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ORIGINAL ARTICLE
Year : 2014  |  Volume : 62  |  Issue : 1  |  Page : 62-65

Sonothrombolysis in acute middle cerebral artery stroke


Department of Neurology, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission27-Oct-2013
Date of Decision07-Dec-2013
Date of Acceptance02-Feb-2014
Date of Web Publication7-Mar-2014

Correspondence Address:
Mohamed Hamdy Ibrahim
Department of Neurology, Ain Shams University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.128308

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 » Abstract 

Objectives: The objective of the following study is to determine the effect of continuous insonation using 2-MHz transcranial Doppler-ultrasound (TCD-US) on the recanalization rate and the short-term outcome in subjects with acute ischemic stroke due to middle cerebral artery (MCA) occlusion. Materials and Methods: A total of 42 patients with acute ischemic stroke due to MCA occlusion within 24 h were recruited and randomly allotted to two groups (21 patients in each group). Group 1 included patients who received 1 h continuous TCD-US for MCA and Group 2 included patients who did not receive 1 h continuous TCD-US. Patients in both groups were received MCA insonation and TCD study to measure mean flow velocity (MFV) in MCA one after the initial study at 20 and 60 min. All patients received aspirin (150-325 mg). The clinical course during hospital stay was assessed before and after 1 h of US insonation, at 24 h after symptom onset using the National Institutes of Health Stroke Scale. Results: Change in MFV after insonation for Group 1 in comparison to Group 2 at 3 time points was significantly high (P < 0.001). Conclusion: Sonothrombolysis is a therapeutic option to improve the outcomes in patients with acute ischemic stroke due to MCA occlusion.


Keywords: Acute ischemic stroke, middle cerebral artery, sonothrombolysis


How to cite this article:
Dwedar AZ, Ashour S, Haroun M, El Nasser AA, Moustafa RR, Ibrahim MH, Elsadek A. Sonothrombolysis in acute middle cerebral artery stroke. Neurol India 2014;62:62-5

How to cite this URL:
Dwedar AZ, Ashour S, Haroun M, El Nasser AA, Moustafa RR, Ibrahim MH, Elsadek A. Sonothrombolysis in acute middle cerebral artery stroke. Neurol India [serial online] 2014 [cited 2019 Nov 12];62:62-5. Available from: http://www.neurologyindia.com/text.asp?2014/62/1/62/128308



 » Introduction Top


Acute ischemic stroke is characterized by the sudden loss of blood circulation to an area of the brain, resulting in sudden onset of a focal neurologic deficit. [1] Transcranial Doppler (TCD) is a non-invasive, inexpensive and safe technique that measures the velocity of blood flow through the cerebral circulation. [2] Thus, it is of use in the diagnosis of acute ischemic stroke as it can provide rapid information about major arterial occlusion or stenosis (especially middle cerebral artery (MCA) occlusion). It also helps in assessing the hemodynamic status of cerebral circulation, monitoring of reperfusion and recanalization. [3] TCD has emerged as a tool to treat ischemic stroke in the last few years. The potential advantage of ultrasound (US) is, it decreases the risk of systemic bleeding complications due to its site-specific effect. Moreover, external application is non-invasive and is readily available. A 2-MHz pulsed-wave diagnostic US beam provides real-time bedside monitoring of thrombolysis. It can augment residual flow and hasten thrombolysis, resulting in rapid and good recovery. [4] US delivers mechanical pressure waves to the clot, thus exposing more thrombus surface to circulating drug. [5] Low-frequency US with high power has been demonstrated to produce cavitations and fluid motion in the thrombus. [6] Some experimental studies use the administration of micro bubbles (MB) (e.g., galactose-based air-filled MB and sulphur hexafluoride-filled MB) as it may augment the effect of US -enhanced systemic thrombolysis in acute stroke. Bubble structural characteristics may influence the effect of MB on sonothrombolysis. [7] Other recent studies suggest that acceleration of thrombolysis using pulsed wave US is effective and can enhance thromblysis even without recombinant tissue plasminogen activator (rt-PA). [8] Although some experimental studies and pilot clinical evidence show that TCD has role in the enhancement of thrombolysis with or even without rt-PA, [5] yet more studies are needed to evaluate the potential of TCD US technology to enhance thrombolysis and to study the effect of vascular risk factors (e.g., DM, hyperlipidemia) as predictors of recanalization. In this study we studied the effect of continuous insonation using 2-MHz TCD-US on the recanalization rate and the short-term outcome of subjects with acute ischemic stroke due to MCA occlusion.


