Introduction 

   Recanalization is as an important topic as ever in the aspect of main object of thrombolysis to rescue ischemic penumbrae by restoring of blood flow, but the effect of the recanalization after thrombolysis is a complex and a controversial theme in ischemic stroke disease. Although so many factors can contribute to clinical outcome and recanalization and favorable clinical outcome cannot be achieved only by arterial recanalization, many authors advocated that good recanalization independently contributes good clinical outcome.^24)25)32)34) 
   There are many reports about clinical outcome, recanalization rate and its predicting factors after intraarterial or combined thrombolysis.^{4)7)10)12)18)23)24)} However, there are few reports about recanalization rate in regard to intravenous recombinant tissue plasminogen activator (IVtPA), and most of the reports about that took in consideration only the clinical outcome.^{5)6)13)16)17)19)22)} Even though the IV-tPA is the only approved medical therapy for acute ischemic stroke and has been approved as effective for decreasing mortality and disability rate by 30%, its recanalization rate has been reported to be very low in a few reports.¹³⁾¹⁶⁾ 
   Meanwhile, atrial fibrillation (AF) has been known as a common cause of embolic infarction of which clinical outcome is very poor.⁵⁾¹⁴⁾ However, in our limited knowledge there is no report about recanalization rate after IV-tPA in the cases with AF-related major cerebral arterial occlusion. 
   Therefore the aim of this study was to investigate the recanalization rate, clinical outcome, and predicting factors affecting recanalization rate after IV-tPA in the major cerebral arterial occlusion and to assess the recanalization rate and clinical outcome in case of stroke with atrial fibrillation. 

Materials and Methods 

   From April 2005 to April 2006, 16 patients with anterior circulation occlusion were treated with IV-tPA in our institute. Mean age was 69.9 (from 49 to 86) years old. Female patients were 7 (43.8%) and male 9 (56.3%) (Table 1). The authors followed the protocol of National Institute of Neurological Disorders and Stroke (NINDS) Recombinant Tissue Plasminogen Activator Stroke Trial.¹³⁾ On admission at ER, all patients who were suspected as stroke patients underwent CT angiography, perfusion CT, and MRI/A to rule out hemorrhagic stroke after initial neurologic examination. All the patients with acute major cerebral arterial occlusion were injected 0.9 / (maximum 90) of tissue plasminogen activator intravenously. After the treatment, we performed the follow-up CT angiography, perfusion CT and MRI/A, and even sometimes conventional digital subtraction angiography to evaluate the treatment result. Recanalization after thrombolysis was appraised according to the thrombolysis in myocardial infarction classification (TIMI) grade, and we classified it as good or poor. TIMI grade 2 and 3 were classified as good, and 0 and 1 were as poor. Complete recanalization was defined as passage of contrast with normal rate of contrast filling and clearance (TIMI 3).¹⁾ The sites of occlusions were classified as ICA, M1 and M2. Early CT signs of ischemia were defined according to the criteria of von Kummer et al.^28)29)30)31) 
   Time intervals from symptom onset to treatment initiation and initial National Institute of Health Stroke Scale (NIHSS) scores were checked. The existence of diabetes mellitus, hypertension and atrial fibrillation was evaluated. Collateral circulation was grouped as positive or negative by investigation of collateral vessel filling pattern in dynamic raw data of perfusion CT and 3-dimensional CT angiography. Clinical outcome was appraised as posttreatment NIHSS score 3 months after treatment. But for the patients who could not survive from the stroke, best posttreatment NIHSS scores were used. Finally we divided the patients into good and poor recanalization groups, and all of the above factors were compared to evaluate the correlations with the recanalization. 

Statistical Analysis 
   We compared continuous variables by using Student's ttests and compared categorical variables by using Chi- Square tests. Comparisons were made according to confidence intervals of 95%. All statistical tests were twosided and all analyses were performed using statistical software (SPSS for Windows, 12.0 standard version). A probability value less than 0.05 was considered statistically significant. 

Results 

   Of 16 patients 9 patients had left sided lesions (56.3%) and the other 7 patients had right sided lesions (43.7%). Five cases were ICA occlusion (31.3%), 8 cases were M1 (50.0%) and 3 cases were M2 (18.7%). Post-treatment hemorrhagic transformation was found in 5 patients (31.3%). The basic data of 16 patients is listed on Table 1. 
   Good recanalization was achieved in 11 patients (68.8%), and the other 5 patients showed poor recanalization. 
   Among the 11 patients with good recanalization 9 patients survived, however only 2 patients survived in the other 5 patients with poor recanalization (81.8%, 20.0%, P=0.036). The clinical and radiological data was assessed according to the recanalization. The data comparison between two groups is shown in Table 2. There were less atrial fibrillations in the group of good recanalization than in the other group (Chisquare test, 27.3%, 100.0%, P=0.013), and lower pretreatment NIHSS score in the former than the later (12.9± 4.8, 20.4±6.6, P=0.022). All other factors, such as age, interval time from symptom onset to treatment, and history of hypertension and diabetes mellitus etc. were not significantly different statistically between the two groups. Several factors, however, such as sex ratio and status of collateral circulation showed contributing tendency, though not reach statistical significance (Table 2). In the case of the later, the status of collateral circulation, we performed the multifactorial analysis to reveal the independency of NIHSS score and AF as the predicting factors. The mean pretreatment NIHSS score of the patients according to the status of collateral circulation was not different significantly between two groups (Table 3). The relationship between the existence of AF and the rate of recanalization also did not reach statistical significance in each circumstances (Table 4). There was a linear relationship between the TIMI grade and the change of NIHSS score between pre- and post-treatment (Y=7.7-3.4X, r²=0.521, p=0.002), and a linear regression plot of TIMI grade versus the change of NIHSS score is shown in Fig. 1. 

