Ultrasound of the brain-supplying arteries is a routine diagnostic procedure in patients with acute stroke and chronic cerebrovascular occlusive disease. Conventional extracranial and intracranial Doppler sonography can identify normal flow, stenoses or occlusions, and pathological collateral flow conditions.

Nonstenotic plaques may operate as a source of arterial embolism and are an indicator of atherosclerosis, the most frequently occurring arterial disease. These lesions can be visualized in great detail with B-mode imaging. Only homogeneous, completely echolucent plaques can, rarely, escape B-mode imaging, but they will be detected by extracranial color-coded duplex scanning (ECCD) because of the narrowing of the color-coded blood flow column during imaging.

Transcranial color-coded duplex scanning (TCCD) via transtemporal and suboccipital insonation permits a continuous representation of blood flow in the large intracranial arteries and depicts their relation to anatomical landmarks such as bony structures, ventricles, and parenchyma. This allows for a refined spatial orientation compared with conventional transcranial Doppler sonography and helps to avoid compression tests. The posterior cerebral artery surrounding the midbrain, for example, is an important landmark that is easily recognized during TCCD.

TCCD is frequently impaired by an insufficient temporal or suboccipital ultrasound window. In our experience, this accounts for approximately 15% to 20% of cerebrovascular patients, depending on their age and sex. Similarly, ECCD has limitations in cases of plaque calcification and the resulting shadowing of the ultrasound beam, in vessel hypoplasia, and in patients with short, thick necks. Weak Doppler signals due to a large insonation angle with low flow velocity or low flow volume are additional problems for ECCD and TCCD. These limitations led to the development of echocontrast agents that can survive the pulmonary and capillary passage and improve the echogenecity of the flowing blood within the cerebral arteries.

Echocontrast agents are microbubble preparations for intravenous administration that provide useful and reproducible signal enhancement on ultrasound scans. In Doppler ultrasound, these microbubbles increase the intensity of the echo signal by 10 to 30 dB. The lower the water solubility of echocontrast agents, the more stable the agents are in vivo. This is why the fluorocarbon- and sulfohexafluoride-containing agents such as SonoVue and EchoGen have a longer lasting effect than the air-containing agents such as Levovist and BY 963.

Levovist from Schering and SonoVue (BR1) from Bracco are the two echocontrast agents approved for neurosonography. Levovist is the most widely used agent in neurosonology. After preparation, it is a suspension of air-filled microbubbles with a palmitic acid layer adherent to galactose microgranules. The median diameter of the microbubbles is about 3 mm. Mean duration of intracranial contrast enhancement after a single IV administration is 163 to 240 seconds.1

SonoVue is an aqueous suspension of phospholipid-encapsulated sulfohexafluoride. It is prepared by injecting 5 mL of normal saline into vials that contain 25 mg of sterile lyophilized powder in a gaseous atmosphere of sulfohexafluoride. The bubble diameter is about 2.5 mm, and 90% of the bubbles are smaller than 8 mm. SonoVue has been proven to provide a dose-dependent contrast effect in the cerebral circulation for up to seven minutes.2,3

Both Levovist and SonoVue are well tolerated by patients, with no serious side effects reported in the literature. Use of an infusion pump has been reported with both agents to prolong the investigation time and to smooth the echoenhancing effect.4,5 Another option that in our experience is technically easier is fractionated injection of, for instance, half the total amount followed by two injections of a quarter each with a delay of one to two minutes.

CLINICAL BENEFIT

In general, echocontrast agents provide better delineation of normal flow conditions, occlusions, pseudo-occlusions, stenosess of the carotid arteries and their intracranial branches, and collaterals, as well as of the extracranial vertebral arteries, basilar artery, and posterior cerebral arteries.5-9

Differentiation between carotid occlusion and pseudo-occlusion is crucial when there is a possibility of carotid endarterectomy. In contrast to a pseudo-occlusion, a total internal carotid artery occlusion should not be operated on. The tiny intra- and poststenotic residual flow in a pseudo-occlusion can better be identified using contrast agents. Contrast-enhanced ultrasound investigations are helpful to support alternative diagnoses.10,11 The vertebral artery is occasionally hard to identify in its intervertebral portion, due to the adjacent bony structures, its deep location, and its lower flow compared with the carotid arteries. Hypoplasia and proximal obstruction with collateral filling cannot always be differentiated reliably. A study conducted by our group found that an unequivocal neurovascular diagnosis could, however, be made by means of echocontrast agents in six out of nine such cases (two occlusions, four hypoplastic arteries).12

Indications for the use of transcranial contrast-enhanced ultrasound, in addition to insufficient foraminal or temporal windows, are assessments of arteriovenous malformations, thromboses of cerebral veins and sinuses, and intracranial aneurysms.13,14 The benefit in these conditions is more evident in the follow-up period than in the primary diagnosis.

