Comparative Analysis of the Diagnostic Value of Several Methods for the Diagnosis of Patent Foramen Ovale

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Methods : We investigated 161 patients who suffered from migraine, cryptogenic stroke, TIA, and cerebral infarction of unknown cause, all patients underwent the transcatheter examination, and put the results of the right heart catheterization (RHC) as the gold standard for PFO diagnosis. A chi-square test was used to compare the sensitivity and specificity between the three methods. A P value of <0.05 indicated statistical significance. Results : The present study revealed that c-TTE with the Valsalva maneuver yielded a higher sensitivity in detecting PFO-RLS, but the rate of misdetection might be higher than c-TCD. Conclusions : For the suspected patients, can examine with c-TCD first, if we get the positive results, then c-TTE and c-TEE should be taking to further confirmed. These findings may be helpful in the diagnosis of patent foramen ovale in practice. Cardiac & Cardiovascular Systems patent foramen ovale contrast transcranial Doppler contrast- transthoracic echocardiography contrast- transesophageal echocardiography Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction In recent years, the definition of embolic strokes of undetermined source (ESUS) emerged as a new clinical construct to characterize cryptogenic stroke (CS),most of the patients were young and had no medical history of hypertension, diabetes or hyperlipidemia, routine imageological examination also failed to detect significant vascular abnormalities (Hart et.al, 2017 ). Currently, patent foramen ovale (PFO) has been reported to be strongly associated with a number of diseases, including cryptogenic stroke (Mojadidi et.al, 2018 ), transient ischemic attack (TIA) (Khan et.al, 2016 ), migraine (Smith and Williams, 2017), peripheral arterial embolism, and decompression sickness (Rushdi et.al, 2011). Foramen ovale is a persistent fetal communication between the right and left atrium due to incomplete closure of the atrial septum. After birth, with the interruption of umbilical blood circulation and the establishment of respiration, the foramen ovale then closed functionally, the complete closure is generally 5 to 7 months after birth. If the foramen ovale is still unclosed in children over 3 years old, PFO can be diagnosed. If the right atrial pressure is higher than left atrium (for example, cough, inspiration, Valsalva manoeuvre), blockages from venous system then can flow to the left atrium. Patent foramen ovale is the cause of 95% of paradoxical embolism (Rushdi et.al, 2011). There are three methods for the diagnosis of PFO, contrast-transcranial doppler(c-TCD), transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), TEE has a major role in the assessment of PFO. The diagnostic sensitivity of PFO-RLS by contrast transcranial Doppler (c-TCD) is similar to that of TEE. However, c-TCD has a limited ability to differentiate cardiac from pulmonary Right-to-Left Shunt (RLS). The use of contrast echocardiography was first reported by Gramiak (1968). Currently, contrast transthoracic echocardiography (c-TTE) with the Valsalva maneuver is extensively used for the detection and semiquantitative assessment of PFO-RLS (Kerut et.al, 2001 ). But the diagnostic criteria is not unified, thus, the aim of this research was to compare the sensitivity and specificity of each examination method, to find which is the best method to diagnose PFO, provides reference for the further improvement of clinical. Materials And Methods Patient Population We investigated 161 patients (86 male, 75 female; mean age, 42.0 ± 15.6 years) admitted to the Departments of Neurology and Cardiology in Qilu Hospital, Shandong University from August 2018 to July 2019 who suffered from migraine, cryptogenic stroke, TIA, and cerebral infarction of unknown cause, including migraine 55 cases, cryptogenic stroke 56 cases, both of the symptoms 20 cases, dizzy or syncope 19 cases, TIA 9 cases, epilepsy 2 cases. Exclusion criteria: (1)Cerebral embolism that can find any cause, for example, cardiac cerebral embolism, arteriosclerosis; (2) Patients who could not afford antiplatelet or anticoagulant therapy, for example, severe bleeding within 3 months, severe retinopathy, history of intracranial hemorrhage and other intracranial disease; (3) Obstruction caused by inferior vena cava or pelvic venous thrombosis, systemic or local infection, septicemia, intracardiac thrombosis etc.; (4) Pregnancy; (5) Combine with pulmonary arterial hypertension or PFO cannot be closed; (6) Acute stroke within 2 weeks. The study was approved by the local ethics committee, and all patients or their relatives provided written informed consent to participate in this study prior to the examination. All patients signed informed consent. Saline contrast preparation: Right anterior elbow vein was selected for an indwelling needle. The contrast agent was prepared by mixing with 3 ml of air, 30 ml of saline solution, and 3–5 ml of patient blood, intensively mixed back and forth 20 times between two 30-ml syringes connected by a T-branch pipe. c-TCD Examination TCD was performed using the Multi-DopX4 Transcranial doppler (DWL Electronic Systems, Sipplingen, Germany) with a 2 MHz probe, Middle cerebral artery flow was monitored through the temporal bone window at a depth of 50–65 mm. The study was performed by a neurologist specialized in this technique and blinded to the results of the echocardiographic study. After the middle cerebral artery blood flow velocity value was obtained, the contrast agent was quickly injected via the established route of the anterior elbow vein. The contrast agent was prepared, right-to-left shunt was diagnosed when TCD detected microsignals in the middle cerebral artery, both in the resting state and performing the Valsalva maneuver. The severity of the shunt was quantified as negative (no microsignals), mlid (1–20 microsignals, 1–10 for one side), moderate (≥ 20 microsignals, ≥ 10 for one side), or extensive (≥ 30 microsignals or rain curtain-like signals) (Fig. 1 ). c-TTE and c-TEE Examination Contrast-TTE was conducted using the GE Vivid E9 or E95 platform equipped with a 3.7–5 MHz M5S transducer (Horten, Norway) or Philips EPIQ7 platform equipped with a 1–5 MHz S5-1 transducer (Philips USA). All patients were asked to keep still in the left lateral position. Conventional 2D echocardiography was carried out to acquire the standard apical, parasternal, and subxyphoid four-chamber views. Color flow Doppler was used to observe whether there was RLS at the foramen ovale of the interatrial septum. First, in rest state, the contrast agent was mixed and injected as the same way as c-TCD. Keep the apical four chamber view, after microbubbles filled the right atrium, keep a persistent observation if microbubbles appeared in the left atrium. Then repeat the operation as described above in Valsalva maneuver. When right atrium was filled with microbubbles, let patients do Valsalva maneuver immediately. RLS was graded according to the highest number of microbubbles observed in the left chamber in a single frame: image-negative (no microbubbles), mild (1–10 microbubbles), moderate (11–30 microbubbles), or extensive (≥ 30 microbubbles or left chamber opacification) (Fig. 2 ). If microbubbles appeared in the left atrium within five cardiac cycles after release, RLS was mostly considered to be derived from a PFO. If microbubbles appeared in the left atrium after more than five cardiac cycles, RLS was assumed to originate from a pulmonary arteriovenous malformation. Contrast-TEE was performed using the same system fitted with a 2–7 MHz multi-frequency transesophageal probe. To improve the tolerance to the test, pharyngeal topical anesthesia was carried out using tetracaine hydrochloride gel 15 min before the examination. The probe was pushed in 30-40cm, rotated within 45°–140° to clearly display ascending aorta root, the septum primum and septum secundum and to obverse whether an opened PFO existed in two-dimensional, measured the PFO width and length at the same time, color Doppler was used to obverse whether there was a shunt across the PFO. Then, in rest and in Valsalva maneuver state, the prepared saline contrast agent was injected as the same way above. To ensure maximal diagnostic yield, a standard apical four-chamber view was performed with the administration of contrast agents. The severity of the microbubbles was quantified as the same way as c-TTE (Fig. 3 ). Right heart catheterization and transcatheter closure All patients who indicated RLS underwent the transcatheter examination, and put the results of the right heart catheterization (RHC) as the gold standard for PFO diagnosis. After localized anesthesia with lidocaine, the femoral vein was punctured with an intravenous cannula, and then a 6-F sheath was inserted over the guidewire, reach the foramen ovale at the right atrial, if the catheter can get though the foramen ovale to