Harmonic imaging—a new method for the sonographic assessment of cerebral perfusion

doi:10.1016/S0929-8266(01)00151-3

European Journal of Ultrasound

Volume 14, Issues 2–3, December 2001, Pages 103-113

https://doi.org/10.1016/S0929-8266(01)00151-3 Get rights and content

Abstract

In this review, methodological aspects of cerebral perfusion imaging with ultrasound signal enhancing agents are described. The various experimental bases, contributing to the understanding of the phenomena are summarised and the resulting human investigation techniques are illustrated. By means of harmonic imaging technology, human cerebral perfusion can be depicted as a two-dimensional scan. The two major principles of contrast measurement are analysis of the bolus kinetics and analysis of the refill kinetics. Using the bolus method, hypoperfused areas in stroke patients can be visualised and parameter images of wash-in and wash-out curves can be generated off-line. The recently developed theory on the refill kinetics of UCA enables us to calculate quantitative parameters for the description of the cerebral microcirculation, being less affected by the depth dependence of the contrast effect. These parameters, too, can be visualised as parameter images. The ultrasound methods described in this article represent new minimal-invasive bedside techniques for analysing brain perfusion. Although their development is still in an early state, the potential of these ultrasound technologies to compete with perfusion-CT, perfusion-MRI or single-photon emission computed tomography in the diagnostic arsenal of brain imaging techniques is becoming evident.

Introduction

Today, visualisation of cerebral perfusion is possible with various imaging techniques. Perfusion- and diffusion-weighted MRI are subject to intensive scientific efforts. They are currently being established as a clinical routine investigation for the diagnostics of ischemic stroke (Albers, 1999, Darby et al., 1999). The roles of perfusion-CT and single-photon emission computed tomography (SPECT) are limited, due to the small amount of scanning planes (Röther et al., 2000) and the insufficient spatial resolution at a high technical expense (Alexandrov et al., 1997, Berrouschot et al., 2000, Liu et al., 2000), respectively. Due to its immense technical and logistic requirements, positron emission tomography (PET) is not suitable for clinical purposes. Its value remains limited to scientific investigations of brain perfusion and brain metabolism (Heiss et al., 2000).

Like transcranial colour-coded duplexsonography (TCCS), ultrasound perfusion imaging techniques are easy to handle and, as a bedside method repeatable and barely disturbing for the patient.

This review, will give a summary on the present status of ultrasound techniques for cerebral perfusion imaging, which experienced rapid development within the last few years. It will be considering the theoretical basis as well as the practical aspects and perspectives of this new technology.

Section snippets

Theoretical basis

A prerequisite for displaying brain perfusion with ultrasound is the administration of ultrasound signal enhancing agents.

These agents consist of a gaseous component with a shell structure for stabilising the microbubbles (Kaps and Seidel, 1999, Seidel et al., 1999a). They are injected intravenously and have mean diameters of less than 10 μm so that they can pass the pulmonary circulation. They cause a significant increase in the signal-to-noise ratio. With increasing ultrasound energy,

Sonographic analysis of cerebral perfusion

Compared to the basal cerebral arteries, cerebral microcirculation provides considerable difficulties for conventional ultrasound technology. Because of the lower concentration of erythrocytes and the minimal blood flow velocity of 1 mm/s, cerebral blood flow cannot be assessed by these techniques (Bauer et al., 1997). These limitations can be overcome by analysing the harmonic signature of ultrasound signal enhancing agents or by detecting bubble destruction within the microcirculation (

Animal model

Investigations with animal models are invaluable for optimising system settings and evaluating different ultrasound signal enhancing agents for cerebral perfusion imaging.

Using conventional harmonic imaging, bolus (Seidel et al., 2000b) and refill (Seidel et al., 2001b) kinetics were being analysed.

Perfluorocarbon- and sulphurhexachloride-containing agents proved to be superior to air-containing contrast agents (Seidel et al., 2000b, Claassen et al., 2001, Seidel et al., 2001a).

