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This section discusses some of the most exciting and technologically complex techniques used in acute stroke imaging: those that study brain tissue not just to determine that an ischemic event has occurred in a particular part of the brain, but also to study the viability of ischemic tissue. This has become especially important with the widespread implementation of thrombolytic therapy, which can be very successful in saving brain tissue and dramatically improving outcomes for acute stroke patients, but can also result in catastrophic intracranial hemorrhage. By studying tissue viability, neuroradiologists hope to identify brain tissue that is threatened by ischemia and may be saved by timely reperfusion and to distinguish this tissue from tissue that already has undergone irreversible damage, cannot be saved, and may be at increased risk of hemorrhagic conversion. This helps the patient and the stroke neurologist to understand better the risks and potential benefits of thrombo-lysis or other therapies.

By far, the most widely used and most empirically studied tissue viability imaging techniques are those that study tissue perfusion, and discussion of perfusion imaging techniques will dominate this section. We will also mention a few emerging techniques that currently are not as widely used in the acute stroke setting, but show promise for the future.

Perfusion Imaging: Introduction and Review of Pathophysiology

Perfusion imaging techniques study pathophysiologic events that occur in capillaries and other microscopic blood vessels that cannot be seen by angiographic techniques like CTA or MRA. The perfusion imaging techniques in most widespread clinical use are performed using CT or MRI, and generally obtain or estimate three particular perfusion measurements in each part of the brain: cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT).

Perfusion imaging performed in the acute stroke setting generally relies upon bolus-tracking techniques, in which a bolus of a standard contrast agent is injected rapidly via a peripheral intravenous catheter, and images of the brain are obtained repeatedly as the contrast agent passes through the brain. In the case of CT, brain tissue increases and then decreases again in density as an iodine-based contrast agent passes through the brain. With MRI, the signal intensity of the tissue decreases and then increases again, due to a transient susceptibility effect caused by a gadolinium-based contrast agent (hence the term dynamic susceptibility contrast imaging or DSC). In either case, the perfusion examination takes only approximately 1 minute to perform. The images obtained in the examination are converted by a computer to contrast agent concentration versus time curves, which are in turn analyzed to yield measurements of CBV, CBF, and MTT in each part of the brain (or approximations of those quantities) in each voxel. This process is illustrated in Figure 2.6.

A brief review of vascular pathophysiology may help to clarify why these measurements are helpful in distinguishing between salvageable and irreversibly injured tissue. When a global or local loss of cerebral perfusion pressure (CPP) exceeds the autoregulatory capacity of the cerebral vasculature, global or local CBF begins to fall. Further vasodilation and capillary recruitment have the effect of increasing the effective vascular cross-sectional surface area, resulting in a lower blood velocity at any given level of CBF. This is detected by perfusion imaging techniques as an increase in the average amount of time that each volume of blood spends in each imaging voxel, that is, an increase in MTT. A decrease in the velocity of blood as it passes through capillaries is adaptive,

FIGURE 2.6 Dynamic susceptibility contrast imaging. Axial images of the brain are acquired repeatedly, in this case every 1.5 seconds. As a bolus of intravenously injected contrast material enters the brain, first arteries, then brain parenchyma, and finally veins demonstrate a transient loss of signal intensity. In this acute stroke patient, hypoperfusion of the left middle cerebral artery territory results in delayed arrival of the contrast bolus and prolonged stasis of contrast within the tissue.

FIGURE 2.6 Dynamic susceptibility contrast imaging. Axial images of the brain are acquired repeatedly, in this case every 1.5 seconds. As a bolus of intravenously injected contrast material enters the brain, first arteries, then brain parenchyma, and finally veins demonstrate a transient loss of signal intensity. In this acute stroke patient, hypoperfusion of the left middle cerebral artery territory results in delayed arrival of the contrast bolus and prolonged stasis of contrast within the tissue.

as it allows time for a greater oxygen extraction fraction (OEF), that is, an increase in the fraction of oxygen molecules that have time to diffuse from erythrocytes into brain tissue.

