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Table of Contents    
NI FEATURE: THE EDITORIAL DEBATE-- PROS AND CONS
Year : 2017  |  Volume : 65  |  Issue : 1  |  Page : 18-19

Sonothrombolysis in acute large vessel ischemic stroke


Department of Neuroradiology, Salford Royal Hospital, Greater Manchester Neurosciences Centre, United Kingdom

Date of Web Publication12-Jan-2017

Correspondence Address:
Amit Herwadkar
Department of Neuroradiology, Salford Royal Hospital Greater Manchester Neurosciences Centre
United Kingdom
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.198176

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How to cite this article:
Herwadkar A. Sonothrombolysis in acute large vessel ischemic stroke. Neurol India 2017;65:18-9

How to cite this URL:
Herwadkar A. Sonothrombolysis in acute large vessel ischemic stroke. Neurol India [serial online] 2017 [cited 2017 Feb 22];65:18-9. Available from: http://www.neurologyindia.com/text.asp?2017/65/1/18/198176


Acute large vessel cerebral artery occlusion leads to ischemic tissue damage. To lessen the severity of ischemic damage, prompt recanalization of the artery is essential. Prompt investigation and treatment are important determinants in the quality and life expectancy of stroke patients and have been the driving force for a multitude of treatment strategies.

The standard recognised treatment for acute ischemic stroke is intravenous (IV) alteplase (recombinant tissue plasminogen activator, tPA), administered during the first 4.5 hours after symptom onset. When administered intravenously, it can lyse the intravascular thrombus in several minutes. Early recanalisation can lead to ischemic tissue reperfusion and lessen the severity of stroke. However, less than 5% of patients with an ischemic stroke receive IV alteplase, only 30–40% of treated patients achieve early recanalization, and the recanalization is complete in only 18% of them.

Therefore, new therapeutic strategies under development are aimed at improving the recanalization rates and clinical outcomes after ischemic stroke.

In 2015, five randomised trials showed the efficacy of endovascular thrombectomy over standard medical care in patients with acute ischaemic stroke caused by occlusion of arteries of the proximal anterior circulation.[1] This treatment is available in specialised stroke centres with an expertise in endovascular treatment. It requires an infrastructure to deliver the service and the resources in terms of personnel, angiography suite availability and operating costs.

Another treatment option to lyse the clot, which has been in practise and under evaluation for over a decade, is ultrasound-enhanced thrombolysis (or sonothrombolysis). This modality of treatment can improve drug action or even generate intrinsic fibrinolysis. This can be performed using transcranial Doppler (TCD), a non-invasive technique available in most stroke-treating hospitals.

Ultrasound energy-induced enzymatic thrombolysis was first described in 1976[2] and is probably related to the mechanical effects of ultrasound resulting in clot disruption. Various mechanisms have been postulated, including the creation of fluid motion and radiation forces which increase the thrombus surface area in contact with the enzymes, the reversible disaggregation of cross-linked fibrin fibers in the clot, the exposed plasmin-binding sites, and the penetration of fibrinolytic enzymes into the clot. Ultrasound can create bubbles of gas from the gases dissolved in a liquid medium, a property called acoustic cavitation, and causes either a direct mechanical breakdown of the clot surface or increases the permeation of alteplase inside the thrombus.

Ultrasound waves with varying frequencies have been tested in experimental and human studies. Higher frequencies are attenuated through the skull. Hence, the earlier models for sonothrombolysis were developed using low frequency ranges. The trial, TRUMBI [3] (Transcranial low-frequency Ultrasound Mediated Thrombolysis in Brain Ischemia) was prematurely stopped because of a significant increase in intracerebral-hemorrhage rates in the target group. The low-frequency ultrasound waves could potentially cause disruption of small arterioles or the blood-brain barrier due to their longer wavelengths.

