Neurology -- Correspondence for Eggers et al., 64 (6) 1052-1054

Correspondence published:

Sonothrombolysis in acute ischemic stroke for patients ineligible for rt-PA: Jaroslaw Krejza, John B. Weigele, Riyadh Alokaili, Michal Arkuszewski, and Robert W. Hurst (13 June 2005)

Reply to Krejza et al: Seidel Günter, Jürgen Eggers (13 June 2005)

Sonothrombolysis in acute ischemic stroke for patients ineligible for rt-PA 13 June 2005

Jaroslaw Krejza,
Department of Radiology, Division of Neuroradiology, University of Pennsylvania
3600 Market Street, Science Building, Ste 370, Philadelphia, PA 19104, United States,
John B. Weigele, Riyadh Alokaili, Michal Arkuszewski, and Robert W. Hurst
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Re: Sonothrombolysis in acute ischemic stroke for patients ineligible for rt-PA

Jaroslaw.Krejza{at}uphs.upenn.edu Jaroslaw Krejza, et al.

We read with interest the article by Eggers et al [1] on sonothrombolysis in acute ischemic stroke but two aspects of their article warrant further clarification.
An inclusion criterion to the study was MCA-M1 occlusion determined with transcranial color-coded duplex sonography (TCCS) and a TIBI (thrombolysis in brain ischemia) score proposed for conventional TCD. [2] If no color flow signal or Doppler signal were detected score 0 was assigned. However, the outcome measures are inconsistent with the inclusion criterion because lack of recanalization was graded as TIBI 0 and also as TIBI 1, which was described as presence of systolic spikes of variable velocity (as high as 20 cm/s based on visual assessment of the waveform in the figure 1 of the paper) and duration, absent diastolic flow during all cardiac cycles, or reverberating flow. [2] Thus, score 1 in TCCS study would result in the presence of color flow signal if the sensitivity of the color scale had been properly adjusted. Neither details of settings are provided nor is any image presented by Eggers et al[1], showing appropriate adjustment of the color scale and noise filter. Inconsistencies in classification of occlusion and recanalization, when inclusion and outcome criteria are based on TIBI scores, and lack of important methodological details raise concerns as to validity of their results.
The safety of prolonged insonation in patients with MCA occlusion is also important since the authors do not provide any settings showing power and intensity output in B-mode and Doppler mode. Admittedly, thermal effects of diagnostic ultrasound on normal brain tissue is not a major concern yet prolonged insonation of ischemic brain regions is a concern because small increases in brain temperature (1-2° C) may grossly affect outcome. Under conditions of normal brain perfusion, local brain temperature increases only slightly during sonographic insonation [3] but substantial increase might be expected in ischemic/infarcted brain tissue because of limited heat dissipation by perfusion.
The study of Alexandrov et al [4] showed that the two hours continuous insonation of patients with acute ischemic stroke with TCD is safe and can augment t-PA-induced recanalization. The output energy of conventional transcranial sonography, however, is lower than of TCCS. Although a few studies showed that temperature increases in the brain can accelerate thrombolysis [5], it is unclear whether the heat generated by prolonged TCCS insonation of the ischemic brain has deleterious or beneficial effects in stroke patients.
References
1. Eggers J, Seidel G, Koch B, Konig IR. Sonothrombolysis in acute ischemic stroke for patients ineligible for rt-PA. Neurology 2005;22:1052- 1054.
2. Demchuk AM, Burgin WS, Christou I, Felberg RA, Barber PA, Hill MD, Alexandrov AV. Thrombolysis in brain ischemia (TIBI) transcranial Doppler flow grades predict clinical severity, early recovery, and mortality in patients treated with intravenous tissue plasminogen activator. Stroke 2001;32:89-93.
3. Mariak Z, Krejza J, Swiercz M, Lyson T, Lewko J. Human brain temperature in vivo: lack of heating during color transcranial Doppler ultrasonography. J Neuroimaging 2001;11:308-312.
4. Alexandrov AV, Molina CA, Grotta JC, et al. CLOTBUST Investigators. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med 2004;351:2170-2178.
5. Sakharov DV, Hekkenberg RT, Rijken DC. Acceleration of fibrinolysis by high-frequency ultrasound: the contribution of acoustic streaming and temperature rise. Thromb Res 2000;100:333-340.

Reply to Krejza et al 13 June 2005

Seidel Günter,
Department of Neurology, University Hospital Schleswig-Holstein, Germany
Ratzeburger Allee 160, D-23538 Lübeck, Germany,
Jürgen Eggers
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Re: Reply to Krejza et al

guenter.seidel{at}neuro.uni-luebeck.de Seidel Günter, et al.

Dr. Krejza et al addressed mainly methodological details and the safety of sonothrombolysis.
In our experience, even an optimized setting for detecting residual flow in a middle cerebral artery does not necessarily lead to positive proof of a color flow signal. The Doppler signal is more sensitive for this purpose and was used in our study. The settings of our ultrasound device were optimized as required by the conditions of the individual patient which was influenced by parameter like acoustic window. Limited publication space did not allow for the presentation of all these data.
The inclusion criterion TIBI 0 instead TIBI 0 to 1 was chosen to warrant a homogeneous sample of patients. As shown by Labiche et al [6] patients with a residual flow (TIBI 1) have a much better recanalization rate than those with TIBI 0. Inclusion criteria and outcome parameters are distinctly different and a high threshold for inclusion is not inconsistent with a definition of the outcome parameter recanalization. Our analysis of recanalization based on the ordinal scale TIBI 0 to 5 showed a statistically significant improvement of recanalization for the target group (2-sided p = 0.04, Mann Whitney U test, not published in [1]).
Regarding the safety concerns, TCCS was used to localize the site of the occlusion and control the correct position of the Doppler sample volume, but the continuous insonation was performed in the pulsed wave transcranial Doppler mode (similar to the CLOTBUST study[4]), not in the color-coded mode. The acoustic power of the Doppler device used in our study was 179 mW/cm² (pulsed wave Doppler mode) and did not exceed the FDA allowed threshold of 750 mW.
The case report by Mariak et al [3] does not support the safety concerns of Dr. Krejza et al because it revealed even in non perfused tissue that, (in this single case in the region of an intracranial hematoma), there was no intracranial temperature rise by transcranial Doppler ultrasound.
The patients from our target group who were continuously insonated showed a much better recovery than the control group. The only bleeding which occurred was a symptomatic one in the control group. A higher number of patients is required to confirm the safety of a one-hour continuous insonation, but so far the results of this preliminary study gave no reason for safety concerns.
References
6. Labiche LA, Malkoff M, Alexandrov AV. Residual flow signals predict complete recanalization in stroke patients treated with TPA. J Neuroimaging 2003;13:28-33.
Both authors have nothing to disclose with respect to our Sonothrombolysis trial and this response.