APPLICATIONS OF MRI CONTRAST IN HIGH-DOSE PROCEDURES

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This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Institute for Advanced Medical Education and Anderson Publishing, Ltd. The Institute for Advanced Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians.

The Institute for Advanced Medical Education designates this continuing medical education activity for 6 hours in Category 1 of the Physician's Recognition Award of the American Medical Association.

Until December 31, 2002, courses approved for AMA Category 1 credit that are relevant to the radiologic sciences are accepted for Category A CE credit on a one-to-one basis by the American Registry of Radiologic Technologists (ARRT). Beginning January 1, 2003, AMA credits will be acceptable for Category B credit.

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LEARNING OBJECTIVES

After completing this program, the reader will:

* Understand the current use of gadolinium contrast agents for MRI, particularly applications that use high-dose contrast media or high injection rate contrast infusions

* Recognize the ways that radiologists use high-dose MRI contrast agents in specific clinical applications

* Understand how the advancements in imaging technology and contrast media can be used to improve MRI procedures in clinical practice.

THIS PUBLICATION WAS SUPPORTED BY AN EDUCATIONAL GRANT FROM AMERSHAM HEALTH, PRINCETON, NJ. THE OPINIONS EXPRESSED IN THIS PUBLICATION ARE THOSE OF THE AUTHORS AND NOT NECESSARILY THOSE OF AMERSHAM HEALTH.

Introduction

Thomas Grist, MD Professor of Radiology, Chief of MRI University of Wisconsin, Madison, WI

In April 2002, I was pleased to serve as the moderator for Applied Radiology 's focus group discussion of high-dose contrast-enhanced magnetic resonance imaging (MRI) procedures. This focus group discussion was aimed at describing a number of issues and challenges facing the use of high-dose MRI procedures. These presentations and discussions are published in this supplement to Applied Radiology to share these important insights with the radiology community.

Since the introduction of MRI, we have seen a significant development in both anatomic and functional imaging procedures, as well as tremendous technological breakthroughs. At the same time, there's also been the important development of gadolinium contrast media for the evaluation of both structure and function with MRI. In the last decade, since the introduction of the gadolinium chelates, there has been a tremendous increase in the use of these agents, which has also presented some challenges.

The physicians using these agents need to understand what dose to use, what injection rate to use, and what the clinical indications are for their use. They must also learn some of the techniques for perfusion imaging, anatomic imaging, and functional imaging. These all increase the complexity of using these contrast agents in humans.

This focus group was designed to discuss these areas and the use of gadolinium agents. We asked each of the speakers to target a specific anatomic area of interest that is under significant change, and address how high-dose contrast agents are being used.

There were several objectives of our discussion. First, we wanted to review the current use of gadolinium contrast agents for MRI, and particularly those applications that use either high-dose contrast media or high injection rate contrast infusions, or have some other nuance related to the media itself. We also reviewed some of the similarities and differences in how the various physicians active in MRI use these agents and how they incorporate them into their clinical practice. Finally, we wanted each participant to determine through their clinical experience and demonstrate exactly how these tools, both the advanced imaging tools and the available contrast media, fit into their approach to patients. I would like to make specific mention of the distinguished panel of experts who participated in this focus group.

Dr. David Bluemke is experienced in all aspects of body MRI, and has been involved in the development of these techniques for some time. He's currently the Clinical Director of MRI at Johns Hopkins University, Baltimore, MD.

Dr. Nola Hylton is an Assistant Professor of Radiology at the University of California at San Francisco. She is a leader in the role of MR in breast imaging.

Dr. Larry Kramer is the director of MRI at Memorial Herman Hospital in Houston, TX and is a very active practitioner of MRI. He has performed body and contrast-enhanced MRI procedures for quite some time, and has incorporated those into his clinical practice, which is a combination of academic and community practice.

Dr. Russell Low is in practice in San Diego and has been developing contrast-enhanced MRI procedures in the abdomen for some time in a private practice setting, with extraordinary results.

Dr. Martin Prince is really credited with bringing forward the use of 3D contrast-enhanced MRA procedures and the use of high-dose contrast media for evaluation of the vascular system anatomy. Many consider him the pioneer of contrast-enhanced MRA. Dr. Prince is currently a Professor of Radiology at the Weill Medical College of Cornell University.

Dr. David Roberts is an Assistant Professor of Radiology at the University of Pennsylvania Medical Center, Philadelphia, PA. He is a recognized leader in MR.

Dr. Howard Rowley is a Professor of Radiology at the University of Wisconsin in Madison and is Chief of Neuroradiology there. Dr. Rowley has specific interests in MR perfusion imaging for CNS evaluation.

Dr. Richard Semelka from the University of North Carolina-Chapel Hill. Dr. Semelka has been a pioneer in the use of abdominal imaging with MR, and is credited with many developments in the use of gadolinium-enhanced imaging, with particular emphasis on the liver.

This focus group offered valuable information on how these leading radiologists in the field of MRI use high-dose contrast in their practices. This supplement shares their experience, articulate presentations, and insightful discussions with the readers of Applied Radiology.

 

Focus Group Participants

Moderator: Thomas Grist, MD Professor of Radiology, Chief of MRI University of Wisconsin Madison, WI

David A. Bluemke, MD, PhD Clinical Director of MRI Johns Hopkins Hospital Baltimore, MD

Nola Hylton, PhD Associate Professor of Radiology University of California--San Francisco San Francisco, CA

Larry A. Kramer, MD Director of MRI Memorial Hermann Hospital Houston, TX

Russell N. Low, MD Medical Director Sharp and Children's MRI Center San Diego, CA

Martin Prince, MD, PhD Professor of Radiology Weill Medical College of Cornell University New York, NY

David Roberts, MD Assistant Professor of Radiology University of Pennsylvania Medical Center Philadelphia, PA

Howard A. Rowley, MD Sackett-Bascom Professor of Radiology Chief of Neuroradiology University of Wisconsin Madison, WI

Richard C. Semelka, MD Director of MR Services, Professor of Radiology Vice Chair of Clinical Research University of North Carolina Hospital Chapel Hill, NC

 

 

CNS Perfusion Imaging: The Role of High-Dose Contrast-Enhanced MRI

Howard A. Rowley, MD Sackett-Bascom Professor of Radiology, Chief of Neuroradiology, University of Wisconsin, Madison, WI

High-dose or rapid-infusion gado-linium contrast MRI has many applications in neuroradiology, including perfusion imaging of the central nervous system (CNS). Ischemic stroke is a natural application of CNS perfusion imaging, as it results from a reduction in blood flow to the brain, and the severity of the resulting injury depends on the duration and degree of oligemia. ^1-4 It is important to note, however, that perfusion imaging can also be used in the assessment of cerebral blood volume in tumors ⁵ and holds promise for future studies into the pathophysiology of such conditions as infection, dementia, and trauma.

Beyond their use in perfusion imaging, high-dose gadolinium techniques offer several advantages. One is an improvement in tissue contrast when imaging small or multiple metastases, or in magnetic resonance angiography (MRA) of the brain, neck, or aortic arch. ⁶ Further, the use of elevated doses of gadolinium can improve the efficiency of scan protocols. For example, when evaluating a patient with suspected stroke, it is possible to conduct both perfusion and angiographic studies quickly, in addition to obtaining parenchymal images.

In some cases, high-dose gadolinium can improve detection rates and hasten oncologic studies. ⁷ The benefits of such an approach are particularly apparent in patients who are difficult to image. A good example is a child with a primary CNS tumor who is being evaluated for subarachnoid metastases (so-called drop metastases). An increase in the gadolinium dose of 50% to 100% enables the entire exam to be done at one time, without the need for reinjection or repeat anesthesia. Increasing the contrast dose may also be necessary when repeating an exam, for example, when evaluating the results of an intervention. Such modest increases in gadolinium dose are well tolerated and adverse reactions are rare. ⁸

Brain Hemodynamics

CNS perfusion refers to the delivery of blood to the brain, along with its essential nutrients and oxygen. There are several MR techniques for evaluating CNS perfusion. ^1,9-12 This article will focus on dynamic susceptibility gadolinium-enhanced contrast mechanisms.

The minimum normal cerebral blood flow is approximately 55 mL/100 g/min (Figure 1). Through a wide range of lower blood flow rates, the brain is able to maintain normal function. Among the brain's autoregulatory mechanisms for responding to low-flow states, the first is usually an increase in collateral flow, which on perfusion studies is reflected in a longer mean transit time (MTT). Initially, there is also vasodilation of the capillary bed, with a corresponding increase in cerebral blood volume (CBV). Eventually, however, perfusion pressure drops low enough that vascular collapse ensues and cerebral blood flow (CBF) is reduced.

At a threshold of approximately 15 to 20 mL/100 g/min, neuronal dysfunction becomes evident. The neurons are stunned, but if perfusion is reestablished quickly enough, they can recover fully. Tissue in this reversible injury zone is known as the ischemic penumbra, a word derived from the astrological term describing the part of a planetary body lost in a partial eclipse.

The brain is particularly susceptible to a shortfall in its blood supply, because it does not have long-term energy stores. If the duration and degree of ischemia are severe enough, infarction will be the ultimate result. A complete interruption of blood flow is followed by irreversible injury within just a few minutes. In many situations, however, the low-flow state or vascular occlusion develops over time, presenting an opportunity to intervene and salvage tissue. Even in acute stroke, MR perfusion techniques can capture and characterize blood flow changes in the critical hours after symptom onset, offering a chance to intervene.

Perfusion Imaging

Gadolinium-enhanced MR studies enable us to evaluate the critical components of perfusion and define the hemodynamic conditions in the brain. There are several goals for MR perfusion imaging of stroke. ^13-15 The first is the characterization of the dynamic pathophysiology of the ischemic state. The second is the use of such data to select patients for therapy, identifying those most likely to benefit from thrombolysis, for example, and withholding therapy from those in whom the risks outweigh the potential benefits. A third goal is to follow-up the effects of an intervention, such as stenting or thrombolysis.

At our institution, perfusion imaging is conducted in the context of a more comprehensive stroke evaluation. We start with an MR of the brain, including diffusion-weighted imaging (Table 1). We use time-of-flight MRA in the head and the neck, then a gadolinium-enhanced double-dose elliptic-centric MRA study to look at the aortic arch, the origin of the great vessels, and the carotid arteries.

Next we do perfusion imaging, using a single-dose gadolinium bolus tracking study captured with a gradient-echo/echo-planar sequence. We inject the gadolinium contrast media at 3 to 5 mL/sec through a standard intravenous catheter, capturing the wash-in and wash-out of the contrast over approximately 1 minute. We then produce parameter maps and signal intensity-time curves to establish region-by-region perfusion characteristics. Finally, we obtain post-contrast images of the brain to look for intravascular stasis and, perhaps, subacute parenchymal ischemia, which are both better visualized after contrast than without it.

The use of gradient-echo/echo-planar perfusion sequences may result in susceptibility artifact in certain regions of the brain, such as the brain stem. We have found in clinical practice that approximately two-thirds of strokes are in the distribution of the middle cerebral artery, where susceptibility is not a major problem. When we suspect that a patient has an infarct of the brain stem or posterior fossa; however, we do perfusion imaging with a spin-echo sequence to reduce artifact and couple it with a double dose of gadolinium.

Perfusion Curves and Maps

The patient in Figure 2 underwent MR imaging approximately 6 hours after an acute infarction of the brain territory supplied by the left middle cerebral artery. On CT and gadolinium-enhanced T1, T2, and fluid-attenuated inversion recovery (FLAIR) MR images (Figure 2A), evidence suggestive of stroke is very subtle. Diffusion-weighted imaging (DWI), however, demonstrates the "lightbulb" sign of restricted diffusion, a hallmark of acute and usually irreversible ischemia. Indeed, today diffusion-weighted imaging conducted with echo-planar sequences is the most sensitive way to detect ischemia.

Selected slices from the patient's perfusion study demonstrate wash-in of a bolus of gadolinium contrast media (Figure 2B). Areas with normal perfusion darken in seconds, but only during the final half-minute of the sequence is it possible to observe the slow arrival of contrast in the infarcted left hemisphere.

Perfusion data can be used to create signal intensity-time curves for selected regions of interest. When evaluating perfusion dynamics, the important attributes to consider are those related to the temporal course of blood delivery, as they reflect the time it takes for gadolinium to arrive and then wash through the microcirculation. These parameters include time to peak and various estimates of transit time. In Figure 2C, the signal intensity-time curve shows a precipitous drop in signal intensity upon arrival of gadolinium in the normal right side of the brain, followed quickly by wash-out. By comparison the arrival of contrast in the ischemic region is delayed, and the washout takes longer.

By measuring the area under the signal intensity-time curve during the first pass of the contrast bolus, it is possible to calculate relative cerebral blood volume. The width of the curve that depicts the wash-in and wash-out of gadolinium contrast conceptually represents an estimate of the mean transit time (MTT). The next step is to calculate the net cerebral blood flow in milliliters per 100 grams of brain per minute, using the central volume principle and an equation that, in its simplest form, can be represented as: CBF = CBV/MTT. Cerebral blood volume is given in milliliters per 100 grams of brain, and transit time, in seconds or minutes. In practice, this is a complicated mathematical problem that requires computation of additional derivatives of the raw curves and can be approached in several ways. ¹¹

The best way to calculate perfusion parameters, and which to use on a routine basis, are the subject of intense research. Fortunately, the rich data sets characteristic of MR perfusion studies offer many hemodynamic parameters to study. Ultimately a measure of the timing of blood delivery, an estimate of blood volume, and a calculation of overall cerebral blood flow will be optimal to fully characterize brain perfusion.

Color-coded parameter maps enable rapid identification of areas of low or slow blood flow, which are depicted in red. In Figure 2D, top row, the mean transit time is much longer in the left hemisphere when compared with the right, and the cerebral blood volume map shows complete vascular collapse, with low blood volume. This defect is perfectly matched in anatomic extent to the diffusion-weighted image, indicating an absence of potentially reversible ischemia, or penumbra, in the surrounding tissue.

The color maps in Figure 2 are created with standard commercial software. We have developed in-house software that rapidly creates similar maps, while automatically deriving the arterial input function. ¹⁶ This additional piece of information can be used to mathematically process the images more precisely, in a process called deconvolution. The result is a family of black-and-white maps (Figure 2D, bottom row) that depict not only mean transit time and cerebral blood volume, but also cerebral blood flow.

Guiding Therapy

In many cases, imaging can identify patients with ongoing ischemia who may potentially benefit from therapy. A small or modest diffusion abnormality, coupled with a very large perfusion abnormality--a perfusion-diffusion mismatch--identifies an area with very low blood flow but no infarction (Figure 3). Such an area is a realistic target for rapid intervention.

