Prehospital stroke diagnosis and treatment in ambulances and helicopters-a concept paper.

Stroke is the second common cause of death and the primary cause of early invalidity worldwide. Different from other diseases is the time sensitivity related to stroke. In case of an ischemic event occluding a brain artery, 2000000 neurons die every minute. Stroke diagnosis and treatment should be initiated at the earliest time point possible, preferably at the site or during patient transport. Portable ultrasound has been used for prehospital diagnosis for applications other than stroke, and its acceptance as a valuable diagnostic tool "in the field" is growing. The intrahospital use of transcranial ultrasound for stroke diagnosis has been described extensively in the literature. Beyond its diagnostic use, first clinical trials as well as numerous preclinical work demonstrate that ultrasound can be used to accelerate clot lysis (sonothrombolysis) in presence as well as in absence of tissue plasminogen activator. Hence, the use of transcranial ultrasound for diagnosis and possibly treatment of stroke bares the potential to add to current stroke care paradigms significantly. The purpose of this concept article is to describe the opportunities presented by recent advances in transcranial ultrasound to diagnose and potentially treat large vessel embolic stroke in the prehospital environment.

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.

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.

Transcranial ultrasound from diagnosis to early stroke treatment. 1. Feasibility of prehospital cerebrovascular assessment.

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 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 brain ultrasound: a new approach to study flow dynamics in intracranial aneurysms.

The aim was to evaluate the potential of contrast-enhanced ultrasound to visualize the hemodynamics in intracranial aneurysms during neurosurgical intervention and to quantify the ultrasound data using digital particle image velocimetry (DPIV) technique. Aneurysms were scanned through the intact dura mater, preclipping and again postclipping after closure of the dura. After intravenous injection of Optison, angio-like views of the vascular tree surrounding the aneurysm, including the aneurysm sac, were obtained. Single ultrasound contrast agent microbubbles could be visualized in the aneurysm sac and the flow dynamics could be assessed in vivo. Spatial and temporal distributions of the velocity in the aneurysm and in the parent vessels were measured with DPIV using the backscattered signals from the microbubbles. Subsequently, the fluid stresses, vorticity, circulation, etc., were calculated from the velocity fields. We demonstrate in this paper that intraoperative contrast-enhanced ultrasound can be used to quantify the flow dynamics within an aneurysm.

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. CONCLUSIONS: The study demonstrates that brain perfusion assessment with an ultrasound contrast-specific imaging mode is comparable between different centers using the same study protocol.

Transcranial ultrasound angiography (T USA): a new approach for contrast specific imaging of intracranial arteries.

The goal was to develop an ultrasound contrast agent-specific imaging mode that offers an angiography-like view of the intracranial arteries and enables lower mechanical index MI settings compared to conventional transcranial duplex sonography. We studied 12 patients with transcranial ultrasound angiography (t USA) via the temporal bone window after an IV bolus injection of a perfluorocarbon-based microbubble contrast agent (Imagent). The aim was to display the intracranial vessel segments of the middle cerebral artery (M1, M2 and M3), the anterior cerebral artery (A1 and A2), the posterior cerebral artery (P1, P2 and P3) and the internal carotid artery (C1/2 and C3/4). t USA is a B-mode phase inversion imaging technique that uses wideband harmonic signals for image generation. We demonstrate, in this report, that t USA provides detailed anatomical display at native B-mode spatial resolution with fewer artifacts, yielding improved delineation of intracranial vessels that are in the 1- to 2-mm range.

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.

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 M(2) 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.

Brain perfusion imaging of a craniopharyngioma by transcranial duplex sonography.

BACKGROUND AND PURPOSE: The aim of this study was to test a new ultrasound software tool to assess pathological perfusion in a brain tumor patient. METHODS: Tissue harmonic imaging (THI) enables an improved depiction of brain morphology, employing nonlinear parenchyma and ultrasound contrast agent (UCA) backscatter information. With specialized software, morphological information can be separated from perfusion information. Both can be superimposed at a preferred mixing ratio in a single image. RESULTS: Using THI and a perfluoropropane-based UCA, a pathologic perfusion pattern described by abnormal perfused areas in the tumor region could be demonstrated. After superimposing morphologic and perfusion information, subtle structural tumor inhomogeneities were depicted. Craniopharyngioma structure and perfusion defect were confirmed by T2-weighted and perfusion-weighted magnetic resonance imaging. CONCLUSION: Transcranial duplex sonography in combination with contrast specific imaging methods might be helpful to visualize perfusion defects without loss of morphological information.

