Thilo Hölscher

Observation on the integrity of the blood-brain barrier after microbubble destruction by diagnostic transcranial color-coded sonography.

To investigate alteration of the blood‐brain barrier from ultrasonic contrast agent destruction by diagnostic transcranial color‐coded sonography using gadolinium‐enhanced magnetic resonance imaging.

Transcranial Ultrasound from Diagnosis to Early Stroke Treatment – Part 2: Prehospital Neurosonography in Patients with Acute Stroke – The Regensburg Stroke Mobile Project

Background and Purpose: The primary aim of this study was to investigate the diagnostic accuracy and time frames for neurological and transcranial color-coded sonography (TCCS) assessments in a prehospital ‘911’ emergency stroke situation by using portable duplex ultrasound devices to visualize the bilateral middle cerebral arteries (MCAs). Methods: This study was conducted between May 2010 and January 2011. Patients who had sustained strokes in the city of Regensburg and the surrounding area in Bavaria, Germany, were enrolled in the study. After a ‘911 stroke code’ call had been dispatched, stroke neurologists with expertise in ultrasonography rendezvoused with the paramedic team at the site of the emergency. After a brief neurological assessment had been completed, the patients underwent TCCS with optional administration of an ultrasound contrast agent in cases of insufficient temporal bone windows or if the agent had acute therapeutic relevance. The ultrasound studies were performed at the site of the emergency or in the ambulance during patient transport to the admitting hospital. Relevant timelines, such as the time from the stroke alarm to patient arrival at the hospital and the duration of the TCCS, were documented, and positive and negative predictive values for the diagnosis of major MCA occlusion were assessed. Results: A total of 113 patients were enrolled in the study. MCA occlusion was diagnosed in 10 patients. In 9 of these 10 patients, MCA occlusion could be visualized using contrast-enhanced or non-contrast-enhanced TCCS during patient transport and was later confirmed using computed tomography or magnetic resonance angiography. One MCA occlusion was missed by TCCS and 1 atypical hemorrhage was misdiagnosed. Overall, the sensitivity of a ‘field diagnosis’ of MCA occlusion was 90% [95% confidence interval (CI) 55.5–99.75%] and the specificity was 98% (95% CI 92.89–99.97%). The positive predictive value was 90% (95% CI 55.5–99.75%) and the negative predictive value was 98% (95% CI 92.89–99.97%). The mean time (standard deviation) from ambulance dispatch to arrival at the patient was 12.3 min (7.09); the mean time for the TCCS examination was 5.6 min (2.2); and the overall mean transport time to the hospital was 53 min (18). Conclusion: Prehospital diagnosis of MCA occlusion in stroke patients is feasible using portable duplex ultrasonography with or without administration of a microbubble contrast agent. Prehospital neurological as well as transcranial vascular assessments during patient transport can be performed by a trained neurologist with high sensitivity and specificity, perhaps opening an additional therapeutic window for sonothrombolysis or neuroprotective strategies.

Comparison Between Echo Contrast Agent-Specific Imaging Modes and Perfusion-Weighted Magnetic Resonance Imaging for the Assessment of Brain Perfusion