 » Materials and Methods Top


The study subjects included 42 patients with acute ischemic stroke due to MCA occlusion admitted to It Ain Shams University Specialized Hospital, Cairo, Egypt [Table 1]. The institution Ethical Committee has approved the study.
Table 1: Age, sex in both groups

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Inclusion criteria and subject selection

Patients with acute ischemic stroke in the MCA territory within 24 h of onset of symptoms in the age ranging between 40 and 70 years.

Exclusion criteria

Onset of stroke more than 24 h, poor acoustic window, or patients intolerant to monitoring.

Ethical consideration

All patients or relatives were informed about the study and its possible benefits.

A total of 42 patients with acute ischemic stroke in the MCA territory within 24 h of onset were enrolled. All patients received 150-325 mg of aspirin/day [Table 1]. All patients had detailed neurologic examination and relevant investigation to determine the mechanism of stroke and also the risk factors. All patients had TCD-US (Multi-Dop x4 Ez Dop), CT brain and MRI brain and MR-angiography (MRA) (Signa Lx-1.5 Tesla), electrocardiogram 2D Echo and carotid Duplex (Logiq-9).

Patients were randomly assigned to two groups, 201 patients in each group. Group 1 Continuous US monitoring group: MCA was insonated through temporal window with TCD-US to measure initial mean flow velocity (MFV) and then patients had continuous insonation for 1 h. Blood flow velocity was recorded using 2-MHz US probe. MCA was then reinsonated at 20 and 60 min after continuous insonation to detect changes in MFV. Partial recanalization is considered when MFV increased by 15-30 cm/s. Complete recanalization is considered when MFV increased more than 30 cm/s. [9] Group 2: Control group: In this group patients were not subjected to continuous TCD-US for 1 h and only to measure the initial MFV. MCA was again reinsonated after 1 h of initial insonated to measure MVF at 20 and 60 min. The clinical course during hospital stay was assessed before and after 1 h TCD-US insonation, at 24 h of onset of symptom onset using National Institutes of Health Stroke Scale (NIHSS).

Statistical analysis

Analysis was performed using Statistical Package for Social Science (SPSS 15, Chicago, IL). Mean and standard deviation (± SD) were used for parametric numerical data, while median and interquartile range for non-parametric numerical data. Student t-test was used to assess the statistical significance of the difference between two group means, whereas Paired t-test was used to assess the statistical significance of the difference between two means measured twice for the same study group. Mann Whitney U test was used to assess the statistical significance of the difference of a non-parametric variable between two study groups. Correlation analysis was done using Pearson's correlation coefficient (r) method. Fisher's exact test: was used to examine the relationship between two qualitative variables when the expected count is less than 5 in more than 20% of cells. A mixed model ANOVA was used to assess the effect of time on recanalization across the study groups. P < 0.05 was considered to be statistically significant for all tests.


 » Results Top


The study subjects aged ranged between 40 years and 70) years and he mean age of the patients included in Group 1 was (59.2 ± 10.6 years and it was 59.2 ± 9.3 years in Group 2. There were 13 (61.9%) patients with complete ipsilateral MCA occlusion in Group 1 and 14 (66.7%) patients in Group 2. Three patients (14.3%) in each group had ipsilateral internal carotid (ICA) stenosis or occlusion.

