High Rate of Recanalization of Middle Cerebral Artery Occlusion During 2-MHz Transcranial Color-Coded Doppler Continuous Monitoring Without Thrombolytic Drug Pascal Cintas, MD; Anne Pavy Le Traon, MD, PhD; Vincent Larrue, MD Background and Purpose—Experimental evidence indicates that ultrasound can accelerate thrombolysis. We report our findings on early recanalization during transcranial color-coded Doppler (TCCD) continuous monitoring in acute stroke patients with middle cerebral artery (MCA) main stem occlusion. Methods—We performed continuous TCCD monitorings in 6 consecutive patients with acute MCA main stem occlusion using a 2-MHz transducer. Patients were not treated with recombinant tissue plasminogen activator. Results—Partial recanalization, defined as blunted waveforms, occurred during monitoring in 5 patients (83%). The mean time to beginning of recanalization was 17.2⫾9.6 minutes. Complete recanalization at 24 hours occurred in only 1 patient. The mean National Institutes of Health Stroke Scale score in the patients who recanalized during monitoring was 21.2⫾4.1 at baseline, 19.2⫾5 at 2 hours, and 15.6⫾3.4 at 24 hours (P⫽0.1). Conclusions—In this short series of patients with acute MCA main stem occlusion, not treated with recombinant tissue plasminogen activator, we found a high rate of early partial recanalization during continuous exposure to 2-MHz ultrasound. (Stroke. 2002;33:626-628.) Key Words: middle cerebral artery 䡲 thrombolysis 䡲 ultrasonography, Doppler, transcranial E xperimental evidence indicates that low-intensity ultrasound, in the range of values used for diagnostic purposes, accelerates thrombolysis by enhancing plasminogen activator-induced fibrinolysis.1,2 Recently, Alexandrov et al3 reported a high rate of recanalization in stroke patients treated with intravenous recombinant tissue plasminogen activator (rtPA) during 1-hour 2-MHz transcranial Doppler (TCD) monitoring, suggesting that ultrasound might have enhanced drug-induced fibrinolysis in these patients. We report our findings on recanalization during 2-MHz transcranial colorcoded Doppler (TCCD) continuous monitoring in patients with acute middle cerebral artery (MCA) main stem occlusion who were not treated with rtPA. Subjects and Methods This study included consecutive patients admitted to our stroke unit with an acute ischemic stroke who could have a TCCD diagnosis of MCA main stem occlusion within 6 hours from symptom onset. All patients had a brain CT scan before inclusion to evaluate the hyperdense MCA sign. Patients were not treated with intravenous rtPA. TCCD scannings were performed through the temporal bone window with a 2-MHz transducer (ATL Ultramark 9 HDI). We first used B-mode imaging to visualize the lateral fissure as a hyperechogenic structure, anterior and lateral to the hypoechogenic butterflyshaped mesencephalic brain stem, in the orbitomeatal plane. A diagnosis of MCA main stem occlusion was made with the use of both color-coded imaging and pulsed-wave Doppler in case of lack of blood flow all along the lateral fissure, with persistent flow in both the ipsilateral anterior cerebral artery and posterior cerebral artery. Then the sample volume (10 mm in length) of the pulsed-wave Doppler was positioned in the initial part of the lateral fissure, where the MCA main stem runs (Figure 1). This allowed us to precisely focus the ultrasound beam on occluded MCAs. In a preliminary study, we found that this method could correctly identify the MCA main stem in 31 of 37 patients (83.8%) without cerebral artery occlusion and had 100% sensitivity compared with color-coded Doppler imaging. The transducer was fixed with a head set, and pulsed-wave ultrasound was continuously delivered on the initial part of the MCA main stem to evaluate possible changes in flow. The spatial-peak temporal average intensity was 415 mW/cm2. The duration of monitoring was 30 minutes in 5 patients and 45 minutes in the remaining patient. Other TCCD scannings (without monitoring) were performed 2 to 6 hours and 24 hours after the first one to evaluate possible delayed recanalization. The clinical severity of stroke was evaluated at baseline, 2 hours, and 24 hours with the use of the National Institutes of Health Stroke Scale. Results Six patients (5 men and 1 woman; mean age, 54.3⫾14.7 years) were included. Four patients had a hyperdense MCA sign. All patients received aspirin 250 mg IV as part of their initial treatment. Received September 26, 2001; final