Contrast-Enhanced Ultrasound

KEY POINTS

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Contrast agents enable visualization of synovial vascularization, and mprove early detection, disease activity assessment, and evaluation of therapeutic response.
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Contrast agents should be inert, administered by intravenous bolus injection or continuous infusion, stable during cardiac and pulmonary passage, persist within the blood pool or a well-specified tissue distribution, provide a duration of effect comparable to that of the imaging examination, have a narrow distribution of bubble diameter, and respond in a well-defined way to the peak pressure of the incident ultrasound.

The use of color Doppler or power Doppler ultrasound can detect vascularity in synovial proliferation caused by inflammatory activity. However, the color Doppler or power Doppler ultrasound technique has limited applicability in the detection of slow flow and flow in small vessels, such as those that occur in angiogenesis. Angiogenesis is a basic principle of inflammatory disease; it refers to the growth of new capillary blood vessels that are crucial in the progress of psoriasis and rheumatoid arthritis. Microscopic examination of synovial biopsies shows angiogenesis from the beginning of the disease. Proliferation of hypervascularized pannus can be seen before joint destruction, and it correlates with disease activity and appears to be crucial to invasive and destructive behaviour.

Serum concentrations of vascular endothelial growth factor (VEGF) are elevated in rheumatoid arthritis, and levels correlate with disease activity. Synovial tissues expressing VEGF show a significantly higher microvascular density. Vascular imaging and serologic markers are more sensitive than clinical assessment of disease activity. Functional imaging of intra-articular vascularization is thought to improve grading of disease activity. Blood flow at the microvascular level, which is of primary interest in assessing inflammatory disease, moves at lower velocities and is therefore less detectable by conventional color or power Doppler ultrasound. Ultrasound contrast administration improves detection of low-volume blood flow in small vessels by increasing the signal-to-noise ratio.

The development of novel treatment options (e.g., biologicals, tumor necrosis factor alpha [TNF-α] inhibitors) that target disease at the microvascular level depends on sensitive vascular imaging techniques for diagnosis and treatment follow-up that are readily available for routine use. Ultrasound is widely available at relatively low cost.

Principles of Ultrasound Contrast Agents

The use of microbubbles to increase backscattering has undergone further development since the technique was first described in 1968 by Gramiak and Shah. The ideal microbubble contrast agent should be inert, capable of being administered as an intravenous bolus injection or continuous infusion, stable during cardiac and pulmonary passage, persist within the blood pool or a well-specified tissue distribution, provide a duration of effect comparable to that of the imaging examination, have a narrow distribution of bubble diameters ,and respond in a well-defined way to the peak pressure of the incident ultrasound.

To increase microbubble stability and persistence in the peripheral circulation, microbubbles are encapsulated or stabilized using a sugar matrix, such as galactose, or they are produced as microspheres with albumin, lipids, or polymers. Low-solubility and low-diffusibility gases, such as perfluorocarbons and sulfur hexafluoride gas, improve microbubble persistence in the peripheral circulation.

Several microbubble-based contrast agents have been approved for human use, and several agents are undergoing the approval procedure :

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Air-filled microbubbles with a galactose shell (e.g., Echovist, Levovist)
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Air-filled microbubbles with an albumin shell (e.g., Albunex, Quantison)
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Air-filled microbubbles with cyanoacrylate shell (e.g., Sonavist)
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Perfluorocarbon-filled microbubbles with a phospholipid shell (e.g., BR14, Definity, Imavist/Imagent, Sonazoid)
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Perfluorocarbon-filled microbubbles with an albumin shell (e.g., Optison)
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Sulfur hexafluoride–filled microbubbles (e.g., SonoVue)

First-Generation Ultrasound Contrast Agents

In 1991, Echovist was introduced in Europe as the first commercially available echo contrast agent. Echovist’s galactose-based microbubbles remain stable in the venous system and in the chambers of the right heart, but they tend to dissolve when passing through the pulmonary capillaries. The first commercially available left-heart contrast agent was Albunex, which was introduced in the United States in 1994, and it has been approved in other countries, including parts of Europe, Asia, and Latin America. The second agent was Levovist (Schering AG, Berlin, Germany), which was introduced in Europe in 1995.