Initial NIHSS score before interventions was 12 ± 3.5 in Group 1 and 12.2 ± 4.4 in points in Group 2 (P = 0.85). The interval between onset of symptoms and insonation with TCD-US was 5.02 ± 1.2 h in Group 1 and 8.0 ± 2.2 h in Group 2, which was significant. Repeated measures mixed-model ANOVA was used to compare the change in MFV in both groups at 3 time points (before insonation, 20 min after insonation and 60 min after insonation). The analysis showed a very significant GROUP × TIME interaction (F {1.4,54.5} = 41.1, P < 0.001) and post hoc analysis using Tukey HSD showed that there was a significant difference for this interaction between all three time points (all P < 0.001 except 20 min vs. 60 min P = 0.03). There was a significant change in MFV after insonation for Group 1 in comparison to Group 2. For patients and controls respectively (before insonation 8.1 ± 5.9 cm/s vs. 17.8 ± 33.9 cm/s; at 20 min after insonation 32.8 ± 17.2 cm/s vs. 19.5 ± 33.9 cm/s; at 60 min after insonation 35.2 ± 15.4 cm/s vs. 20.7 ± 33.8 cm/s). We found that there was significant change in MFV 60 min after insonation (27.12 ± 14.61 cm/s) among Group 1 and on the other hand, limited change of MFV (2.83 ± 6.80 cm/s) among Group 2. Comparison between Group 1 and Group 2 as regard to change in blood flow velocity 60 min after TCD showed that there was highly significant difference between Group 1 and Group 2 as regard change in MFV 60 min after insonation [Table 2]. As for recanalization 60 min after TCD in Group 1, there was complete recanalization (increase of MFV > 30 cm/s) in 42.9% of patients and partial recanalization (increase of MFV 15-30 cm/s) in 42.9% of patients, while in Group 2 there was complete recanalization in only one patient (4.8%). Comparison between Group 1 and Group 2 as regard to recanalization at 60 min after TCD-US showed that there was a very significant difference between two groups regarding complete and partial recanalization. Comparison between patients among Group 1with no/partial recanalization and patients with complete recanalization as regard to change sin NIHSS score, there was significant improvement of NIHSS in patients with complete recanalization at three time points (end of insonation, 1 day, 7 days after insonation) in comparison to patients with partial recanalization (this improvement was highly significant 7 days after insonation) as shown in [Table 2].
Table 2: Comparison between Group 1 and Group 2 as regard change in blood fl ow velocity 60 min after TCD

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 » Discussion Top


Recanalization in acute ischemic stroke is considered as an important predictor of clinical outcome in all the modalities of thrombolysis. Most of the studies of thrombolysis were done on MCA as it is easy to be insonated and has the most constant location during insonation among all intracranial arteries. [10] Diagnostic 2-MHz TCD is routinely used in patients with stroke to obtain spectral velocity measurements in intracranial arteries. The US beam is focused at the intracranial clot location and its interface with surrounding, often minimal, blood flow. [4]

This study results show high rate of complete and partial recanalization (42.9%) suggesting acceleration of thrombolysis using pulsed wave US even without rt-PA. These observations are in agreement with the study other studies. [8] Our study included larger sample than this study. A study by Ricci et al. [14] also pointed out that sonothrombolysis in MCA occlusion increases recanalization rates.

There was a significant improvement in NIHSS score in Group 1 in comparison to Group 2 at three time points (around 2 points improvement in NIHSS). This was marked at day-7 after onset and was marked in patients with complete recanalization of MCA (around 4 point's improvement in NIHSS). Although this is a promising result, yet there were five patients who did not improve clinically in spite of complete recanalization. This may be due to mismatch between size of infarction and size of penumbra, which was not available in our study. In our study recanalization was associated with changes in MFV of insonated MCA before and after 1 h of insonatio. These results are in agreement with Combined Lysis of Thrombus in Brain ischemia Using Transcranial Ultrasound and Systemic TPA (CLOTBUST) study. [6] This trial was done on large sample of patients and also used the additional effect of systemic tissue plasminogen activator (tPA) thrombolysis which remain the only approved thrombolytic therapy for acute ischemic stroke. Yet our results are also promising even without use of systemic tPA. This may be related to the ability of US alone to enhance fibrinolysis through disaggregation of non-cross-linked fibrin strands. Continuous 2-MHz TCD energy transmission promotes thrombolysis by simply exposing more clot surface to residual flow. In our study the rate of recanalization was less than in a large study (55%). [11] In this study patients received air-filled glalactose - based MB-enhanced sonothrombolysis, tPA and patients received continuous high-frequency, low-intensity diagnostic TCD monitoring for 2 h. Experimental data suggests that MBs can also increase sonothrombolysis. [9],[11] When a MB passes through an US energy field, it experiences translations and size oscillations (static cavitation), which generate harmonic signals that increase the acoustic impedance mismatch between the blood and surrounding tissue, thereby improving the diagnostic vascular US. This harmonic emission also releases energy and agitates the fluid in which the bubbles are dissolved, improving the delivery and penetration of tPA into the clot. If the US negative pressure is increased, the bubble collapses (inertial cavitation), leading to intense localized stresses and microjets, which could cause mechanical fragmentation of the thrombus. [12] In our study other predictors associated with change in MVF included: interval between onset to TCD-US, NIHSS score before TCD-US, atrial fibrillation, presence of ICA stenosis, total cholesterol, LDL, fasting blood sugar, random blood Sugar, mean blood pressure.