The patient in Figure 4 was experiencing transient ischemic attacks in the right hemisphere of the brain. Diffusion-weighted imaging (Figure 4A) demonstrates a few abnormalities in the deep white matter, while perfusion imaging reveals a very prolonged transit time and very low blood flow in a larger surrounding area. The color maps clearly show prolonged transit through the right hemisphere (Figure 4B). Angiography revealed a tight carotid stenosis, which was corrected with stenting. The same-day post-stent perfusion study shows a complete reversal of the perfusion abnormality (Figure 4C). On clinical follow-up, the patient demonstrated no neurological deficits.

A comprehensive approach to CNS imaging can be used to follow the effects of other interventions, such as thrombolysis, as well as to evaluate vascular compromise in trauma. For example, Figure 5 depicts a patient with a skull fracture resulting from a rollover motor vehicle accident. There is no apparent blood flow on the T2-weighted images (Figure 5A), and a carotid occlusion can be seen down to the level of the bifurcation on angiography (Figure 5B). Perfusion parameter maps (Figure 5C), however, demonstrate that there is no resting perfusion abnormality and no need for intervention.

Conclusion

The ability to perform perfusion studies in combination with MRA enables global assessment of the patient with stroke or CNS compromise. It is an approach that can be summarized by the "4 P's": We look at the pipes , which are the great vessels supplying blood to the brain; the perfusion ; the parenchyma , and the penumbra , the surrounding area of ischemia that requires intervention if infarction is to be avoided. This global approach is possible only through the use of gadolinium contrast media. Its use will undoubtedly be expanded to include other applications of CNS imaging in the future. *

References

1. Detre JA. MR perfusion imaging of hyperacute stroke. AJNR Am J Neuroradiol . 2001;22:806-807.

2. Kidwell CS, Saver JL, Mattiello J, et al. Diffusion-perfusion MRI characterization of post-recanalization hyperperfusion in humans. Neurology . 2001;57:2015-2021.

3. Wittsack HJ, Ritzl A, Fink GR, Wenserski F, et al. MR imaging in acute stroke: Diffusion-weighted and perfusion imaging parameters for predicting infarct size. Radiology. 2002;222:397-403.

4. Wu O, Koroshetz WJ, Ostergaard L, et al. Predicting tissue outcome in acute human cerebral ischemia using combined diffusion- and perfusion-weighted MR imaging. Stroke. 2001;32:933-942.

5. Provenzale JM, Wang GR, Brenner T, et al. Comparison of permeability in high-grade and low-grade brain tumors using dynamic susceptibility contrast MR imaging. AJR Am J Roentgenol . 2002;178:711-716.

6. Randoux B, Marro B, Koskas F, et al. Carotid artery stenosis: Prospective comparison of CT, three-dimensional gadolinium-enhanced MR, and conventional angiography. Radiology. 2001;220:179-185.

7. Van Dijk P, Sijens PE, Schmitz PI, Oudkerk M. Gd-enhanced MR imaging of brain metastases: Contrast as a function of dose and lesion size. Magn Reson Imaging . 1997;15:535-541.

8. Shellock FG, Kanal E. Safety of magnetic resonance imaging contrast agents. J Magn Reson Imaging . 1999;10:477-484.

9. Ball WS Jr, Holland SK. Perfusion imaging in the pediatric patient. Magn Reson Imaging Clin N Am . 2001;9:207-230.

10. Barbier EL, Lamalle L, Decorps M. Methodology of brain perfusion imaging. J Magn Reson Imaging . 2001;13:496-520.

11. Yamada K, Wu O, Gonzalez G, et al. Magnetic resonance perfusion-weighted imaging of acute cerebral infarction: Effect of the calculation methods and underlying vasculopathy. Stroke. 2002;33:87-94.

12. Sunshine JL, Bambakidis N, Tarr RW, et al. Benefits of perfusion MR imaging relative to diffusion MR imaging in the diagnosis and treatment of hyperacute stroke. AJNR Am J Neuroradiol. 2001;22:915-921.

13. Rowley HA. The four Ps of acute stroke imaging: Parenchyma, pipes, perfusion, and penumbra. AJNR Am J Neuroradiol. 2001;22:599-601.

14. Schlaug G, Benfield A, Baird AE, et al. The ischemic penumbra: Operationally defined by diffusion and perfusion MRI. Neurology. 1999;53:1528-1537.

15. Warach S. New imaging strategies for patient selection for thrombolytic and neuroprotective therapies. Neurology . 2001;57(5Suppl 2):S48-S52.

16. Carroll TJ, Rowley HA, Haughton VM. Automatic determination of the arterial input function for assessment of cerebral blood flow with DSC-MRI. Radiology. 2002; In press.

Discussion

THOMAS GRIST, MD: Thank you very much, Dr. Rowley, for an excellent discussion of the role of perfusion techniques in the CNS system. In the specific technique for perfusion, you mentioned that you're using a gradient echo-planar perfusion sequence. I noticed in some of the images that it looked like there was a little susceptibility artifact at the base of the brain.

Some people are using spin-echo echo-planar imaging (EPI), I think with perhaps a higher dose of contrast agent, because the spin-echo EPI may be less sensitive to the T2* effects. But on the other hand, it reduces the susceptibility of artifact. Do you have any comments on that?

HOWARD ROWLEY, MD: Yes, I think that either approach can be successful, depending on the susceptibility artifacts. Of course, susceptibility is a dual-edged sword. You need some susceptibility to see the perfusion changes. But the more susceptibility you have in your sequence, the greater the extent of the skull-based and brain-stem region artifacts. We've found that in clinical practice, two-thirds of the strokes are in the middle cerebral distribution, so susceptibility isn't a major problem. When we suspect a brain stem or posterior fossa infarct, we have chosen to do a spin-echo planar technique. In that situation, we would use a double-dose of gadolinium, and process it in a similar way. There are several groups around the country that prefer that method. Spin echo also gives you better sensitivity to the capillary bed, as opposed to some large veins, at least if you don't use deconvolution.

TG: So then at the brain stem is where you're using it, brain-stem spin echo. Then you give a double dose of contrast agent, just for the perfusion sequence.

HR: That's right.

MARTIN PRINCE, MD: You mentioned that you use a first significant dose of contrast for your 3D MRA of the arch carotid vessels. Then after that, the perfusion study is done. So, does that then limit the amount of gadolinium you have available to use on the perfusion study? Also, what effect does the gadolinium that has already been introduced into the circulation have for your MRA study?

HR: Great question. Well, I think one reason that we have chosen the gradient echo technique is that it only requires a single dose of contrast. We performed the gadolinium-enhanced MRA with a double dose, 0.2 per kilo. Then, we follow it with a single dose, which keeps us within a triple-dose range. However, in situations in which we might need a spin echo technique, for example, we'd be up to four times the standard dose, which we still feel very comfortable with. Also, one of the benefits of the perfusion sequence is that you can perform that after other standard imaging, or after gadolinium-enhanced MRA, because you are only looking at the relative change compared with the baseline. So baseline signal changes don't interfere with the measurement of perfusion.

TG: With regard to the dose rate for these perfusion sequences, in order to identify the arterial input function, it's nice to have as compact a bolus as possible. So at what rate do you give the gadolinium? Can you inject this by hand; or do you use a power injector?

HR: We strongly prefer a power injector, because of the reliability and sequencing of the time that we acquire the data. So our standard procedure is to use a single dose injected through a standard IV catheter. We like at least a 22-gauge catheter. We'll go as low as 2 mL per second in an infant (we've done a number of infants successfully), up to about 5 mL, if we have a large patient with a large-bore IV. The arterial input function can be derived manually using a region of interest drawn near a vessel or on a vessel; or, as in our case, it can be acquired automatically. To some extent, that removes the problem of needing to have a very tight bolus, because the arterial input function is used to deconvolve that curve, no matter what its shape.

RICHARD SEMELKA, MD: Do you find that it's essential to have an imaging window in which to perform the study­­particularly looking for the penumbra from the start of patient symptoms to when you image them­­ to have maximum therapeutic benefit? What is the time that you look at?

HR: That's a terrific question, Richard. The only FDA-approved therapy right now for stroke is IV tPA within 3 hours. So technically, we would be doing these studies within 3 hours, to try to help determine what's going on with the patient and whether there is a target for intervention. However, I think that there have been a number of studies, including the intra-arterial PROACT study, which have shown time windows out to 6 hours. There have also been many case series and anecdotes showing success in individual cases, at least carefully selected, out to 12 or even 20 hours.

The important point is that we're not looking as much at time windows anymore. We're actually looking at physiology, and we are looking at the individual patient, and it's a status of their collateral blood flow that may allow one patient to go many hours and still have a successful intervention. Another patient who might be only at 1 hour could potentially be excluded. So it's the physiologic window as opposed to time window that I think is important, and that's what perfusion is giving us.

MP: Well, even in this time window, there is both the time required to acquire the data, and then there is the time required to do the color mapping and various other post-processing. What is your sense of how long it takes you from the time you've completed the data acquisition, to the time when you can confidently say whether or not there is a penumbra?

HR: The sequence itself takes about 72 seconds. We run on the console using our in-house software, which uses an algorithm that produces these maps within 1 minute. Those maps are deconvolved. With our vendor-supplied software, we are able to pull it across a network, which is actually a rate-limiting step. It takes 4 or 5 minutes for a large study like this to come across to my workstation. Then, even my fellows and residents can perform this offline analysis in 2 or 3 minutes per case. It's actually quite easy, once you've done a couple of them.

MP: You also mentioned that the number of images is extraordinary. It can't possibly be that you could film such a study and get it to the interventionalist who might act on the results. How do you provide this information to the referring physicians?

HR: There are two components of that. One is the review of these studies, which I think is best done on a workstation, as opposed to on film. We don't film the source images, the 504 images that are standard for our sequence. But instead, we have 14 slices for each of the different parameter maps. Those are filmed as part of clinical routine, put in the jacket, and conveyed to the referring physician.

 

Total Body MRA

Martin Prince, MD, PhD Professor of Radiology, Weill Medical College of Cornell University, New York, NY

The ability to use gadolinium contrast in MR angiography represents a tremendous opportunity to improve imaging results and reduce risk. For this reason, over the past decade we have observed an expansion in the use of MRA to encompass the entire body. A search of Medline, for example, shows that the number of papers citing MRA grew from a mere trickle before 1988, when gadolinium contrast was approved by the Food and Drug Administration, to more than 600 in 2000.

The popularity of MRA is understandable. It provides an accurate depiction of the vascular anatomy over large regions of the body. It produces images of luminal anatomy that can be combined with other MR sequences to show physiological information. It is three-dimensional, enabling the creation of an essentially infinite number of projections of the vascular anatomy, even after the patient has left the MR scanner. More important, it eliminates the risks of ionizing radiation, and gadolinium contrast agents have no clinical nephrotoxicity ^1,2 and are very rarely associated with allergic reactions. ³ Last, MRA is highly accurate. ⁴

There are disadvantages to MRA. Some patients cannot be scanned because of claustrophobia. In older scanners with a long bore, as many as 10% to 20% of patients may experience claustrophobia, but the incidence is greatly reduced in newer scanners with shorter bores. MRA is more expensive than many other noninvasive imaging techniques, though it is certainly much less costly than conventional angiography. Because top-of-the-line scanners are needed for MRA, its availability is limited. And a high level of skill is required to run those scanners, which may also be in short supply in some locations. Finally, there are important contraindications to MRA, including implanted pacemakers, brain aneurysm clips, and orbital metal. ⁵

The opportunity to eliminate ionizing radiation deserves special note. In general, the exposure to ionizing radiation from computed tomographic angiography (CTA) and conventional angiography is within acceptable limits. Nonetheless, a technique that completely eliminates ionizing radiation offers the opportunity to repeat scans over and over, and acquire multiple phases of time-resolved information as the contrast bolus passes through the body. It is also possible to repeat the examination day after day, without worrying about cumulative radiation exposure.

Advantages of Contrast

MR angiography can be performed without contrast, and such techniques often provide excellent information and may, in many instances, produce images of adequate quality. It is important, however, to be aware of the limitations of non-contrast techniques. In Figure 1A, a two-dimensional time-of-flight (TOF) sequence gives a false appearance of only moderate disease of the carotid bifurcation. But on the three-dimensional high-dose gadolinium-enhanced MRA (Figure 2B), it is clear that bifurcation anatomy is more complex. A maximum intensity projection that zooms in on the bifurcation shows that, although the degree of luminal narrowing is only moderate, there is a large ulceration in the atherosclerotic vessel wall that may be contributing to the patient's symptoms (Figure 2C). This abnormality is not visualized by flow-based, non-contrast MRA techniques.

Another shortcoming of flow-based MR techniques, such as 2D TOF, is the tendency for the signal to drop out in sites of very severe stenosis as a result of jet flow--so-called spin dephasing. ^6,7 As shown in Figure 2, 3D gadolinium-enhanced MRA, which is not flow-based, more accurately depicts the true lumen and enables more precise appreciation of anatomic details.

Artifact associated with metal objects in the body represents a challenge for MR imaging. The 3D gradient echo sequence we use for high-dose gadolinium-enhanced MRA employs a very short echo time that helps to eliminate this artifact. Nevertheless, some metal produces such a severe artifact that it cannot be eliminated. The stainless steel Palmaz stent is an example. In the case of platinum stents, the metal stent configuration creates a Faraday cage phenomenon that attenuates the penetration of radiofrequency (RF) energy both into and out of the stent. By increasing the flip angle to 75°, however, it is possible to deliver sufficient RF penetration into the stent to enable visualization of the vessel lumen (Figure 3). ⁸

Another important advantage of 3D contrast-enhanced MRA is the elimination of in-plane saturation. This is critically important in patients with alteration of the normal vascular anatomy. ⁹ In Figure 4, the patient has an occlusion of the left subclavian artery, and flow to the left subclavian is provided by a carotid-to-left subclavian artery graft. Three-dimensional contrast-enhanced MRA readily depicts the unpredictable course and direction of such vessels and, in this case, reveals a complex plaque at the carotid bifurcation.

Patient safety in the MR scanner is an issue that must be considered. In general, MR is not suited to imaging high-risk patients. For example, in the evaluation of dissection, MR would typically be reserved for evaluating Type 3, stable dissections. It is, however, capable of imaging high-risk patients, and may represent the best approach even in an emergency if the risk of subjecting a particular patient to radiation or iodinated contrast is sufficiently high.

