Diagnostic Value of Micro-Bubble Transcranial Doppler Combined with Contrast Transthoracic Echocardiography in Cryptogenic Stroke Patients with Patent Foramen Ovale
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.355122
Source of Support: None, Conflict of Interest: None
Keywords: Contrast transthoracic echocardiography, micro-bubble transcranial Doppler, patent foramen ovale, transesophageal echocardiography
Most congenital patent foramen ovale (PFO) can close gradually with the development of body and some just persist there. The study reported that about 10%–35% of adults complicated with PFO without symptoms in general population, but the rate was noticeably higher in patients with cryptogenic stroke (CS).,, PFO was considered as a nonserious clinical presentation because PFO shunt is small., However, recently more and more studies found that people with PFO more likely to have stroke. Therefore, the relationship between PFO and stroke receive more and more attentions.
TTE was widely available in diagnosis of patients with suspected PFO for a longtime. However, TTE is limited to make the right diagnosis in every patient. Consequently, transcranial Doppler (TCD) sonography was applied to the diagnosis of PFO. TCD is an sensitive and non-invasive examination for right-to-left cardiac shunts. Despite its sensitivity, TCD fail to provide full evaluation about the morphological features of the atrial septum or other cardiac structures. Because transesophageal echocardiography (TEE) has almost 100% sensitivity and specificity, it is considered as the gold standard examination for PFO.,, But as an invasive examination, TEE test present some risks. So, this study aimed to explore value of MB-TCD combined with cTTE for the diagnosis of cryptogenic stroke (CS) patients related to PFO.
From January 2014 to January 2019, patients who were confirmed with stroke by MRI and diagnosed as CS by neurological physician were retrospectively recruited into this study. The diagnostic criteria of CS refered to TOAST that was brain infarction but not attributable to source of large artery atherosclerosis, cardiac, definite cardioembolism, or small artery disease despite extensive vascular., All patients were divided into two groups: cTTE examination only and MB-TCD combined with cTTE. All patients were further checked by transesophageal echocardiography (TEE). Written consent was obtained from patients before TEE.
After fasting food for eight (8) hours, a certain mount of 0.02% oral lidocaine was administrated to patients for local pharyngeal anesthesia before transesophageal echocardiography examination. The operation was performed with a Philips iE Elite Ultrasound machine using a X7-2t multiplane transesophageal probe. All images and data are recorded in real time.
Contrast transthoracic echocardiography
Before the examinations, all patients were trained to perform the Valsalva maneuver by the same nurse. X5-1 probe by Philips iE Elite Ultrasound machine was used for cTTE examination. Patients were supine position and cannulated in the right antecubital with an 18-gauge cannula. The cannula was connected with an extension tube, to which is connected a three-way tap and three ten (10)-mL Luer-Lock syringes, respectively 8 mL of sterile saline, one (1) mL of air, and 1 mL of particitant's own blood drawn through a bacterial filter. They were thoroughly exchanged among three syringes at least 10 times to produce an air suspension and injected into the resting patient immediately. Then all patients were instructed to blow the plunger out as forcefully as possible for at least 5 seconds to produce about 40 mmHg of intra-thoracic pressure, just a qualified Valsalva maneuver (VM). The atrial septal protrusion could be monitored in the left atrium after exhalation if the VM was really effective. Once any micro-bubble (MB) was observed in the left atrium, PFO was diagnosed.
Micro-bubble transcranial Doppler
The MB-TCD (Delica EMS-9PB, 1.6 MHz or two (2) MHz probe) was performed by monitoring the corresponding cerebral arteries through bilateral bone windows simultaneously with cTTE by two independent operators and one nurse. When more than 1 micro-embolic appeared within 25 seconds after contrast agent injection, we regarded the MB-TCD result as positive and assumed cardiac RLS passage through the PFO. When the micro-embolic appeared in the Doppler spectrum later than 25 seconds, pulmonary passage shunt was assumed.
SPSS, version 19.0 was used for statistical analysis. Chi-square test was used to assess the significant differences in expected frequencies between two groups. P < 0.05 was considered statistically significant in a twosided test.