These first-generation ultrasound contrast agents have revolutionized the potential applications of noninvasive, economically attractive, diagnostic ultrasound. However, the diagnostic utility of the first-generation agents has been limited by their transient nature. The air-filled agent have a short half-life (<5 minutes), and the contrast effect is over in few minutes.

Second-Generation Ultrasound Contrast Agents

Advances in microsphere technology, particularly the substitution of certain gases with higher densities, decreased diffusion, and lower concentrations of saturation to fill the microspheres instead of room air, have improved the stability and echogenic properties. The second-generation ultrasound contrast agents are more stable and have longer half-lives (>5 minutes).

In Europe, SonoVue (Bracco Diagnostics, Milan, Italy) is the most widely used microbubble-based, second-generation contrast agent. Originally approved for cardiac and liver imaging, some publications described the usefulness of this contrast agent in other applications.

Ultrasound contrast agents are considered safe compared with other radiographic contrast agents. However, in 2004, the European Agency for the Evaluation of Medicinal Products (EMEA) issued new guidelines regarding contraindications for its use in patients with heart disease. ( http://www.emea.europa.eu/pdfs/human/press/pus/021204en.pdf ). In view of the possible side effects and contraindications, patients must be selected carefully.

How Ultrasound Contrast Agents Work

Microbubble-based ultrasound contrast agents are injected intravenously. Because they are smaller than erythrocytes, they pass through the pulmonary capillary bed and are eliminated through the respiratory system. For example, SonoVue has an elimination half-life of 6 minutes. More than 80% is exhaled within 11 minutes. When injected as a bolus, contrast enhancement exhibits a time intensity curve with a rapid first pass followed by a wash-out, whereas in slow-flow administration, the enhancement is more stable, reaching a plateau pattern 1 to 2 minutes after injection. Within this period, insonation of tissue at the specific resonance frequency of the microbubbles and selective registration of the harmonic echo frequencies enables detection of blood flow and provides an examination window of 3 to 5 minutes.

Use of Ultrasound Contrast Media in Rheumatic Diseases

First-Generation Ultrasound Contrast Media

Several studies address the use of first-generation contrast media (e.g., Levovist) with the application of color or power Doppler ultrasound and a high mechanical index (MI) scanning protocol in rheumatologic applications. The studies comparing unenhanced and enhanced color or power Doppler ultrasound reported improved diagnostic accuracy with contrast administration in assessing large and small joints.

Carotti and colleagues found contrast-enhanced power Doppler ultrasound useful in assessing synovial activity in the knee joint and the therapeutic response to treatment in 42 rheumatoid arthritis patients. In their calculations, the investigators found an increased area under the curve for active joints, and they concluded that contrast administration was useful in the assessment of synovial activity.

Doria and coworkers assessed 31 knees in patients with juvenile rheumatoid arthritis. Objective assessment by overall mean pixel intensity was found to be different in active compared with inactive disease. Based on their observations of this difference, the investigators suggested that contrast-enhanced ultrasound was helpful for detection of inflammatory activity in subclinical disease and that the findings had an impact on treatment.

Magarelli and associates reported contrast enhancement administered as a bolus injection in rheumatoid arthritis patients. By subjective estimation of power Doppler ultrasound signals in 27 knees, they showed good correlation with the findings of contrast-enhanced magnetic resonance imaging (MRI). Limitations of this study included the bolus injection technique, which results in initial vascular blooming and in a shorter examination time.

Qvistgaard and colleagues performed contrast-enhanced ultrasound examination of finger joints in rheumatoid arthritis patients and found that the use of contrast medium helped to differentiate fibrous from active synovitis. The investigators concluded that contrast-enhanced ultrasound was a reliable tool for assessing synovial activity as measured by the degree of vascularization.

Klauser and coworkers used continuous slow-flow infusion of a first-generation ultrasound contrast agent. They found that the infusion technique achieved improved, uniform enhancement with fewer blooming artifacts than bolus administration. This approach to contrast-enhanced color Doppler ultrasound improved detection of vascularity in 198 finger joints of 46 early-stage rheumatoid arthritis patients. Bolus administration results in a shorter duration of contrast enhancement, and color or power Doppler ultrasound may cause an early and higher level of microbubble destruction, so that microbubbles cannot enter the small vessels of the synovium. This may explain the false-negative contrast-enhanced findings for color or power Doppler ultrasound. Continuous slow-flow infusion technique at a rate of 1 mL/min reduces the color Doppler blooming artifacts and enables uniform, subjectively optimal enhancement with a mean duration of about 15 to 20 minutes.