In summary, gadolinium-enhanced MRA is able to visualize the origins of the great vessels; it is fast and, therefore, produces less motion artifact than non-contrast techniques; it is associated with less spin dephasing; it can demonstrate plaque features and luminal anatomy in enough detail to reveal ulcerations; it is not hampered by in-plane saturation; it enables the evaluation of small vessels, such as the vertebral arteries; and postprocessing is very simple. Moreover, if gadolinium is already being used for brain MR, there is no extra cost associated with obtaining 3D gadolinium-enhanced MRA at the same time.

Contrast Administration

Several factors must be considered when selecting the dose of gadolinium contrast. ¹⁰ First, it is important to realize that the bolus of contrast evolves as it travels through the body. Initially, at the point of injection, it is very compact. It spreads out as it passes through the pulmonary circulation, and becomes even less concentrated after it passes through the systemic capillary bed.

The selection of gadolinium dose, therefore, must take into account the distance between the injection site and the area of the body that will be imaged, as well as how much gadolinium will be extracted along the way. As might be expected, the higher the dose of contrast, the greater the visualization of vascular detail. This is demonstrated in Figure 5. At a gadolinium dose of 0.1 mmol/kg, it is not possible to see the venous anatomy in the liver, but as the dose is increased to 0.2 mmol/kg and 0.3 mmol/kg, the portal venous anatomy can be appreciated.

The injection method itself is also important to consider. ¹¹ Manual injection has several advantages in MRA, because so many factors must be coordinated perfectly. The delivery of the bolus, the breathholding of the patient, and the initiation of the acquisition all have to occur simultaneously. In my experience, it is easier to coordinate each of these factors while standing next to the patient and performing the injection by hand.

In addition, hand injection necessitates consideration of the viscosity of the contrast agent, which in turn influences decisions on the size of angiocatheter, length and caliber of intravenous tubing, and type of gadolinium contrast to use.

In subclavian venography, for example, two operators are required in order to simultaneously inject the right and left antecubital veins with dilute gadolinium contrast media (20 mL gadolinium in 250 mL normal saline) in order to image the subclavian veins and superior vena cava (Figure 6).

Optimal contrast administration requires an understanding of the basic physics of k-space and how it influences the features of an image. In particular, the center of k-space dominates the contrast features of the image, whereas the periphery of k-space dominates the details. ¹² It is important, therefore, to time the delivery of the contrast bolus so that arterial contrast is at its maximum during the central portion of k-space, to achieve the maximum contrast effect. ¹³

A perfectly timed injection of contrast may provide excellent quality with a relatively low dose of contrast media. But with a small contrast dose, small bolus timing errors can ruin a study. Increasing the contrast dose allows for a greater margin of error in bolus timing. In essence, contrast dose can make up for variations in the skill of the operator. The most talented operators may be able to use a lower contrast dose. On the other hand, if the operator is less skilled or performs MRA infrequently, a larger contrast dose may be warranted in order to demonstrate more angiographic features.

Expanding Coverage

MRA offers the exciting opportunity to expand beyond a scanner's usually limited field of view to image extensive regions of anatomy, simply by moving the table during contrast injection. ^14-16 For example, after performing an initial image in the pelvis, we can pull the table and acquire another image of the thigh, then pull the table again and image the calf. It is also possible to deliver several small injections of gadolinium contrast as the scan moves from the feet to the knees, then finish with a bolus chase. The ability to scan large regions of the body is especially exciting because of the systemic nature of atherosclerotic disease.

Bolus-chase MRA has been extrapolated to cover arteries of the entire body, beginning with the aortic arch and carotid arteries, and moving sequentially down the body to image arteries of the chest, abdomen, pelvis, thigh, calf, and feet. ¹⁷ The patient in Figure 7 was unable to undergo conventional angiography, because access through the iliac and common femoral arteries was not possible. But with MRA, only a peripheral intravenous line in the arm was needed before imaging the arteries of the entire body with a single bolus injection.

Conclusion

Contrast-enhanced MRA offers important advantages over other forms of angiography. It poses no risk of ionizing radiation or nephrotoxicity. Source data can be reformatted for any view. It can depict anatomy and physiology in great detail, and it is highly accurate. As researchers continue to work on refining and advancing the techniques of MR angiography, its future looks bright. *

References

1. Runge VM. Safety of magnetic resonance contrast media. Top Magn Reson Imaging . 2001;12:309-314.

2. Prince MR, Arnoldus C, Frisoli JF. Nephrotoxicity of high-dose gadolinium compared to iodinated contrast. J Magn Reson Imaging . 1996;6:162-166.

3. Murphy KJ, Brunberg JA, Cohan RH. Adverse reactions to gadolinium contrast media: A review of 36 cases. AJR Am J Roentgenol. 1996;167:847-849.

4. Prince MR, Grist TM, Debatin J. Berlin . 3D Contrast MR Angiography . 2 ^nd ed. New York: Springer; 1999.

5. Shellock FG. Reference Manual for Magnetic Resonance Safety . Salt Lake City, UT: AMIRSYS; 2002.

6. Evans AJ, Blinder RA, Herfkens RJ, et al. Effects of turbulence on signal intensity in gradient echo images. Invest Radiol. 1988;23:512-518.

7. Urchuk SN, Plewes DB. Mechanisms of flow-induced signal loss in MR angiography. Magn Reson Imaging. 1992;2:453-462.

8. Meyer JM, Buecker A, Spuentrup E, et al. Improved in-stent magnetic resonance angiography with high flip angle excitation. Invest Radiol. 2001;36:677-681.

9. Prince MR. Gadolinium-enhanced MR aortography. Radiology. 1994;191:155-164.

10. Hany TF, Schmidt M, Hilfiker PR, et al. Optimization of contrast dosage for gadolinium-enhanced 3D MRA of the pulmonary and renal arteries. Magn Reson Imaging . 1998;16:901-906.

11. Schoenberg SO, Knopp MV, Prince MR, et al. Arterial-phase three-dimensional gadolinium magnetic resonance angiography of the renal arteries. Strategies for timing and contrast media injection: Original investigation. Invest Radiol. 1998;33:506-514.

12. Maki JH, Prince MR, Londy FJ, Chenevert TL. The effects of time varying intravascular signal intensity and k-space acquisition order on three-dimensional MR angiography image quality. J Magn Reson Imaging. 1996;6:642-651.

13. Wilman AH, Riederer SJ, King BF, et al. Fluoroscopically triggered contrast-enhanced three-dimensional MR angiography with elliptical centric view order: Application to the renal arteries. Radiology. 1997;205:137-146.

14. Meaney JF, Ridgway JP, Chakraverty S, et al. Stepping-table gadolinium-enhanced digital subtraction MR angiography of the aorta and lower extremity arteries: Preliminary experience. Radiology. 1999;211:59-67.

15. Wang Y, Lee HM, Khilnani NM, et al. Bolus-chase MR digital subtraction angiography in the lower extremity. Radiology . 1998;207:263-269.

16. Ho KY, Leiner T, van Engelshoven JM. MR angiography of run-off vessels. Eur Radiol. 1999;9:1285-1289.

17. Ruehm SG, Goyen M, Barkhausen J. Rapid magnetic resonance angiography for detection of atherosclerosis. Lancet. 2001;357:1086-1091.

Discussion

TG: Thank you, Dr. Prince. Let me ask a few specifics about how you administer the contrast, and what doses you use. You mentioned that you give this by hand injection, and that viscosity is an issue. Does that effect your decision to use different agents?

MP: Yes, if you need a small caliber angiocatheter, then the higher viscosity agents are going to be more difficult to inject, especially by hand. Or especially if you are going to be imaging a baby with a very small caliber angiocatheter, then the viscosity becomes very important. So, we would prefer agents that have the lowest viscosity.

Another important detail is that viscosity is related to temperature. So if you find that the resistance to injection is too great, you can warm up the gadolinium to body temperature. And that will drop its viscosity by approximately a factor of two. Then that reduces the force required to inject the contrast by hand.

DAVID ROBERTS, MD: We routinely give high-dose gadolinium for peripheral bolus-chase MRA applications. We find that the injection protocol is critically important for these studies. If we inject too quickly, certainly anything above 1 mL/sec, we notice significant superficial femoral venous (SFV) enhancement and tibial venous enhancement, which can really degrade the studies. For that reason, we have found that we really can't get by with hand injection, because many of the fellows and residents, despite training and stressing this point, simply inject too quickly. Therefore, we found power injectors fairly mandatory for these studies. What's your take on this?

MP: We've had the same experience. When we are performing a multistation examination with one bolus and are trying to share that bolus between multiple stations, if we time it for the first station, our timing for the second and third station may not be accurate, depending on whether the patient has fast or slow flow. So we have begun doing a test bolus at the calf. Then that gives us a better sense of the timing for all three stations. If a patient has very fast flow, if it is <20 seconds to the calf, for example, then we won't even attempt to do a bolus-chase exam, because we know that we just cannot move the table fast enough to keep up with really fast flow.

DR: How do you address the problem of asymmetry, left to right, in a patient?

MP: Our pattern has been to try to figure out which leg is the clinically significant leg, which is the one that's on track for being operated on first or is providing the most difficulty for the patient. Then we time for that leg, and hope for the best on the other leg.

HR: I have a question about a potential pitfall with great vessel and carotid imaging. Most of these patients, of course, are going to be injected in one arm or the other and as that tight bolus goes past the common carotid artery, especially with a left-sided injection, we sometimes get a false drop-out in signal over a short segment related to the venous gadolinium passing there. How do you approach that? Do you routinely inject the right arm? Do you sometimes inject a femoral vein?

MP: That's an excellent point. It brings up one of the advantages of the hand injection. We always try to inject the right arm. As we are injecting, we want to get the bolus in and flushed out of the vein before we start collecting the central k-space data. So we use a fluoroscopic triggering technique for our carotids, If we are injecting and also tracking the pace of the passage of the contrast through the lungs and as it reaches the great vessels, if we see that it is going quickly and we are not going to get all the contrast in and flushed, I may actually terminate the gadolinium and immediately switch to flush earlier, just to get it flushed out of the subclavian vein and innominate vein.

If you have to inject the left arm, you may not be able to escape some venous artifact, superimposing it over the great vessel origins. Part of the reason for that is that in a lot of older patients, the aorta is unfolded and very hard and it pinches the brachycephalic vein between the aorta and the sternum. It causes the gadolinium to hang up there, and despite with your best efforts to flush it through, you may not be able to clear that.

LARRY KRAMER, MD: Martin, you showed in one graph that as you increase your contrast dose, that you see more and more detail. Is there a point at which as you increase dose, susceptibility takes over and you actually decrease signal and detail?

MP: Yes, that's an excellent question. I think it's more related to injection rate. There's going to be an injection rate at which the concentration of gadolinium in the blood becomes so high that you begin to have T2* effects, which actually cause the signal to drop. In my experience, with hand injecting, it's hard to inject fast enough to reach that point. But if you are performing venography and injecting that vein, you have to dilute the gadolinium to avoid that T2* effect. So that is a very important point.

LK: For venography, how much do you dilute the gadolinium?

MP: I typically take a bottle of 15 or 20 mL of gadolinium and inject that into a 250 mL bag of normal saline. Then I'll load up four 60-mL syringes. That gives me a very large volume of diluted contrast to work with, so I can slam that diluted gadolinium in, in such a way that it will tend to distend the veins. Yet it will not be excessively concentrated. I'll inject a full 60 mL before beginning the 3D acquisition. Then I will continue to inject another 60, then that would be two syringes on each arm, so that I can get bilateral information.

 

MRI of the Myocardium

David A. Bluemke, MD, PhD Clinical Director of MRI, Johns Hopkins Hospital, Baltimore, MD

Although magnetic resonance imaging of the heart does not always necessitate the use of contrast media, increasingly the most interesting and clinically important applications do. Today, for example, we are using high-dose contrast in new ways to evaluate myocardial viability, perfusion, and atherosclerotic disease.

Advanced MR scanners also play a key role in myocardial imaging, not only by offering tremendous imaging speed--crucial for functional studies--but also by helping to achieve the goal of conducting examinations in a single breathhold, an important advantage in using MR to image patients who are very ill.

Myocardial Viability

The evaluation of patients who have had a myocardial infarction (MI) often starts with functional imaging, which usually consists of the acquisition of cine images and their analysis for wall motion abnormalities. Figure 1 demonstrates the use of myocardial tagging, a technique that aids in the evaluation of regional wall motion throughout the myocardium. In this case, it reveals severely disordered contraction of the myocardium. Wall motion analysis is unable to answer a crucial question, however: whether the areas of abnormal contraction are still viable or represent infarction. An assessment of myocardial viability using contrast techniques is, therefore, the next step.

In assessing myocardial viability, we acquire first-pass myocardial perfusion images following a single dose of gadolinium contrast media delivered at a 5 mL/sec, a fairly high injection rate (Table 1). We use power injectors for all viability and perfusion studies. Because these patients often are quite sick, they typically have a large-bore catheter already in place, which enables us to inject using a large-bore Angiocath.

We image the entire heart every 2 heart beats for about 1 minute after contrast injection to assess microvascular integrity. Next, we inject a second dose of gadolinium contrast, wait for 10 to 20 minutes, and obtain myocardial viability images using gradient-echo techniques with myocardial suppression.

Consider the application of MR viability imaging in a patient with an extensive MI. Even though many such patients have the infarct-related artery opened in the cardiac catheterization laboratory and undergo implantation of a coronary stent, some still have small-vessel disease or capillary occlusion. MR is the only noninvasive method that can assess disease at the capillary level reliably, and this is accomplished during first-pass perfusion imaging.

If on the first-pass images the capillaries remain occluded--evident as a dark area that is not perfused--we inject the second dose of contrast and wait for approximately 10 minutes. During this time, as contrast washes out from the rest of the myocardium, there is a redistribution of contrast between areas of nonviable and normal myocardium, such that the contrast agent is retained in the area of infarction. Figure 2 demonstrates this concept in a patient with large transmural infarction of the inferior and basal walls.

Even though infarcted myocardium can be mapped on delayed viability imaging, it is the core of the infarct, which appears on first-pass images and corresponds to microvascular obstruction, that predicts patient prognosis. Wu et al ¹ found that patients with evidence of microvascular obstruction following MI were more likely to experience a cardiovascular event during follow-up when compared to those without microvascular obstruction (45% versus 9%). The size and presence of microvascular obstruction predicted an increase in left ventricular mass and volume, and a decrease in ejection fraction, at 6 months.