reach the left atrium, then PFO can be diagnosed. If the sheath failed, then the guidewire was exchanged for a 0.035-in hydrophilic wire, if the hydrophilic wire can get though the foramen ovale to reach the left atrium, then PFO can also be diagnosed. At last, if the hydrophilic wire failed, we injected intravascular contrast media though the catheter, if the contrast media cannot reach the left atrium, PFO cannot be diagnosed. If the PFO cannot be diagnosed, then pulmonary arteriovenous fistula (PAVF) was excluded by pulmonary angiography (Fig. 4 ). Statistical Analysis A chi-square test was used to compare the sensitivity and specificity between the three methods. A P value of < 0.05 indicated statistical significance. All data were analyzed using SPSS software (version 18.0.1, SPSS Inc.). Results Diagnosis of PFO As put the results of the right heart catheterization (RHC) as the gold standard for PFO diagnosis, 141 of the 161 patients studied were diagnosed with PFO, 18 patients cannot be diagnosed with PFO, 2 patients were diagnosed as pulmonary arteriovenous malformation, the morbidity of PFO was 88.17% (Table 1 ). Table 1 Baseline characterization of patients Items Cases Total cases 161 Male 86 Famale 75 Age(years) 42.0 ± 15.6 migraine 55 cryptogenic stroke (CS) 56 migraine + CS 20 TIA 9 dizzy or syncope 19 epilepsy 2 Diagnosed of PFO 141 Diagnostic value of c-TCD Two patients did not accept the c-TCD examination, the right-to-left shunt was visualized at baseline by c-TCD in 97 patients (70.28%, 97/138), the degree of mild included 44 patients (31.88%, 44/138), moderate included 22 patients (15.94%, 22/138), extensive included 31 patients (22.46%, 31/138), the Valsalva maneuver was effective in all c-TCD studies, then RLS was identified 128 patients (92.75%, 128/138), the degree of mild included 36 patients (26.09%, 36/138), moderate included 28 patients (20.29%, 28/138), extensive included 64 patients (46.38%, 64/138), the difference between baseline and Valsalva maneuver was statistically significant (Table 2 ). Table 2 , Results of c-TCD, c-TTE and c-TEE in 141 cases Baseline Valsalva maneuver c-TCD* n = 138 negative 41 10 mild 44 36 moderate 22 28 extensive 31 64 c-TTE # n = 135 negative 54 9 mild 41 24 moderate 15 35 extensive 25 67 TTE 2D (+), n = 141 12 TTE color (+), n = 141 17 c-TEE & n = 130 negative 61 17 mild 37 32 moderate 12 15 extensive 20 66 TEE 2D (+), n = 132 119 TEE color (+), n = 132 40 *: Two patients did not accept the c-TCD examination; # : Six patients did not accept the c-TTE examination; & :Seven patients did not accept the TEE examination. Diagnostic value of c-TTE and c-TEE The loss of echo was identified in 12 patients (8.51%, 12/141) by TTE, included 3 atrium septal aneurysms, the color shunt was identified in 17 patients (12.06%, 17/141), six patients did not accept the c-TTE examination, TEE bubble was identified in 81 patients (60.00%, 81/135) at baseline, the degree of mild included 41 patients (30.37%, 41/135), moderate included 15 patients (11.11%, 15/135), extensive included 25 patients (18.52%, 25/135), the Valsalva maneuver was effective in all c-TTE studies, then RLS was identified 126 patients (93.33%, 126/135), the degree of mild included 24 patients (17.78%, 24/135), moderate included 35 patients (25.93%, 37/135), extensive included 67 patients (49.63%, 67/135); There were eight patients did not tolerate TEE examination, include seven PFOs and one without PFO. Two-dimensional TEE displayed a “slit-like” channel ≥ 2 mm between the septum primum and the septum secundum in 119 patients (90.15%, 119/132). The color shunt was identified in 40 patients (30.30%, 40/132), and then, two patients did not accept c-TEE examination, TEE bubble was identified in 69 patients (53.08%, 69/130) at baseline, the degree of mild included 37 patients (28.46%, 37/130), moderate included 12 patients (9.23%, 12/130), extensive included 20 patients (15.38%, 20/130), the Valsalva maneuver was effective in all c-TEE studies, then RLS was identified 113 patients (86.92%, 113/130), the degree of mild included 32 patients (24.62%, 32/130), moderate included 15 patients (11.54%, 15/130), extensive included 66 patients (50.77%, 66/130) (Table 2 ). Diagnosis of patients without PFO In the total 161 patients, 18 patients cannot be diagnosed with PFO, among of them, results of c-TCD in 4(22.22%, 4/18) patients were positive both at baseline and Valsalva maneuver, 7(38.89%, 7/18) patients were positive only after Valsalva maneuver effected. Besides, results of c-TTE in 6(33.33%, 6/18) patients were positive both at baseline and Valsalva maneuver, 7(38.89%, 7/18) patients were positive only after Valsalva maneuver. The slit-like channel between the septum primum and the septum secundum by TEE was identified 5 (29.41%, 5/17) patients, TEE bubble was identified in 4(23.53%, 4/17) patients both at baseline and Valsalva maneuver, 6 (35.29%, 6/17) patients only after Valsalva maneuver (Table 3 ). Table 3 Diagnosis of patients without PFO (18 cases) Baseline Valsalva maneuver c-TCD negative 14 7 mild 3 8 moderate 0 1 extensive 1 2 c-TTE negative 12 5 mild 5 6 moderate 1 5 extensive 0 2 TTE 2D (+) 0 0 TTE color (+) 0 0 c-TEE* negative 13 7 mild 3 4 moderate 0 3 extensive 1 3 TEE 2D (+) 5 5 TEE color (+) 0 0 *: One of the 18 patients did not tolerate TEE. Diagnostic value between the different methods In total, the sensitivity of c-TCD at baseline was 70.28% (97/138), 22.46% (31/138) for the degree of extensive, 38.40% (53/138) for moderate and extensive; the sensitivity of c-TCD after Valsalva maneuver was 92.75% (128/138), 46.38% (64/138) for the degree of extensive, 66.67% (92/138) for moderate and extensive; the sensitivity of the loss of echo by TTE was 8.51% (12/141), the color shunt was 12.06% (17/141); the sensitivity of the total c-TTE at baseline was 60.00% (81/135), 18.52% (25/135) for the degree of extensive, 29.63% (40/135) for moderate and extensive; the sensitivity of the total c-TTE after Valsalva maneuver was 93.33% (126/135), 49.63%(67/135) for the degree of extensive, 75.56% (102/135) for moderate and extensive; the sensitivity of the slit-like channel between the septum primum and the septum secundum by TEE was 90.15% (119/132), the color shunt was 30.30% (40/132); the sensitivity of the total c-TEE at baseline was 53.08% (69/130), 15.38% (20/130) for the degree of extensive, 24.62% (32/130) for moderate and extensive; the sensitivity of the c-TEE after Valsalva maneuver was 86.92% (113/130), 50.77% (66/130) for the degree of extensive, 62.31% (81/130)for moderate and extensive. For the comparison among groups, there were no significant difference between the sensitivity of total c-TCD, c-TTE and c-TEE at baseline, when compared by pairs other, c-TCD was significantly higher than c-TEE ( P = 0.004); After Valsalva maneuver, the sensitivity of total c-TTE was significantly higher than c-TEE ( P = 0.041). For the comparison within groups, if the bubbles were extensive in the examination of c-TTE at baseline, the sensitivity was significantly higher than c-TCD ( P = 0.011) and c-TEE ( P = 0.009). The positive predictive value of total c-TCD at baseline was 96.04% (97/101), 96.88% (31/32) for the degree of extensive, 98.15% (53/54) for moderate and extensive. After Valsalva maneuver, the positive predictive value of total c-TCD wes 92.09% (128/139), 96.97% (64/66) for the degree of extensive, 96.84% (92/95) for moderate and extensive. The false negative rate of total c-TCD at baseline was 29.71% (41/138), 7.25% (10/138) after Valsalva maneuver. The positive predictive value of c-TTE at baseline was 93.10% (81/87), 100.00% (25/25) for the degree of extensive, 97.56% (40/41) for moderate and extensive; after Valsalva maneuver, the positive predictive value was 90.65% (126/139), 97. 