Second-Generation Ultrasound Contrast Media

Development of ultrasound techniques that produce images based on nonlinear acoustic effects of ultrasound interaction with microbubble contrast agents has refocused attention on gray-scale ultrasound. Contrast-specific imaging techniques, by displaying microbubble enhancement in gray scale, maximize contrast and spatial resolution and enable evaluation of the microcirculation, stimulating the evolution of contrast-enhanced ultrasound for vascular imaging to use in imaging perfused tissues.

Administration of second-generation contrast agents has relied on bolus injection. This enables quantitative assessment of several parameters, such as time intensity, maximum peak enhancement, area under the curve, time to peak, and wash-out. High-frequency probes have been improved for the use of contrast, opening new possibilities of application in rheumatology, in which the use of higher frequencies is required because of near-field application. The development of contrast media for higher frequencies can be expected to further improve the diagnostic potential in musculoskeletal applications. Newer techniques based on the higher harmonic emission capabilities of second-generation contrast agents use a lower, nondestructive ultrasound power (i.e., very low MI), which enables continuous imaging without the need for intervals between scans for contrast replenishment. Very low MI and low acoustic output optimize the detection of perfusion in microvessels. Continuous infusion of second-generation contrast agents may be useful when the examination time is prolonged. However, for a successful application of this method, adequate infusion devices are needed to avoid dissolving contrast medium, and their value needs to be established in future studies.

Objective, quantitative analysis using software developments such as parametric imaging can be used to improve quantification and grading of contrast enhancement ( Fig. 24-1 ).

Quantification

With the increased use of ultrasound to detect inflammation in the musculoskeletal system, there has been a growing awareness that the standardization and validation of this method are not adequate, because reliability data with respect to intra-occasion and intrareader and interreader reliability are lacking. Two approaches to assessing joint inflammation exist: those that use gray-scale and Doppler techniques (with or without contrast agent enhancement) and those based on methods for assessing changes qualitatively (presence/absence), semiquantitatively (scoring), or quantitatively (measurement of synovial thickness, indices (e.g., resistive index [RI]) or slope values).

Because disease activity, prognosis, and therapeutic decisions depend on the extent of vascularity within the suspect region and new therapies (e.g., biologics) are targeted there, it is highly desirable to have a scoring system (subjective or objective) based on the amount of vascularization. Several scoring systems have been used in musculoskeletal contrast-enhanced ultrasound studies:

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Semiquantitative grading of intra-articular enhancement by comparing periarticular tissue enhancement to intra-articular enhancement. Grading includes no intra-articular enhancement toward detectable enhancement, but compared with periarticular tissue, lower intra-articular enhancement to finally higher uniform enhancement than seen in periarticular structures (see Fig. 24-1 )
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Time-intensity analysis by Q-LAB (Phillips Medical Systems), with calculation of the area under the curve (AUC) and quantitative evaluation
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Time-intensity analysis by CnTI (Esaote) and calculation of slope values using the following formula:

Slope = ( Int peak − Int min ) × 100% ( Int min × time to peak )

In the formula, Int peak is the intensity at peak or maximum, Int min is the intensity at minimum, time to peak is the time at the end point minus the time at the start of the contrast medium enhancement measurement. From these calculations, a semiquantitative scale was derived: 0, no contrast medium enhancement; 1, mild enhancement; 2, moderate enhancement; 3, strong enhancement.

When using power Doppler or contrast-enhanced ultrasound, a system of thirds for vascularized joint thickening is used to describe the amount of activity; this system ensures content validity independent of the joint dimension (i.e., small versus large joint). In this context, subjective grading before and after the application of contrast media is a practical tool for clinical routine because it is relatively easy, quick to perform, and reliable ( Table 24-1 ).

Table 24-1

Subjective Grading of Joint Inflammation

Grade	No. of Vessels ^∗	Extent of Vascularization ^†	Intra-articular or Extra-articular Enhancement
0	0	No signal or enhancement	No enhancement
1	1-5	Extent < ⅓	Intra-articular < extra-articular
2	6-10	Extent ⅓ to ⅔	Intra-articular = extra-articular
3	>10	>⅔	Intra-articular > extra-articular