Sonothrombolysis for acute ischemic stroke - Break on through to the other side
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.198213
Source of Support: None, Conflict of Interest: None
Background: Intravenous (IV) tissue plasminogen activator (tPA) infusion combined with transcranial low-frequency ultrasound waves targeted on the occluded arterial segment (sonothrombolysis) can increase recanalization in large artery-acute ischemic stroke (LA-AIS).
Keywords: Acute ischemic stroke, developing countries, sonothrombolysis, tissue plasminogen activator, transcranial Doppler ultrasound
The treatment of acute ischemic strokes (AISs) is primarily aimed at recanalization and restoring the blood flow. Treatment with intravenous (IV) tissue plasminogen activator (tPA) is an approved therapy for arterial recanalization in AIS.
Understandably, the strongest predictor for a favorable outcome following ischemic strokes due to a large vessel occlusion is the recanalization achieved within the shortest possible time. However, even if given well within the window period, IV tPA does not guarantee recanalization in all cases of AIS. Bhatia et al., showed a low rate (21%) of acute recanalization with IV tPA, especially with proximal vessel occlusions.
Recent trials have shown the superiority of second-generation mechanical thrombectomy devices over IV thrombolysis for anterior circulation ischemic strokes caused by large artery (LA) occlusion.,, However, in many developing countries like ours, mechanical thrombectomy is not yet widely available and IV thrombolysis may be the only treatment option available.
Ultrasound targeting of the occluded artery in combination with IV tPA (sonothrombolysis) has been shown to increase the rate of recanalization, both through its direct mechanical effect on the thrombus and indirectly by augmenting the effect of tPA on the clot. Sonothrombolysis is safe and does not add to the door to needle time. In addition, one has the added advantage of observing the flow through the occluded artery in real time. It does not involve sophisticated equipment or intensive training.
Here, we present a series of AIS caused by large vessel occlusion which were treated using sonothrombolysis. To the best of our knowledge, this is the first such case series from the Indian subcontinent.
Patients presenting to a quaternary care teaching hospital with anterior circulation AIS caused by large artery (LA) occlusion within the window period (<4.5 h) with no contraindications for receiving IV-recombinant tPA (rtPA) were considered for sonothrombolysis. As per the hospital protocol, all patients were imaged using various (diffusion-weighted imaging [DWI]/apparent diffusion coefficient [ADC], fluid-attenuated inversion recovery [FLAIR], susceptibility weighted imaging [SWI], and magnetic resonance angiography [MRA]) MR sequences.
All patients received a standard dose of IV-rtPA (0.9 mg/kg body weight) and transcranial Doppler (TCD) ultrasound head frame was fixed immediately. Using a 2 MHz Probe (Nicolet ® SONARA ®, TCD system) [Figure 1], the occluded artery was identified through the temporal window. First, the flow in the proximal part of the occluded artery was identified and then the depth was reduced slowly till absent flow (no regular pulsatile flow signals) was seen at the occluded segment. This occluded segment was continuously resonated. The corresponding segment on the normal side was also identified and the flow monitored and compared with the occluded side. In all cases, the interventional neuroradiologists were informed regarding the potential need for mechanical thrombectomy in case there was no clinical improvement with sonothrombolysis.
Arterial recanalization was checked and graded using the thrombolysis in brain ischemia (TIBI) flow criteria [Figure 2]. The TCD resonation was continued for the full duration of IV-rtPA infusion even if recanalization was established.
At the end of IV-rtPA infusion, if there was no clinical improvement or no flow was established (TIBI Grade 0 or 1), the patient was immediately imaged using DWI/ADC, FLAIR, SWI, and MRA; also MR perfusion was done in selected cases. If the vessel was still remaining occluded with salvageable parenchyma, the patient was taken up for mechanical thrombectomy.
Arterial recanalization was further evaluated by comparing the pre- and post-treatment time of flight (TOF) – MRAs using a modified thrombolysis in myocardial infarction (TIMI) Score on TOF-MRA. The scoring included the following categories: TIMI 0: no recanalization, TIMI 1: minimal recanalization corresponding to flow signal detectable beyond the area of obstruction but not in most of the distal vascular bed, TIMI 2: partial recanalization defined by an incomplete recanalization but filling most of the vascular bed, and TIMI 3: complete recanalization.
