| Background and ObjectivesRight-to-left shunt(RLS),mainly caused by inborn defects in the circulation system,consists of intracardiac shunt and extracardiac shunt.The former includes patent foramen ovale,vertricular septal defect,atrial septal defect,with PFO being the most common cause,while the latter includes rare causes like pulmonary arteriovenous malformation.With RLS,paradoxical embolism from right ventricle system may enter into the left heart and the circulatory system,leading up to embolic infarction in brain,kidney,stomach and intestines.The current oft-used methods to diagnose PFO-RLS are transesophageal echocardiography(TEE),contrast enhanced transthroracic echocardiography(c-TTE),contrast-transcranial Doppler(c-TCD).TEE features the highest relevance to autopsy and hence is considered the golden standard as to diagnosis of PFO at present.But as a semi-invasive examination,TEE is defected with less patient tolerance and compliance.c-TTE features high specificity but low sensitivity,c-TCD high sensitivity but low specificity.The combined use of non-invasive c-TTE and c-TCD is expected to improve both sensitivity and specificity in diagnosis of RLS,but regrettably so far there has been little research in this respect.The operation of c-TCD requires RLS grade should be decided by the number of micrbubbles detected in middle cerebral artery through transtemporal window,but as some patients have poor transtemporal penetration,alternative method has yet to be found.As many as 25%to 39%of strokes have no identifiable cause and are classified as cryptogenic stroke(CS).Numerous studies demonstrate that PFO-RLS is closely related to CS5 and there is still controversy over whether PFO-RLS is an independent risk factor for CS.Risk of paradoxical embolism(RoPE),which has been worked out by foreign researchers,helps judge the probability of PFO in CS,decide whether PFO is a causative factor.However,test and verification are deficient in different patient groups.There still lacks verification as to whether CS patients with PFO have iconographic specificity.Controversy exists over whether closure is preferable to medical therapy for CS with PFO,and not much research in this respect has ever been conducted in China.This study is composed of three parts.Part ? discusses the combined application of c-TTE and c-TCD,as well as the feasibility of detecting siphon carotid artery RLS with c-TCD.Part ? deals with the relevance of PFO-RLS to CS:1.to compare the differences between PFO-RLS group and contrast group in terms of age and sex(middle age?55 years,old age>55 years);2.to discuss risk factors related to CS and assess whether PFO-RLS is an independent risk factor to CS or not;3.to compare the differences in RoPE(>6 and<6)between CS patients with PFO and without PFO so as to testify the validity of RoPE in deciding PFO is an causative factor to CS;4.to analyze the iconographic specificity of CS with PFO.Part ? addresses the recurrence difference between percutaneous closure and medical therapy,as well as residual shunt and complications after closure.Part ? Combined Application of c-TTE and c-TCD in Detecting PFO-RLSSubjects and Methods1 Comparison of c-TTE and c-TCD and the Combined Application of the Two Tests in Detecting PFO-RLS536 Eligible participants were enrolled in the trial group when they were diagnosed as CS according to TOAST at Department of Neurology,Luoyang Center Hospital Affiliated to Zhengzhou University during the period from January 2014 to December 2015.Included in the contrast group were 314 patients who took clinical checkup and ruled out as strokes at the above-mentioned hospital during the same period.Simultaneous c-TTE and c-TCD tests were conducted to all the participants to compare the differences in detection rate both at rest and during Valsalva maneuver,as well as the differences in RLS grades.82 cases were further examined by TEE in which c-TCD and c-TTE examination were positive,and c-TCD grade were 2-3 level.2 Feasibility of Detecting S-ICA with c-TCDChoose some patients recruited from January 2015 to December 2015 for this trial.Conduct c-TCD to all of them and observe the microbubbles in middle cerebral artery through transtemporal window and transorbital window siphon portion of internal carotid artery(S-ICA),then compare the detection rates of RLS and the respective grades.Statistical analysis was processed by SPSS 21.0,2*2 contingency table data adopted McNemar test,and R*R contingency table data adopted Bowker test(R?3).Results1.RLS positive results by c-TCD and c-TTE were respectively 43.76%and 41.76%,and hence the difference had statistical significance(p =0.001).2.Valsalva motor(VM)can increase the detection rate of c-TCD by 27.29%,and that of c-TTE by 24.47%,as opposed to at rest.Such difference was of statistical significance(p<0.001).3.There was difference in RLS grade between c-TCD and c-TTE(Bowker test value is 13.389,p =0.033),with the RLS grade of the former higher than the latter.4.82 CS patients were sampled whose c-TCE and c-TTE tests were both positive and whose c-TCD grades were ? or ?.A TEE test found out PFO in all of them.5.Compared with transtemporal window monitoring,transorbital window monitoring detected more RLS(40.89%vs 38.93%).Although such difference was of no statistical significance(p =0.118),difference did exist in RLS grades(Bowker test value is 21.182,p =0.001).RLS grade II and grade III positive results were higher through transorbital window(10.08%,10.92%)than through transtemporal window(8.12%,8.96%).Part II Relevance of PFO-RLS to Cryptogenic Stroke Subjects and MethodsEligible participants were the same as Part I.Demographic and clinical data of all participants were recorded in detail,including sex,age,past medical history,smoking and drinking history,relevant examinations.Compare RoPE