10% (67/69) for the degree of extensive, 93.58% (102/109) for moderate and extensive. The false negative rate of total c-TTE at baseline was 40.00% (54/135), 6.67% (9/135) after Valsalva maneuver. The positive predictive value of c-TEE at baseline was 94.52% (69/73), 95.24% (20/21) for the degree of extensive, 96.97% (32/33) for moderate and extensive; after Valsalva maneuver, the positive predictive value was 91.87% (113/123), 95.65% (66/69) for the degree of extensive, 93.10% (81/87) for moderate and extensive. The false negative rate of total c-TEE at baseline was 46.92% (61/130), 13.08% (17/130) after Valsalva maneuver (Table 4 ). Table 4 , Diagnostic value of c-TCD, c-TTE and c-TEE Baseline Valsalva maneuver Sensi(%) PPV(%) FNR (%) Sensi (%) PPV (%) FNR (%) c-TCD Total 70.29** 96.04 29.71 92.75 92.09 7.25 extensive 22.46 96.88 56.94 46.38 96.97 13.51 moderate + extensive 38.40 98.15 43.62 66.67 96.84 9.80 c-TTE Total 60.00 93.10 40.00 93.33* 90.65 6.67 extensive 18.52 100 # 68.35 49.63 97.10 11.84 moderate + extensive 29.63 97.56 57.44 75.56 93.58 8.10 TTE 2D 8.51 100 TTE color 12.06 100 c-TEE Total 53.08 94.52 46.92 86.92 91.87 13.08 extensive 15.38 95.24 75.30 50.77 95.65 20.48 moderate + extensive 24.62 96.97 65.59 62.31 93.10 17.35 TEE 2D 90.15 94.17 9.85 TEE color 30.30 100 PPV: positive predictive value; Sensi: Sensitive; FNR: false negative rate. **: P ༜0.005(0.004) vs c-TEE; *: P ༜0.05(0.041) vs c-TEE; # : P ༜0.05(0.011) vs extensive of c-TCD, (0.009) vs extensive of c-TEE. Discussion Foramen ovale is a persistent fetal communication between the right and left atrium due to incomplete closure of the atrial septum, after birth, the foramen ovale closed. But the morbidity of PFO was about 30% (Homma et.al, 2001). PFO has no obvious symptoms in usual times, and hard to heard the heart murmur, there were no abnormal in the electrocardiogram and chest X-ray, so it was easy to be neglected. Recently, patients who suffered from migraine headaches, cryptogenic stroke, TIA, and cerebral infarction, if did not have acute cerebral infarction or anterior circulation transient ischemic attack on admission, the possibility of being caused by the right-to-left shunt then be considered. Our study assessed a large series of patients to find out the presence of right-to-left shunt, the results demonstrated that the sensitivity of c-TTE is superior to c-TEE in the diagnosis of PFO both at baseline and Valsalva maneuver, c-TCD performed simultaneously with c-TEE but maybe gave a false positive. TEE was lack of sensitivity contrast with c-TCD, the probability false-negative was higher than c-TCD, so the c-TCD can be used as an effective supplement to diagnose PFO; the sensitivity of TEE was highest in the three methods, still can be the gold standard. But the results of c-TCD can only point out that right-to-left shunt, cannot exclude extracardiac shunt, so combined application should be used. PFO was a three-dimensional structure, which will change the shape with the cardiac cycle. Therefore, it is difficult to fully display the PFO simply by using TEE's two-dimensional technology, as our results, three was some false positive cases when we used 2D image of TEE (5 cases). The three-dimensional (3D) technology can solve the one-sidedness problem, but 3D image quality due to the 2D image, sometimes, 3D image was just for the reference (Shanks et.al, 2012 ). In terms of sensitivity,total c-TTE after Valsalva maneuver was the highest, especially for extensive, so we consider that sensitivity was increased with the quantity of bubbles in left heart. Moreover, if we observed the color shunt from the slit-like channel between the septum primum and the septum secundum by TEE, the positive predictive value was 100.00%, so in our daily clinical work, the observation of TEE color shunt is very important. But the sensitivity of c-TEE was lower than c-TTE after Valsalva maneuver, based on our observations, patients sometimes cannot make the Valsalva maneuver perfectly during TEE examination, that might be the most probable reason. c-TCD has the greatest value in diagnosing PFO, almost all the PFO patients had positive results in c-TCD examination, but c-TCD can only point out that right-to-left shunt, cannot exclude extracardiac shunt (Wessler et.al, 2015 ), c-TTE and c-TEE can observe the structure of oval foramen, were more convincing. The positive predictive value can reflect the possibility of prevalence rate in patients with positive results. In all the three methods (c-TCD, c-TTE, c-TEE), if three were a large number of bubbles in the left heart, especially with the color shunt from the slit-like channel, the positive predictive value was the highest. Although c-TCD has the highest positive predictive value, some unsolved problems still existed, for example, some bubbles can get though the pulmonary circulation, be detected in the cerebral arteries, so we will get a false positive result. On the other hand, c-TTE and c-TEE had more false negatives, the rate of misdetection might be higher than c-TCD. So, for the suspected patients, can examine with c-TCD first, if we get the positive results, then c-TTE and c-TEE should be taking to further confirmed. The results sometimes were different between resting state and Valsalva maneuver, the positive rate is higher with Valsalva maneuver. At the resting state, not all the patients could be observed the RLS. In some PFO patients, the foramen ovale is closed in resting state, only under some particular situation, for example, cough, cry, constipation, Valsalva maneuver and so on, that’s also the causes of nervous system symptoms on PFO patients (Zhao et.al, 2015). Only under those situations, the right atrial pressure can higher than the left atrial transiently, the foramen ovale then opened, so we could observe the RLS. So, for the situation when the left heart didn’t exist bubbles, Valsalva maneuver was necessary, results were positive no no matter Valsalva or not when bubbles existed in left heart. Pulmonary arteriovenous fistula (PAVF) is abnormal pulmonary vascular structures that connect a pulmonary artery to a pulmonary vein, bypassing the normal capillary bed resulting in an intrapulmonary right-to-left shunt (Abdel Aal et.al, 2018 ). In our study, 2 patients were diagnosed as PVAF. At first, we didn’t give much attention to this disease, the results of c-TCD, c-TTE and c-TEE showed a strongly positive reaction, so we did the transcatheter examination, but the result was unexpected, PFO cannot be diagnosed. Then pulmonary angiography was performed, the results showed that the contrast medium can get to pulmonary vein from pulmonary artery, so we did a diagnose mistake before. We looked back the examinations, find that the slit-like channel by TEE was not very sure, and the bubbles seemed to be from la roof, the entrance of pulmonary vein, these findings could help us to diagnose PVAF. So, in conclusion, we have to consider the following points to diagnose PVAF: first, the results of c-TCD, c-TTE and c-TEE show a positive sometimes a strongly reaction; second, TEE image cannot make sure the slit-like channel existed, or the width of foramen ovale cannot match the quantity of bubbles; third, he bubbles seemed to be from la roof, the entrance of pulmonary vein, not from the foramen ovale. Conclusion In conclusion, the present study revealed that c-TTE with the Valsalva maneuver yielded a higher sensitivity in detecting PFO-RLS, but the rate of misdetection might be higher than c-TCD. Therefore, for the suspected patients, can examine with c-TCD first, if we get the positive results, then c-TTE and c-TEE should be taking to further confirmed. These findings may be helpful in the diagnosis of patent foramen ovale in practice. Abbreviations PFO patent foramen ovale c-TCD contrast transcranial Doppler c-TTE contrast- transthoracic echocardiography c-TEE contrast- transesophageal echocardiography TIA transient ischemic attacks ESUS embolic strokes of undetermined source CS cryptogenic stroke RLS Right-to-Left Shunt RHC right heart catheterization PAVF pulmonary arteriovenous fistula Declarations Ethics approval and consent to participate The study was approved by the local ethics committee, and all patients or their relatives provided written informed consent to participate in this study prior to the examination. All patients signed informed consent. Consent for publication Not applicable. Availability of data and materials ../PFO初稿/PFO病人资料.xlsx">..\PFO初稿\PFO病人资料.xlsx Competing interests The authors declare that they have no competing interests. Funding Research reported in this research was supported by the technology capture project of Shandong province under award number 2017GGX90104. Authors' contributions QK and JZ analyzed the data of right cardiac catheterization, YL analyzed the data of c-TCD, FL SL and HS analyzed the data of c-TEE and c-TTE, FL performed the data statistics and was a major contributor in writing the manuscript. All authors read and approved the final manuscript. Acknowledgements Not applicable. References Abdel Aal AK, Eason J, Moawad S, Mahmoud K, Hamed BF, Massoud MO, Ertel N, Gunn A, Oser R, Saddekni S. Persistent Pulmonary Arteriovenous Malformations: Percutaneous Embolotherapy. Curr Probl Diagn Radiol. 2018 Nov;47(6):428–36. Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ. 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Ali Kausar Rushdi Y, Hina H, Patel B, Cross FW. The Incidence of Peripheral Arterial Embolism in Association With a Patent Foramen Ovale (Right-To-Left Shunt). JRSM Short Rep. 2011 May;2(5):35. Hildick-Smith D, Williams TM. Patent Foramen Ovale and Migraine Headache. Interv Cardiol Clin 2017 Oct;6(4):539–545. Shanks M, Manawadu D, Muhll IV, Khan K, Becher H, Choy J. Detection of Patent Foramen Ovale by 3D Echocardiography. JACC Cardiovasc Imaging. 2012 Mar;5(3):329–31. Wessler BS, Kent DM, Thaler DE, Ruthazer R, Lutz RS, Serena J. The RoPE Score and Right-to-Left Shunt Severity by Transcranial Doppler in the CODICIA Study. Cerebrovasc Dis. 2015;40(1–2):52–8. Zhao E, Wei Y, Zhang Y, Zhai N, Zhao P, Liu B. A Comparison of Transthroracic Echocardiograpy and Transcranial Doppler With Contrast Agent for Detection of Patent Foramen Ovale With or Without the Valsalva Maneuver. Medicine (Baltimore).2015 Oct;94(43):e1937. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-63042","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":2131940,"identity":"f7edf6e8-2e44-466c-a02a-94c9a08a1c2e","order_by":0,"name":"Fangfang liu","email":"","orcid":"","institution":"Shandong University Qilu Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fangfang","middleName":"","lastName":"liu","suffix":""},{"id":2131941,"identity":"548561af-1b6b-47c1-a58b-175cb8e9f8d8","order_by":1,"name":"Qingyu Kong","email":"","orcid":"","institution":"Shandong University Qilu Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qingyu","middleName":"","lastName":"Kong","suffix":""},{"id":2131942,"identity":"53924e1d-5999-4ad2-aaee-7aec559958f7","order_by":2,"name":"Xiaojun Zhang","email":"","orcid":"","institution":"Rongjun General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaojun","middleName":"","lastName":"Zhang","suffix":""},{"id":2131943,"identity":"a946fe1e-a1d7-448f-a7fa-313b89029f35","order_by":3,"name":"Yan Li","email":"","orcid":"","institution":"Shandong University Qilu Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Li","suffix":""},{"id":2131944,"identity":"31f18282-bc35-4a02-aff0-31e13737448c","order_by":4,"name":"Shimin Liang","email":"","orcid":"","institution":"The Fifth Hospital of Jinan","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shimin","middleName":"","lastName":"Liang","suffix":""},{"id":2131945,"identity":"9efa586d-30d8-416e-b479-bba54568f6fb","order_by":5,"name":"Shuang Han","email":"","orcid":"","institution":"The First Hospital of shandong First Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shuang","middleName":"","lastName":"Han","suffix":""},{"id":2131946,"identity":"e10bcd50-c214-49e5-9b45-718cb08999d9","order_by":6,"name":"guishuang Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBUlEQVRIiWNgGAWjYBACPmYgkcBwAMRmfJBQISHHxt5+AK8WNiQtzAYfztgY8/GcScCvBUKBtbBJzmxLS5wn4WCAXws7+zWJB3/uJPbPbr8gzcN2OL1NAmjrj4pteBzGUyaR2PYsccadMwXGPDyHc9ukGw8w9py5jU9LmkRiw+HEhhs5Cck8EkAtMgcSmBnbCGhJ+HM4cT5Qy2Eeg8PpbBIJBgS0sB+TSGA7nLjhRvrBxhkJaQlEaOFhtkhsO2y88UYOM8OHAzaGbcBAPojPL/z8xx/e/PHnsOy8G+nPfyT+k5CXb28/+OBHBW4tDAw8BugMaDThBuwP0BmjYBSMglEwClABAMV9XdqQGs/gAAAAAElFTkSuQmCC","orcid":"","institution":"Shandong University Qilu Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"guishuang","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2020-08-20 12:03:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-63042/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-63042/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":2320377,"identity":"c84feb3c-0043-42ac-8c54-85bce6ba65cf","added_by":"auto","created_at":"2020-09-09 15:58:41","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":221516,"visible":true,"origin":"","legend":"Quantification of the shunt by c-TCD. (A) Grade I, mild signals. (B) Grade II, moderate signals. (C) Grade III, extensive signals.","description":"","filename":"Onlinefloatimage1.Png","url":"https://assets-eu.researchsquare.com/files/rs-63042/v1/Onlinefloatimage1.Png"},{"id":2320378,"identity":"0bbece5d-bca1-4f02-a69d-684f4ca18674","added_by":"auto","created_at":"2020-09-09 15:58:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":51657,"visible":true,"origin":"","legend":"Quantification of the shunt by c-TTE. (A) Grade I, mild signals. (B) Grade II, moderate signals. (C) Grade III, extensive signals. LA: left atrium; LV: left ventricle; RA: right atrium; RV: right ventricle.","description":"","filename":"Onlinefloatimage2.Png","url":"https://assets-eu.researchsquare.com/files/rs-63042/v1/Onlinefloatimage2.Png"},{"id":2320379,"identity":"3ead504a-adc7-439a-8df8-ee52492acf18","added_by":"auto","created_at":"2020-09-09 15:58:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":76844,"visible":true,"origin":"","legend":"Two-dimensional and color Doppler TEE, Quantification of the shunt by c-TTE. (A) Two-dimensional TEE displayed the “slit-like” channel between the septum primum and the septum secundum. (B) Color Doppler displayed the right-to-left color shunt. (C) Grade I, mild signals. (D) Grade II, moderate signals. (E) Grade III, extensive signals. LA: left atrium; LV: left ventricle; RA: right atrium; RV: right ventricle.","description":"","filename":"Onlinefloatimage3.Png","url":"https://assets-eu.researchsquare.com/files/rs-63042/v1/Onlinefloatimage3.Png"},{"id":2320380,"identity":"c660d90b-c7b3-46f9-a067-810c3981a606","added_by":"auto","created_at":"2020-09-09 15:58:42","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":137024,"visible":true,"origin":"","legend":"Right heart catheterization with angiography. (A) After injected intravascular contrast media though the catheter, if the contrast media cannot reach the left atrium, PFO cannot be diagnosed. (B \u0026 C) If the PFO cannot be diagnosed, then pulmonary arteriovenous fistula (PAVF) was excluded by pulmonary angiography. (D) Pulmonary arteriography showed the PAVF.","description":"","filename":"Onlinefloatimage4.Png","url":"https://assets-eu.researchsquare.com/files/rs-63042/v1/Onlinefloatimage4.Png"},{"id":13588993,"identity":"a0ab297f-baeb-4466-a099-9d74a2b1a7c3","added_by":"auto","created_at":"2021-09-17 04:58:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2740058,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-63042/v1/0143cc91-b7e3-49f0-a871-239d2dd31fa0.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eComparative Analysis of the Diagnostic Value of Several Methods for the Diagnosis of Patent Foramen Ovale\u003c/p\u003e","fulltext":[{"header":"Introduction","content":" \u003cp\u003eIn recent years, the definition of embolic strokes of undetermined source (ESUS) emerged as a new clinical construct to characterize cryptogenic stroke (CS),most of the patients were young and had no medical history of hypertension, diabetes or hyperlipidemia, routine imageological examination also failed to detect significant vascular abnormalities (Hart et.al, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Currently, patent foramen ovale (PFO) has been reported to be strongly associated with a number of diseases, including cryptogenic stroke (Mojadidi et.al, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), transient ischemic attack (TIA) (Khan et.al, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), migraine (Smith and Williams, 2017), peripheral arterial embolism, and decompression sickness (Rushdi et.al, 2011).\u003c/p\u003e \u003cp\u003eForamen ovale is a persistent fetal communication between the right and left atrium due to incomplete closure of the atrial septum. After birth, with the interruption of umbilical blood circulation and the establishment of respiration, the foramen ovale then closed functionally, the complete closure is generally 5 to 7\u0026nbsp;months after birth. If the foramen ovale is still unclosed in children over 3\u0026nbsp;years old, PFO can be diagnosed. If the right atrial pressure is higher than left atrium (for example, cough, inspiration, Valsalva manoeuvre), blockages from venous system then can flow to the left atrium. Patent foramen ovale is the cause of 95% of paradoxical embolism (Rushdi et.al, 2011).\u003c/p\u003e \u003cp\u003eThere are three methods for the diagnosis of PFO, contrast-transcranial doppler(c-TCD), transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), TEE has a major role in the assessment of PFO. The diagnostic sensitivity of PFO-RLS by contrast transcranial Doppler (c-TCD) is similar to that of TEE. However, c-TCD has a limited ability to differentiate cardiac from pulmonary Right-to-Left Shunt (RLS). The use of contrast echocardiography was first reported by Gramiak (1968). Currently, contrast transthoracic echocardiography (c-TTE) with the Valsalva maneuver is extensively used for the detection and semiquantitative assessment of PFO-RLS (Kerut et.al, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2001\u003c/span\u003e). But the diagnostic criteria is not unified, thus, the aim of this research was to compare the sensitivity and specificity of each examination method, to find which is the best method to diagnose PFO, provides reference for the further improvement of clinical.\u003c/p\u003e "},{"header":"Materials And Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient Population\u003c/h2\u003e \u003cp\u003eWe investigated 161 patients (86 male, 75 female; mean age, 42.0\u0026thinsp;\u0026plusmn;\u0026thinsp;15.6\u0026nbsp;years) admitted to the Departments of Neurology and Cardiology in Qilu Hospital, Shandong University from August 2018 to July 2019 who suffered from migraine, cryptogenic stroke, TIA, and cerebral infarction of unknown cause, including migraine 55 cases, cryptogenic stroke 56 cases, both of the symptoms 20 cases, dizzy or syncope 19 cases, TIA 9 cases, epilepsy 2 cases. Exclusion criteria: (1)Cerebral embolism that can find any cause, for example, cardiac cerebral embolism, arteriosclerosis; (2) Patients who could not afford antiplatelet or anticoagulant therapy, for example, severe bleeding within 3 months, severe retinopathy, history of intracranial hemorrhage and other intracranial disease; (3) Obstruction caused by inferior vena cava or pelvic venous thrombosis, systemic or local infection, septicemia, intracardiac thrombosis etc.; (4) Pregnancy; (5) Combine with pulmonary arterial hypertension or PFO cannot be closed; (6) Acute stroke within 2 weeks.