Symptomatic intracranial hemorrhages were defined as intracranial hemorrhage appearing on the follow-up MR imaging (MRI) [SWI]/computed tomography (CT) scans with an increase in National Institutes of Health Stroke Scale (NIHSS) score of ≥4 points.
The extent of parenchymal changes pre- and post-sonothrombolysis was assessed and compared using the CT/DWI-Alberta Stroke Programme Early CT Score (ASPECTS)., After discharge, the modified Rankin Scale (mRS) was used to assess the outcome.
Over a period of 14 months, 18 patients (6 females and 12 males) were treated with sonothrombolysis. The mean age was 55 years (range 32–76 years). Of the 18 patients, 11 (61%) had total anterior circulation involvement and 7 (39%) had partial anterior circulation involvement using the Oxfordshire Community Stroke Project clinical classification (Bamford classification).
Of the 18 patients, 11 (61%) had involvement of the left side and 7 (39%) had right sided involvement. The baseline MRI ASPECTS was above 6 in all patients. Using the TOAST criteria, the etiology was large artery (LA) atherosclerosis in 9 of 18 patients (50%) and cardio-embolic stroke in 8 of 18 patients (44%). One patient was found to have an adenocarcinoma causing a hypercoagulable state.
The mean onset to needle (sonothrombolysis time) was 138 min (range 65–256). A TIBI residual flow [Figure 1] of Grade 2 or more was seen in 15 of 18 patients (83%). In 2 of 18 patients (11%; patients 12 and 17), there was no flow (TIBI 0) at the end of tPA infusion with no clinical improvement [Table 1] (the change in NIHSS was unremarkable). They were immediately imaged using MRI DWI/ADC, FLAIR, and MRA. In one patient, there was no salvageable penumbra and in another, mechanical thrombectomy was done.
The NIHSS score improved in all the recanalizers in the immediate sonothrombolysis period and continued to improve except in two patients (patients 10 and 15). These two patients, even though they had a TIBI Grade of 3 and 5, did not show much improvement in their NIHSS [Table 2].
One patient had a re-occlusion. This patient, who had achieved a TIBI Grade 3 with good clinical improvement (patient 18) immediate postsonothrombolysis, later worsened after 1 h. Repeat imaging was done immediately which showed the vessel remaining occluded; however, the MR perfusion still showed a large salvageable penumbra. This patient was also taken up for mechanical thrombectomy with a good outcome.
Follow-up MRI with MRA was done in 14 of 18 patients (78%) and in the remaining, only a noncontrast CT scan was done within 24 h. Of the 14 patients, 8 (57%) had a TIMI of 2 or more (partial to complete recanalization) [Figure 3]. It was also noted that in cases where the internal carotid artery (ICA) was occluded with the thrombus extending to the proximal middle cerebral artery (MCA), sonothrombolysis achieved flow in the MCA (with collateral blood from the circle of Wills); however, there was little effect on the occluded ICA itself with only 1 of 5 patients (20%) of the occluded ICA showing flow.
Hemorrhage was seen in 3 patients (16%). Only one was symptomatic (5.5%). There were 2 deaths (11%). One patient who failed sonothrombolysis did not show recanalization even after attempting mechanical thrombectomy. This patient was subsequently diagnosed to have a disseminated adenocarcinoma. The second mortality was in a patient who had failed sonothrombolysis and was not considered for mechanical thrombectomy as the subsequent MRI did not show a demonstrable penumbra. This patient subsequently improved to an NIHSS of 10, but died following aspiration pneumonia and septic shock.
At 6 months, out of the remaining 16 patients, one patient was lost for follow-up. Of the 15 patients, 10 (67%) had a mRS of 2 or less.