With modest impairment of blood flow, this mechanism allows for preservation of oxidative metabolism without alteration in electrical function. However, when CPP and therefore CBF are sufficiently low, OEF reaches a maximum and cannot increase further. Brain tissue ceases to function electrically, resulting in a neurologic deficit. Microvascular collapse occurs, and CBV falls. If the oxygen supply falls low enough, the tissue dies. Of critical clinical importance is the observation that the amount of time it takes for tissue to suffer irreversible damage is inversely related to the severity of the ischemic insult. Tissue that is completely deprived of blood will die within a few minutes, but less severely hypoperfused tissue may survive for many hours, and may be saved by timely thrombolysis that restores perfusion, or perhaps by another therapeutic intervention.

To summarize this account of cerebrovascular pathophysiology, a mild decrease in CBF is accompanied by a concomitant increase in MTT and preserved or increased CBV. Tissue with severely decreased CBF also demonstrates increased MTT, but decreased CBV.

Perfusion Imaging: Interpretation of MRI Perfusion Images

At first glance, it might seem that perfusion imaging could distinguish salvageable tissue from irreversibly infarcted tissue simply by measuring levels of CBF and assuming that tissue with CBF below a certain level cannot be saved. Indeed, absolute quantification of perfusion parameters can be achieved with both CT-63-67 and MRI-based68-74 perfusion imaging techniques, and some have used absolute quantification to assess tissue viability.

However, in practice it may be difficult to draw conclusions from absolute measurements of perfusion parameters for at least three reasons. First, in patients with chronic atherosclerotic disease, tissue that has adapted to conditions of mild ischemia may have thresholds of viability that differ from those of normal tissue. Second, CBV and CBF are approximately two to three times greater in gray matter than in white matter, and these two types of brain tissue have very different thresholds of viability. Therefore, interpreting absolute measurements of perfusion parameters correctly requires distinguishing between gray matter and white matter. Because ischemic gray matter resembles normal white matter in CT images, it is probably impossible to do this with CT, and methods for doing it with MRI are not routinely used. Finally, absolute measurements of perfusion may not be as accurate as desired. Absolute measurements are made by first generating relative perfusion maps, in which perfusion in different parts of the brain is represented in arbitrary units without absolute meaning. These relative measurements are then converted to absolute ones by a scaling process that may introduce increased uncertainty and reduce the reliability of the measurements in assessing tissue viability.

For all of these reasons, neuroradiologists and stroke neurologists often interpret perfusion maps not by absolute measurement of perfusion levels, but by visually inspecting them for "lesions" representing abnormal CBV, CBF, or MTT. In this interpretation, the terms "infarct core'' and "ischemic penumbra'' are often used. The core, which often (but not always) lies near the center of the ischemic region, is defined as the tissue that has been irreversibly damaged and is unlikely to survive, regardless of therapeutic intervention. The term "ischemic penumbra,'' which originally had a slightly different meaning among neurologists and neuroscientists, is now often used to describe a region of tissue that is threatened by ischemia, but may be saved by rapid reperfusion. This only moderately ischemic tissue most often lies around the periphery of an ischemic lesion, where collateral vessels may serve to provide some degree of residual perfusion (Fig. 2.7).

Qualitative analysis of perfusion images is usually based on two assumptions that are derived from the pathophysiologic principles discussed above. First, tissue with visibly decreased CBV is so severely ischemic that it is unlikely to survive and lies within the "core'' of the infarct. Second, tissue with decreased CBF or prolonged MTT may be mildly or severely ischemic and may or may not be salvageable. If this tissue does not appear abnormal in another, more specific type of image (such as CBV or DWI), it represents the "ischemic penumbra'' and may potentially be rescued by immediate therapy.