\u003c/p\u003e \u003cp\u003eThe study was approved by the local ethics committee, and all patients or their relatives provided written informed consent to participate in this study prior to the examination. All patients signed informed consent.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSaline contrast preparation:\u003c/h2\u003e \u003cp\u003eRight anterior elbow vein was selected for an indwelling needle. The contrast agent was prepared by mixing with 3\u0026nbsp;ml of air, 30\u0026nbsp;ml of saline solution, and 3\u0026ndash;5\u0026nbsp;ml of patient blood, intensively mixed back and forth 20 times between two 30-ml syringes connected by a T-branch pipe.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ec-TCD Examination\u003c/h2\u003e \u003cp\u003eTCD was performed using the Multi-DopX4 Transcranial doppler (DWL Electronic Systems, Sipplingen, Germany) with a 2\u0026nbsp;MHz probe, Middle cerebral artery flow was monitored through the temporal bone window at a depth of 50\u0026ndash;65\u0026nbsp;mm. The study was performed by a neurologist specialized in this technique and blinded to the results of the echocardiographic study. After the middle cerebral artery blood flow velocity value was obtained, the contrast agent was quickly injected via the established route of the anterior elbow vein. The contrast agent was prepared, right-to-left shunt was diagnosed when TCD detected microsignals in the middle cerebral artery, both in the resting state and performing the Valsalva maneuver. The severity of the shunt was quantified as negative (no microsignals), mlid (1\u0026ndash;20 microsignals, 1\u0026ndash;10 for one side), moderate (\u0026ge;\u0026thinsp;20 microsignals, \u0026ge;\u0026thinsp;10 for one side), or extensive (\u0026ge;\u0026thinsp;30 microsignals or rain curtain-like signals) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ec-TTE and c-TEE Examination\u003c/h2\u003e \u003cp\u003eContrast-TTE was conducted using the GE Vivid E9 or E95 platform equipped with a 3.7\u0026ndash;5\u0026nbsp;MHz M5S transducer (Horten, Norway) or Philips EPIQ7 platform equipped with a 1\u0026ndash;5\u0026nbsp;MHz S5-1 transducer (Philips USA). All patients were asked to keep still in the left lateral position. Conventional 2D echocardiography was carried out to acquire the standard apical, parasternal, and subxyphoid four-chamber views. Color flow Doppler was used to observe whether there was RLS at the foramen ovale of the interatrial septum. First, in rest state, the contrast agent was mixed and injected as the same way as c-TCD. Keep the apical four chamber view, after microbubbles filled the right atrium, keep a persistent observation if microbubbles appeared in the left atrium. Then repeat the operation as described above in Valsalva maneuver. When right atrium was filled with microbubbles, let patients do Valsalva maneuver immediately. RLS was graded according to the highest number of microbubbles observed in the left chamber in a single frame: image-negative (no microbubbles), mild (1\u0026ndash;10 microbubbles), moderate (11\u0026ndash;30 microbubbles), or extensive (\u0026ge;\u0026thinsp;30 microbubbles or left chamber opacification) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). If microbubbles appeared in the left atrium within five cardiac cycles after release, RLS was mostly considered to be derived from a PFO. If microbubbles appeared in the left atrium after more than five cardiac cycles, RLS was assumed to originate from a pulmonary arteriovenous malformation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eContrast-TEE was performed using the same system fitted with a 2\u0026ndash;7\u0026nbsp;MHz multi-frequency transesophageal probe. To improve the tolerance to the test, pharyngeal topical anesthesia was carried out using tetracaine hydrochloride gel 15\u0026nbsp;min before the examination. The probe was pushed in 30-40cm, rotated within 45\u0026deg;\u0026ndash;140\u0026deg; to clearly display ascending aorta root, the septum primum and septum secundum and to obverse whether an opened PFO existed in two-dimensional, measured the PFO width and length at the same time, color Doppler was used to obverse whether there was a shunt across the PFO. Then, in rest and in Valsalva maneuver state, the prepared saline contrast agent was injected as the same way above. To ensure maximal diagnostic yield, a standard apical four-chamber view was performed with the administration of contrast agents. The severity of the microbubbles was quantified as the same way as c-TTE (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eRight heart catheterization and transcatheter closure\u003c/h2\u003e \u003cp\u003eAll patients who indicated RLS underwent the transcatheter examination, and put the results of the right heart catheterization (RHC) as the gold standard for PFO diagnosis. After localized anesthesia with lidocaine, the femoral vein was punctured with an intravenous cannula, and then a 6-F sheath was inserted over the guidewire, reach the foramen ovale at the right atrial, if the catheter can get though the foramen ovale to reach the left atrium, then PFO can be diagnosed. If the sheath failed, then the guidewire was exchanged for a 0.035-in hydrophilic wire, if the hydrophilic wire can get though the foramen ovale to reach the left atrium, then PFO can also be diagnosed. At last, if the hydrophilic wire failed, we injected intravascular contrast media though the catheter, if the contrast media cannot reach the left atrium, PFO cannot be diagnosed. If the PFO cannot be diagnosed, then pulmonary arteriovenous fistula (PAVF) was excluded by pulmonary angiography (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eA chi-square test was used to compare the sensitivity and specificity between the three methods. A \u003cem\u003eP\u003c/em\u003e value of \u0026lt;\u0026thinsp;0.05 indicated statistical significance. All data were analyzed using SPSS software (version 18.0.1, SPSS Inc.).\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":" \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eDiagnosis of PFO\u003c/h2\u003e \u003cp\u003eAs put the results of the right heart catheterization (RHC) as the gold standard for PFO diagnosis, 141 of the 161 patients studied were diagnosed with PFO, 18 patients cannot be diagnosed with PFO, 2 patients were diagnosed as pulmonary arteriovenous malformation, the morbidity of PFO was 88.17% (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characterization of patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eItems\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCases\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e161\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge(years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42.0\u0026thinsp;\u0026plusmn;\u0026thinsp;15.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emigraine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecryptogenic stroke (CS)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emigraine\u0026thinsp;+\u0026thinsp;CS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003edizzy or syncope\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eepilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiagnosed of PFO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e141\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eDiagnostic value of c-TCD\u003c/h2\u003e \u003cp\u003eTwo patients did not accept the c-TCD examination, the right-to-left shunt was visualized at baseline by c-TCD in 97 patients (70.28%, 97/138), the degree of mild included 44 patients (31.88%, 44/138), moderate included 22 patients (15.94%, 22/138), extensive included 31 patients (22.46%, 31/138), the Valsalva maneuver was effective in all c-TCD studies, then RLS was identified 128 patients (92.75%, 128/138), the degree of mild included 36 patients (26.09%, 36/138), moderate included 28 patients (20.29%, 28/138), extensive included 64 patients (46.38%, 64/138), the difference between baseline and Valsalva maneuver was statistically significant (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e, \u003cem\u003eResults of c-TCD, c-TTE and c-TEE in 141 cases\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eValsalva maneuver\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" morerows=\"3\" nameend=\"c2\" namest=\"c1\" rowspan=\"4\"\u003e \u003cp\u003ec-TCD*\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003enegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003emild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003emoderate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eextensive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003ec-TTE\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003enegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003emild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003emoderate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eextensive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eTTE 2D (+), n\u0026thinsp;=\u0026thinsp;141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eTTE color (+), n\u0026thinsp;=\u0026thinsp;141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" morerows=\"3\" nameend=\"c2\" namest=\"c1\" rowspan=\"4\"\u003e \u003cp\u003ec-TEE\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003enegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003emild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003emoderate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eextensive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eTEE 2D (+), n\u0026thinsp;=\u0026thinsp;132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eTEE color (+), n\u0026thinsp;=\u0026thinsp;132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*: Two patients did not accept the c-TCD examination; \u003csup\u003e#\u003c/sup\u003e: Six patients did not accept the c-TTE examination; \u003csup\u003e\u0026amp;\u003c/sup\u003e:Seven patients did not accept the TEE examination.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eDiagnostic value of c-TTE and c-TEE\u003c/h2\u003e \u003cp\u003eThe loss of echo was identified in 12 patients (8.51%, 12/141) by TTE, included 3 atrium septal aneurysms, the color shunt was identified in 17 patients (12.06%, 17/141), six patients did not accept the c-TTE examination, TEE bubble was identified in 81 patients (60.00%, 81/135) at baseline, the degree of mild included 41 patients (30.37%, 41/135), moderate included 15 patients (11.11%, 15/135), extensive included 25 patients (18.52%, 25/135), the Valsalva maneuver was effective in all c-TTE studies, then RLS was identified 126 patients (93.33%, 126/135), the degree of mild included 24 patients (17.78%, 24/135), moderate included 35 patients (25.93%, 37/135), extensive included 67 patients (49.63%, 67/135); There were eight patients did not tolerate TEE examination, include seven PFOs and one without PFO. Two-dimensional TEE displayed a \u0026ldquo;slit-like\u0026rdquo; channel\u0026thinsp;\u0026ge;\u0026thinsp;2\u0026nbsp;mm between the septum primum and the septum secundum in 119 patients (90.15%, 119/132). The color shunt was identified in 40 patients (30.30%, 40/132), and then, two patients did not accept c-TEE examination, TEE bubble was identified in 69 patients (53.08%, 69/130) at baseline, the degree of mild included 37 patients (28.46%, 37/130), moderate included 12 patients (9.23%, 12/130), extensive included 20 patients (15.38%, 20/130), the Valsalva maneuver was effective in all c-TEE studies, then RLS was identified 113 patients (86.92%, 113/130), the degree of mild included 32 patients (24.62%, 32/130), moderate included 15 patients (11.54%, 15/130), extensive included 66 patients (50.77%, 66/130) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eDiagnosis of patients without PFO\u003c/h2\u003e \u003cp\u003eIn the total 161 patients, 18 patients cannot be diagnosed with PFO, among of them, results of c-TCD in 4(22.22%, 4/18) patients were positive both at baseline and Valsalva maneuver, 7(38.89%, 7/18) patients were positive only after Valsalva maneuver effected. Besides, results of c-TTE in 6(33.33%, 6/18) patients were positive both at baseline and Valsalva maneuver, 7(38.89%, 7/18) patients were positive only after Valsalva maneuver. The slit-like channel between the septum primum and the septum secundum by TEE was identified 5 (29.41%, 5/17) patients, TEE bubble was identified in 4(23.53%, 4/17) patients both at baseline and Valsalva maneuver, 6 (35.29%, 6/17) patients only after Valsalva maneuver (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cem\u003eDiagnosis of patients without PFO (18 cases)\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eValsalva maneuver\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003ec-TCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003enegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emoderate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eextensive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003ec-TTE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003enegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emoderate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eextensive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eTTE 2D (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eTTE color (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003ec-TEE*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003enegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emoderate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eextensive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eTEE 2D (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eTEE color (+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e*: One of the 18 patients did not tolerate TEE.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eDiagnostic value between the different methods\u003c/h2\u003e \u003cp\u003eIn total, the sensitivity of c-TCD at baseline was 70.28% (97/138), 22.46% (31/138) for the degree of extensive, 38.40% (53/138) for moderate and extensive; the sensitivity of c-TCD after Valsalva maneuver was 92.75% (128/138), 46.38% (64/138) for the degree of extensive, 66.67% (92/138) for moderate and extensive; the sensitivity of the loss of echo by TTE was 8.51% (12/141), the color shunt was 12.06% (17/141); the sensitivity of the total c-TTE at baseline was 60.00% (81/135), 18.52% (25/135) for the degree of extensive, 29.63% (40/135) for moderate and extensive; the sensitivity of the total c-TTE after Valsalva maneuver was 93.33% (126/135), 49.63%(67/135) for the degree of extensive, 75.56% (102/135) for moderate and extensive; the sensitivity of the slit-like channel between the septum primum and the septum secundum by TEE was 90.15% (119/132), the color shunt was 30.30% (40/132); the sensitivity of the total c-TEE at baseline was 53.08% (69/130), 15.38% (20/130) for the degree of extensive, 24.62% (32/130) for moderate and extensive; the sensitivity of the c-TEE after Valsalva maneuver was 86.92% (113/130), 50.77% (66/130) for the degree of extensive, 62.31% (81/130)for moderate and extensive.\u003c/p\u003e \u003cp\u003eFor the comparison among groups, there were no significant difference between the sensitivity of total c-TCD, c-TTE and c-TEE at baseline, when compared by pairs other, c-TCD was significantly higher than c-TEE (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004); After Valsalva maneuver, the sensitivity of total c-TTE was significantly higher than c-TEE (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041). For the comparison within groups, if the bubbles were extensive in the examination of c-TTE at baseline, the sensitivity was significantly higher than c-TCD (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011) and c-TEE (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009).\u003c/p\u003e \u003cp\u003eThe positive predictive value of total c-TCD at baseline was 96.04% (97/101), 96.88% (31/32) for the degree of extensive, 98.15% (53/54) for moderate and extensive. After Valsalva maneuver, the positive predictive value of total c-TCD wes 92.09% (128/139), 96.97% (64/66) for the degree of extensive, 96.84% (92/95) for moderate and extensive. The false negative rate of total c-TCD at baseline was 29.71% (41/138), 7.25% (10/138) after Valsalva maneuver. The positive predictive value of c-TTE at baseline was 93.10% (81/87), 100.00% (25/25) for the degree of extensive, 97.56% (40/41) for moderate and extensive; after Valsalva maneuver, the positive predictive value was 90.65% (126/139), 97. 10% (67/69) for the degree of extensive, 93.58% (102/109) for moderate and extensive. The false negative rate of total c-TTE at baseline was 40.00% (54/135), 6.67% (9/135) after Valsalva maneuver. The positive predictive value of c-TEE at baseline was 94.52% (69/73), 95.24% (20/21) for the degree of extensive, 96.97% (32/33) for moderate and extensive; after Valsalva maneuver, the positive predictive value was 91.87% (113/123), 95.65% (66/69) for the degree of extensive, 93.10% (81/87) for moderate and extensive. The false negative rate of total c-TEE at baseline was 46.92% (61/130), 13.08% (17/130) after Valsalva maneuver (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e, \u003cem\u003eDiagnostic value of c-TCD, c-TTE and c-TEE\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" morerows=\"1\" nameend=\"c3\" namest=\"c1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eValsalva maneuver\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSensi(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePPV(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFNR\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSensi\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePPV\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eFNR\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" morerows=\"2\" nameend=\"c2\" namest=\"c1\" rowspan=\"3\"\u003e \u003cp\u003ec-TCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70.29**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e96.