revision received November 8, 2001; accepted November 14, 2001. From the Department of Neurology, University of Toulouse (France). Correspondence to Professor Vincent Larrue, Service de neurologie, Hopital de Rangueil, 1 avenue Jean Poulhes, 31403 Toulouse, France. E-mail larrue.v@chu-toulouse.fr © 2002 American Heart Association, Inc. Stroke is available at http://www.strokeaha.org 626 Downloaded from http://stroke.ahajournals.org/ by guest on October 24, 2015 Cintas et al TCCD in Acute Ischemic Stroke 627 Characteristics of Recanalization Pt Recanalization During TCCD 1 1 ⫺ Time to Beginning of Recanalization, min MCA Waveforms TCCD 1 TCCD 2 TCCD 3 None Blunted Blunted Blunted 2 ⫹ 䡠䡠䡠 23 Blunted Blunted 3 ⫹ 16 Blunted Blunted ND 4 ⫹ 5 Blunted Blunted Blunted 5 ⫹ 12 Blunted Stenotic Stenotic 6 ⫹ 30 Blunted Blunted Blunted TCCD 1 indicates initial monitoring; TCCD 2, 2 to 6 hours after initial monitoring; TCCD 3, 24 hours after initial monitoring; and ND, not done. The mean time from symptom onset to beginning of TCCD monitoring was 210⫾86 minutes. Recanalization of the initially occluded MCA main stem occurred during monitoring in 5 patients. Time to beginning of recanalization ranged from 5 to 30 minutes (mean, 17.2⫾9.6 minutes) after the beginning of monitoring. Peak systolic velocities were reduced and waveforms were blunted (rounded systolic complex) in all cases (Table and Figure 1), suggesting that recanalization was only partial.4 On the second TCCD scan, performed 2 to 6 hours after the first one, all arteries had recanalized. Peak systolic velocities were reduced and waveforms were blunted in 5 patients, including the patient without recanalization during the monitoring. In the remaining patient, there was a stenotic pattern (focally increased peak systolic velocity and aliasing) of the initially occluded MCA (Table). Figure 1. TCD focused on MCA main stem in the lateral fissure, with the use of B-mode imaging. Note the partial recanalization with localized color-coded blood flow and blunted waveforms on Doppler. Evolution of pulsed-wave Doppler in this patient is shown in Figure 2. A third TCCD scan performed 24 hours later in 5 patients showed no further change. The mean National Institutes of Health Stroke Scale score in the 5 patients with recanalization during initial monitoring was 21.2⫾4.1 at baseline, 19.2⫾5 at 2 hours, and 15.6⫾3.4 at 24 hours (P⫽0.1, ANOVA). Discussion In this study of patients with acute MCA main stem occlusion, who were not treated with rtPA and who were scanned within 6 hours of symptom onset, we could document early recanalization in 5 of 6 patients (83%). Recanalization began after a few minutes of continuous exposure to low-intensity ultrasound. In previous studies of early spontaneous recanalization in similar patients not continuously exposed to ultrasound, the rates of recanalization were much lower. Thus, in a recent series of 32 patients with proximal MCA occlusion first seen between 40 minutes and 5.3 hours from the onset of symptoms, only 2 (6.3%) had recanalized on a repeated TCD performed at 6 hours.5 Similarly, in the Duplex Sonography in Acute Stroke (DIAS I) study, among 12 patients with M1 occlusion first scanned within 6 hours of symptom onset, none had recanalized on a control TCCD performed 2 hours after inclusion.6 Finally, in the Prolyse in Acute Cerebral Thromboembolism (PROACT I and PROACT II) studies, which included patients with angiographically proven M1 or M2 occlusion within 6 hours of symptom onset, the recanalization rates at 120 minutes for control patients were 14.3% and 18%, respectively.7,8 Several in vitro studies have established that ultrasound at low intensity enhances enzymatic fibrinolysis, while it has no effect on clot dissolution without plasminogen activator.1,2,9 Figure 2. Evolution of recanalization in patient 5. a, Initial partial recanalization 12 minutes after beginning of monitoring. b, Increase in peak flow velocity with persistent blunted waveforms 30 seconds later. c, Stenotic flow signal 6 hours later with increased peak systolic velocity up to 300 cm/s. Downloaded from http://stroke.ahajournals.org/ by guest on October 24, 2015 628 Stroke February 2002 Recently, in an in vitro model using the same 2-MHz ultrasound system as in the present study, we found that 30-minute insonation of whole blood clots enhanced rtPAinduced thrombolysis by 47% (P⫽0.01).10 Mechanisms whereby low-intensity ultrasound increases enzymatic fibrinolysis