Byline: Maher Saqqur, Georgios Tsivgoulis, Francois Nicoli, David Skoloudik, Vijay K. Sharma, Vincent Larrue, Jurgen Eggers, Fabienne Perren, Paris Charalampidis, Dale Storie, Ashfaq Shuaib, Andrei V. Alexandrov Keywords: Transcranial Doppler; microsphere; sonolysis; sonothrombolysis ABSTRACT OBJECTIVES To assess the evidence on the safety and efficacy of sonothrombolysis in acute stroke. SEARCH METHODS Electronic databases and grey literature were searched under different MeSH terms from 1970 to present. SELECTION CRITERIA Randomized control trials (RCTs) and case control studies (CCSs) on sonolysis and sonothrombolysis alone or with microsphere in acute stroke patients ( 18 old). Outcome measures included complete recanalization (CR) at 1-2 and 24 hours, 3 months modified Rankin Scale (mRS), and symptomatic intracerebral hemorrhage (sICH). Data was extracted to Review Manager software. RESULTS Fifty-seven studies were retrieved and analyzed. Ten studies (7 RCTs and 3 CCSs) were included in our meta-analysis, which revealed that sonolysis and sonothrombolysis are safe (OR of sICH: 1.14; 95% confidence interval (CI): 0.56- 2.34;P=0.71) and effective (OR of CR at 1-2 hours: 2.95;95% CI: 1.81-4.81;P CONCLUSIONS This novel treatment appears safe and effective. The evidence of microsphere as an enhancement of sonothrombolysis is evolving.