Response to Letter by Gerriets et al
We greatly appreciate the thoughtful comments by Dr Gerriets and coworkers. Our finding of blood-brain barrier disruption after 300 kHz insonation in a 62-year-old man with cerebral small-vessel disease1 is substantiated by their remarkable animal study demonstrating vasogenic edema on MRI after 20 kHz insonation.2 Mechanical and not thermal effects3 thus seem to be responsible for the possibly deleterious side effects of low-frequency ultrasound. The dilemma is that the better bone penetration and thus recanalizing efficacy of low-frequency ultrasound in vitro is apparently foiled by a higher rate of mechanical side effects in vivo. In a randomized clinical study, 2 MHz sonothrombolysis was safe and resulted in a higher rate of recanalization,4 whereas an in vitro skull model could not demonstrate any sonothrombolytic efficacy of 1.8 MHz insonation.5 The only sonothrombolysis study in humans using low-frequency ultrasound of 300 kHz6 showed hemorrhagic, most probably mechanical side effects but (unlike in vitro studies) not a higher recanalization rate compared with recombinant tissue plasminogen activator alone. In the light of these conflicting results between in vitro and in vivo studies, there is a sincere need for in vivo animal studies balancing different ultrasound frequencies (between 300 kHz and 2 MHz), powers and target volumes against optimal clinical efficacy and lowest side effects. We fully agree with Dr Gerriets and colleagues that an extensive preclinical evaluation of this topic is needed before future clinical studies in humans.
Reinhard M, Hetzel A, Kruger S, Kretzer S, Talazko J, Ziyeh S, Weber J, Els T. Blood-brain barrier disruption by low-frequency ultrasound. Stroke. 2006; 37: 1546–1548.
Schneider F, Gerriets T, Walberer M, Mueller C, Rolke R, Eicke BM, Bohl J, Kempski O, Kaps M, Bachmann G, Dieterich M, Nedelmann M. Brain edema and intracerebral necrosis caused by transcranial low-frequency 20-kHz ultrasound: a safety study in rats. Stroke. 2006; 37: 1301–1306.
Fatar M, Stroick M, Griebe M, Alonso A, Hennerici MG, Daffertshofer M. Brain temperature during 340-kHz pulsed ultrasound insonation: a safety study for sonothrombolysis. Stroke. 2006; 37: 1883–1887.
Pfaffenberger S, Devcic-Kuhar B, Kollmann C, Kastl SP, Kaun C, Speidl WS, Weiss TW, Demyanets S, Ullrich R, Sochor H, Woeber C, Zeitlhofer J, Huber K, Groeschl M, Benes E, Maurer G, Wojter J, Gottsauner-Wolf M. Can a commercial diagnostic ultrasound device accelerate thrombolysis? An in vitro skull model. Stroke. 2005; 36: 124–128.
Daffertshofer M, Gass A, Ringleb P, Sitzer M, Sliwka U, Els T, Sedlaczek O, Koroshetz WJ, Hennerici MG. Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator: results of a phase II clinical trial. Stroke. 2005; 36: 1441–1446.