include acoustic microstreaming at clot/blood flow boundary and reversible changes in fibrin structure, which both result in increased plasminogen activator binding to fibrin and transport into the clot.11 In the present study patients were not treated with rtPA. Thus, if we assume that our findings are not coincidental, the high rate of early recanalization and the close temporal relationship between the beginning of continuous exposure to ultrasound and recanalization suggest that low-intensity ultrasound focused on the occluded MCA main stem under control by B-mode imaging may have enhanced endogenous enzymatic fibrinolysis. However, early recanalization was only partial in all patients. Previous work with angiographic correlation suggests that blunted waveforms correspond, at best, to partial deobstruction with delayed filling of distal branches.4 This may explain, at least in part, why the clinical improvement in patients with early recanalization did not reach statistical significance in our study. The present study has several limitations. The sample size was small, we did not use a control group, and the assessment of MCA patency at the end of monitoring was unblinded. Thus, the findings should be interpreted with caution. In conclusion, in a short series of consecutive patients with acute MCA main stem occlusion, not treated with rtPA, we found a high rate of early recanalization during continuous exposure to low-intensity, 2-MHz ultrasound. The findings suggest that ultrasound may have played a role in thrombolysis. These findings need to be confirmed in other laboratories before a prospective, controlled study is considered. References 1. Francis CW, Önundarson PT, Carstensen EL, Blinc A, Meltzer RS, Schwarz K, Marder VJ. Enhancement of fibrinolysis in vitro by ultrasound. J Clin Invest. 1992;90:2063–2068. 2. Blinc A, Francis CW, Trudnowski JL, Carstensen EL. Characterization of ultrasound-potentiated fibrinolysis in vitro. Blood. 1993;81:2636 –2643. 3. Alexandrov AV, Demchuk AM, Felberg RA, Christou I, Barber PA, Burgin WS, Malkoff M, Wojner AW, Grotta JC. High rate of complete recanalization and dramatic clinical recovery during tPA infusion when continuously monitored with 2 MHz transcranial Doppler monitoring. Stroke. 2000;31:610 – 614. 4. Burgin WS, Malkoff M, Felberg RA, Demchuk AM, Christou I, Grotta JC, Alexandrov AV. Transcranial Doppler ultrasound criteria for recanalization after thrombolysis for middle cerebral artery stroke. Stroke. 2000;31:1128 –1132. 5. Molina C, Montaner J, Abilleira S, Ibarra B, Romero F, Arenillas JF, Alvarez-Sabin J. Timing of spontaneous recanalization and risk of hemorrhagic transformation in acute cardioembolic stroke. Stroke. 2001;32: 1079 –1084. 6. Gerriets T, Postert T, Goertler M, Stolz E, Sclachetzki F, Sliwka U, Seidel G, Weber S, Kaps M, for the DIAS (Duplex Sonography in Acute Stroke) Study Group. DIAS I: duplex-sonographic assessment of the cerebrovascular status in acute stroke: a useful tool for future stroke trials. Stroke. 2000;31:2342–2345. 7. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M, for the PROACT Investigators. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke: Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998;29:4 –11. 8. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F. Intra-arterial prourokinase for acute ischemic stroke: the PROACT II study: a randomized controlled trial. JAMA. 1999;282:2003–2011. 9. Spengos K, Behrens S, Daffertshofer M, Dempfle CE, Hennerici M. Acceleration of thrombolysis through the cranium in a flow model. Ultrasound Med Biol. 2000;26:889 – 895. 10. Cintas P, Nguyen F, Pavy le Traon A, Boneu B, Larrue V. Enhancement of rtPA-induced thrombolysis by exposure to low-intensity, highfrequency ultrasound. Cerebrovasc Dis. 2001;11(suppl 3):20. Abstract. 11. Francis CW, Blinc A, Lee S, Cox C. Ultrasound accelerates transport of recombinant tissue plasminogen activator into clots. Ultrasound Med Biol. 1995;21:419 – 424. Downloaded from http://stroke.ahajournals.org/ by guest on October 24, 2015 High Rate of Recanalization of Middle Cerebral Artery Occlusion During 2-MHz Transcranial Color-Coded Doppler Continuous Monitoring Without Thrombolytic Drug Pascal Cintas, Anne Pavy Le Traon and Vincent Larrue Stroke. 2002;33:626-628 doi: 10.1161/hs0202.103073 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2002 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. 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