The ideal signal

Human studies

Several studies on the visualisation of cerebral perfusion by means of harmonic imaging technique after signal enhancing agent injection have been published since 1997 (Federlein et al., 2000, Meairs et al., 2000, Postert et al., 1998, Postert et al., 1999, Postert et al., 2000a, Postert et al., 2000b, Seidel et al., 1997, Seidel et al., 1999b, Seidel et al., 2000a, Wiesmann and Seidel, 2000). All studies except for one (Postert et al., 2000a, Postert et al., 2000b) used the bolus method and

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Citation Excerpt :
In our study the assignment of standard parameters like AUC, TTP, and PI seemed to be reliable. Therefore TTP prolongation could be seen as a sign of impaired microvascular perfusion and an increased AUC could be a sign of hyperperfusion [25,26]. Using the CBI method we detected a significant prolonged TTP in the tumor hemisphere in comparison to the non-tumor side.
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Six patients with glioblastoma (WHO Grade IV) in the temporoparietal region within the defined axial diencephalic scanning plane were examined by TPS during follow-up. All subjects had an adequate acoustic temporal bone window. Transtemporal insonation on brain tumor and non-tumor hemisphere was performed with a bolus-injection of sulphur hexafluoride-based contrast agent (10 mg IV, 5 mg/ml – SonoVue®, Bracco, Altana, Switzerland). Recorded images were analysed off-line by Quanticon Software (3D-Echotech, Munich, Germany) and time intensity curve parameters [area under the curve (AUC, dB s), peak intensity (PI, dB), time to peak (TTP, s)] in five regions of interest (ROI) [thalamus anterior, thalamus posterior, nucleus lentiformis, white matter, whole hemisphere] were evaluated. Statistical analyses were performed.
Perfusion differences between brain tumor and non-tumor hemispheres were detected with contrast burst imaging (CBI) technique with a significantly greater mean AUC (5343.69 dB s vs. 4625.04 dB s, $p < 0.028$ ) and a significantly prolonged TTP (32.72 s vs. 28.91 s, $p < 0.046$ ) in the tumor hemisphere.
Within our study population, TTP and AUC seem to be the most robust parameters for the evaluation of cerebral perfusion differences assessed by transcranial perfusion sonography with CBI technique. We hypothesize that these results correlate with microvascular changes due to treatment regimens, such as microvessel necrosis after irradiation and chemotherapy. Above that, TPS may be of value for the long-term follow-up of brain tumor therapy concept.
Ultrasound Perfusion Imaging of Cerebrovascular Disease
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Ultrasound perfusion imaging of the cerebral microcirculation is a new semi-invasive bedside technique to evaluate human brain perfusion. Several approaches have been evaluated for the qualitative assessment of brain perfusion in healthy subjects and in patients suffering from acute ischemic stroke. The analysis of ultrasound contrast agent bolus kinetics yields various time-intensity curve parameters that qualitatively describe regional brain perfusion. In healthy subjects, there is a close correlation between the time to peak intensity measurements as performed by perfusion ultrasound and perfusion-weighted MRI. In the acute phase of ischemic stroke, the peak signal increase is the most useful curve parameter to predict the area of definite infarction. Ultrasound perfusion imaging performed in the early phase can predict the outcome of the individual stroke patient. Diminution and Replenishment kinetics are new modalities for the visualization of brain perfusion, the latter being more promising because of the fast imaging time resulting in a lower vulnerability to movement artifacts. The different approaches will have to be compared regarding their ability to provide valid thresholds for differentiation between normal and abnormal perfusion in the acute stroke situation. At present, the foremost limitations of transcranial ultrasound perfusion imaging are attenuation phenomena, caused by the temporal bone, which might be overcome by new imaging systems that are currently under development.
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Ultrasound contrast agents (UCA) consist of shell-encapsulated air- or gas-filled microbubbles, which are capable of surviving the heart transit and are able to pass through the lung’s capillary bed when injected intravenously. They massively increase the backscattered ultrasound signals, which is clinically useful in all situations of slow and low flow as well as insufficient ultrasound penetration. Because UCA act as intravascular contrast agents, diagnosis of vessel occlusion can be made with high diagnostic confidence based on a lack of contrast enhancement. In the first section of this review, the acoustical properties, the intricate balance of forces, which act on UCA in the human circulation, and UCA-specific ultrasound imaging modes are summarized. In the second section, current clinical applications are summarized and the level of evidence regarding key statements is evaluated using the American Academy of Neurology rating system. The final section is devoted to yet experimental applications, where accumulating data suggest that use of UCA has the potential to be clinically useful and to become incorporated into routine clinical practice.
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The aim of this paper was to obtain a parametric description of ultrasound (US) contrast dilution curves obtained in piglet brain after a bolus injection of contrast agent (Sonovue™). Several models for so-called dye-dilution curves were considered, and a choice for the gamma probability density function (pdf) was made. This function was chosen primarily because of the elegant mathematical opportunities to achieve a practical one-parameter curve fitting and to extend this model for incorporating recirculation. The model was fitted to US contrast data obtained in piglet brain. The software enables interactive insertion of curve landmarks and a single parameter (i.e., order of gamma pdf) iterative least squares fit was then made to the first bolus passage part of the curve. Sequential recirculation curve fits were calculated from this fit. A preliminary result for 24 experimental curves is a median value of 3 (range 3 to 5) for the order of the gamma function (κ) and a median of 0.6/s (range 0.3 to 0.9) for the event rate (λ). The theoretical background for obtaining the relative plasma flow and volume in tissue (i.e., “blood flow index”, BFI, and “blood volume index”, BVI, respectively) from the reconstructed first passage curve is given as well. The potential of assessment of the relative fraction of left-to-right shunting of the cardiac output in case of persistent ductus arteriosis is outlined. The requirements for an absolute measurement of tissue blood flow and tissue perfusion are discussed. The conclusion is that the gamma model can well be fitted to the experimental contrast curves; thus, yielding the parameters κ and λ. Assessment of BFI and BVI is feasible. (E-mail: [email protected])
Correct outcome prognostication via sonographic volumetry in supratentorial intracerebral hemorrhage
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ReviewHarmonic imaging—a new method for the sonographic assessment of cerebral perfusion