MR can be used to evaluate both acute and chronic MI. The purpose of the study is often quite different in these two settings, however. In acute MI, the primary issue is the size of the infarction, an assessment that can sometimes be difficult to make clinically. For example, cardiac enzyme levels may be challenging to interpret in a patient who has received a thrombolytic agent. In another example, a woman may delay coming to the hospital for chest pain because her symptoms are atypical, thus skewing interpretation of the troponin levels.

In chronic MI, patients typically are being evaluated before revascularization procedures, and the question is one of viability, rather than infarct size. If the target myocardium is dysfunctional, but still viable, bypass grafting could markedly improve cardiac function.

In both acute and chronic MI, cine images demonstrate an absence of motion in the area of infarction. In the acute infarct, there may also be areas of dysfunctional myocardium that is stunned but will eventually recover.

Wall thickness can be analyzed by anatomic imaging. In acute MI, the myocardium typically does not show thinning, whereas after 3 to 6 months, the chronic infarct is characterized by thinning and remodeling of the myocardium with scar formation.

Both acute and chronic infarction demonstrate marked enhancement with gadolinium contrast, although the pathophysiologic mechanisms
are quite different. It is hypothesized that in acute MI, there is an increase in the distribution volume of the contrast agent in areas of nonviable myocardium, where myocytes have died. In the case of chronic infarction, in which the myocardium is replaced by fibrosis and scar, it is hypothesized that there is a difference in contrast distribution between the nonviable myocardium and the scar, when compared with the adjacent myocardium.

Viability imaging can also be useful in the assessment of patients with idiopathic hypertrophic subaortic stenosis, following alcohol ablation of the enlarged ventricular septum. ² In such patients, the anterior motion of the mitral valve leaflet is obstructed by the enlarged septum during systole, which obstructs aortic outflow. The standard treatment at our institution is coronary alcohol injection to ablate a portion of the myocardium. These procedures are done empirically and guided by evidence of decreased wall motion. Gauging how much of the myocardium has been treated can be quite difficult angiographically, however.

Using MR, functional images are obtained before the procedure to assess outflow obstruction. Following injection of alcohol into the coronary artery, first-pass perfusion images demonstrate areas without blood flow (Figure 3). On delayed imaging, approximately 10 minutes after injection, the areas of nonviable myocardium are clearly mapped out. Patients can also be followed over time to assess overall cardiac function as well.

Myocardial Perfusion

Myocardial perfusion imaging is typically used to evaluate patients with ischemic heart disease, rather than MI. An infusion of the vasodilator Adenoscan (Fujisawa Healthcare, Inc., Deerfield, IL), 140 µg/kg/min, augments coronary blood flow. After approximately 2 minutes, 0.1 mmol/kg gadolinium contrast media is delivered as a single, rapid-infusion bolus (5 mL/sec), as in the myocardial viability protocol described previously. Gradient echo, echo-planar notched interleaved pulse sequences are used to image the entire myocardium for about 1 minute after a contrast injection.

Because the protocol involves the use of the vasodilator adenosine to augment coronary blood flow, there are several contraindications to MR perfusion imaging, including wheezing, hypertension, the use of caffeine or aminophylline, or greater than first-degree atrioventricular heart block. Depending on the patient population, approximately 5% of patients are likely to experience discomfort during the exam. Approximately 0.5% experience a potentially serious adverse reaction to adenosine, such as arrhythmias or heart block. During stress testing, a staff member with Advanced Cardiac Life Support certification must be present.

Figure 4 shows a patient with reduced perfusion in the septal and anterior portion of the myocardium, and another patient with left ven-tricular hypertrophy and small subendocardial areas of decreased enhancement.

A major area of investigation involves the quantification of perfusion defects, as a better alternative to visual estimation of the extent of stenosis. ^3-6 Nonetheless, even with visual estimation, the overall correlation between perfusion abnormalities that are physiologically significant and angiographic stenosis has been quite good (Table 2)

Atherosclerosis

The imaging of atherosclerosis represents a major new and developing application of contrast administration. Often, MR angiography of patients with suspected heart disease shows an essentially normal coronary lumen. However, there can be tremendous amounts of disease in the vascular walls. Assessment of the atheromatous components of plaque represents an important and active area of investigation today. Key questions in determining whether a plaque is vulnerable to rupture include whether it has a large lipid core or is covered by a thin fibrous cap. Both are thought to increase the risk of plaque rupture, with the ultimate result being obstruction of the coronary artery and MI.

Figure 5 demonstrates the use of contrast in imaging atherosclerosis of the carotid artery, where most of the initial studies have been done. ^7,8 The area of fibrous cap is well enhanced, enabling assessment of cap thickness. The lumen is quite small, and adjacent to the fibrous cap is the lipid core. Within the lipid core is an area of calcification. All of the plaque components are well delineated on the MR image, which correlates closely with the histology specimen.

The imaging of atherosclerosis can be applied to other vascular beds as well. ⁹ Probably the most interesting and important are the coronary arteries. Patients with atherosclerosis may have only mild degrees of coronary arterial narrowing on angiographic sequences, but still have significant amounts of disease inside the vessel wall (Figure 6). The true extent of disease and risk for subsequent plaque rupture is probably best assessed using contrast-enhanced MR.

Conclusion

The use of contrast for myocardial viability imaging is a major new application of MR. Myocardial perfusion, stress imaging, and the evaluation of myocardial ischemia are active subjects of investigation as well. Contrast-enhanced imaging for atherosclerotic disease, particularly in combination with MR coronary angiography, holds great promise for evaluating the risk of cardiac events. *

References

1.Wu KC, Zerhouni EA, Judd RM, et al. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation . 1998;97:765-772.

2. Wu KC, Heldman AW, Brinker JA, et al. Microvascular obstruction after nonsurgical septal reduction for the treatment of hypertrophic cardiomyopathy. Circulation . 2001;104:1868.

3. Schwitter J, Nanz D, Kneifel S, et al. Assessment of myocardial perfusion in coronary artery disease by magnetic resonance: A comparison with positron emission tomography and coronary angiography. Circulation. 2001;103:2230-2235.

4. Al-Saadi N, Nagel E, Gross M, et al. Noninvasive detection of myocardial ischemia from perfusion reserve based on cardiovascular magnetic resonance. Circulation. 2000;101:1379-1383.

5. Zhao S, Croisille P, Janier M, et al. Comparison between qualitative and quantitative wall motion analyses using dipyridamole stress breath-hold cine magnetic resonance imaging in patients with severe coronary artery stenosis. Magn Reson Imaging . 1997;15:891-898.

6. Bremerich J, Buser P, Bongartz G, et al. Noninvasive stress testing of myocardial ischemia: comparison of GRE-MRI perfusion and wall motion analysis to 99 mTc-MIBI-SPECT, relation to coronary angiography. Eur Radiol . 1997;7:990-995.

7. Yuan C, Hatsukami TS, O'Brien KD. High-resolution magnetic resonance imaging of normal and atherosclerotic human coronary arteries ex vivo: Discrimination of plaque tissue components. J Invest Med . 2001;49:491-499.

8. Wasserman BA, Smith WI, Trout HH 3rd, et al. Carotid artery atherosclerosis: In vivo morphologic characterization with gadolinium-enhanced double-oblique MR imaging initial results. Radiology. 2002;223:566-573.

9. Fayad ZA, Fuster V. Clinical imaging of the high-risk or vulnerable atherosclerotic plaque. Circ Res . 2001;89:305-316.

Discussion

TG: Thank you very much, Dr. Bluemke. Let me ask a question specifically about the perfusion. You mentioned that you give the bolus at a high rate of injection. Do you use a power injector for that, or do you do that by hand?

DAVID BLUEMKE, MD: We are using power injectors for all of our studies. For first-pass perfusion studies, we typically inject at about 5 mL/sec. These patients are quite often very sick patients and they typically have large-bore catheters already in place. So it is quite feasible to inject using a large-bore angiocatheter with a high injection rate.

MP: I'd like to ask you about the tendency in nuclear medicine to obtain rest and stress images. Where do you think that fits in? Concerning injection, when you have to give dynamic gadolinium injection and pharmacologic injection simultaneously, then you would need multiple IVs. Or can they be piggybacked?

DB: As far as the the use of stress and rest images, the initial studies that were done with perfusion MRI definitely considered that model of application. The reason for doing stress and rest images is to distinguish viable from nonviable myocardium, ischemic myocardium versus infarction. That model was used initially. Now it is a development of these viability MR sequences, where the normal myo-cardium is suppressed with inversion recovery pulse sequences.

The standard model now is to do stress images during adenosine infusion, and then wait for 10 to 20 minutes, then look at the areas that are nonviable on the delayed images. There's been a movement then to not require multiple injections for those images, during first-pass conditions.

TG: The reason for that is because you don't need the resting image, because the viability image tells you where the infarct is, if it is there.

DB: That's right. The nonviable myocardium will light up very nicely, and can be delineated at about 10 to 20 minutes after contrast injection.

MP: So are you then suggesting that the need to image under stress may be completely eliminated by these new MR perfusion and viability sequences?

DB: No, we think that stress conditions are going to be necessary to distinguish narrowing prior to infarction. If a patient presents with chest pain and typical anginal type symptoms, the question is, is that coronary heart disease or is it some other cause of chest pain. In those conditions, in which an infarction has not occurred, it is very likely that only under stress conditions will those areas of coronary narrowing be revealed on the perfusion images, the first-pass images.

DR: During the stress imaging, who is monitoring the patients? Do you do it with the cardiologist?

DB: Yes, during the stress cases, someone who is ACLS certified has to be there. We typically have a very competent nursing assistant addressing the medication issues. They can be quite complicated procedures, although they are of relatively short duration. After 4 to 6 minutes, the stress imaging is completely done and the adenosine has a very short half life of about 1 to 2 minutes. So when we are done with that stress component, we can rapidly assess the patient to determine if there is any evidence of heart block, or any chest pain associated with the stress condition.

RUSSELL LOW, MD: What's the incidence of complications or symptoms?

DB: Well, the incidence of symptoms can be relatively high, depending on the patient population you are studying. Some discomfort can occur in probably <5% of the patients. As far as overall severe life-threatening conditions, the incidence for adenosine is on the order of about 0.5%, at least in the literature. If you talk to labs that do a lot of these studies, I think they believe that that number is a little bit high. But if you document a large number of cases in which arrhythmias and heart block are delineated accurately, it may very well be that those numbers are quite accurate. So you have to be prepared to treat patients and get them out of the room rapidly if complications should occur.

DR: In the first-pass images that you showed, I noticed some misregistration, which I presumed was motion artifact from breathing. Do you find that interferes with the creation of color maps of the mean transit time and other parameters?

DB: Yes, we try to do the first-pass images during an extended breath-hold and ask the patient to hold his or her breath for as long possible. For some patients, it is about one image. Other patients do quite well, and hold their breath for 30 or 40 seconds. The key time is the first 20 to 30 seconds. We have a pretty good success rate in having patients coordinated with the technologist in terms of the injection and the scanning, to be able to hold their breath during that period of time.

Right now most of these images are evaluated qualitatively. With quantitative evaluation, it's a huge issue. But there are motion correction software packages that will re-register the images, so we can place cursors over the areas of interest to map those signal changes quantitatively.

LK: How soon after a patient arrives in the emergency room, do you feel safe to do a stress perfusion study? At some point, you have to decide whether the patient's had an infarction or not.

DB: Well, there are a couple of issues there. Let's say the patient comes into the emergency room with chest pain. First of all, there are not a lot of MR centers that are set up to handle that patient in the acute setting. There have been studies in which MR scanners have been sited next to the emergency rooms. They have been used not so much for stress studies, but for nonstress studies for viability, since the areas of dead myocardium will light up very rapidly after the event occurs.

In animal studies with 90-minute occlusions of a LAD, immediately after imaging, those areas will show on the delayed enhancement images. The more common scenario is with someone with chest pain who was triaged and is in the CCU when we image them, if they need to be imaged at all. Usually it's patients who have more complicated courses, or who have atypical conditions that are imaged. Women may present differently; the troponin levels may have been missed because of delayed presentation in the emergency room. So usually it's a combination of factors.

Not all patients need viability imaging necessarily. We think that some routine myocardium infarction cases are treated very nicely, and they get very little imaging whatsoever in the hospital. It's probably in the sicker patients, more atypical presentations, that this will be a useful technique.

MP: Do you think MR has the potential in these emergency room patients to determine whether there has been a myocardium infarction? Would a normal MR allow safe discharge of the patient; thereby eliminating the more common pattern of watching the patient overnight and checking enzymes and so forth?

DB: Yes, and it is a very significant issue for hospital administrators, because of the substantial costs of keeping people in the hospital for 24 hours. So, there is a major reason to triage these patients quickly. Whether that will have an impact, I think will still unfold.

There have been studies at Washington Hospital, for example, in which they have triaged patients using MR to determine if they will be admitted, or if they will be observed for just a short period of time. Overall, they've shown reasonable success for mapping areas of myocardium infarction. One of the issues in the nonstress state is whether you can assess nonviable myocardium versus ischemic changes. You probably cannot. So in the acute setting, mapping the myocardium infarction to determine if an infarct has occurred may be quite useful. But these patients will still need some triaging and ischemic testing or stress testing, if they go home.

LK: Howard talked about perfusion imaging the brain, and measuring MTT blood volume and blood flow. Is there any use for those measurements in the myocardium?

DB: As I mentioned, most studies have looked at qualitative changes. There is a lot of investigation in the use of quantitative evaluation. Personally, I think it would be quite valuable. But the techniques are not widely applied at this point and the software is not widely available. There are many people who have subtle perfusion changes, which may be in the realm of normal, that we'd like to quantify. We think we can triage between the abnormal patient with ischemia or infarction, versus the normal individual.

Contrast-Enhanced MRI of the Breast

Nola Hylton, PhD Associate Professor of Radiology, University of California--San Francisco, San Francisco, CA

As research and clinical experience in breast MRI grow, two fundamental issues are being debated. The first concerns the circumstances under which MRI is indicated in the evaluation of breast disease, if at all. Answering this question is made more challenging by the necessity of determining not only whether MRI yields valuable information, but also how it compares to a combination of mammography and clinical breast examination.

The second question involves the optimal technique to use. Contrast is essential for the diagnosis and characterization of breast cancer by MRI. It remains to be established, however, whether the morphologic features of the lesion or information about its function is of greater importance. This article will review evolving techniques in and clinical indications for breast MRI as an adjunct to mammography.

MRI versus Mammography

MRI has certain advantages that make it attractive for the evaluation of breast disease: Virtually all malignancies enhance after contrast injection, MRI has a high sensitivity for the detection of breast cancer--95% or greater, according to several studies ^1,2 --and it is able to visualize very small tumors (<5 mm). Defining precisely how small a tumor MRI
can visualize has been challenging. It is possible to see submillimeter enhancement that comprises only a few pixels, but this is a fleeting effect that is impossible to validate pathologically.