Contrast-Enhanced Transcranial and Extracranial Duplex Sonography: Preliminary Results of a Multicenter Phase II/III Study with SonoVuetrade mark.

Transcranial sonography is an ultrasonographic application with real problems of insufficient signal to noise ratio, which make it a primary candidate for applying ultrasonographic contrast enhancing agents. Within an international randomized multicenter phase II/III study, we investigated ten patients with insufficient Doppler signal retrieval using transcranial and extracranial color-coded duplex sonography to define safety, toxicity, optimal dosing, and the potential of the new ultrasound contrast agent SonoVue(trade mark). Patients were studied with standard color duplex systems. SonoVue(trade mark) was administered by IV bolus injection at four different doses. Efficacy parameters included the assessment of global quality of Doppler investigations, color Doppler (CD), and spectral Doppler (SD) evaluated by semiquantitative analysis using a four-point scale from 0 to 3 (very poor to excellent) and the duration of clinically useful signal enhancement. In addition, CD enhancement, evaluated at best signal enhancement, was assessed using a five-point scale, from no enhancement, slight, moderate, optimal to excessive (0-4). All examinations were compared to "gold" standard imaging (magnetic resonance imaging, digital subtraction angiography) to evaluate diagnostic confidence at optimum dosage. No serious adverse events were observed. Mean signal increase over baseline in CD or SD was 2 out of 4 points. Mean time to appearance of contrast enhancement was 22.8 seconds (9-52 sec) at the optimal dosage. The mean duration of enhancement was 281 seconds(20-593 sec) at the optimal dosage, which was of 2.4 ml of SonoVuetrade mark in nine patients. CD and SD signal enhancement (n = 20, CD + SD) was considered optimal in 12 of 20, excessive in 1 of 20, and moderate or insufficient in 5 of 20 and 2 of 20 cases, respectively. There was a tendency for superior improvement in CD signal enhancement. Diagnostic confidence was improved in 8 of 10 cases without false diagnostic conclusions. SonoVuetrade mark has been demonstrated to be a powerful and safe echo signal enhancing agent, which significantly improves transcranial and extracranial ultrasound investigations and increases the confidence in diagnosis.

Parametric mapping and quantitative analysis of the human calvarium.

In this paper we report how thickness and density vary over the calvarium region of a collection of human skulls. Most previous reports involved a limited number of skulls, with a limited number of measurement sites per skull, so data in the literature are sparse. We collected computer tomography (CT) scans of 51 ex vivo human calvaria, and analyzed these in silico using over 2000 measurement sites per skull. Thickness and density were calculated at these sites, for the three skull layers separately and combined, and were mapped parametrically onto the skull surfaces to examine the spatial variations per skull. These were found to be highly variable, and unique descriptors of the individual skulls. Of the three skull layers, the thickness of the inner cortical layer was found to be the most variable, while the least variable was the outer cortical density.

Prehospital stroke diagnostics based on neurological examination and transcranial ultrasound.

BACKGROUND: Transcranial color-coded sonography (TCCS) has proved to be a fast and reliable tool for the detection of middle cerebral artery (MCA) occlusions in a hospital setting. In this feasibility study on prehospital sonography, our aim was to investigate the accuracy of TCCS for neurovascular emergency diagnostics when performed in a prehospital setting using mobile ultrasound equipment as part of a neurological examination. METHODS: Following a '911 stroke code' call, stroke neurologists experienced in TCCS rendezvoused with the paramedic team. In patients with suspected stroke, TCCS examination including ultrasound contrast agents was performed. Results were compared with neurovascular imaging (CTA, MRA) and the final discharge diagnosis from standard patient-centered stroke care. RESULTS: We enrolled '232 stroke code' patients with follow-up data available in 102 patients with complete TCCS examination. A diagnosis of ischemic stroke was made in 73 cases; 29 patients were identified as 'stroke mimics'. MCA occlusion was diagnosed in ten patients, while internal carotid artery (ICA) occlusion/high-grade stenosis leading to reversal of anterior cerebral artery flow was diagnosed in four patients. The initial working diagnosis 'any stroke' showed a sensitivity of 94% and a specificity of 48%. 'Major MCA or ICA stroke' diagnosed by mobile ultrasound showed an overall sensitivity of 78% and specificity of 98%. CONCLUSIONS: The study demonstrates the feasibility and high diagnostic accuracy of emergency transcranial ultrasound assessment combined with neurological examinations for major ischemic stroke. Future combination with telemedical support, point-of-care analysis of blood serum markers, and probability algorithms of prehospital stroke diagnosis including ultrasound may help to speed up stroke treatment.

