performed and recorded by at least 2 experienced sonographers.

Imaging Examination

All patients underwent brain MRI, including the diffusion-weighted image, apparent diffusion-weighted image, and MRA within 7 days of the onset of stroke. Diffusion-weighted image and MRA results were mandatory for enrollment in the study to confirm an ischemic lesion and to exclude other causes of embolization, respectively. The diffusion-weighted image lesions were analyzed by location, size, and number. Each lesion location was classified into supratentorial, infratentorial, and both regions. The size of each lesion was assessed based on the maximum diameter and divided into one of two groups: small! lesion size (those that were smaller than 1.5 cm) and large lesion size (those that were larger than 1.5 cm) The number of ischemic lesions was characterized as single (cortical or subcortical) or multiple (small and scattered in 1 vessel territory confluent lesion with additional lesions, or multiple vascular territories)