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e92.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e92.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eextensive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e96.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e56.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e46.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e96.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e13.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003emoderate\u0026thinsp;+\u0026thinsp;extensive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e98.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e43.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e66.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e96.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9.80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ec-TTE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e93.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e40.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e93.33*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e90.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eextensive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e100\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e68.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e49.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e97.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e11.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003emoderate\u0026thinsp;+\u0026thinsp;extensive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e97.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e57.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e75.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e93.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eTTE 2D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eTTE color\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" morerows=\"2\" nameend=\"c2\" namest=\"c1\" rowspan=\"3\"\u003e \u003cp\u003ec-TEE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e94.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e46.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e86.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e91.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e13.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eextensive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e75.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e50.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e95.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e20.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003emoderate\u0026thinsp;+\u0026thinsp;extensive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e96.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e65.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e62.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e93.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e17.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eTEE 2D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e94.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eTEE color\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003ePPV: positive predictive value; Sensi: Sensitive; FNR: false negative rate. **:\u003cem\u003eP\u003c/em\u003e༜0.005(0.004) vs c-TEE; *: \u003cem\u003eP\u003c/em\u003e༜0.05(0.041) vs c-TEE; \u003csup\u003e#\u003c/sup\u003e: \u003cem\u003eP\u003c/em\u003e༜0.05(0.011) vs extensive of c-TCD, (0.009) vs extensive of c-TEE.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e "},{"header":"Discussion","content":" \u003cp\u003eForamen ovale is a persistent fetal communication between the right and left atrium due to incomplete closure of the atrial septum, after birth, the foramen ovale closed. But the morbidity of PFO was about 30% (Homma et.al, 2001). PFO has no obvious symptoms in usual times, and hard to heard the heart murmur, there were no abnormal in the electrocardiogram and chest X-ray, so it was easy to be neglected. Recently, patients who suffered from migraine headaches, cryptogenic stroke, TIA, and cerebral infarction, if did not have acute cerebral infarction or anterior circulation transient ischemic attack on admission, the possibility of being caused by the right-to-left shunt then be considered.\u003c/p\u003e \u003cp\u003eOur study assessed a large series of patients to find out the presence of right-to-left shunt, the results demonstrated that the sensitivity of c-TTE is superior to c-TEE in the diagnosis of PFO both at baseline and Valsalva maneuver, c-TCD performed simultaneously with c-TEE but maybe gave a false positive. TEE was lack of sensitivity contrast with c-TCD, the probability false-negative was higher than c-TCD, so the c-TCD can be used as an effective supplement to diagnose PFO; the sensitivity of TEE was highest in the three methods, still can be the gold standard. But the results of c-TCD can only point out that right-to-left shunt, cannot exclude extracardiac shunt, so combined application should be used.\u003c/p\u003e \u003cp\u003ePFO was a three-dimensional structure, which will change the shape with the cardiac cycle. Therefore, it is difficult to fully display the PFO simply by using TEE's two-dimensional technology, as our results, three was some false positive cases when we used 2D image of TEE (5 cases). The three-dimensional (3D) technology can solve the one-sidedness problem, but 3D image quality due to the 2D image, sometimes, 3D image was just for the reference (Shanks et.al, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). In terms of sensitivity,total c-TTE after Valsalva maneuver was the highest, especially for extensive, so we consider that sensitivity was increased with the quantity of bubbles in left heart. Moreover, if we observed the color shunt from the slit-like channel between the septum primum and the septum secundum by TEE, the positive predictive value was 100.00%, so in our daily clinical work, the observation of TEE color shunt is very important. But the sensitivity of c-TEE was lower than c-TTE after Valsalva maneuver, based on our observations, patients sometimes cannot make the Valsalva maneuver perfectly during TEE examination, that might be the most probable reason. c-TCD has the greatest value in diagnosing PFO, almost all the PFO patients had positive results in c-TCD examination, but c-TCD can only point out that right-to-left shunt, cannot exclude extracardiac shunt (Wessler et.al, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), c-TTE and c-TEE can observe the structure of oval foramen, were more convincing. The positive predictive value can reflect the possibility of prevalence rate in patients with positive results. In all the three methods (c-TCD, c-TTE, c-TEE), if three were a large number of bubbles in the left heart, especially with the color shunt from the slit-like channel, the positive predictive value was the highest. Although c-TCD has the highest positive predictive value, some unsolved problems still existed, for example, some bubbles can get though the pulmonary circulation, be detected in the cerebral arteries, so we will get a false positive result. On the other hand, c-TTE and c-TEE had more false negatives, the rate of misdetection might be higher than c-TCD. So, for the suspected patients, can examine with c-TCD first, if we get the positive results, then c-TTE and c-TEE should be taking to further confirmed.\u003c/p\u003e \u003cp\u003eThe results sometimes were different between resting state and Valsalva maneuver, the positive rate is higher with Valsalva maneuver. At the resting state, not all the patients could be observed the RLS. In some PFO patients, the foramen ovale is closed in resting state, only under some particular situation, for example, cough, cry, constipation, Valsalva maneuver and so on, that\u0026rsquo;s also the causes of nervous system symptoms on PFO patients (Zhao et.al, 2015). Only under those situations, the right atrial pressure can higher than the left atrial transiently, the foramen ovale then opened, so we could observe the RLS. So, for the situation when the left heart didn\u0026rsquo;t exist bubbles, Valsalva maneuver was necessary, results were positive no no matter Valsalva or not when bubbles existed in left heart.