Efficacy of sonothrombolysis in a rat model of embolic ischemic stroke

Daffertshofer, Michael; Huang, Zhihong; Fatar, Marc; Popolo, Margherita; Schroeck, Helmut; Kuschinsky, Wolfgang; Moskowitz, Michael A.; Hennerici, Michael G.

doi:10.1016/j.neulet.2004.02.003

Cited by 50 publications

(40 citation statements)

References 26 publications

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“…This results in failure of clot degradation in experimental settings that involve temporal bone obstacles. 7 Using lower frequencies (20 kHz to 1 MHz), tPA-mediated clot degradation was as much as 50% more efficient when ultrasound was added, 2,8,9 even when applied transcranially. 8,10,11 In the thromboembolic middle cerebral artery, rat mode low-frequency ultrasound (185 kHz and 33 kHz) is more efficacious than the higher frequencies used in commercially available diagnostic devices.…”

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confidence: 99%

Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia

Daffertshofer

Gass

Ringleb

et al. 2005

Stroke

389

204

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Background— Clinical studies using ultrasound at diagnostic frequencies in transcranial Doppler devices provided encouraging results in enhancing thrombolysis with tissue plasminogen activator (tPA) in acute stroke. Low-frequency ultrasound does not require complex positioning procedures, penetrates through the skull better, and has been demonstrated to accelerate thrombolysis with tPA in animal experiments in wide cerebrovascular territories without hemorrhagic side effects. We therefore conducted the first multicenter clinical trial to investigate safety of tPA plus low-frequency ultrasound (300 kHz). Methods— Acute stroke patients within a 6-hour time window were included (National Institutes of Health Stroke Scale scores >4). Magnetic resonance imaging (MRI) was used to document vascular occlusion and to rule out cerebral hemorrhage. Patients were allocated to combination therapy alternately; the first patient received tPA only, the second patient received tPA plus ultrasound, etc. Follow-up included serial MRI directly thereafter and 24 hours later to confirm recanalization and tissue imaging. Clinical recovery was measured after treatment and 3 months later. Results— 26 patients (70.4±9.7 years) entered the trial (12 tPA, 14 tPA plus ultrasound). The study was prematurely stopped because 5 of 12 patients from the tPA only group but 13 of 14 patients treated with the tPA plus ultrasound showed signs of bleeding in MRI ( P <0.01). Within 3 days of treatment, 5 symptomatic hemorrhages occurred within the tPA plus ultrasound group. At 3 months, neither morbidity nor treatment-related mortality or recanalization rates differed between both groups. Conclusions— This study demonstrated bioeffects from low-frequency ultrasound that caused an increased rate of cerebral hemorrhages in patients concomitantly treated with intravenous tPA.

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confidence: 99%

Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia

Daffertshofer

Gass

Ringleb

et al. 2005

Stroke

389

204

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“…Moreover, a reduction of cerebral infarct volume by means of low-frequency TUS has been reported in a rat middle cerebral artery (MCA) stroke model. 9 However, unexpected hemorrhagic complications occurred in the TRUMBI trial. 10 Some studies were subsequently performed to investigate the reasons for these complications.…”

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confidence: 99%

Effective and Safe Conditions of Low-Frequency Transcranial Ultrasonic Thrombolysis for Acute Ischemic Stroke

Saguchi

Onoue

Urashima

et al. 2008

Stroke

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Background and Purpose-Transcranial ultrasound (TUS) enhances thrombolysis and is expected to be useful for the treatment of ischemic stroke. However, neither its effectiveness in improving neurologic outcome nor its safety in living tissue has been fully established. We examined the efficacy and safety of low-frequency TUS under appropriate conditions of ultrasound for thrombolytic treatment in a rat middle cerebral artery stroke model. Methods-Sixty-five male Wistar rats were used. Rats with right middle cerebral artery stroke exhibiting left hemiparesis were blindly selected and randomly assigned to 1 of 3 groups: (1) control, no therapy; (2) tPA, intravenous administration of tissue plasminogen activator 3 hours after middle cerebral artery stroke, or (3) TUS, tPA administration and application of TUS (490 kHz, continuous wave, at an intensity of 0.8 W/cm 2 ). Twenty-four hours after the onset of stroke, neurologic improvement was evaluated and brains were then removed. Thrombolysis at the origin of the right middle cerebral artery was examined. Thrombolysis ratio, cerebral infarct ratio, and rate of histologic evidence of hemorrhage were compared in the 3 groups. Results-Significantly better neurologic improvement (Pϭ0.008), a higher thrombolysis ratio (Pϭ0.041), and a reduction of cerebral infarct volume (Pϭ0.047) were obtained in the TUS group compared with the tPA group, without an increase in hemorrhagic transformation. Conclusions-Our findings suggest that thrombolytic treatment with low-frequency TUS under appropriate conditions could be an effective and safe method of treatment for ischemic stroke.

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“…Indeed, preclinical work in rats 47 was unable to demonstrate harmful secondary effects of US using the TRUMBI parameters. One study suggests that hemorrhages in TRUMBI were related to abnormal permeability of the human blood-brain barrier that was induced by wide-field low-frequency insonation.…”

Section: Us-enhanced Thrombolysis Of Ischemic Strokementioning

confidence: 99%