In addition, MRI is not limited by breast density, which is a major advantage in comparison with mammography, and is effective even in women who have breast implants or have undergone previous breast surgery. Finally, MRI has a very high negative predictive value. Therefore, when no enhancement is seen after a successful injection of contrast, it is very unlikely that malignant disease is present.

One of the disadvantages of breast MRI is that its specificity appears to be moderate at best, although the specificity has been difficult to define. Reports in the scientific literature cite values of 37% to 97%, ^1,3-11 but these findings appear to depend heavily on the selection of both the MRI technique and the criteria for determining malignancy.

Additional disadvantages of breast MRI are its relatively long scan times (multiple sets of images are usually acquired during a 30- to 45-minute examination) and its requirement for contrast injection, which is unnecessary in mammography. The high cost of breast MRI is also a disadvantage.

Although mammography and breast MRI are different in many ways, they are in fact complementary procedures and work well in combination. Mammography, for example, readily detects calcifications, whereas MRI does not. Mammography loses some of its effectiveness in dense breast tissue, whereas MRI appears to work better in dense breast tissue than in fatty tissue, because fewer fat-water boundaries mean a better, more homogeneous signal.

Breast MRI Technique

Contrast is considered essential for the evaluation of breast cancer. A single dose of gadolinium contrast media, 0.1 mmol/kg body weight, is used in most breast MRI studies. Early studies with spin-echo techniques used double-dose contrast, but today most examinations involve gradient-echo sequences in which a single dose of contrast is most effective. Precision isn't critical in contrast administration. Injections need to be consistent but do not necessarily require the delivery of a fast bolus. Manual injection is acceptable.

A dedicated breast coil is required. Patients generally lie in the prone position in order to minimize the image blurring that can be caused by cardiac and respiratory motion. Some devices have compression plates for holding the breast stable, but in most cases, with a little coaching, patients remain still during the scan, and image registration is not a problem. With certain coils, patients can go into the magnet feet first, which seems to reduce feelings of claustrophobia substantially.

T1-weighted imaging is required for the best sensitivity to the gadolinium contrast agent; however, the selection of other imaging parameters depends on the clinical question at hand, the available equipment, and the radiologist's preference. Variables include slice thickness and orientation (transaxial, coronal, or sagittal); the tradeoffs between temporal and spatial resolution; and choices between unilateral or bilateral acquisition, 2- or 3-dimensional imaging, spin-echo or gradient-echo sequence, and injection of contrast by hand or by power injector.

Morphology or Function?

The strategies used in breast MRI depend on whether the goal is diagnosis or staging. In staging, it is important to determine the size and extent of a cancerous lesion and whether it is multifocal. The priority is the sensitivity of imaging. Three-dimensional spoiled gradient echo techniques are generally used (Table 1) because of their high spatial resolution, ability to cover the full volume of the breast, and inclusion of fat suppression. Scans are longer when the goal is staging, usually taking 2 to 4 minutes to ensure both adequate coverage and a high signal-to-noise ratio, a measurement of image quality.

When the purpose of MR is to diagnose a suspicious lesion, specificity is the priority. In this case, dynamic techniques using 2D spin echo sequences are generally used (Table 2); however, 3D techniques can be used with reduced resolution, and scan times will be similar to those of dynamic 2D methods. Dynamic scans, used to observe contrast uptake, usually take 1 minute or less. In fact, 15-second scans are not uncommon. To achieve high temporal resolution, it is often necessary to limit coverage, reduce spatial resolution, and/or forego fat suppression. From time-intensity curves, pharmacokinetic parameters related to vessel permeability and blood volume can be calculated.

The approaches to high-resolution and dynamic scans are beginning to converge. Faster 3D sequences equivalent in speed to 2D spin-echo techniques are possible and, as a result, dynamic scanning is increasingly using 3D methods. In general, the 3D methods are not extremely high in either temporal or spatial resolution; however, they balance the need for both enhancement morphology and enhancement kinetics. For now, most practitioners prefer image quality to be high enough to identify specific features that raise diagnostic confidence--for example, the interior and border of lesions. Once image quality is adequate, temporal resolution can be increased as much as possible.

Finally, the limited availability of computer-aided kinetic analyses also influences the preference for studies that emphasize morphology over function. There is a general consensus that MRI should be integrated into breast imaging practices, and that breast radiologists should do the interpretations. However, without the aid of effective computer tools to process data rapidly, the interpretation of functional information and generation of parametric images is too time-consuming for most mammography practices.

Figure 1 shows a 3D contrast-enhanced breast MR image acquired with high spatial resolution in a woman with invasive carcinoma in the lower half of the breast. The lesion is very well characterized morphologically, and spiculations and dark areas within the lesion are clearly evident.

Figure 2 depicts the same lesion, in this case acquired using a 2D dynamic MR sequence, a 15-second scan time, and no fat suppression. The lesion is visible, but the internal morphology is not as apparent as on the 3D image. It is possible on the dynamic image, however, to observe the time course of tumor enhancement. Contrast washout after 2 minutes, or a fast increase with either stabilization or washout of contrast, as seen in Figure 2, are both considered suspicious findings. A more gradual uptake without washout is considered less suspicious. The specificity of these patterns is a problem, however. The gradual pattern of enhancement could also be consistent with ductal carcinoma in situ (DCIS). In cases of DCIS, a linear or segmental morphologic pattern is extremely helpful in making a diagnosis.

Whether to do bilateral or unilateral imaging is also a source of ongoing debate. The argument for unilateral imaging is that keeping spatial resolution as high as possible enables careful evaluation of symptomatic lesions, particularly their morphology.

There is also a strong argument for the importance of symmetry, which can be evaluated only with bilateral imaging. For example, a regional area of enhancement is considered less suspicious for malignancy if it is observed in both breasts. When referring a patient for surgical staging following detection of a symptomatic breast lesion, physicians increasingly request evaluation of the other breast. This represents a screening application of breast MRI--however, one that is the subject of going research but is not yet ready for clinical use.

Emerging Applications

Differential diagnosis represents an emerging application of breast MRI. Indications that fit in this category include an inconclusive mammogram, a palpable abnormality without mammographic findings, and nipple discharge without mammographic findings. MRI is also used to differentiate recurrent breast cancer from scar tissue.

For these indications, MRI has a high sensitivity, but only a moderate specificity. The frequency of its use for differential diagnosis depends on how heavily minimally invasive biopsy procedures, including fine-needle aspiration, stereotactic core biopsy, and ultrasound-guided core biopsies, are used in a particular practice. In many areas of the United States, where these invasive procedures are common, there is less demand for MRI to determine whether a lesion is malignant. In Europe, however, breast MRI is more widely used for differential diagnosis.

The patient in Figure 3 had a spiculated mass on mammography, which may have been either recurrent carcinoma or scar. On MRI, a distortion caused by a previous biopsy is apparent, but there is no contrast enhancement. Incidental enhancing foci found elsewhere in the breast were determined to be ductal carcinoma in situ.

Staging is another emerging application of breast MRI. It is useful for staging in the case of a biopsy that shows cancer, tissue margins that test positive for cancer cells following lumpectomy, or a cancerous lymph node whose source lesion has not been identified in the breast. There is an increasing need to stage the extent of disease preoperatively, as needle biopsy procedures provide no surgical margins for pathological examination, as excisional biopsy does.

Assessment of the response to preoperative chemotherapy is an additional staging application. In this indication MRI can be used to: 1) stage the extent of disease to determine the appropriateness of preoperative chemotherapy; 2) monitor the response during treatment and, potentially, change the course of treatment for patients with non-responsive tumors; and 3) measure the extent of disease following chemotherapy to determine if breast conserving surgery is an option.

In staging applications, MRI is proving to be more effective than mammography. There are several reasons for this. Contrast-enhanced MRI is very sensitive to breast carcinoma. Its 3D format results in a superior anatomical representation. Breast MRI is more accurate for demonstrating tumor extent. Both mammography and MRI demonstrate malignancy; however, concordance with the pathological determination of the extent of disease was found in one study to be considerably higher for MRI: 98%, as compared with 55% for mammography ¹² (Table 3).

MRI offers a particular advantage when DCIS is present (Table 4). As shown in Figure 4, MRI easily depicts multifocal disease, as well as significant axillary involvement, and the distribution of DCIS over an entire segment of the breast.

Screening represents the most challenging application of breast MRI, but it may offer the greatest potential to improve patient outcomes. Genetic testing and statistical models can identify women at high-risk for breast cancer, but early detection has been more difficult. High-risk women are likely to develop cancer at a young age, when breast tissue is still very dense, and mammography is less effective. Until recently, one of the few options for reducing breast cancer risk has been bilateral prophylactic mastectomy.

MRI may offer an effective alternative for screening and surveillance. It is not considered practical in a general population, but MRI screening is proving useful in women who have dense breasts or have been determined to be at high risk--those who carry BRCA1 or BRCA2 gene mutations, have a personal or family history of breast cancer, or have cancer in the contralateral breast.

MRI does have shortcomings when used for screening, however. Incidental enhancing lesions are identified in many patients. Most will turn out to be benign, but positive findings on MRI create a high level of anxiety. Biopsy is difficult, as the lesions are neither palpable nor seen on mammography, and MR-guided biopsy tools are insufficiently developed.

Several trials of MRI for breast cancer screening are under way in the United States, Canada, and Europe. Participants are BRCA1 or BRCA2 mutation carriers, or have a high risk for breast cancer on the basis of family history or statistical modeling. They undergo an initial screening MRI, with follow-up examinations at least annually. Data from these studies will be pooled for the evaluation of sensitivity and specificity. Early results suggest that MRI screening detects breast cancer in 2% to 3% of high-risk women, a reasonably high rate. ^13-15

Future Developments

As effective computer-aided analyses become widely available, a greater emphasis may be placed on fast imaging. The specificity of MRI could be improved by the introduction of better contrast agents that yield more accurate pharmacokinetic measurements or that target cancer cells specifically. These agents would likely reduce lesion conspicuity, however, so their overall benefit is not clear.

Improvements are clearly needed in localization and biopsy methods. This might involve localization of lesions for subsequent ultrasound-guided, stereotactic, or excisional biopsy, or the development of MR-guided biopsy tools. Finally, there is intense interest in the development of tools for noninvasive tumor ablation by MR-guided cryotherapy, radiofrequency energy, or focused ultrasound heating. *

References

1. Harms SE, Flamig DP, Hesley KL, et al. MR Imaging of the breast with rotating delivery of excitation off resonance: Clinical experience with pathologic correlation. Radiology . 1993;187:493-501.

2. Orel SG, Schnall MD, LiVolsi VA, Troupin RH. Suspicious breast lesions: MR imaging with radiologic-pathologic correlation. Radiology. 1994;190:485-493.

3. Kaiser WA, Zeitler E. MR imaging of the breast: Fast imaging sequences with and without Gd-DTPA. Preliminary observations. Radiology . 1989;170:681-686.

4. Heywang SH, Wolf A, Pruss E, et al. MR imaging of the breast with Gd-DTPA: Use and limitations. Radiology . 1989;171:95-103.

5. Stack JP, Redmond OM, Codd MB, et al. Breast disease: Tissue characterization with Gd-DTPA enhancement profiles. Radiology. 1990;
174:491-494.

6. Gribbestad IS, Nilsen G, Fjosne H, et al. Contrast-enhanced magnetic resonance imaging of the breast. Acta Oncologica . 1992;31:833-842.

7. Flickinger FW, Allison JD, Sherry RM, Wright JC. Differentiation of benign from malignant breast masses by time-intensity evaluation of contrast-enhanced MRI. Magn Reson Imag . 1993;11:617-620.

8. Gilles R, Guinebretiere JM, Shapeero LG, et al. Assessment of breast cancer recurrence with contrast-enhanced subtraction MR imaging: Preliminary results in 26 patients. Radiology . 1993;188:473-478.

9. Rubens D, Totterman S, Chacko A, et al. Gadopenetate dimeglumine-enhanced chemical-shift MR imaging of the breast. AJR Am J Roentgenol. 1991;157:267-270.

10. Boetes C, Barentsz JO, Mus RD, et al. MR characterization of suspicious breast lesions with a gadolinium-enhanced turbo FLASH subtraction technique. Radiology . 1994;193:777-781.

11. Hulka CA, Smith BL, Sgroi DC, et al. Benign and malignant breast lesions: Differentiation with echo-planar MR imaging. Radiology. 1995;197:33-38.

12. Esserman L, Hylton N, Yassa L, et al . Utility of magnetic resonance imaging in the management of breast cancer: Evidence for improved preoperative staging. J Clin Oncol. 1999;17:110-119.

13. Warner E, Plewes DB, Shumak RS, et al. Comparison of breast magnetic resonance imaging, mammography, and ultrasound for surveillance of women at high risk for hereditary breast cancer. J Clin Oncol. 2001;19:3524-3531.

14. Kuhl CK, Schmutzler RK, Leutner CC, et al. Breast MR imaging screening in 192 women proved or suspected to be carriers of a breast cancer susceptibility gene: Preliminary results. Radiology. 2000;215:267-279.

15. Schnall MD. Application of magnetic resonance imaging to early detection of breast cancer. Breast Cancer Res . 2001;3:17-21.

Discussion

TG: Thank you very much, Dr. Hylton. You mentioned that specificity is still an issue. There have been some recent reports using dynamic susceptibility imaging, following the initial T1-weighted gradient echo. So, this could be analogous to what Dr. Rowley showed in the brain, where altered perfusion could be identified, probably reflecting angiogenesis in the lesion.

That would have an impact on the most desirable contrast agent, because you may want to give that at a high rate of injection. What do you think about that in the future?

NOLA HYLTON, MD: I think that it's likely that in the future that we'll do something like that. Once the ability is there to augment the morphologic information with a functional over-lay, then perfusion makes sense, and actually Christiane Kuhl, in Germany, published some work comparing T2 perfusion imaging in breast lesions. I think her specificity was either equivalent or slightly better than dynamic T1-weighted contrast evaluation. These are types of things where the diffusion information would be added.

But as I mentioned earlier, I believe it could be useful as long as it doesn't compromise what you can see morphologically about the lesion. There are important features that have become associated with certain types of important histologies, for example ductal carcinoma in situ has some patterns that requires high resolution in order to be identified on MR. A lot of the ability to diagnosis depends on what we see at the borders and interior of enhancing lesions. So, as long as those features are maintained, this is an early detection method. Clearly, we also want to be able to characterize small lesions, because we hope to use this in a screening capacity, so we will need to see these lesions and characterize them when they're still fairly small. So the addition of techniques that add physiologic or functional information would likely be done with a second bolus, and would likely be used to overlay functional information on what we can already see anatomically.