Echocontrast agents are especially valuable in acute stroke, when the patient's vascular status requires immediate, rapid, and reliable assessment to initiate further patient management.8,12,15 In these cases, echocontrast agents should largely be used when the unenhanced investigation does not provide a fast and unequivocal disclosure of large artery occlusion or stenosis.16 Echo-contrast agents can thus help minimize the time that elapses before therapeutically induced lysis. With ultrasound monitoring of the exact time of recanalization, intravenous thrombolysis can be stopped to minimize the risk of bleeding ("tailored thrombolysis").17

Additional investigations such as MRI, MR angiography, CT angiography, and intra-arterial angiography are potentially harmful. They are also expensive and not generally available, all of which provides additional arguments for the use of echocontrast agents in neurosonology. Figures 1, 2, and 3 illustrate the benefit of these agents.

We wish to stress the importance of a normal neurovascular finding, which can reduce the number of additional investigations in the case of vague symptoms. The direct diagnostic and therapeutic consequences of the use of echocontrast agents are summarized in the table.

RECENT DEVELOPMENTS

Harmonic imaging, pulse inversion, stimulated acoustic emission, and targeted drug delivery are among the latest developments in the field of ultrasonography.

Harmonic imaging is a novel technique that relies on the emission of ultrasound at a given frequency and the reception of the echoes at twice the transmitted frequency. Microbubbles from echocontrast agents produce more harmonics than solid tissue. The combination of harmonic imaging with echocontrast provides effective suppression of tissue-related artifacts and detection of blood flow in very small vessels.18 Seidel and Kaps demonstrated that the time of clinically useful signal enhancement, the number of vessels visible, and the spatial resolution can be increased using harmonic imaging and echocontrast in the vertebrobasilar system.19

Ultrasound imaging of brain perfusion in stroke patients would help choose the appropriate blood pressure to maintain perfusion within the penumbra without increasing the risk of bleeding and brain edema. Itoh et al reported on the use of echocontrast for the measurement of cerebral tissue perfusion in an animal model.20 Intermittent, triggered ultrasound exposure (transient response imaging) entails less microbubble destruction and increased videointensity from a constant number of microbubbles. Transient response harmonic imaging in echocardiography produces myocardial contrast and can accurately identify regional myocardial perfusion abnormalities. Echocontrast and transient response harmonic imaging have also been applied to assessment of brain perfusion.21

Wiesmann and Seidel published their impressive results of brain perfusion measurements in healthy volunteers. Echocontrast-enhanced harmonic gray-scale imaging showed strong echo enhancement in the brain parenchyma.22

Rim et al assessed cerebral perfusion in nine dogs after craniotomy, using the pulse-inversion ultrasound technique and echocontrast.23 Two pulses of opposite polarities are transmitted sequentially along the same sector line. The bubbles, being compressible, produce nonlinear signals that are distorted. The ultrasound device adds the signals from the two ultrasound pulses emitted. The signals from the contrast bubbles, not being mirror images of each other, are not canceled, in contrast to mirror images from tissue. Thus, brain perfusion could be measured by quantifying the echoes from the contrast agent in the flowing blood.23,24

With a high ultrasound pressure, specially designed microbubbles can be made to burst intra-arterially. The resulting echoes-so-called stimulated acoustic emission-are similar to the Doppler shift and can be visualized as color signals. This novel technique has been used to detect liver tumors. Initial steps have been taken in brain tissue and brain perfusion imaging, but the technique has not yet entered clinical practice.25

In addition to supporting conventional neurovascular ultrasound in poor examination conditions resulting from the patient's anatomy or pathology, echocontrast agents may allow novel applications in the diagnosis and treatment of cerebrovascular patients.26

Dr. Droste, Dr. Nabavi, Mr. Ritter, Dr. Dittrich, and Dr. Ringelstein are members of the department of neurology at the University of Munster in Germany. Dr. Schulte-Altedorneburg is a member of the department of radiology at Klinikum Augsburg in Germany.

References

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