Sonothrombolysis for acute ischemic stroke in the era of endovascular therapy

Aliona Nacu, Department of Neurology, Haukeland University Hospital, Bergen, Norway

Stroke is one of the leading causes of long-term disability and mortality worldwide. Intravenous thrombolysis in combination with mechanical thrombectomy improves recanalisation, reduces disability and mortality in patients with large arterial occlusion. However, only a minority of patients is eligible for this treatment and a substantial number of patients are left with lasting disability after the treatment.

Neurosonology is a reliable, fast, non-invasive, relatively inexpensive imaging diagnostic tool for evaluation of cerebral hemodynamics and it is widely used. During the last years there has been a growing interest in the therapeutic potential of microbubble contrast agents, especially because of the enhancement effect and potential use in combination with ultrasound in acute ischaemic stroke treatment. However, while preclinical studies have demonstrated safety and beneficial effect of contrast-enhanced sonothrombolysis treatment on early recanalisation, infarct volume and outcome, large randomised clinical trials on contrast-enhanced sonothrombolysis are lacking. Importantly, data from systematic reviews and meta-analyses of published clinical sonothrombolysis trials in patients with stroke due large artery occlusion suggested that transcranial ultrasound and alteplase with and without microbubbles was safe and increased recanalisation rate compared with intravenous alteplase alone.

The Norwegian Sonothrombolysis in Acute Stroke Study (NOR-SASS) was the first clinical trial on contrast-enhanced sonothrombolysis including also mild stroke patients and extended the therapeutic time window till 4½ hours from stroke symptom onset. This trial included 183 patients with ischemic stroke, which were randomized to receive either contrast-enhanced sonothrombolysis or a sham procedure. Although prematurely stropped for lack of funding and neutral as to clinical effect, NOR-SASS showed encouraging results, particularly in patients with mild stroke without defined arterial occlusion, a specific population of acute ischaemic stroke who has not been investigated before. This trial also suggested that contrast-enhanced sonothrombolysis is a safe treatment among ischaemic stroke patients, with or without a visible arterial occlusion

This is particularly important since approximately 80% of acute ischaemic stroke patients present with mild stroke symptoms and without a defined arterial occlusion on admission imaging scan. However, many of those patients are left with significant disability.

Therefore, pragmatic testing of sonothrombolysis in specific ischaemic stroke populations is now needed. If effective in future randomized controlled clinical trials with patients without large artery occlusion, this technique could have substantial impact on the management of ischemic stroke patients.


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  1. Kvistad CE, Nacu A, Novotny V, Logallo N, Waje-Andreassen U, Naess H,Thomassen L. Contrast-enhanced sonothrombolysis in acute ischemic stroke patients without intracranial large-vessel occlusion.  Acta Neurol Scand. 2018 Feb;137(2):256-261.PMID:29068044


  1. Novotny V, Nacu A, Kvistad CE, Fromm A, Neckelmann GF, Khanevski AN,Tobro H, Waje-Andreassen U, Naess H, Thomassen L, Logallo N. Clinical Importance of Temporal Bone Features for the Efficacy of Contrast-Enhanced Sonothrombolysis: a Retrospective Analysis of the NOR-SASS Trial. Transl Stroke Res. 2018 Aug;9(4):333-339.PMID: 29119369