TG: But it would be in a second bolus situation. So you would do your T1-weighted gradient echo and then the second bolus with susceptibility imaging or some other function.

NH: Well, there are a few other clever pulse sequences that people are developing to combine both high spatial resolution and high temporal resolution. I believe it came out of your own work and you are familiar with it. But, in terms of taking cores or samples of k-space, you need to get the high temporal resolution and information about contrast enhancement, then combine it to create one higher resolution 3D, longer time scan, imaged to see the morphology.

DR: I've been working with a method based on a similar idea to TRICKS, but using a different geometry of acquisition in the k-space. It offers surprisingly good spatial resolution and temporal resolution, sort of an optimal solution to that problem.

NH: I think something like that is very attractive. As long as the reconstruction tools, etc., are there to apply these techniques, we'll get the best of both worlds out of the data.

DB: Ultimately, you need to cover both breasts very rapidly with high spatial resolution. How fast do you think we need to image, what temporal resolution behind which is no longer worthwhile? As you go to faster acquisitions, do the injection rates start to matter more and have to be controlled more?

NH: My personal belief is that anything below 30 seconds is going to compromise imaging, compromise the spatial resolution. But I am very influenced by the argument that we do need to be imaging bilaterally, which is actually going against getting better spatial resolution. So if we realize any improvements in imaging, it would probably be to get more effective bilateral techniques. I don't see in the near future that we'll be going incredibly fast in scanning, unless we're doing two different types of techniques, and looking at them in combination.

For the implications for contrast and contrast injection, I would only speculate that if you do some sort of sequential type of an approach, the secondary functional information would be very dependent on the injection dose, mode of administration, and rate, etc., and that those things would need to be very controlled, likely would be best done with a power injector. The practicality of the use of a power injector is that if you're not there for every exam, at least you have some confidence that it was done in a consistent way. So, you are not asking yourself on any given study, if there could have been a problem with the injection.

MP: There's an emerging concept in SMASH, in so-called parallel imaging, which can help to solve the trade-off of being able to image fast and simultaneously at high resolution, but introducing the additional trade-off of sacrificing signal-to-noise. One way of buying back signal-to-noise is to increase your dose of gadolinium. Right now since you are only operating at a single dose of contrast, you have a lot of room to increase the dose.

What do you think about this possibility that with techniques that sacrifice signal-to-noise to address the temporal and spatial resolution issues, that you'd be willing to buy that back by bumping your dose up?

NH: You know, at the moment, we're hitting an over-sensitivity with respect to the objects that enhance. I think by increasing the dose, we tend to see more of the hyperplasias of fibrocystic disease, or proliferative diseases that tend to light up, and that we have a lot of problems trying to decipher them. A lot of the attempts to differentiate hyperplasias from DCIS have to do with seeing if you can see changes in the very initial uptake. If you pump up the contrast dose, you might wash some of that out, you might lose some of that. I'm not sure that dose as a method of getting better signal-to-noise is necessarily what the issue is.

I think that the signal-to-noise needs simply to allow us to see anatomically what's there. But I think if you use contrast to get that effect, you are going to lose information about border differentiation, the rate of enhancement over time, and whether you have a rim versus a central enhancement, etc. Those are things that we actually look at and make decisions about.

 

Dynamic Contrast-Enhanced MRI of the Liver and Pancreas

Richard C. Semelka, MD Director of MR Services, Professor of Radiology, Vice Chair of Clinical Research, University of North Carolina Hospital, Chapel Hill, NC

The role of magnetic resonance imaging (MRI) in the liver is well established, and gadolinium-enhanced studies represent the state of the art. ¹ One variation, the use of high-dose gadolinium, holds a more limited place in liver MRI. Nonetheless, it has the potential to play a much larger part in clinical management by improving the detection and characterization of cancerous lesions and, thereby, guiding treatment decisions.

There are both practical and theoretical roles for high-dose gadolinium MRI of the liver. The practical role, which encompasses applications in clinical use today, involves a combination of tissue imaging and magnetic resonance angiography (MRA). This combination can be achieved through two approaches, either a three-dimensional (3D) technique that enables simultaneous acquisition of both tissue imaging and MR angiographic information (VIBE, or volumetric interpolated breath-hold examination), or a combination of a two-dimensional (2D) spoiled gradient-echo technique, followed by 3D MRA.

When image quality is paramount, it is preferable to choose the 2D spoiled gradient-echo technique, followed by 3D MRA. This approach is often used for surgical planning, involving either a living related transplant donor scheduled for hemiliver donation, or a patient with liver metastases, in whom a complex surgical procedure necessitates the creation of a high-quality vascular road map. ²

Imaging Protocol

The first step is high-quality tissue imaging using a 2D gradient-echo sequence and a single dose of gadolinium contrast. On the first-pass postgadolinium image, we look for the presence of contrast in the portal veins and a lack of contrast in the hepatic veins (Figure 1, top left). Approximately 60 to 90 seconds after the contrast injection, we image with fat suppression (Figure 1, bottom right), looking specifically look for such abnormalities as peritoneal disease, capsule-based disease of the liver, and certain neoplasms such as cholangiocarcinoma, which are well visualized on delayed imaging.

Approximately 15 to 20 minutes after the initial injection of gadolinium, we do high-definition MR angiography, using a 3D gradient-echo sequence and, typically, 20 mL of contrast (Figure 2). We routinely use power injection at a rate of 2 mL/sec. At that rate, the temporal resolution is good and it is possible to capture the hepatic arterial dominant phase, as well as specific enhancement characteristics of liver lesions.

Magnetic resonance angiography is especially useful when imaging patients with vascular anomalies. Figure 3 is an example of a replaced right hepatic artery. The source image on the top left shows the left hepatic artery arising from the celiac artery. The source image on the bottom left shows the take-off of the replaced right hepatic artery from the superior mesenteric artery, and a distal branch of the right hepatic artery. The combined multiple intensity projection (MIP) image shows both the left hepatic artery coming off the celiac artery, and a portion of the replaced right hepatic artery.

Detection and characterization

Although little has been reported or written about the theoretical roles for high-dose gadolinium MRI of the liver, its potential to improve the detection and characterization of liver lesions is very intriguing. One of the few reports on this topic came from Taupitz et al from the Charité University in Berlin. In 2000, they found that double-dose gadolinium contrast administration improved the definition of both enhancing nodules and the progression of enhancement in small hemangiomas when compared with single-dose contrast administration (M. Taupitz, personal communication). This finding may be important, as correct characterization of liver lesions is an essential part of evaluating patients with malignant disease. ^3-5 Double-dose contrast may be useful in improving characterization of lesions, such as hemangiomas, in patients being evaluated for possible malignancy. ⁵

High-dose gadolinium contrast may also be of value in improving lesion detection, particularly in assessing malignant lesions that are amenable to resection or other local therapy. The two most important of these lesions are colon cancer liver metastases, which typically are hypovascular, and hepatocellular carcinoma, which typically is hypervascular. ⁴

In imaging hypovascular colon cancer metastases, high-dose gadolinium contrast may improve the conspicuity of lesions by increasing enhancement of the ring. Appreciating ring enhancement is the single most important evaluation to make in correctly characterizing metastatic colon cancer metastases ^3,4 (Figure 4). Often, enhancement is best on delayed imaging, 90 seconds after contrast administration.

It is relatively easy to evaluate large lesions with a combination of T2-weighted, T1-weighted, and early and delayed postcontrast imaging. High-dose contrast, therefore, is likely to be most important in detecting small lesions, a crucial factor in selecting the type of therapy that is most appropriate for each patient.

In hepatocellular carcinoma, the tumors are usually small and hypervascular. Often, however, they must be imaged on the background of a heterogeneously enhancing cirrhotic liver. Although such lesions can be very difficult to see on precontrast T2- and T1-weighted images, they are easily appreciated on immediate post-gadolinium images. ⁶ The appearance of hepatocellular carcinoma as hyperintense lesions immediately following contrast administration once again raises the possibility that high-dose gadolinium studies may improve lesion detection and help guide patient management.

Figure 5 shows a typical small hepatocellular carcinoma. On T2-weighted precontrast imaging, it is difficult to appreciate the lesion at all, although it is slightly hyperintense on the T1-weighted sequences. On immediate post-gadolinium images, hepatocellular carcinoma shows very intense enhancement, surrounded by a hypoenhancing capsule around the lesion. On delayed post-contrast images, we appreciate rapid washout of the lesion and late capsular enhancement, which are very specific for hepatocellular carcinoma.

Pancreatic Imaging

In pancreatic imaging, just as in hepatic imaging, high-dose gadolinium contrast studies have the potential to improve the detection of both hypovascular and hypervascular lesions. For example, we would expect better definition of small hypovascular pancreatic ductal adenocarcinomas by showing improved enhancement of the surrounding pancreas.

We would expect even more consistently positive results when high-dose gadolinium contrast is used in the imaging of islet cell tumors, insulinomas in particular. These tumors are initially very small, in the range of 1 to 2 cm, and can be difficult to detect. It is likely that the use of high-dose gadolinium contrast media will improve the detection of small insulinomas, but this needs to be demonstrated in clinical studies.

Conclusion

High-dose gadolinium contrast plays a small role in hepatic and pancreatic imaging today. We use it primarily in studies that combine tissue imaging with MRA, but it is also valuable for the evaluation of 2 different organ systems in the same study. For example, high-dose gadolinium is useful when examining the liver, followed by MRA of the renal arteries.

In the future, high-dose contrast-enhanced MRI may fill a much larger and more important clinical role in the evaluation of malignant disease, enabling better detection and characterization of cancerous lesions in patients who are being considered for surgical management. Controlled clinical studies comparing low- and high-dose contrast MRI, as well as high-dose contrast-enhanced MRI and other imaging modalities, such as CT, are now needed to determine whether this potential will become a reality. *

References

1. Semelka RC, Helmberger TK. Contrast agents for MR imaging of the liver. State of the art. Radiology . 2001;218:2-38.

2. Semelka RC, Braga L, Armas D, et al. Liver. In: Semelka RC, ed. Abdominal Pelvic MRI . New York: Wiley-Lyss; 2002:33-318.

3. Semelka RC, Worawattanakul S, Kelekis NL, et al. Liver lesion detection, characterization, and effect on patient management: Comparison of single-phase spiral CT and current MR techniques. J Magn Reson Imaging . 1997;7:1040-1047.

4. Semelka RC, Martin DR, Balci C, Lance T. Focal liver lesions: Comparison of dual-phase CT and multisequence multiplanar MR imaging including dynamic gadolinium enhancement. J Magn Reson Imaging . 2001;13:397-401.

5. Noone TC, Semelka RC, Balci NC, Graham ML. Common occurrence of benign liver lesions in patients with newly diagnosed breast cancer investigated by MRI for suspected liver metastases. J Magn Reson Imaging . 1999;10:165-169.

6. Kelekis NL, Semelka RC, Worawattanakul S, et al. Hepatocellular carcinoma in North America: A multi-institutional study of appearance on T1-weighted, T2-weighted, and serial gadolinium-enhanced gradient-echo images. AJR Am J Roentgenol . 1998;170:1005-1013.

Discussion

TG: Thank you very much for an excellent presentation. We have some time for discussion. Dr. Kramer?

LK: Can you distinguish between doses; that is, quantity of contrast versus injection rate, in trying to define margins, and having greater sensitivity?

RS: That's a good question. At this point in time, since most of the work that we've done has been with single-dose contrast, most people have been focusing on contrast injection rates. In the past, we used hand injection, and now we routinely use machine power injection at 2 mL/sec. At that rate, we have fairly good temporal resolution that we can get very nicely. We can capture the hepatic arterial dominant phase, and also the specific enhancement characteristics of liver lesions.

Going with a higher dose, I think we would still have to at least match that ejection rate. It's very important to maintain that very early enhancement, the hepatic arterial dominant phase. So with higher dose, it will still be very essential. We can't get away from fast injections. I think if anything, there may be more importance attached to fast injections.

HR: I had a question about your approach, which is dynamic in the sense of over several minutes, and is mostly driven by morphologic characteristics. Do you think there is any potential for parametric imaging of the earliest wash-in phases, washout of some of these lesions, region of interest, or maps as we've seen for brain or breast?

RS: Yes, I think that at this point in time I haven't appreciated that that is important. The reason is that in the liver, there are very specific enhancement characteristics. So we don't have to resort to temporal handling of contrast, because the various benign lesions and malignant lesions have very specific morphologic features in how they enhance. It's a very interesting topic for the same reasons that it's interesting in the brain and the breasts, in that angiogenesis and the pattern of blood supply, is crucial. But I think we have the advantage that there's better morphologic characteristics of the various liver lesions, so we haven't had to rely on dynamic handling or looking at enhancement rates and so on. But, as with many things, you borrow from one area to go to the next. One of the nice things about the relationship between brain and body imaging is that, generally speaking, many of the advancements have first come in imaging the brain. Then as things have become well developed in the brain, then other applications, like body, have developed. So it's interesting to see if the various approaches that are used in the brain can also be translated into, for instance, liver imaging. I think that may be very intriguing.

DR: I'd like to comment on that. I think we probably will see that coming, because just this year there was a paper showing that the risk of recurrence of hepatoma was a function of microvessel density, which we can probe with our dynamic contrast-enhanced methods. Therefore, we may not only have the ability to provide a specific diagnosis, but also to provide an estimate of prognosis or recurrence. So, these are intriguing functional methods that I think we are going to see applied more frequently to the liver in the future.

RS: Right, and along the same lines as angiogenesis, I think what is also very important is the response to various treatment methods. In those settings, looking at the different patterns of enhancement, different rates of enhancement may prove very important. So we're now starting a number of different studies, looking at angiogenic qualities of metastases, following chemotherapy and how it alters. I think that may be where physiologic information will become important.

MP: In the double-injection scheme, where you want to do some lesion characterization followed by vascular depiction, is there any effect from the first injection on the second injection that either makes it better or worse?

RS: Well, I think there certainly is some effect of the first injection on the second. But we've generally found that, most often, those kinds of effects are also worse. But we found that by waiting approximately 15 minutes, that enough of the gadolinium has left the system that there isn't much of an impact on the MRA. In addition, since we routinely now look at the images on PACS, and we page the source images, we found that the presence of contrast hanging around another structure becomes less important than it had been in the past, when we weren't using the PACS system. In fact, in some areas, as I think Martin may have shown, it may in effect be of some interest that you can see at 15, 20 minutes contrast in the renal collecting system. So you can use that as further information on how the renal collecting system appears. So that is the one positive thing that we've observed in that approach.