Since the 1970s, the ability of ultrasound waves (USW) to enhance clot lysis was noted in experimental animal studies. It was observed by Alexandrov's group in Houston that patients being monitored with 2 MHz TCD during IV tPA infusion had a better outcome. This paved the way for therapeutic use of ultrasound in AIS treatment and clinical trials looking at the benefit of sonothrombolysis. It has been shown that ultrasound in combination with rtPA can drastically increase the rate at which a blood clot dissolves.,
USWs can accelerate clot lysis through multiple mechanisms. USW can break the molecular linkages of fibrin polymers, thus increasing the penetration of IV tPA and also exposing more areas of the clot to the action of IV tPA. When a clot forms, there will be some microbubbles which will get trapped inside. When the clot is exposed to pulsed USW, these microbubbles can have repeating oscillations. This is termed as stable cavitation (since these microbubbles do not collapse). This repeated oscillations will lead to a process called acoustic microstreaming caused by shear stress by a gas body oscillating near a rigid structure (here the arterial wall); this microstreaming can enhance the effects of the IV tPA., As the USW pressure increases, the cavitation becomes unstable, leading to destruction of the gas bubble. This is called inertial cavitation (unstable cavitation), which can cause violent collapse of the microbubble producing shock waves and micro jets. This can agitate the clot but can also cause potential damage to the adjacent tissues. Ultrasound can also increase the activity of the endothelial nitric oxide syntheses and increase the nitric oxide release leading on to vasodilatation and improvement in the microcirculation.
In the phase II clinical randomized multicenter international trial, using the combined lysis of thrombus in brain ischemia using transcranial ultrasound and systemic tPA (CLOTBUST) trial, patients with MCA occlusions were randomized to receive sonothrombolysis. This study showed complete recanalization on TCD or dramatic clinical recovery with a total NIHSS score ≤3 points or improvement by ≥10 NIHSS points within 2 h after tPA bolus in 49% versus 30% of the control patients receiving only tPA (P = 0·03).
In our series, such dramatic improvement was seen in 6 of 18 patients (30%) on immediate postsonothrombolysis, and by the next 24 h (50%), 9 of 18 patients had achieved an NIHSS score ≤3 points or improvement by ≥ 10 NIHSS.
In the CLOTBUST trial where a 2 MHz TCD was used, there was no increase in the rate of symptomatic intracerebral hemorrhage (4·8% in both arms). However, when nondiagnostic 3.30 KHz ultrasound was used with the aim of increasing the recanalization rate in the transcranial low-frequency ultrasound mediated TIBI trial, symptomatic hemorrhage occurred in 36%. It is interesting to note that in this trial, hemorrhages occurred even in areas not affected by ischemia. In our series where 2 MHz TCD was used, the symptomatic ICH rate was 5.5% (1/18).
Most of the mechanisms that promote clot lysis can be amplified by the co-administration of microbubbles. These are small, gas-filled microspheres with an inert gas core and a biodegradable shell. They are small enough to pass through all major and minor capillaries of the human body and reach the clot in the occluded segment to interact with the ultrasonic source to augment the process of sonothrombolysis., Most of the clinical trials on sonothrombolysis using microbubbles have used the common diagnostic galactose-based microbubbles given in bolus. The concomitant use of microbubbles to augment recanalization was also seen to be associated with a slightly higher hemorrhage rates., The increase in the hemorrhagic transformation is due to the endothelial damage caused by the unstable cavitation of the microbubbles leading to blood–brain barrier disruption.
Only ultrasound targeting of the intra-arterial thrombus without using thrombolytics is termed sonolysis. This may be an option for patients ineligible for rtPA., A randomized controlled trial to test the superiority of both microbubbles enhanced sonothrombolysis and sonolysis is underway.
Systematic reviews and meta-analyses show that sonothrombolysis is safe and effective in reducing death or dependency at 3 months by increasing the recanalization rate in AIS.,,
In clinical practice, sonothrombolysis requires trained personnel to identify the occluded intracranial artery, deliver the ultrasound through the appropriate cranial window, and pick up the recanalization. This limits the use of this therapy to selected specialized stroke treatment centers. To overcome this, a device which can be easily attached to a patient's head to deliver 2 MHz ultrasound pulsed-waves has been developed. This device is currently being tested in an ongoing phase III efficacy trial.
We had treated these patients before the American Heart Association/American Stroke Association released their focused update of the 2013 guidelines for the early management of patients with AIS with endovascular treatment. Even though the latest recommendation for anterior circulation ischemic strokes caused by LA occlusion is a mechanical thrombectomy device over IV thrombolysis, in resource-scarce countries like ours, facilities for intra-arterial thrombolysis are not widely available. In centers where only IV tPA is available and are far away from hospitals offering endovascular therapy and also in centers offering the drip and ship option  to a nearby tertiary center, sonothrombolysis can be an easily affordable and cheap way to improve the efficacy of IV tPA.
The authors acknowledge the contribution of Mr. Panickar Anbalagan M. Sc., for his help during administering sonothrombolysis.
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Conflicts of interest
There are no conflicts of interest.
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