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. *

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.