Abstract

Introduction

Section snippets

Theoretical basis

Sonographic analysis of cerebral perfusion

Animal model

Human studies

Ultrasound Med. Biol.

J. Am. Soc. Echocardiogr.

Lancet

Eur. J. Ultrasound

Ultraschall. Med. Biol.

Ultraschall. Med. Biol.

Expanding the window for thrombolytic therapy in acute stroke. The potential role of acute MRI for patient selection

Stroke

Brain single-photon emission CT with HMPAO and safety of thrombolytic therapy in acute ischemic stroke. Proceedings of the meeting of the SPECT Safe Thrombolysis Study Collaborators and the members of the Brain Imaging Council of the Society of Nuclear Medicine

Stroke

Cerebral blood flow determination by rapid-sequence computed tomography

Radiology

Acoustically stimulated microbubbles in diagnostic ultrasound: properties and implications for diagnostic use

Reperfusion and metabolic recovery of brain tissue and clinical outcome after ischemic stroke and thrombolytic therapy

Stroke

Harmonic imaging with ultrasound contrast agents

Clin. Radiol.

Pathophysiological topography of acute ischemia by combined diffusion-weighted and perfusion MRI

Stroke

Ultrasonic evaluation of pathological brain perfusion in acute stroke using second harmonic imaging

J. Neurol. Neurosurg. Psychiatry

Contrast echocardiography

Measurement of regional cerebral blood flow in the dog using ultrafast computed tomography—experimental validation

Stroke

Echo-enhancing agents in tumors

Early [(11)C]Flumazenil/H(2)O positron emission tomography predicts irreversible ischemic cortical damage in stroke patients receiving acute thrombolytic therapy

Stroke

Pulse inversion Doppler: a new method to detect nonlinear echoes from microbubble contrast agents

IEEE Trans. Ultrasonics, Ferroelectrics Frequency Control

Review
Harmonic imaging—a new method for the sonographic assessment of cerebral perfusion