Background and Purpose— Contrast burst imaging (CBI) and time variance imaging (TVI) are new ultrasonic imaging modes enabling the visualization of intravenously injected echo contrast agents in brain parenchyma. The aim of this study was to compare the quantitative ultrasonic data with corresponding perfusion-weighted MRI data (p-MRI) with respect to the assessment of brain perfusion. Methods— Twelve individuals with no vascular abnormalities were examined by CBI and TVI after an intravenous bolus injection of 4 g galactose-based microbubble suspension (Levovist) in a concentration of 400 mg/mL. Complementary, a dynamic susceptibility contrast MRI, ie, p-MRI, of each individual was obtained. In both ultrasound (US) methods and p-MRI, time-intensity curves were calculated offline, and absolute time to peak intensities (TPI), peak intensities (PI), and peak width (PW) of US investigations and TPI, relative cerebral blood flow (CBF) and relative cerebral blood volume (CBV) of p-MRI examinations were determined in the following regions of interest (ROIs): lentiform nucleus (LN), white matter (WM), posterior (PT), and anterior thalamus (AT). In addition, the M2 segment of the middle cerebral artery (MCA) was evaluated in the US, and the precentral gyrus (PG) was examined in the p-MRI examinations. In relation to a reference parenchymal ROI (AT), relative TPIs were compared between the US and p-MRI methods and relative PI of US investigations with the ratio of CBF (rCBF) of p-MRI examinations in identical ROIs. Results— Mean TPIs varied from 18.3±5.0 (AT) to 20.1± 5.8 (WM) to 17.2±4.9 (MCA) seconds in CBI examinations and from 19.4±5.3 (AT) to 20.4±4.3 (WM) to 17.3±4.0 (MCA) seconds in TVI examinations. Mean PIs were found to vary from 581.9±342.4 (WM) to 1522.9±574.2 (LN) to 3400.9± 621.7 arbitrary units (MCA) in CBI mode and from 7.5±4.6 (WM) to 17.5±4.9 (LN) to 46.3±7.1 (MCA) arbitrary units in TVI mode. PW ranged from 7.3±4.5 (AT) to 9.1±4.0 (LN) to 24.3±12.8 (MCA) seconds in CBI examinations and from 7.1±3.9 (AT) to 8.7±3.5 (LN) to 26.7±18.2 (MCA) seconds in TVI examinations. Mean TPI was significantly shorter and mean PI and mean PW were significantly higher in the MCA compared with all other ROIs (P <0.05). Mean TPI of the p-MRI examinations ranged from 22.0±6.9 (LN) to 23.0±6.8 (WM) seconds; mean CBF ranged from 0.0093± 0.0041 (LN) to 0.0043±0.0021 (WM). There was no significant difference in rTPI in any ROI between US and p-MRI measurements (P >0.2), whereas relative PIs were significantly higher in areas with lower insonation depth such as the LN compared with rCBF. Conclusions— In contrast to PI, TPI and rTPI in US techniques are robust parameters for the evaluation of cerebral perfusion and may help to differentiate physiological and pathological perfusion in different parenchymal regions of the brain.

Transcranial Ultrasound from Diagnosis to Early Stroke Treatment

Background: To test whether portable duplex ultrasound devices can be used in a prehospital ‘911’ emergency situation to assess intracranial arteries. Methods: Non-contrast-enhanced transcranial duplex ultrasound studies were performed either immediately at the site of the emergency (i.e. private home) or after transfer into the emergency helicopter/ambulance vehicle. Results: A total of 25 patients were enrolled. In 5/25 cases, intracranial vessels could not be visualized due to insufficient quality of the temporal bone window. In 20/25 cases, bilateral visualization and Doppler flow measurements of the middle cerebral artery could be assessed in a mean time less than 2 min. Conclusion: Emergency assessment of intracranial arteries using portable duplex ultrasound devices is feasible shortly after arrival at the patient’s site.

Transcranial Ultrasound Brain Perfusion Assessment With a Contrast Agent-Specific Imaging Mode Results of a Two-Center Trial

Background and Purpose— The purpose of this study was to assess brain perfusion with an ultrasound contrast-specific imaging mode and to prove if the results are comparable between 2 centers using a standardized study protocol. Methods— A total of 32 individuals without known cerebrovascular disease were included in the study. Perfusion studies were performed ipsilaterally in an axial diencephalic plane after intravenous administration of 0.75 mL of Optison. Offline time intensity curves (TIC) were generated in different anatomic regions. Both centers used identical study protocols, ultrasound machines, and contrast agent. Results— In both centers, the comparison of the parameter time to peak intensity (TPI) revealed significantly shorter TPIs in the main vessel structures compared with any parenchymal region of interest (ROI), whereas no significant differences were seen between the parenchymal ROIs. The parameter peak intensity (PI) varied widely interindividually in both centers, whereas the inter-ROI comparison revealed statistical significance (P<0.05) in most of the cases according to the following pattern: (1) lentiforme nucleus > thalamus and white matter region, (2) thalamus > white matter region, and (3) main vessel > any parenchymal structure. Similar results were achieved in both centers independently. Conclusion— The study demonstrates that brain perfusion assessment with an ultrasound contrast-specific imaging mode is comparable between different centers using the same study protocol.

