Acute Ischemic Stroke - Workshop Discussion
Discussion: Best Current Treatment
The best current therapy is tissue Plasminogen Activator (tPA) administered intravenously, but the fact that it must be given within 3 hours of symptom onset makes this a very limited approach. Based on more recent data, Europe has now extended the time window to 4.5 hours after symptom onset. tPA may take hours to have an effect, and many patients do not gain benefit from tPA treatment. Some patients develop side effects of neurotoxicity or hemorrhage.
There are some recent clot retrieval devices that are FDA-approved, but none have been shown to have efficacy in clinical studies. However, their use may constitute the standard-of-care in some larger centers.
Patients with carotid artery occlusion have a particularly poor prognosis, and often do not benefit from tPA administration. If FUS is shown to be an effective noninvasive mechanism for thrombolysis, it may represent a major step forward in treating these difficult patients.
Issues in Study Design
If the MRI in a stroke patient demonstrates an ischemic penumbra, or area of diffusion-perfusion “mismatch,” then one might successfully proceed with FUS dissolution of the clot even out to eight hours after symptom onset. Given the critical need to reopen the clotted vessel as quickly as possible, bypassing the CT scan and relying entirely on MRI for determination of hemorrhage, as well as FUS treatment-related skull correction and guidance of the FUS procedure, is desirable.
First experimental data show that transcranial sonothrombolysis with FUS can be achieved within seconds and without the use of a lytic agent, such as tPA. However, in selected cases FUS may be utilized as an adjunct to tPA administration, which might shorten the time to recanalization of the vessel. A corresponding protocol would assess FUS as a facilitator of tPA clot lysis, and not compare the two treatments against each other.
Alternatively, FUS could be evaluated as an alternative to mechanical thrombectomy. One would expect them to carry similar risks of hemorrhage into the reperfused region if too much time had elapsed before recanalization. It seems reasonable that FUS might allow restoration of flow sooner than mechanical thrombolysis, given the logistics of the procedures, but this remains to be seen. The entire FUS treatment could probably be accomplished in just under an hour. Time to administration of intra-arterial tPA takes more than an hour just to get the drug on board.
FUS and mechanical thrombectomy require visualization of the clotted vessel with MR Angiography (MRA) and Digital Subtraction Angiography (DSA), respectively. tPA administration does not demand anatomic clot localization prior to treatment. Visualization of the occlusion point is clearly a prerequisite for FUS and mechanical thrombectomy.
FUS also offers great potential for modulation of the microcirculation. There remains much in the way of basic investigation of the effects of different acoustic pressures and other non-thermal effects of FUS that influence the behavior of the microvasculature. FUS may also offer direct neuroprotective effects through modulation of the endothelial nitric oxide synthase (eNOS) system.
Much of the current understanding of sonothrombolysis comes from in vitro analysis of the effects of the brain unit on various clot models. Early results indicate that clot resolution will be more rapid in vivo than in vitro, especially using high intensity FUS. There is some controversy over the relative utility of high intensity vs. low intensity. Current studies are assessing the patterns of fragmentation of large clots, yielding preliminary information on the risk of distal emboli of the fragmentation material. These could also compare the toxicity of the hemolysate from FUS with that found after administration of TPA.
The specific question indicates which model would be best. The mouse model would be sufficient for evaluation of synergistic effects of short pulses of FUS on TPA activity. The baboon stroke model reported from France might be better to assess the risk of bleeding with FUS.
Initial animal studies have involved rats, dogs, pigs, sheep and baboons, depending one which variable was being examined. Short transcranial FUS pulses could be performed (in mouse or rat, but not rabbit) using a thrombotic clot in an artery to show that it can be opened with FUS, and to assess the optimal parameters to do so and minimize injury to the artery. Preliminary work might even be performed in a peripheral artery, not necessarily requiring a cerebral artery. The nature of the dissolved clot, including the risk of smaller fragments embolizing to distal vascular territories, could be evaluated in this model.
The stroke research community will clearly require demonstration of FUS safety in the brain with these sonothrombolysis treatment parameters. Safety studies evaluating FUS effect on brain could be performed in a porcine model, using the same sonication parameters that are effective for clot dissolution in the rat or mouse arterial occlusion model.
Fundamental questions that must be answered include:
- What is the exact nature of the clots to be treated in humans?
- How can we expedite treatment, given that time is of the essence? Can ultrashort TE (UTE) sequences provide fast simulation and obviate the need for CT scan in accomplishing skull modeling for the MRgFUS treatment? Radiation force imaging might totally bypass the need for CT simulation.
- How sensitive is MRA at identifying the locus of occlusion?
- Should FUS sonothrombolysis begin proximally and move distally, or vice versa?
Clinical Pilot Studies
An initial feasibility and safety study of MRgFUS will consist of 30 patients who present within the three-hour window, but are not candidates for tPA (eg. those who are on coumadin, have any kind of tumor, or any source of bleeding including recent surgery, etc.). The occlusion site would need to be well-visualized on MRA (preferably 3D), and ultrashort TE (UTE) sequences would provide skull modeling in order to bypass the time in CT. Patients demonstrating perfusion-diffusion mismatch on MRI might also be included, if presenting within eight hours of symptom onset. Those with occlusion of the distal ICA, M1 and M2 would all be candidates. This study would include patients with carotid occlusion. Thrombolysis would be performed from proximal to distal if that is shown to be free of generating particulate emboli.
In some major centers in the US, clot retrieval devices have become standard, even though they have not been proven effective. Interventional radiologists at some of those centers might be unwilling to participate in a trial. However, a Randomized Clinical Trial might be performed to directly compare one of the clot retrieval devices against MRgFUS sonothrombolysis. The randomization would need to occur very quickly, because, in the event of mechanical thrombectomy, time is used gaining arterial access. Randomization might not be required if the study was performed in Canada or Germany.
One would need to demonstrate that the risk from hemorrhage was not unacceptably high. Given that 20% of TPA cases experience hemorrhage outside of the original infarct zone, avoidance of systemic anticoagulation would be desirable.
Patients with atrial fibrillation and embolic stroke might also make a good study population.
Trying to treat patients who have failed tPA would take too long, and should not be pursued in the initial feasibility studies.
In those that do present within the time window, another simple study would be to see if MRgFUS can accelerate the time to recanalization in those patients receiving tPA.
The majority of stroke patients present too late to be candidates for tPA, and those that do not have an ischemic penumbra in the first eight hours after symptom onset might be recruited into a later study of MRgFUS sonothrombolysis.
Centers interested in pursuing the early studies include the Brigham & Women's Hospital in Boston, the University of Virginia, The University of California at San Diego, and the University of Cincinnati.