EVALUATION OF EARLY RECANALIZATION AFTER SONOTHROMBOLYSIS IN ACUTE ISCHEMIC STROKE

Basem HamdyFouda, Yasser Abu Al Fotouh ElHeneedy, Azza Abbas Ghali and El-Sayed Ali Mohamed Tag El-Din ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History Received: 10 February 2020 Final Accepted: 12 March 2020 Published: April 2020


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Follow up of the patients: Patients were followed up clinically and radiologically by CT scan done after 24 hours from stroke onset to detect any neurological complication appears during the study like hemorrhagic transformation.
Follow up ultrasound was done for all groups after 24 hours from stroke onset to assess recanalization using the same parameters.
Patients were followed clinically after one hour, 24 hours and one week to assess the early functional outcome of each intervention.

Statistical analysis:
Analysis was performed using Statistical Package for Social Science (SPSS 17, Chicago, IL). Mean and standard deviation (± SD) were used for parametric numerical data, while median non-parametric numerical data. Student ttest was used to assess the statistical significance of the difference between two group means, and Paired t-test to assess the statistical difference between two means measured twice for the same study group.
Chi-square test proposed the hypothesis that the row and column variables are independent, without indicating strength or direction of the relationship. Correlation analysis was done using Pearson's correlation coefficient (r) method. ANOVA test was used for comparison among different times in the same group in quantitative data. P < 0.05 was considered to be statistically significant for all tests.

Results:-
During the study, 2 patients were died, the first one died after failure of thrombolytic therapy (group II) with progressing malignant MCA infarction, occurred at the second day and the patient died two days later. The second one (group III) died because of aspiration pneumonia after 6 days from stroke onset.
Primary end points of the study were assessed after one hour of different interventions done for each group, aimed at evaluation of MCA recanalization as evidenced by TCCS and graded according to TIBI score. Secondary end points of the study were assessed after 24 hours of stroke intervention regarding maintained and late recanalization of MCA, clinical outcome by NIHSS score which was then re-evaluated after 1week as a short clinical follow up.Evaluation of safety of these interventions were evaluated after 24 hours regarding spontaneous intracranial hemorrhage while other possible complications had not occurred.   The study results showed no significant statistical difference concerning stroke onset to treatment initiation time. However, this long time (207.27 ± 24.04 min -208.1 ±25.84 min -212.7±18.16 min) for group I, II and III respectively might be considered one of the drawbacks of this study reflecting a major health problem for early stroke management. It is well known that early initiation of rtPA therapy following stroke onset is directly proportionate to better outcome (11) . This is in turn might have a negative impact on the study end results.    Secondary to randomization of cases, it was noticed that there were some clinical differences in the clinical severity and degree of stenosis of MCA among the groups as described in tables (4,5). However, these differences are not statistically significant when compared among each other. In addition, follow up of clinical improvement and arterial recanalization is mainly evaluated in comparison to the baseline levels of the same group and such rate of change is then compared to other groups.
Thrombolysis in brain ischemia (TIBI) score was used to assess the occlusion and recanalization of MCA. This variability in the median scores among the groups is partly related to alternating randomization in a relatively small sample size (Randomization bias) and partly to disruption of randomization for group III where we were obligated to start just sonolysis for a non-blinded selected group (Selection bias).To avoid these bias, patients were longitudinally assessed and compared to their baseline median score and then compared in relation to the rate recanalization and clinical improvement.
The study results showed a substantial improvement of the degree of recanalization of MCA for group (I). Therate of recanalization was much higher for group I compared to other groups after the follow up timing intervals particularly after 60 minutes (p= 0.040) and on a longitudinal comparison in the same group from the first baseline TIBI score and after 30 minutes, 60 minutes and 24 hours (p<0.001*) The recanalization state was further analyzed. It was found that,in group I (sonthrombolysis group), (55 %) of patients had a complete recanalization of MCA (TIBI score equals to 5) after 1 hour. While in group II (rtPA alone), (35 %) of patients had a complete recanalization. It is to be noted that two patients in this group had a re-occlusion during the one-hour infusion period and obtained slight partial recanalization after 24 hours scan. For group III, only (15 %)of patients had a complete recanalization. There was a marked difference in favor of the sonothrombolysis group concerning early recanalization after 1 hour (p= 0.030).
Percentage of patients in group I with full recanalization had been increased to become (75%)after 24 hours which is markedly higher than other groups (45% for group II, 30% for group III).  Clinical severity was assessed and followed up by the National Institute of Health Stroke Scale (NIHSS) scoring system, with slightly different variation for group II without statistical difference as detailed in table (5).
Immediately after one hour of medical intervention for all groups, NIHSS score was re-evaluated to determine the effect on the clinical recovery. There was a considerable improvement as compared to the baseline evaluation scores for each group with significant statistical difference for group I compared to other groups. This clinical improvement is maintained after 24 hours in favor of group I with statistically significant differencecompared to the median baseline scores of each group (p= 0.001*). After 1 week of clinical follow up, patients in group (I) had a marked clinical improvementwith residual mild deficit and statistically significant difference compared to other groups (p= 0.001*).
It was noted that(25%) of patients in group I had full clinical recovery as defined by improving NIHSS score for 10 or more points or total NIHSS score is less than 4 (12), compared to (10%) of patients in group II while no patients in group III had a full clinical recovery with also a statistically significant difference for group I (p= 0.046*). More patients had a full clinical recovery after 24 hours in group I (45%) while there were no more cases with full clinical recoveryin group II (10%) and improvement was just for the median score for the range of recovery. Noticeably, 3 out of 20 patients (15%) in group III had a full clinical recovery denoting the late ameliorating effect of sonolysis on the functional outcome. There was also a significant correlation between improving recanalization (measured by increasing TIBI values) and clinical recovery (measured by decreasing NIHSS values) after 24 hours suggesting a better outcome for each maneuver done in group (I and II) with significant statistical values for both groups (p= 0.002 and 0.022 respectively). No significant changeamong the studied groups in terms of hemorrhagic transformation with 2 patients in group I and 1 patient in group II only who had such a complication during the study as shown in figure (5). However, all were asymptomatic.