\u003c/p\u003e \u003cp\u003ePulmonary arteriovenous fistula (PAVF) is abnormal pulmonary vascular structures that connect a pulmonary artery to a pulmonary vein, bypassing the normal capillary bed resulting in an intrapulmonary right-to-left shunt (Abdel Aal et.al, \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). In our study, 2 patients were diagnosed as PVAF. At first, we didn\u0026rsquo;t give much attention to this disease, the results of c-TCD, c-TTE and c-TEE showed a strongly positive reaction, so we did the transcatheter examination, but the result was unexpected, PFO cannot be diagnosed. Then pulmonary angiography was performed, the results showed that the contrast medium can get to pulmonary vein from pulmonary artery, so we did a diagnose mistake before. We looked back the examinations, find that the slit-like channel by TEE was not very sure, and the bubbles seemed to be from la roof, the entrance of pulmonary vein, these findings could help us to diagnose PVAF. So, in conclusion, we have to consider the following points to diagnose PVAF: first, the results of c-TCD, c-TTE and c-TEE show a positive sometimes a strongly reaction; second, TEE image cannot make sure the slit-like channel existed, or the width of foramen ovale cannot match the quantity of bubbles; third, he bubbles seemed to be from la roof, the entrance of pulmonary vein, not from the foramen ovale.\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eIn conclusion, the present study revealed that c-TTE with the Valsalva maneuver yielded a higher sensitivity in detecting PFO-RLS, but the rate of misdetection might be higher than c-TCD. Therefore, for the suspected patients, can examine with c-TCD first, if we get the positive results, then c-TTE and c-TEE should be taking to further confirmed. These findings may be helpful in the diagnosis of patent foramen ovale in practice.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003ePFO patent foramen ovale\u003c/p\u003e\n\u003cp\u003ec-TCD contrast transcranial Doppler\u003c/p\u003e\n\u003cp\u003ec-TTE contrast- transthoracic echocardiography\u003c/p\u003e\n\u003cp\u003ec-TEE contrast- transesophageal echocardiography\u003c/p\u003e\n\u003cp\u003eTIA transient ischemic attacks\u003c/p\u003e\n\u003cp\u003eESUS embolic strokes of undetermined source\u003c/p\u003e\n\u003cp\u003eCS cryptogenic stroke\u003c/p\u003e\n\u003cp\u003eRLS Right-to-Left Shunt\u003c/p\u003e\n\u003cp\u003eRHC right heart catheterization\u003c/p\u003e\n\u003cp\u003ePAVF pulmonary arteriovenous fistula\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the local ethics committee, and all patients or their relatives provided written informed consent to participate in this study prior to the examination. All patients signed informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e../PFO初稿/PFO病人资料.xlsx\"\u003e..\\PFO初稿\\PFO病人资料.xlsx\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearch reported in this research was supported by the technology capture project of Shandong province under award number 2017GGX90104.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQK and JZ analyzed the data of right cardiac catheterization, YL analyzed the data of c-TCD, FL SL and HS analyzed the data of c-TEE and c-TTE, FL performed the data statistics and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e \u003cspan\u003eAbdel Aal AK, Eason J, Moawad S, Mahmoud K, Hamed BF, Massoud MO, Ertel N, Gunn A, Oser R, Saddekni S. Persistent Pulmonary Arteriovenous Malformations: Percutaneous Embolotherapy. Curr Probl Diagn Radiol. 2018 Nov;47(6):428\u0026ndash;36.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eHart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ. Embolic Stroke of Undetermined Source: A Systematic Review and Clinical Update. Stroke. 2017 Apr;48(4):867\u0026ndash;72.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eHomma S, Mess\u0026eacute; SR, Rundek T, Sun YP, Franke J, Davidson K, Sievert H, Sacco RL, Di Tullio MR. Patent Foramen Ovale. Nat Rev Dis Primers. 2016 Jan;21:2:15086.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eGramiak R, Shah PM, Kramer DH. Ultrasound cardiography: contrast studies in anatomy and function. Radiology. 1969 Apr;92(5):939\u0026ndash;48.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eKerut EK, Norfleet WT, Plotnick GD, Giles TD. Patent Foramen Ovale: A Review of Associated Conditions and the Impact of Physiological Size. J Am Coll Cardiol. 2001 Sep;38(3):613\u0026ndash;23.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eKhan R, Chan AK, Mondal TK, Paes BA. Thrombosis and Hemostasis in Newborns (THIN) Group. Patent Foramen Ovale and Stroke in Childhood: A Systematic Review of the Literature. Eur J Paediatr Neurol. 2016 Jul;20(4):500\u0026ndash;11.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eMojadidi MK, Zaman MO, Elgendy IY, Mahmoud AN, Patel NK, Agarwal N, Tobis JM, Meier B. Cryptogenic Stroke and Patent Foramen Ovale. J Am Coll Cardiol. 2018 Mar;6(9):1035\u0026ndash;43. 71(.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eAli Kausar Rushdi Y, Hina H, Patel B, Cross FW. The Incidence of Peripheral Arterial Embolism in Association With a Patent Foramen Ovale (Right-To-Left Shunt). JRSM Short Rep. 2011 May;2(5):35.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eHildick-Smith D, Williams TM. Patent Foramen Ovale and Migraine Headache. Interv Cardiol Clin 2017 Oct;6(4):539\u0026ndash;545.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eShanks M, Manawadu D, Muhll IV, Khan K, Becher H, Choy J. Detection of Patent Foramen Ovale by 3D Echocardiography. JACC Cardiovasc Imaging. 2012 Mar;5(3):329\u0026ndash;31.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eWessler BS, Kent DM, Thaler DE, Ruthazer R, Lutz RS, Serena J. The RoPE Score and Right-to-Left Shunt Severity by Transcranial Doppler in the CODICIA Study. Cerebrovasc Dis. 2015;40(1\u0026ndash;2):52\u0026ndash;8.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eZhao E, Wei Y, Zhang Y, Zhai N, Zhao P, Liu B. A Comparison of Transthroracic Echocardiograpy and Transcranial Doppler With Contrast Agent for Detection of Patent Foramen Ovale With or Without the Valsalva Maneuver. Medicine (Baltimore).2015 Oct;94(43):e1937.\u003c/span\u003e \u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"patent foramen ovale, contrast transcranial Doppler, contrast- transthoracic echocardiography, contrast- transesophageal echocardiography","lastPublishedDoi":"10.21203/rs.3.rs-63042/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-63042/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: In recent years, patent foramen ovale (PFO) has been reported to be strongly associated with embolic strokes of undetermined source (ESUS), including cryptogenic stroke, transient ischemic attack (TIA), migraine, and so on.The aim of this research was to compare the sensitivity and positive\u0026nbsp;predictive value of contrast transcranial Doppler (c-TCD), contrast- transthoracic echocardiography (c-TTE) versus contrast- transesophageal echocardiography (c-TEE), to find which is the best method to \u003ca href=\"about:blank\" rel=\"noopener noreferrer\" target=\"_blank\"\u003ediagnose\u003c/a\u003e patent foramen ovale (PFO), provides reference for the further improvement of clinical. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: We investigated 161 patients who suffered from migraine, cryptogenic stroke, TIA, and cerebral infarction of unknown cause, all patients underwent the transcatheter examination, and put the results of the right heart catheterization\u0026nbsp;(RHC) as the gold standard for PFO diagnosis. A chi-square test was used to compare the sensitivity and specificity between the three methods. A \u003cem\u003eP\u003c/em\u003e value of \u0026lt;0.05 indicated statistical significance. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: The present study revealed that c-TTE with the Valsalva maneuver yielded a higher sensitivity in detecting PFO-RLS, but the rate of misdetection might be higher than c-TCD. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: For the suspected\u0026nbsp;patients, can examine with c-TCD first, if we get the positive results, then c-TTE and c-TEE should be taking to further\u0026nbsp;confirmed. These findings may be helpful in the diagnosis of patent foramen ovale in practice.\u003c/p\u003e","manuscriptTitle":"Comparative Analysis of the Diagnostic Value of Several Methods for the Diagnosis of Patent Foramen Ovale","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-09-09 15:58:37","doi":"10.21203/rs.3.rs-63042/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a9f85ed0-2acf-4d20-a52a-2ba4beaa1ca2","owner":[],"postedDate":"September 9th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":470182,"name":"Cardiac \u0026 Cardiovascular Systems"}],"tags":[],"updatedAt":"2020-09-09T15:58:40+00:00","versionOfRecord":[],"versionCreatedAt":"2020-09-09 15:58:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-63042","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-63042","identity":"rs-63042","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}