Development of transcranial sonothrombolysis as an alternative stroke therapy: incremental scientific advances toward overcoming substantial barriers.

Transcranial ultrasound and high intensity focused ultrasound technologies have been developed as a method of thrombolysis to be applied to the treatment of acute ischemic stroke. The originating idea to apply ultrasound to treat disease states dates back from the 1930s to 1940s when seminal research findings suggested that ultrasound could have an effect on biological systems and the brain, but the mechanism(s) involved in the effects were unknown. This exciting field of research has flourished since the potential exists to effectively utilize ultrasound to induce thrombolysis noninvasively or perhaps in combination with a thrombolytic agent, such as tissue plasminogen activator or secondary pharmaceutical such as microbubbles to promote cerebral reperfusion and clinical improvement. While there is great enthusiasm in this field of stroke treatment, specific parameters required for optimal sonothrombolysis such as output power, duty cycle, pulse width, and exposure time, as well as the impact of skull bone characteristics and flow mechanics, remain to be defined. This article analyzes relevant ultrasound studies to provide a synthesis of insight in the field of sonothrombolysis to attempt to provide direction for possible future use in stroke patients.

Effects of varying duty cycle and pulse width on high-intensity focused ultrasound (HIFU)-induced transcranial thrombolysis.

The goal was to test the effects of various combinations of pulse widths (PW) and duty cycles (DC) on high-intensity focused ultrasound (HIFU)-induced sonothrombolysis efficacy using an in vitro flow model. An ExAblate™ 4000 HIFU headsystem (InSightec, Inc., Israel) was used. Artificial blood clots were placed into test tubes inside a human calvarium and exposed to pulsatile flow. Four different duty cycles were tested against four different pulse widths. For all study groups, an increase in thrombolysis efficacy could be seen in association with increasing DC and/or PW (p < 0.0001). Using transcranial HIFU, significant thrombolysis can be achieved within seconds and without the use of lytic drugs in vitro. Longer duty cycles in combination with longer pulse widths seem to have the highest potential to optimize clot lysis efficacy.

Transcranial sonothrombolysis using high-intensity focused ultrasound: impact of increasing output power on clot fragmentation.

BACKGROUND: The primary goal of this study was to investigate the relationship between increasing output power levels and clot fragmentation during high-intensity focused ultrasound (HIFU)-induced thrombolysis. METHODS: A HIFU headsystem, designed for brain applications in humans, was used for this project. A human calvarium was mounted inside the water-filled hemispheric transducer. Artificial thrombi were placed inside the skull and located at the natural focus point of the transducer. Clots were exposed to a range of acoustic output power levels from 0 to 400 W. The other HIFU operating parameters remained constant. To assess clot fragmentation, three filters of different mesh pore sizes were used. To assess sonothrombolysis efficacy, the clot weight loss was measured. RESULTS: No evidence of increasing clot fragmentation was found with increasing acoustic intensities in the majority of the study groups of less than 400 W. Increasing clot lysis could be observed with increasing acoustic output powers. CONCLUSION: Transcranial sonothrombolysis could be achieved in vitro within seconds in the absence of tPA and without producing relevant clot fragmentation, using acoustic output powers of <400 W.

Introduction of a rabbit carotid artery model for sonothrombolysis research.

The goal of this study was to develop an in vivo sonothrombolysis model for stroke research. The rabbit carotid artery has average vessel diameters similar to human M1/M2 segments and allows generation of a thrombotic occlusion using various kinds of thrombus material as well as thrombus placement under visual control. It further allows real-time monitoring of flow and clot mechanics during the sonothrombolysis procedure using high-frequency diagnostic ultrasound. In the present study, the model will be introduced and first results to show feasibility using diagnostic as well as high-intensity focused ultrasound will be presented.