A study with limited sample size of MCA main stem occlusion has indicated that this method might be a possible alternative to interventional therapy. [15] The occurrence of an increased rate of symptomatic hemorrhagic transformation with sonothrombolysis with diagnostic US has not been confirmed thus far. [16] In the absence of other therapies, this method may be an alternative treatment option.


 » Conclusion Top


Sonothrombolysis is a therapeutic option to improve the outcomes in acute ischemic stroke. It is associated with immediate increase of MFV in the occluded artery this improving the clinical condition of patients with acute ischemic stroke. Based upon on our study results we suggest the TCD-US protocol given in [Figure 1] for MCA occlusion. The limitations of our study are small sample size and lack of use of use of intravenous thrombolysis.
Figure 1: Protocol for transcranial Doppler in middle cerebral artery occlusion

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 » References Top

1.Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: Systematic analysis of population health data. Lancet 2006;367:1747-57.  Back to cited text no. 1
    
2.Sarkar S, Ghosh S, Ghosh SK, Collier A. Role of transcranial Doppler ultrasonography in stroke. Postgrad Med J 2007;83:683-9.  Back to cited text no. 2
    
3.Tsivgoulis G, Alexandrov AV, Sloan MA. Advances in transcranial Doppler ultrasonography. Curr Neurol Neurosci Rep 2009;9:46-54.  Back to cited text no. 3
    
4.Mikulik R, Alexandrov AV. Acute stroke: Therapeutic transcranial Doppler sonography. Front Neurol Neurosci 2006;21:150-61.  Back to cited text no. 4
    
5.Tsivgoulis G, Alexandrov AV. Ultrasound-enhanced thrombolysis in acute ischemic stroke: Potential, failures, and safety. Neurotherapeutics 2007;4:420-7.  Back to cited text no. 5
    
6.Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, 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. 6
    
7.Rubiera M, Ribo M, Delgado-Mederos R, Santamarina E, Maisterra O, Delgado P, et al. Do bubble characteristics affect recanalization in stroke patients treated with microbubble-enhanced sonothrombolysis? Ultrasound Med Biol 2008;34:1573-7.  Back to cited text no. 7
    
8.Eggers J, Seidel G, Koch B, König IR. Sonothrombolysis in acute ischemic stroke for patients ineligible for rt-PA. Neurology 2005;64:1052-4.  Back to cited text no. 8
    
9.Alexandrov AV. Current and future recanalization strategies for acute ischemic stroke. J Intern Med 2010;267:209-19.  Back to cited text no. 9
    
10.Wolpert SM, Bruckmann H, Greenlee R, Wechsler L, Pessin MS, del Zoppo GJ. Neuroradiologic evaluation of patients with acute stroke treated with recombinant tissue plasminogen activator. The rt-PA Acute Stroke Study Group. AJNR Am J Neuroradiol 1993;14:3-13.  Back to cited text no. 10
    
11.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. 11
    
12.Tachibana K, Tachibana S. Albumin microbubble echo-contrast material as an enhancer for ultrasound accelerated thrombolysis. Circulation 1995;92:1148-50.  Back to cited text no. 12
    
13.Prokop AF, Soltani A, Roy RA. Cavitational mechanisms in ultrasound-accelerated fibrinolysis. Ultrasound Med Biol 2007;33:924-33.  Back to cited text no. 13
    
14.Ricci S, Dinia L, Del Sette M, et al.Sonothrombolysis for acute ischemic stroke. Stroke 2013;44:e6.  Back to cited text no. 14
    
15.Eggers J, König IR, Koch B, Händler G, Seidel G. Sonothrombolysis with transcranial color-coded sonography and recombinant tissue-type plasminogen activator in acute middle cerebral artery main stem occlusion: Results from a randomized study. Stroke 2008;39:1470-5.  Back to cited text no. 15
    
16.Tsivgoulis G, Eggers J, Ribo M, Perren F, Saqqur M, Rubiera M, et al. Safety and efficacy of ultrasound-enhanced thrombolysis: A comprehensive review and meta-analysis of randomized and nonrandomized studies. Stroke 2010;41:280-7.  Back to cited text no. 16
    


    Figures

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    Tables

  [Table 1], [Table 2]

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