In vitro Sonothrombolysis with Duplex Ultrasound: First Results Using a Simplified Model

Background: The main aim was to study the effects of ultrasound (US) alone, in combination with an US contrast agent (UCA), tissue plasminogen activator (tPA), or the combination of both upon blood clots. Methods: In order to learn about sonothrombolysis with diagnostic duplex US, a simplified in vitro test model, using human whole blood clots in Petri dishes, was established. Results: A total of 286 blood clots were analyzed. Improved sonothrombolysis due to insonation with diagnostic duplex US could be achieved, whether it was used alone or in combination with tPA. Although already described, a beneficial effect of UCA microbubbles on sonothrombolysis could not be confirmed due to the study design. Conclusion: Diagnostic duplex US improves thrombolysis significantly, even when it is used without tPA. To study the effect of UCA microbubbles on sonothrombolysis appropriately, any experimental design should provide continuous replenishment of microbubbles at the target site.

Validation of the depletion kinetic in semiquantitative ultrasonographic cerebral perfusion imaging using 2 different techniques of data acquisition

Objective.To validate the potential of ultrasonographic depletion imaging for semiquantitatively visualizing cerebral parenchymal perfusion with contrast burst depletion imaging (CODIM) in comparison with phase inversion harmonic depletion imaging (PIDIM) in healthy volunteers. Methods.Thirteen healthy adults were examined with both CODIM and PIDIM in accordance with previously described criteria. In addition to the perfusion coefficient, the time to decrease image intensity to 10% above equilibrium intensity from the initial value and the relative error (deviation of measured data from the fitted model) were evaluated to compare the reliability of both techniques in 3 different regions of interest. Results.Perfusion coefficient values did not show significantly differing values in both groups (1.57–1.64 • 10−2 s−1 for CODIM and 1.42–1.58 • 10−2 s−1 for PIDIM). The relative error was significantly smaller in the PIDIM group (0.38–0.53 for CODIM and 0.18–0.25 for PIDIM; P < .002). Conclusions. Phase inversion harmonic depletion imaging proved to be more reliable than CODIM because values of the relative error were significantly lower in PIDIM even in this relatively small cohort. This is of interest because the underlying technique, phase inversion harmonic imaging, is more widely available than contrast burst imaging.

TRANSCRANIAL SOUND FIELD CHARACTERIZATION

In the scope of therapeutic ultrasound applications in the adult brain, such as sonothrombolysis in stroke, a better understanding of the intracranial acoustic properties during insonation through the temporal bone is warranted. Innovative ultrasound imaging techniques, like transcranial duplex sonography, may open new avenues to apply ultrasound for therapeutic purposes and to visually monitor the effect using the same device. The aim was to study the transcranial sound field aberrations and the changes of acoustic parameters, using a high-end duplex machine. Six cadaver skulls were insonated through the temporal bone window, using a diagnostic duplex ultrasound device. The measurements were done in a water tank, using a needle hydrophone to assess and compute acoustic parameters, such as peak intensity, peak-to-peak, peak-positive, peak-negative acoustic pressure, beam area etc. in a 2-D plane. It could be shown that the absorption and wavefront distortion effects of the temporal bone are variable among different skulls. Because of signal absorption of the bone, the mechanical index of the incident ultrasound wave drops by a factor > or =10 in most cases. However, the beam area might be increased by a factor of almost 4, because of phase aberration (i.e., defocusing). (