Discussion 

   Current study deals with 3 major themes as recanalization rate, associated factors of recanalization, and relationship between recanalization and clinical outcome. 
   Usefulness of IV-tPA has been widely and deeply studied since NINDS IV-tPA stroke study.²⁾ Its clinical outcome for acute ischemic stroke has been reported by many authors, but its radiological outcome, especially recanalization has not been. Lindsberg et al. reported high recanalization rate of 53% after treatment of basilar artery occlusion. However, that was only about the posterior circulation occlusion.¹⁹⁾ Most recent report about recanalization rate after IV-tPA was presented by Lee et al. They reported low rate of recanalization for major arterial occlusion as 22.6%.¹⁶⁾ Other articles report various recanalization rate from 33% to 83% after intra-arterial thrombolysis (IAT) or IAT combined IV thrombolysis.^{4)7)10)12)18)23)} Current study shows high recanalization rate, TIMI grade II and III was 68.8% (11/16) and complete recanalization was achieved in 5 patients (31.3%). Even though it is small number of cases, this high recanalization rate after IV-tPA itself might be meaningful because there is no report about recanalization rate after IVtPA in the cases with AF-related major cerebral arterial occlusion. Nowadays IAT is replacing IV-tPA for acute ischemic stroke treatment, but results of current study support the opinion of Mielke et al.²⁰⁾ who reported that the evidence is inadequate to conclude which route of thrombolytic agent administration is the best, by showing equal or even higher recanalization rate comparing with that of IAT of other reports. 
   We analyzed statistically various factors, such as gender, age, initial NIHSS score, time interval from onset of symptom to treatment, collateral circulation, early CT sign, diabetes mellitus, hypertension and AF which are known as predictors of clinical outcome or recanalization in various articles.^{5)8)17)24)25)33)} In current study, male patients showed the tendency with good recanalization, but did not reach statistical significance (p=0.077). This tendency is suspected to be attributed to small number of cases and selection bias. The good status of collateral circulations also showed the tendency with good recanalization, but did not reach statistical significance (p=0.077). It is suspected to be an important factor theoretically and practically. Therefore we ascribe to this result to the small size of the sample. Initial NIHSS score and AF were strongly associated with recanalization. This result emphasize initial neurological status contributes radiological and clinical outcome and atrial fibrillation is important as cofactor or source of embolic ischemia. Di Carlo et al⁹⁾ categorized infarction subtype and researched its risk factors and concluded that AF is the most frequent risk factor in anterior circulation infarction and that its clinical outcome is poor. In our series, half of the patients had AF as the cause of the cerebral embolisms. Its recanalization rate was very poor (37.5%) and mortality rate was high as 75%. These results might be supportive to the aforesaid reports that anterior circulation major arterial occlusion is frequently associated with AF and AF affects adversely the recanalization and survival rate. The authors hypothesized the cause of difficult clot lysis in AF patients. First, increased viscosity can affect on clot lysis by slow-down of blood flow. During AF, regional cerebral blood flow decreases and atrial natriuretic peptide is elevated and then viscosity of blood increases.^15)21)27) Second, clot pathogenic characteristics may play a role. Fibrin rich clot and platelet rich clot act differently.^3)11)26) Meanwhile, the association with recanalization and the initial NIHSS score and AF did not reach statistical significance in each circumstance of collateral circulations (Table 3, 4). The authors thought that the size of the study was too small to assess the multifactorial relationship, and further investigation was warranted to reveal these relationships. 
   As described by many authors, recanalization has been thought as correlated with neurological improvement. By showing negative linear regression relationship between recanalization grade and change of NIHSS score (post NIHSS-pre NIHSS), the authors revealed that recanalization affected clinical outcome independently. In the analysis of the other possible contributing factors, there were no significant factors except AF and the initial NIHSS score. 

Conclusion 

   IV-tPA administration could be a feasible and effective treatment modality of anterior circulation major arterial occlusion in selective cases without atrial fibrillation. While, it is suspected that the lower the initial NIHSS score, the better the recanalization result. As a most common cause of anterior circulation major ischemia, AF is strongly associated with poor recanalization and eventually poor outcome. For suitable treatment strategy for this disease entity, multimodal treatment should be considered. 

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