The safety and efficacy of a higher frequency (2 MHz) ultrasound device was studied in the CLOTBUST (Combined Lysis of Thrombus in Brain ischemia using transcranial Ultrasound and Systemic TPA) trial.[4] The main limitation of TCD is its extreme operator dependency.

Transcranial colour-coded duplex sonography (TCCS) has also been used in sonothrombolysis. TCCS generates multiple small beams at dual-emitting frequencies, i.e., one for Doppler (1.8 MHz) and one for gray scale imaging (4 MHz). However, the rate of hemorrhage in patients who receive continuous TCCS tends to be higher. This could be due to an increased area of insonated brain tissue, the dual frequencies of TCCS transducers and their higher mechanical index. TCCS is a frameless technique that leads to the use of a continuous hand-held approach, which probably would prevent an easy use of this treatment method on a large scale.

Microbubbles (MBs) are gas- or air-filled lipid-shell microspheres in the micron size range that have been used as diagnostic ultrasound echo-contrast and have also been used to increase sonothrombolysis. When MBs pass through an ultrasound energy field, they experience translations and size oscillations. This generates harmonic signals, which release energy and agitate the fluid in which the bubbles are dissolved, improving the delivery and penetration of alteplase into the clot. If the ultrasound negative pressure is increased, the bubble collapses (inertial cavitation), leading to intense localized stresses and microjets, which could cause mechanical fragmentation of the thrombus. In human stroke, the first and largest study published to date, using MB-enhanced sonothrombolysis, tested the synergistic effect of three boluses of air-filled MBs in association with 2 hours of continuous, high-frequency, low-intensity diagnostic TCD monitoring and IV alteplase.[5] However, the rate of intracranial hemorrhage in the target group was 23%.

Sonothrombolysis is another armament in the therapeutic option to improve the treatment of acute ischemic stroke.[6] It is less invasive, and the economic burden on health service is less than that seen in the newer intra-arterial strategies. It can be performed without an anaesthetic and is relatively easier to carry out than the intra-arterial thrombectomies. However, to apply continuous, transcranial ultrasound monitoring requires technical skills, which limits its general acceptance. The development of operator-independent devices may increase the number of centres that are able to apply sonothrombolysis. The safety profile of this technique can be increased by a better understanding of the mechanism by which low frequencies cause bleeding and may lead to the design of potentially safer systems for sonothrombolysis.

MB sonothrombolysis is a further advance in this portfolio. A detailed understanding of the influence of ultrasound on MBs, as well as their interaction with the thrombus and the endothelium will determine the best parameters required to activate the MBs at the target sites and to minimise the risk of haemorrhage.

 
  References Top

1.
Goyal M, Menon BK, van Zwam WH, Dippel DWJ, Mitchell PJ, Demchuk AM, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet 2016; 387:1723–31.  Back to cited text no. 1
    
2.
Trübestein G, Engel C, Etzel F, Sobbe A, Cremer H, Stumpff U, et al. Thrombolysis by ultrasound. Clin Sci Mol Med Suppl 1976; 3:697–8.  Back to cited text no. 2
    
3.
Daffertshofer M, Gass A, Ringleb P, Sitzer M, Sliwka U, Els T, et al. Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: Increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator. Stroke 2005; 36:1441–6.  Back to cited text no. 3
    
4.
Alexandrov, A, Molina, C Grotta, J Zsolt G, Ford S R, Alvarez-Sabin J, et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med 2004; 351:2170–8.  Back to cited text no. 4
    
5.
Molina CA, Ribo M, Rubiera M, Montaner J, Santamarina E, Delgado-Mederos R, et al. Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator. Stroke 2006;37:425–9.  Back to cited text no. 5
    
6.
Aaron S, Mani S, Prabhakar AT, Suresh Babu P, Kumar S, Benjamin RN, et al. Sonothrombolysis for acute ischemic stroke: Break through to the other side. Neurol India 2017;65:52-7.  Back to cited text no. 6
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