Response to Letter by Eggers
We appreciate the comments by Dr Eggers regarding our recent editorial on a single-center pilot trial of sonothrombolysis with transcranial color-coded sonography (TCCS) and intravenous tissue plasminogen activator (tPA).1 Dr Eggers, who was the primary investigator of this trial,2 has raised 2 points that we would like to address.
First, he underlines that our assumption concerning the potential association between the multibeam configuration of TCCS and the increased rate of symptomatic intracranial hemorrhage is not justified because the overwhelming part of the insonation was performed with pulsed-wave Doppler, whereas color-coded Duplex was used only for vessel identification. Because Eggers et al used no head frame in their study to ensure a stable angle of insonation, a 1-hour hand-held insonation period would have likely required probe readjustments and vessel location using B-mode and color flow, reintroducing multiple frequencies. Acute stroke patients are often noncompliant, frequently restless and moving their heads continuously during the insonation period. Even if multifrequency exposure is reduced to as little time as necessary to locate occlusion in these patients, TCCS technology still differs from nonimaging transcranial Doppler (TCD) because it deploys multiple beams that expose larger areas of the brain to ultrasound and may lead to standing wave formations at higher pulse repetition frequencies. In view of these considerations the impact of frequencies and intensities of multibeam TCCS and ultrasound dose escalation (ie, intermittent versus continuous insonation) on the rate of symptomatic intracranial hemorrhage should be investigated before embarking on a pivotal multicenter trial.3,4
This is further supported by the results of a recent meta-analysis of 6 randomized and 3 nonrandomized studies of ultrasound-enhanced thrombolysis presented at the 2008 International Stroke Conference.5 There was a nonsignificant trend toward higher rates of symptomatic intracranial hemorrhage in patients treated with TCCS and tPA in comparison to patients treated with transcranial Doppler (TCD) and tPA (9.7% versus 3.7%, P=0.147; Fisher exact t test).
The second point raised is related to our statement about a trend toward better functional outcomes in the study by Eggers et al. Although there was no difference between the 2 groups (P=0.106) on the modified Rankin Scale scores, a substantial improvement was noted in the Barthel Index scores (P=0.003). Of note, both modified Rankin Scale and Barthel Index were obtained by telephone interview and not by clinical assessment. Because there was no sample-size estimation before the study and only a small number of patients were recruited in the study, we tried to be cautious when interpreting the findings of this pilot trial in our editorial.
Finally, our group recently published results of a pilot trial of microsphere-potentiated ultrasound-enhanced thrombolysis where safe augmentation of arterial recanalization rates was achieved with a combination of tPA, microspheres and TCD.6 Further development of microspeheres would require their coupling with a safe ultrasound technology, and currently we have more clinical data about safety of a single-beam 2-MHz TCD. Although we agree with Dr Egger’s final comment that both TCD and TCCS seem to enhance the thrombolytic activity of tPA, the safe dose of multibeam or multifrequency ultrasound configurations remains to be determined.
A.V.A. served as a consultant to ImaRx Therapeutics and has a US patent in the area of sonothrombolysis.
Tsivgoulis G, Alexandrov AV. Ultrasound-enhanced thrombolysis from bedside to bench. Stroke. 2008; 39: 1404–1405.
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: 1470–1475.
Tsivgoulis G, Molina CA, Eggers J, Perren F, Rubiera M, Larrue V, Alexandrov AV. Safety and efficacy of ultrasound-enhanced thrombolysis: a meta-analysis of randomized and non-randomized studies. Stroke. 2008; 39: 593–594[Abstract].
Alexandrov AV, Mikulik R, Sharma VK, Lao AY, Tsivgoulis G, Sugg RM, Barreto A, Sierzenski P, Malkoff MD, Grotta JC. A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres (μS) for acute ischemic stroke. Stroke. 2008; 39: 1464–1469.