A total of 130 patients accepted cTTE examination and 109 patients accepted MB-TCD combined with cTTE. There was no significant difference in demographic characteristics between two groups [Table 1]. In cTTE group, 52 of the 54 positive patients were finally confirmed by TEE with PFO, and 12 of the 76 negative patients were finally confirmed by TEE with PFO.
In combined group, 50 patients were negative on both two examination (Negative group), 54 patients were positive on both two examination (Positive group) and all of them were finally confirmed by TEE indeed with patent foramen ovale (PFO), while remaining 5 patients were positive only on MB-TCD (Suspected group). The classifications of the MB-TCD and cTTE test in both positive patients present significant inconsistencies [Table 2]. MB-TCD medium, showed 100% sensitivity and a missdiagnosis rate of 0. After checked by TEE, three (3) of 5 patients with MB-TCD positive were confirmed by TEE indeed with PFO [Table 3].
The sensitivity, specificity, positive likelihood ratio (+LR), and Youden's index of cTEE in diagnostic of cryptogenic stroke patients with PFO were 81.25%, 96.97%, 26.82 and 0.78, respectively, and these for MB-TCD combined with cTTE were 100%, 96.15%, 25.97 and 0.96, respectively [Table 4].
Generally speaking, the left atrium has a higher pressure compared with the right atrium. So the pressure of the right atrium rise abruptly when coughing or doing a sustained VM and., The development gradient pressure of right to the left atriuma results in right-to-left shunts (RLSs). Previous study found that it was more easier to predict RLSs during VM than at rest. At present, the study about the sensitivity and specificity of cTTE and MB-TCD were a bit different from each other. Maffè et al. previously reported that the sensitivity of cTTE and MB-TCD were 89% and 85% respectively, while another study confirmed that the sensitivity and specificity of TCD were almost 96.8 and 78.4% to identify right-to-left cardiac shunts., The possible reason may be that the final diagnostic criteria of these studies are different. It was demonstrated that MB-TCD had a high sensitivity and specificity for assessing the functional impact of cardiac and extra-cardiac right-to-left shunts, which was related to ischaemic stroke. Other studies found that the sensitivity of TCD was also higher for detecting cardiac PFO if compared with TEE. Hence, MB-TCD should be taken as a complementary examination. We recorded the result of shunt of MB-TCD according to criteria of the Consensus Conference of Venice. In this data, we discovered that the sensitivity of MB-TCD was obviously better than that of TTE. MB-TCD medium, showed 100% sensitivity and a missdiagnosis rate of 0.
The advantage for transesophageal echocardiography is that it could directly observe the anatomy of the atrial septum and associated structures. And the disadvantage is that it just could discover the gap but no shunts. Due to the use of anesthetic that leading to poor cooperation, VM cannot be done during TTE inspection. Hence, TEE is just more sensitive to RLSs in rest while is not available for tiny shunts that can only be observed by VM., According to this study, MB-TCD combined with cTTE have similar specificity but obviously higher sensitivity and Youden's index compared with TTE to preliminarily sreen if cryptogenic stroke patients related to PFO. In fact the sensitivity of MB-TCD combined with cTTE in this study was 100% and the Youden's index was 0.96 indicate that combination of MB-TCD and cTTE had comparable diagnostic value compared with TEE. Although the use of percutaneous PFO closure cannot be generalized to the entire population of patients with cerebral ischemia and PFO, but is indicated in highly selected patients with non-lacunar cryptogenic cerebral infarction with a large right-to-left shunt, an atrial septal aneurysm, and no evidence of atrial fibrillation. This increases the chances that patients with PFO will be treated and possibly cured.
However, the study has some limitations. This is a single-center study, so the study population is not representative of the entire CS ppopulation. Furthermore, We did not further finish TEE examination for those patients who were negative on both tests because we considered that neither ethical nor informed was approved.
In conclusion, both cTTE and MB-TCD have high diagnostic value for cryptogenic stroke patients with patent foramen ovale. When MB-TCD and cTTE were combined to diagnose cryptogenic stroke patients with PFO, the efficiency was obviously better compared with just cTTE, especially MB-TCD medium, with 100% sensitivity and a missdiagnosis rate of 0.
Ethical approval was obtained from the Fujian Union Hospital Ethics Committee (2019KY062).
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4]