Discussion:-
This study showed that there was no any further delay when ultrasound is added to usual intravenous thrombolytic treatment with a substantial improvement of the degree of recanalization of MCA for sonothrombolysis group after 60 minutes and 24 hours (p<0.001*).
For rtPA applied alone in group II, the study results came in accordance with the usual and well-known recanalization percentage of IV thrombolysis which lies between 30-40%. (13) But because of this percentage, many patients are left with a substantial brain damage, with high rates of disability and mortality. (14) The earliest trial to combine ultrasound to rtPA was CLOTBUST trial - 290 along with rtPA. A complete reperfusion was observed for 49% of the patients in the target group (rtPA+US) and for only 30% of the control group which are closely related to the current study results. (15) However, there were some limitations of the CLOTBUST trial including inhomogenous patient sample (patients with main stem and branch MCA stenosis) which is avoided in the current study as we just include main stem (M1-MCA) and exclude branch arterial occlusion.
The Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA-Hands-Free study is a multicenter, double-blind, phase 3, randomized controlled trial done at 76 medical centers in 14 countries(CLOTBUST-ER), using of t-PA plus a novel operator-independent US device in patients with ischemic stroke caused by proximal intracranial occlusion. (16) Recently, the trial was stopped after the second interim analysis with results showing thatsonothrombolysis was feasible and most likely safe, but no clinical benefit was seen at 90 days. (17) However, in the current study the long term functional outcome is not assessed, and clinical recovery was just assessed after one week showing a significant clinical improvement.
Another monocenter study (Lübeck study) in Germany, in which, 37 Patients with exclusively main stem MCA were randomly selected to receive TCCS instead of TCD allowing better orientation of the arterial thrombus and they were insonated for just one hour. 58% of sonothrobolysis group had a complete recanalization versus 22% of the rtPA group. These results are so close to the current study results. (18) In a smaller study of 18 patients with acute ischemic stroke ineligible to rtPA treatment, divided into two arms. 62% of sonolysis group (first arm) showed MCA recanalization (all of them were partial) versus 0% recanalization for a group with a conservative treatment alone (second arm). (19) This comes in accordance with the current study results for 20 patients treated by sonlysis alone (group III) with 55.55% showed recanalization after 1 hour (15% complete, 40% partial). In terms of clinical recovery, the current study results came in accordance with that of CLOTBUST trial showed that clinical recovery occurred within 2 hours (Total NIHSS score ≤3 or Reduction in NIHSS score by ≥10 points) was higher in the ultrasound group (29%)than in the non-ultrasound group (21%). Patients who had both clinical recovery and complete recanalization within 2 hours were 28% in the ultrasound group compared to the nonultrasound group (8%)with clear trend towards better outcome after 3 months follow up. (15) The study results also come in accordance with that of Eagers and co-workers, 2008 who found that 55.6% of patients received sonothrombolysis had a clinical improvement (NIHSS improvement more than 4) compared to 27.8% of the rtPA group and a similar percentage after 4 days of follow up denoting the positive effect of ultrasound on the functional clinical recovery. (18) They also concluded that compared with baseline, at day 1, the NIHSS values improved more strongly in the US group than in the no-US group (median 10.5, IQR 12.5 versus median 15.5, IQR 7.0). At day 4, the NIHSS values had improved more strongly in the US group compared with the no-US group (median 14, IQR 14.0 versus median 17.5, IQR 9.5). (18) In a study done for patients ineligible to rtPA and had received sonolysis and randomized against another group with conservative treatment, significant improvement of the clinical course after 4 days and functional independence after 3 months were found in 2 out of 8 patients of the sonolysis group compared to none of 7 patients in the control group. (19)