INTRAOPERATIVE ULTRASOUND USING PHASE INVERSION HARMONIC IMAGING: FIRST EXPERIENCES

OBJECTIVE To study the feasibility of intraoperative ultrasound using the phase inversion harmonic imaging (PIHI) technique. METHODS Eight patients with intracranial middle cerebral artery aneurysms and five patients with arteriovenous malformations were studied after written informed consent. A first ultrasound study was performed through the intact dura mater after cranial trepanation to assess the pathology, its feeding artery, and downstream segments. A second ultrasound study was performed immediately after intervention to monitor the success of the procedure. All patients were studied using a Siemens Sonoline Antares ultrasound machine (Siemens Medical Solutions USA, Inc., Malvern, PA) before and after intravenous administration of an ultrasound contrast agent (Optison; GE Healthcare, Milwaukee, WI). Other than conventional brightness mode, PIHI is sensitive to the nonlinear acoustic response of tissue, and especially to ultrasound contrast agent microbubbles. The latter enables contrast-specific vascular imaging. RESULTS PIHI provided anatomically detailed information. In combination with an ultrasound contrast agent, angiography-like views of the vascular pathologies, including their surrounding vessels, could be obtained. Flow velocities in afferent and downstream vascular segments, as well as inside the pathology, could be assessed. Flow dynamics inside the aneurysm sac or the arteriovenous malformation could be studied in real-time. Postintervention, contrast-enhanced PIHI could be used to immediately monitor the success of the surgical procedure. CONCLUSION PIHI enables intraoperative visualization and morphological assessment of neurovascular pathologies, such as middle cerebral artery aneurysms or arteriovenous malformations. In combination with an ultrasound contrast agent, the flow dynamics of these lesions can be displayed in real-time.

Transcranial Near-Infrared Laser Transmission (NILT) Profiles (800 nm): Systematic Comparison in Four Common Research Species.

Background and Purpose Transcranial near-infrared laser therapy (TLT) is a promising and novel method to promote neuroprotection and clinical improvement in both acute and chronic neurodegenerative diseases such as acute ischemic stroke (AIS), traumatic brain injury (TBI), and Alzheimer’s disease (AD) patients based upon efficacy in translational animal models. However, there is limited information in the peer-reviewed literature pertaining to transcranial near-infrared laser transmission (NILT) profiles in various species. Thus, in the present study we systematically evaluated NILT characteristics through the skull of 4 different species: mouse, rat, rabbit and human. Results Using dehydrated skulls from 3 animal species, using a wavelength of 800nm and a surface power density of 700 mW/cm2, NILT decreased from 40.10% (mouse) to 21.24% (rat) to 11.36% (rabbit) as skull thickness measured at bregma increased from 0.44 mm in mouse to 0.83 mm in rat and then 2.11 mm in rabbit. NILT also significantly increased (p<0.05) when animal skulls were hydrated (i.e. compared to dehydrated); but there was no measurable change in thickness due to hydration. In human calvaria, where mean thickness ranged from 7.19 mm at bregma to 5.91 mm in the parietal skull, only 4.18% and 4.24% of applied near-infrared light was transmitted through the skull. There was a slight (9.2-13.4%), but insignificant effect of hydration state on NILT transmission of human skulls, but there was a significant positive correlation between NILT and thickness at bregma and parietal skull, in both hydrated and dehydrated states. Conclusion This is the first systematic study to demonstrate differential NILT through the skulls of 4 different species; with an inverse relationship between NILT and skull thickness. With animal skulls, transmission profiles are dependent upon the hydration state of the skull, with significantly greater penetration through hydrated skulls compared to dehydrated skulls. Using human skulls, we demonstrate a significant correlation between thickness and penetration, but there was no correlation with skull density. The results suggest that TLT should be optimized in animals using novel approaches incorporating human skull characteristics, because of significant variance of NILT profiles directly related to skull thickness.