difference between CS with PFO and CS without PFO,analyze the DWI cerebral infarction of the two groups,with the purpose to address the iconographic specificity of CS with PFO by analyzing the number and position of infarction.Statistical analysis was processed by SPSS 21.0,quantitative data of the two independent samples adopted t-test,normally distributed data were presented in(x ąs).Qualitative data adopted chi-square test,and paired data adopted Mcnemar and Bowker tests.Single-factor analysis of variance was performed to compare the multiple index of data with both normal distribution and homogeneity of variance In terms of CS risk factor assessment,single-factor analysis of variance was performed to select valid variables and afterwards logistic regression analysis was performed.There was statistical significance when P<0.05.Results1.In all 536 CS patients(CS group)were recruited in this study,with male accounting for 57.28%(307/536);308 patients were in middle age(57.46%),228 in old age(42.54%).The contrast group included 314 patients,with male accounting for 54.46%(171/314);146 patients were in middle age(46.50%),168 in old age(53.50%).2.PFO-RLS positive results in CS group(54.10%,290/536)were higher than that in contrast group(19.43%,61/314),the difference being of statistical significance(p<0,001).3.The difference in PFO-RLS positive results between middle age group and old age group(p =0.643),as well as between male group and female group(p =0.227),was of no statistical significance.4.Single factor regression analysis with respect to clinical data of CS group and contrast group was performed and statistical difference(p<0.05)existed in high blood pressure,RLS,LDL,fibrinogen,C-reactive protein between the two groups.Non-conditional logistic regression analysis was performed to indicate that RLS(OR=1.709,95%CI[1.334?2.191]),fibrinogen(OR=2.075,95%CI[1.599?2.692]),C-reactive protein(OR=1.676,95%CI[1.464?1.918])were related to CS.The RLS grade regression coefficient ? was 0.536,indicating that with higher RLS grade,OR was bigger,and risks increased.5.There was RoPE difference between the subgroup of CS with PFO and the subgroup of simple CS(x2 =154.222,p<0.05),with RoPE in the former subgroup mostly higher than 6(68.97%),and RoPE in the latter subgroup mostly lower than 6(84.55%).6.CS with PFO subgroup was more likely to present with posterior circulation infarction(x2 =9.477,p =0.009),as opposed to the simple CSsubgroup.No statistical difference arosed in number(x2 =1.015,p =0.314)ofcerebral infarction.Part ? Treatment of CS with PFO and RecurrenceSubjects and MethodsRecruited participants were the patients in CS group whose c-TTE and c-TCD tests were both positive and with RLS grade ? and ?.They were divided into medical therapy group and percutaneous transcatheter closure group in accordance with professional advice and patients' personal wills.The medical therapy group went through antiplatelet or anticoagulation treatment.The closure group first took percutaneous closure plus two antiplatelet drugs for 3 months(aspirin 100mg per day plus clopidogrel 75mg per day),then took one antiplatelet drug for 3 months.The Cardi-O-Fix PFO was provided by Hua Yi Sheng Jie Company in Beijing.Follow-up was conducted 3,6 and 12 months after discharge to register stroke recurrence in the two groups.Residual shunt and complication were also registered.Then all the data were processed by SPSS 21.0,qualitative data adopted Chi-square test,and p<0.05 was considered statistically significant.Results1.There were 290 cases of CS with PFO in all,of which grade ? and grade? shunt took up 171 cases.The medical therapy group included 125cases(73.10%),closure group 46(26.90%).In terms of age,there were103 cases in the middle age,32 cases of which belonged to closure group(31.07%);68 cases in old age,14 cases of which belonged to closure group(20.59%).2.Recurrence rate within one year for the two groups was 2.2%and 12.8%.The results showed statistical significance(x2 =0.421,p =0.039).Death did not occur in either closure group or medical therapy group.3.Of all the participants who took medical treatment had different RLS grades,both 3-month and 6-month follow-ups revealed no statistical difference in recurrence(p>0.05),but 12-month follow-up revealed statistical difference(p =0.011),and higher RLS grade denoted higher recurrence.4.There was no recurrence difference at 3-month and 6-month follow-ups between middle age group,closure group and medical therapy group,but 12-month follow-up revealed recurrence rate in medical therapy group(12.68%)was higher than that in closure group(0.00%)(p =0.035).As for old age group,there was no statistical difference in recurrence at all the three follow-ups(p>0.05).5.Residual shunts recorded at 3,6 and 12 month follow-ups after closure respectively accounted for 26.19%,21.43%,and 19.05%,with all of them being potential,grade ? or grade ?.Grade ? shunts during VM accounted for 18.18%,11.11%and 0.00%,one-year follow-up grade ? shunt was 0.00%.6.No severe complication was reported after closure.Conclusions1.Compared with c-TTE test,c-TCD test is more sensitive to detecting RLS.The combined application of c-TCD and c-TTE,safe and non-invasive,turns out to increase the accuracy in diagnosing PFO-RLS.2.In a c-TCD test,we have firstly confirmed transortital window S-ICA can serve as an alternative method when the patients have poor transtemporal window penetration.3.PFO-RLS is an independent risk factor to CS,and higher shunting grade indicates higher risk.4.This thesis verifies the validity of RoPE in recognizing PFO as a causative factor to CS with PFO.5.Grades of PFO-RLS are related to stroke recurrence,which verifies that closure is preferable to medical therapy for CS patients with PFO. |
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