RL: You certainly have the option of retracting if it were a problem.

LK: We're doing more and more CTAs at our institution. We're picking up more and more asymptomatic liver metastases. After we do that, we go back and we get a conventional imaging study. In a lot of cases, it's MR, and we do it according to our standard protocols. We're not finding those metastases. We are now using the second-generation multidetector CTs with very high doses, and very rapid administrations of contrast. I suspect that you're correct, in that we may have to look at higher doses of gadolinium at higher rates of injection. But right now we don't have a lot of data on that. If we decide today to double the dose of contrast, are we doing research or is it practical non-research to go ahead and do right now?

RS: My approach is that you really have to show that there is a value. It is probably necessary to identify initial studies involving patients who have lesions already demonstrated on single dose, and then administer a double dose and compare the images. I think a perfect patient population for that are those with hepatocellular carcinoma, because it is quite often multifocal. I think that's a great way to evaluate initially, to see if it really is doing empirically what we think it should do, which is improving the demonstration of lesions.

I think, though, that the comparison between CT and MR always enters everything. When you talk about doing CTA, of course you could also do MRA for evaluating hepatic injection on MR rather than on CT. I think one of the compelling things that Martin said is that MR is fundamentally a much safer modality, that will always be the case, and the contrast agent is much safer.

We haven't compared it with CTA. But we've compared MR to CTAP. In fact, we stopped doing CTAP mainly because of the higher specificity of MR using the kind of protocol we're using. But I think you're right, insofar as if you are going to be looking at absolute detection of every lesion, you have to do something different. So either go with the interarterial injection on MR or start with higher doses and see if that makes a difference. I always prefer being noninvasive or less invasive to start with. It may be a good starting point to compare CTA with high-dose gadolinium, and look at patients with liver metastases who are being considered for surgical resection.

 

Gadolinium-Enhanced MRI of Crohn's Disease

Russell N. Low, MD Medical Director, Sharp and Children's MRI Center, San Diego, CA

At Sharp and Children's MRI Center, body MRI accounts for 30% of cases, approximately the same proportion as neurological studies. One of the primary reasons for the large volume of body MRI is our ability to image not only the liver but also the extrahepatic abdomen, including the gastrointestinal (GI) tract. The techniques we use to image Crohn's disease serve as a model, but they are equally effective in other types of GI disease.

Crohn's disease is characterized by chronic inflammation of the gastrointestinal tract. It can occur anywhere in the GI tract, from the mouth to the anus, but involves the distal ileum in about 35% of cases, the right colon in about 35%, and the gastroduodenal area and small bowel in about 5% of cases each. In 20% of cases, only the colon is affected. ¹

The etiology of Crohn's disease is unclear but may include immunologic and bacterial factors. The symptoms, which can be quite debilitating, range from cramping and abdominal pain to diarrhea; fever; weight loss; bloating; and anal discomfort, bleeding and drainage. Rectal fissures are quite common, as are skin lesions and other extraintestinal complications, such as joint pain. ¹

Enter MRI

Upper and lower endoscopy, which enable direct visualization and biopsy of diseased GI tissue, represent the gold standard for the evaluation of Crohn's disease. Radiology plays a significant role as well, one that traditionally has centered on the use of barium studies, including the barium enema and upper GI study with small bowel follow-through. It is important to realize, however, that barium studies show only the GI lumen and not the diseased intestinal wall.

Helical CT holds the predominant role in cross-sectional imaging of Crohn's disease and the evaluation of its complications. Magnetic resonance imaging (MRI), however, has many advantages for the evaluation of the GI tract in general, and Crohn's disease in particular.

We first described the double-contrast technique--combining intraluminal contrast agents and intravenous gadolinium--for MR evaluation of gastrointestinal disease in 1997. ² This MR technique takes advantage of the high contrast resolution of MR imaging to depict enhancement of the inflamed bowel wall. We subsequently performed a study comparing helical CT and MRI in Crohn's disease, using double-contrast techniques. ³ Among our conclusions were that MRI is superior for depicting both normal and inflamed bowel wall; shows more marked enhancement of inflamed areas; is superior to CT for the depiction of subtle bowel disease; and is equivalent for depicting such complications as fistula, abscess, or phlegmon.

Some of the challenges that arise in MRI of the GI tract include peristaltic motion, respiratory motion, and variability in the position of the small intestine and colon. In addition, it is necessary to distend the bowel during imaging, and, until recently, inexpensive intraluminal contrast agents have not been widely available. It is also necessary to distinguish subtle changes in the bowel wall from artifact that may be related to the MR acquisition or from collapsed bowel. Faster pulse sequences and improved hardware have overcome many of these challenges, enabling MR to move to the forefront of GI imaging.

Double-Contrast Protocol

We use a double-contrast protocol for MR of the GI tract (Table 1). ⁴ First, the patient drinks two to three bottles of ReadiCat 2 (E-Z-Em, Westbury, NY) or an equal amount of water to provide intraluminal contrast. Water is effective if scanning is accomplished very quickly. The disadvantage, however, is that it is reabsorbed by the colon. If the patient drinks slowly, water may not be effective in distending the bowel.

Next, we administer 500 to 1000 mL of rectal water through a balloon-tipped enema. We fill the balloon with water to decrease susceptibility to artifact from the balloon.

We use single-shot spin-echo sequences to obtain very rapid, heavily T2-weighted images in both the axial and coronal planes. It takes approximately 19 seconds on our scanner to acquire a set of 12 images. Multiple breathholds are performed to image the abdomen and pelvis in the axial and coronal planes.

One mg of glucagon is injected intravenously to decrease peristalsis. This is followed immediately with a double dose of gadolinium contrast media (0.2 mmol/kg). We then acquire two-dimensional images using a breathhold fast spoiled gradient-echo (SGE) sequence with fat suppression. We typically image at high resolution, using a matrix of 512 * 192. The bandwidth is about +20 kHz, and we use a three-quarter field of view to shorten the time of acquisition. It takes 20 to 24 seconds to acquire 12 images. We set up two passes in the axial plane, each of which requires 4 breathholds, and then acquire 1 set of coronal images. The study is performed very rapidly and takes about 15 minutes from start to finish.

Another technique we often apply is MR enteroclysis. Using the same bowel preparation and single-shot spin-echo sequence, we acquire a 10-cm thick section using a very long TE (600 msec), similar to that used in magnetic resonance cholangiopancreatography (MRCP). This acquisition takes only 2 sec to obtain, and the resulting image looks very much like a barium study. This technique may be used to perform dynamic MR imaging of the GI tract by obtaining multiple sequential 2-second images following the administration of oral contrast material. By placing these images in a cine loop, one can review gastric and small intestinal motility.

Among the advantages of the double-contrast approach are the low cost and ready availability of intraluminal agents, and the effectiveness of these agents in distending and separating the bowel. In addition, very rapid breathhold imaging sequences reduce motion artifact, particularly when glucagon is administered to reduce peristalsis.

Perhaps most important, the double-contrast technique creates a set of biphasic images that facilitate depiction of both the bowel lumen and the bowel wall (Figure 1). On the T2-weighted single shot fast spin echo images, for example, the water or ReadiCat 2 is bright, thereby functioning as a positive agent that shows the lumen of the bowel and intestines. This is useful for demonstrating changes in the caliber of the lumen and in looking for stricture. In the same patient, the same intraluminal contrast functions as a negative agent on T1-weighted fat-suppressed gradient echo imaging. This enables visualization of the wall of the bowel, which normally appears as multiple thin lines or rings.

In interpreting MR images, it is important to look at the thickness of the bowel wall and at its enhancement. The normal bowel wall should measure 3 mm or less; anything more is considered thickened. For defining mural enhancement, we use a non-fatty liver as our standard. If mural enhancement is the same or less than that of the liver, we consider it normal. Enhancement that exceeds that of the liver is considered mildly abnormal, and enhancement equal to that of the intravascular gadolinium is considered markedly abnormal.

MR versus Helical CT

Most radiologists use helical CT to evaluate patients with Crohn's disease. Nonetheless, the ability to image the bowel wall is essential for defining pathology in Crohn's disease and other intestinal disorders, and represents a critical advantage of MRI over CT or barium studies.

Figure 2 offers a good example. In this patient, helical CT demonstrates some mural thickening in the wall of the ileum. With the MRI double-contrast technique, however, the lumen is distended nicely, and the thickened wall of the ileum shows intense enhancement. Superior conspicuity of enhancement in the inflamed wall is a consistent advantage of MRI, one that accounts for its having become the exam of choice for the evaluation of Crohn's disease at our center.

Clear differences in the sensitivity of MRI and helical CT become even more evident in subtle cases of Crohn's disease, as depicted in Figure 3. Much of the bowel appears normal on CT. On MRI, however, the entire bowel wall is distinctly abnormal, a conclusion that was confirmed by endoscopic findings of pancolitis and ileitis. We consistently find that the distribution of disease is much better visualized on MRI than on helical CT.

Correlations with Endoscopy

Because of its close correlation with endoscopy, MRI is able to guide clinical decision-making. We have discovered that the activity of Crohn's disease correlates with the degree of gadolinium enhancement, so that a thickened bowel wall that doesn't enhance signifies inactive disease. This is an important finding, as a patient who has chronic inactive disease will receive different treatment than a patient with acute, actively inflamed Crohn's disease.

Figure 4 demonstrates the ability of MRI to distinguish active from inactive Crohn's disease. Barium enema shows a stricture, but it is impossible to determine whether the Crohn's disease is acute or chronic. On MRI, the degree of enhancement is minimal and the T2-weighted image is very dark. In our experience, this pattern correlates with inactive disease. Endoscopy confirmed this impression, demonstrating a perfectly smooth mucosa. Biopsy found some chronic inflammation but no active disease.

By comparison, in patients with active disease, marked thickening and enhancement of the bowel wall correlate well with endoscopic findings of erythema, ulceration, pseudopolyps, and a cobblestone-like mucosa, an appearance that signifies very severe Crohn's disease (Figure 5). Similarly, MRI is a valuable tool for the assessment of complications of Crohn's disease. Figure 6 shows a patient with an enterovesicle fistula. On MRI, the inflammatory mass in the terminal ileum is well visualized, as is an eccentric thickening of the wall of the bladder near the fistula.

MRI is able to detect very focal disease as well, even though it can be subtle. An example of this would be a patient who returns with abdominal pain after surgical resection. In such a case, focal, localized recurrent disease at the site of bowel anastomosis may be seen on gadolinium-enhanced MR images with good bowel distension.

Beyond Crohn's Disease

The same double-contrast MRI techniques that work in Crohn's disease are equally well suited to other types of GI disease. We use this approach not only in inflammatory bowel disease, but also to evaluate patients with infectious enteritis and colitis, mesenteric ischemia, and cancer. We use MRI fairly regularly to stage colon cancer, for example, looking at the depth of penetration of the tumor through the wall. It works well for evaluating gastric and small bowel malignancies, and serosal metastases from ovarian cancer and other primary tumors.

Figure 7 serves as another example of the range of applications of double-contrast MRI. This patient had a 1-month history of diarrhea. The helical CT was unremarkable. MRI showed that the terminal ileum demonstrated marked thickening and enhancement, which was not depicted on the helical CT scan. On endoscopy, there were ulcerations at the ileocecal valve and in the distal ileum, as well as ulcerated plaques in the right colon. This case of probable infectious colitis again demonstrates the superior depiction of relatively subtle changes by MRI when compared with helical CT.

Conclusion

Superior conspicuity of enhancement gives double-contrast MRI a clear advantage over helical CT in the imaging of patients with Crohn's disease. This approach is effective for imaging not only inflammatory bowel disease, but other forms of GI disease, including such conditions as infectious colitis, mesenteric ischemia, and cancer. *

References

1. Farmer RG, Hawk WA, Turnbull RB. Clinical patterns in Crohn's disease: A statistical study in 615 cases. Gastroenterology . 1975;68:627-635.

2. Low RN, Francis IR. MR imaging of the gastrointestinal tract with IV gadolinium and diluted barium oral contrast media compared with unenhanced MR imaging and CT. AJR Am J Roentgenol. 1997;169:1051-1059.

3. Low RN, Francis IR, Politoske D, Bennett M. Crohn's disease evaluation: Comparison of contrast-enhanced MR imaging single-phase helical CT scanning. J Magn Reson Imag. 2000;11:127-135.

4. Low RN, Sebrechts CP, Politoske DA, et al. Crohn disease endoscopic correlation: Single shot fast spin-echo and gadolinium-enhanced spoiled gradient-echo MR imaging. Radiology . 2002;222:652-660.

Discussion

TG: Thank you very much, Dr. Low. We have some time for discussion of this very interesting topic.

RS: I have a couple of questions. The first one relates to early and later enhancement. I guess the early enhancement I like to think of as perfusional, and later as sort of interstitial space. Do you find that it's very important to keep those two data sets separate? How do you treat them when you evaluate the bowel?

RL: Particularly, when you are trying to distinguish or determine the degree of activity, you need to look at the perfusional information from the first pass. We look at that and then try to distinguish if it is enhancing a lot or a little. The second set, everything tends to enhance on those. We do not use those in terms of determining the activity. That's a good point.

RS: The other question is if you have also used that to distinguish between Crohn's disease and ulcerative colitis? I noticed in your cases the same thing we've found in our studies, and that is that with Crohn's you get transmural enhancement, whereas in ulcerative colitis, we've seen submucosal sparing consistently.

RL: Right. I think because of the incidence of the disease, our experience with ulcerative colitis is clearly less. But I think our experience tends to be less intramural thickening. Although at end-stage ulcerative colitis, we do tend to see more significant enhancement.

MP: Russell, I noticed in some of your 2D gradient-echo gadolinium-enhanced images, that you were getting some dropout where surgical clips were evident. Have you tried the 3D to minimize this?

RL: We played around with the 3D pulse sequence. But as Richard said, we tend to like the appearance of the 2D better. There are certainly some advantages of the 3D in terms of the thickness of the sections. At this point, we haven't used that significantly. The single-shot image is probably in that saline one, you have a lot of bowel gas or something, and with artifact, tend to work pretty well too.

LK: Russell, you said you used double dose for these studies, why? Did you try single dose and it didn't work?

RL: It would work with single dose. It's based on our experience looking at a lot of extrahepatic disease, particularly peritoneal tumor. We did a lot of comparisons of single versus high dose for peritoneal tumor. We found that for particularly things outside the liver, they enhance more, anything that you are waiting for awhile to enhance. So it's a logical next step to assume that it would also work in Crohn's disease. I think clearly that does show us more. Any time you are looking at subtle enhancement, with the degree of enhancement of something relatively thin, it's important and more is logically better.

 

Panel Discussion

TG: Now we will begin an open panel discussion to link up many of these different areas together. One common link they have, of course, is the use of gadolinium contrast agents. I'd like to start with a discussion of the ideal contrast agent characteristics, and some of the features that we would like to see and that have relevance to clinical practice as it stands today. Each of the contrast agents can be characterized by their viscosity. We had a discussion about the approved dose, the ability to give bolus or not, as well as the osmolarity and the ionicity of the contrast agent.

Let me start by saying that all of the presentations discussed, of course, applications for patients who were sick or may have cancer, who may have poor venous access, etc. One question to the panelists is do you notice a difference in the use of the gadolinium agents, if you have problems in these patients, such as extravasation? Low-ionic contrast media is likely to create less of a problem with extravasation. What do you do if you have extravasation? We talked a lot about bolus injections, but we didn't talk about the problems with that. What kind of problems have you seen?

MP: Well, I've had a lot of experience with extravasation. That's partly because with CT, we had a very rigorous protocol of meticulously checking the IV: are you getting a good blood return only using large caliber IVs. But with MR, we have smaller volume, and we've been less rigorous about checking the function of the IV before doing the study. We even will accept IVs that might be in the hand or the wrist that may not be as reliable as an IV in a large antecubital fossa vein. So one of the things I've noticed is that if you have an ionic high-osmolality contrast agent, the patient will let you know immediately when there is extravasation. They may want to terminate the study at that point.

But the lower osmolality nonionic features make the agent much better tolerated in the event of accidental extravasation. I've had a number of cases where the image would be blank. When I'd examine the patient, I'd see a huge volume of contrast there that got extravasated, and the patient hadn't even noticed that extravasation was occurring. That makes it easy to talk the patient into just redoing the IV and repeating it.

HR: I think there is one particular instance in which we have to be very careful: that's when we are doing sedated or anesthetized patients, because whether the contrast is ionic or not, they won't notice the extravasation. So, for example, in babies who are asleep for the MRs, we are always very vigilant to make sure we get a good blood return before injecting. The other cautionary tale is to avoid things like PICT lines when you are injecting high doses at high rates, because they can actually come apart internally with high injection rates. So we like to have an intercath, not a butterfly. We want to make sure if we are injecting a central line, that it is of sufficient size to handle the volume.

TG: We routinely also inject PICT lines in some cases. There I think the low viscosity really helps because the problem at the PICT line appears to be at the coupling of the IV to the catheter and the hub. That's what can blow, if the viscosity is high, because of the pressures that are developed.

MP: I think the use of the central line is an area where hand injection should be considered over power injection, because a low viscosity agent with hand injection might be able to go through a PICT line or other central line, you might be able to obtain an adequate study. Whereas using the power injection through a central line may destroy it and create an even worse situation.

TG: Does anybody else have any experience related to the specific injection local extravasations?

DB: I think when using a nonionic agent, we're more comfortable because the patient might be more uncomfortable while they're in our MR suite. But certainly with CT, we know we've had patients who were asymptomatic from large volume injections with CT contrast agents, and these can occur later. So I do think we need to emphasize when these occur, to maintain good contact with the patient, phone numbers, symptomatic treatment, and surgical consultation if it's needed.

MP: I have a rule that 50 mL is a dividing line between more serious and less serious extravasation. Has anyone else heard of the 50 mL rule? If you extravasate more than 50 mL, you must have a surgical or plastic surgical evaluation, but extravasations less than 50 mL are more likely to resolve on their own.

LK: We do a lot of contrast injections, and we're very meticulous in our technique, in placing the catheter and checking it after we place it. Or if it has been in there for while, in a patient coming down from the ward, we meticulously check it again. But we've recently been going to a higher dose, higher rates of injection, and we are seeing more and more extravasation. I think it's a little bit of a comfort margin, in theory, that we are using nonionics. One, as Martin said, the patients are very asymptomatic. But I'm hoping that there's less tissue necrosis associated with nonionic agents, versus the ionic agents, although I don't know if there's enough data to support that.

TG: We've noticed the lack of any thrombophlebitis that we've ever been able to identify in thousands and thousands of injections. We use a nonionic agent, and we haven't done the comparison of ionic versus nonionic agents, but it's interesting that we just don't see thrombophlebitis. Has anybody seen that post-gadolinium?

MP: I have had a case of a patient who received an ionic gadolinium contrast injection; at the time of the examination there was just a little bit of perivenous erythema. But the patient subsequently came back to the emergency room with a full-blown thrombophlebitis, and was admitted to the hospital and heparinized. Then eventually made a complete recovery.

TG: So it reiterates what Dr. Bluemke was saying, that these patients really need to be followed carefully and treated accordingly.

Now, let's discuss one of the other features about giving a bolus. Some of us use bolus injection in particular applications, some don't. Do you think that the contrast agents today have adequate "bolus-ability"? Do we need agents that could be given at higher rates? Have we reached a maximum?

DR: I've been giving gadolinium at tremendous rates, intra-arterially, which is a very rapidly growing area within interventional radiology. Many interventional renal cases are now done solely with gadolinium; and that's our practice. We often inject these at rates in excess of 5 mL/sec, so in aortic injections we can go as high as 20. In these applications, I like to use a nonionic agent. I don't have data to support this, but I expect that it's better tolerated by the patients, and also that the viscosity issues would make for a lower pressure injection. We've been using a nonionic agent for several years now in arteriography with wonderful results.

TG: Currently, none of the agents are approved for the arterial injection, but what is your experience clinically?

DR: It's a judgment; it's off-label usage of the agent. The patient outcome has been superb, especially in view of the lack of nephrotoxicity of the agent, when you are dealing with a patient who has underlying renal insufficiency. This is an area that's growing rapidly within the IR community.

TG: Right, because of the lack of nephrotoxicity of the agents.

MP: How do you compensate for the relatively lower concentration of gadolinium molecules within the gadolinium contrast, compared with the higher concentration of iodine molecules in the iodine contrast?

DR: It's a weaker radiodensity; it's not as radiodense as iodine. However, modern fluoroscopy units coming out have specific kV settings dedicated for gadolinium. You can select those settings and get more optimal images that approach the quality of iodine. But it's not as good, but often good enough to do the procedure safely.

HR: But better for the patient.

TG: Related to other factors that influence the choice of bolus, the highest bolus rate that we saw in the presentations was Dr. Bluemke. You spoke about 5 or 6 mL/sec for myocardial perfusion imaging. Dr. Rowley, what are you using in the CNS?

HR: Typically 3 or 4 mL/sec. For babies we'll go down to 2 mL/sec. It hasn't been necessary to go to 5 or 6, at least for our applications.

TG: Do you think that there is any reason to go higher for intravenous injections? Probably not, I imagine.

DB: I guess there's probably not a lot of reason to think that we should go higher. I think we tend to use 5 as our maximum, both for our neuro and cardiac applications. The doses we've looked at more seriously in CT work, and most of the highest CT doses, other people have certainly used 8 and 10 mL. Most people believe that 5 mL seems to be as high as we could go and I think there's probably a lot of parallels to what we are doing in MR so far.

TG: But then there is an important factor on the lowest injection rate that you would use for these perfusion studies, because an injection rate slower than a certain rate will give a problem in the arterial input function. It's no longer just a bolus function. So what do you think is the lowest injection rate that you like to use for perfusion imaging? It may be different in children versus adults, so let's talk about adults.

DB: For most of our injections we try not to go below 2 mL/sec. But empirically, I think that if you are going to capture first-bolus processes, which may take 10 to 15 seconds for the transit of contrast, at most, that we feel that you really need to deliver the contrast in a short concise bolus and get it in there. But we do feel compromised when we are using that slow an injection rate.

NH: There's actually been interest in modeling the pharmacokinetics for transfer constance, just with the T1 dynamic techniques, that actually you might be better able to model the slower infusion. So even at 1 mL/sec rates, if you know in fact that it's a steady infusion, than you can model that a little better. You might have more accuracy when you compute your transfer constance later. So there's published data suggesting that infusions are better than bolus methods.

TG: In some situations, such as T1-weighted imaging.

NH: Exactly. In T1-weighted dynamic images, when you are trying to derive for transfer consistence and permeability for breast cancer.

TG: On the other hand, most of the data is on susceptibility T2* imaging, which really indicates a higher injection rate.

NH: Right, there is much more.

RS: Tom, while we are still on this topic, for the body we typically use 2 mL/sec, that probably translates in Martin's lexicon as a fast hand-injection rate. I think that's approximately correct. We used to do hand injections routinely, and it was important to get a good firm injection. Now going to machine power injection using a standard dose, 2 mL/sec, seems to be quite adequate. But I think it's also intriguing if we start talking about higher doses, and using higher doses to look for small lesions and characterizing smaller lesions better in the liver; I think it may be essential to go with faster injection rates. So if we are using double or triple doses, I think it would make a lot of sense to look at going to 5 mL/sec.

In fact, there is some literature comparing MR with standard and spiral CT; MR is routinely better. We found in our studies that, if you look in the same patients, MR sees more lesions in at least 50% of patients, and has an impact on patient management, probably in that range too, when we compare standard MR with the 2 mL injection rate, and standard CT with the 2 mL injection rate. But I think it has been shown that if you increase the injection rate with CT on spiral or multidetector CT to 5 mL/sec, your results are much better as far as lesion detection. I think that would be the exact parallel we'd expect with MR, and maybe that should be the first step in looking at improving detection in evaluating patients for surgery. That probably is the more logical first step before going to looking at a combination of CTA and CTAP, to really look at increasing the dose and increasing the injection rate.

MP: To parallel CT, it's interesting also from the point of view of the nature by which we calculate the dose, there is a tendency at our institution to give a standard volume to every patient for CT. But in MR, we have a tendency to adjust the volume according to the patient's weight. There's a difference of opinion, whether the rate should also be adjusted based on weight, which sometimes can be done by diluting the gadolinium or if it should be a standard volume that you use in everyone for a standard rate. So this brings up several questions. Should we be dosing based on weight? Or should we go with the CT model of giving everybody the standard same volume? Should we be adjusting our injection rate based on weight as well?

NH: The reason to adjust by weight in MR is to get reasonably sane blood concentration, so that you might give rise to the same amount of single intensity change for the same amount of material there. That is the rationale to adjust for body weight.

MP: Okay, but if you are going to inject patients outside of the scanner, and then put them in and get your image, then adjusting by weight means that you've given the same amount of contrast per gram of tissue. But if you are going to image during the dynamic evolution of the contrast passage through the tissues, the amount that you inject is not as important as the rate at which you inject. So to have a correct matching to the patient size, you would really need to adapt your rate of injection to the patient weight.

NH: That makes sense.

MP: Then also, if you don't adapt the rate but you have the same duration of scan, then what's going to happen is your bolus duration is going to be different from patient to patient. So how it matches up with your mapping of k-space can vary as well. So I think there is just an enormous complexity in the sort of features of these injections that remains to be further analyzed.

RS: Cardiac input is also very important in this setting.

TG: Right. If the arterial concentration is related to the injection rate divided by the cardiac output, people with different heart functioning have different performance.

Let's get back to the issue of what rate you chose, in the liver, for example. Richard, you were suggesting that maybe then we ought to look at higher injection rates. Dr. Kramer, you pointed out that as the MR technology changes, we are able to image faster and then may capture the image in a shorter period of time. So that allows you to increase the rate, and that may in fact improve the detectability of liver lesions, or it could improve the MRA, for example.

Let's talk a little bit about dose. Currently, the high-dose indications for contrast agents is evaluation of intracranial metastatic disease. Dr. Rowley, do you want to comment on the merit there?

HR: Well, I think in most cases, we are still using single dose for most brain tumors, including metastases. But the enhancement that you see depends on the tumor itself, the dose, the delay after the injection, and, of course, the specific sequence. Our approach has been that when it is going to make a clinical difference. For example, a patient who is found to have one or two metastases is a candidate for either curative surgery or targeted radiotherapy. So, we'll go ahead and give the triple dose at the time of their treatment planning scan, at all the radiotherapy, and all the surgeries being done with a 3D MR. That is, we are anticipating that some patients may end up being excluded as surgical candidates, because we may find additional metastatic disease.

Another approach would be to use, for example, magnetization transfer in combination with single or double dose to improve the conspicuity. But in our hands, the key features are really getting at that triple-dose study, a volumetric acquisition, so we are not going to lose lesions between slices in inner-slice gaps. To get good T1 weighting, I see a problem with a lot of people trying to get better coverage, and letting it creep up toward a proton density-
looking scan. At that point, you don't know what you are looking at. So our approach is really two-fold, the standard imaging and then, at the time of treatment planning, we'll go ahead and give the triple dose if it is indicated.

MP: Do you think it's better to know that you need a high-dose study to look for absolutely every metastasis? Is it better to do a staged injection; or is it better just to give the triple dose right from the start?

HR: Well, that's a great question, because, of course, some tumors will take up contrast over the several minutes after the injection. In our shop, we'll usually know if we are going after a triple dose anyway. It's our approach to just give triple dose and we'll perhaps get, for example, the routine T1 or a T2 FLAIR, and then follow that with the 3D SPGR or an NP-RAGE to capture both the time and the added features of the volumetric acquisition.

TG: Well, I think that that should conclude our panel discussion. I'd like to thank all of the panelists as well as our coordinator, Oliver Anderson, from Applied Radiology . I'd also like to thank Amersham Health for their unrestricted educational grant to Applied Radiology , to support this symposium. Once again, thanks to all the speakers.

 

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Date of release: September 2002

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Dr. Hylton and Dr. Low state that no such relationships exist. Dr. Bluemke discloses relationships with GE Medical Systems as a consultant; Bracco Diagnostics via research support; and Amersham Health and Berlex Imaging as a member of their speakers bureaus. Dr. Grist discloses relationships with Amersham Health as a consultant and through research support, GE Medical Systems through research support, and ISG-Medical Advances as a consultant. Dr. Prince discloses relationships with GE Medical Systems, Siemens, Bracco, MedRad, and Mallinckrodt through patent agreements; with Topspins, Inc. as a major stockholder; and with GE Medical Systems, Bracco, and AMI through research support. Dr. Rowley discloses relationships with Amersham Health and Abbott Laboratories as a consultant and with GE Medical Systems as a member of their speakers bureau. Dr. Semelka discloses relationships with Berlex Imaging and Amersham Health through their speakers bureaus.

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