FIGURE 2.7 Core and penumbra in acute stroke imaging. The infarct core, presumptively identified by an abnormality in a DWI image or CBV map, represents tissue that cannot be salvaged. The ischemic penumbra represents tissue that is threatened by ischemia, but may still be saved by timely therapy. The penumbra is presumptively identified as that tissue that is normal in early DWI images or CBV maps, but abnormal in maps of CBF or MTT. According to the model that is often used in guiding stroke therapy, acute infarcts may grow, during the several days after stroke onset, to encompass some or all of the ischemic penumbra.

FIGURE 2.7 Core and penumbra in acute stroke imaging. The infarct core, presumptively identified by an abnormality in a DWI image or CBV map, represents tissue that cannot be salvaged. The ischemic penumbra represents tissue that is threatened by ischemia, but may still be saved by timely therapy. The penumbra is presumptively identified as that tissue that is normal in early DWI images or CBV maps, but abnormal in maps of CBF or MTT. According to the model that is often used in guiding stroke therapy, acute infarcts may grow, during the several days after stroke onset, to encompass some or all of the ischemic penumbra.

FIGURE 2.8 Growth of an acute infarct into a region of diffusion-perfusion mismatch. An early DWI image (a) shows an acute infarct in the right insula and temporal lobe. An MTT map (b) shows a somewhat larger perfusion abnormality, which extends posteriorly into a mismatch region (arrows) that appears normal in the DWI image. In a follow-up CT examination (c), the infarct has extended into the region of diffusion-perfusion mismatch.

FIGURE 2.8 Growth of an acute infarct into a region of diffusion-perfusion mismatch. An early DWI image (a) shows an acute infarct in the right insula and temporal lobe. An MTT map (b) shows a somewhat larger perfusion abnormality, which extends posteriorly into a mismatch region (arrows) that appears normal in the DWI image. In a follow-up CT examination (c), the infarct has extended into the region of diffusion-perfusion mismatch.

These assumptions have been tested most often using MRI-based perfusion imaging (MRP), also called perfusion-weighted imaging or PWI, which has been in existence for a longer time than CT perfusion imaging (CTP). MRP images are usually interpreted in conjunction with DWI images that are concurrently obtained as part of a rapid MRI protocol that may require as little as 2 minutes of imaging time. In doing this, the lesion seen on early DWI images, rather than CBV maps, is usually taken to represent tissue at the core of the infarct, which is unlikely to recover. Examples of the interpretation of acute DWI and MRP images are shown in Figures 2.8-2.11.

FIGURE 2.9 Partial growth of an acute infarct into a region of diffusion-perfusion mismatch. An early DWI image (a) shows a small acute infarct in the left frontal lobe (arrow). The MTT map (b) shows a much larger perfusion abnormality, theoretically reflecting a large volume of penumbral tissue at risk of infarction. A follow-up T2-weighted MRI image (c) shows that the infarct has grown to include some but not all of the threatened tissue.

FIGURE 2.9 Partial growth of an acute infarct into a region of diffusion-perfusion mismatch. An early DWI image (a) shows a small acute infarct in the left frontal lobe (arrow). The MTT map (b) shows a much larger perfusion abnormality, theoretically reflecting a large volume of penumbral tissue at risk of infarction. A follow-up T2-weighted MRI image (c) shows that the infarct has grown to include some but not all of the threatened tissue.

FIGURE 2.10 Failure of an acute infarct to grow into a region of diffusion-perfusion mismatch. An early DWI image (a) shows several small closely clustered acute infarcts in the left corona radiata. An MTT map (b) shows a much larger region of impaired perfusion, theoretically representing tissue at risk. However, a follow-up T2-weighted FLAIR image (c) shows that the infarct has not grown substantially. Preservation of penumbral tissue, as demonstrated by this case, is the goal of acute stroke therapy.

FIGURE 2.10 Failure of an acute infarct to grow into a region of diffusion-perfusion mismatch. An early DWI image (a) shows several small closely clustered acute infarcts in the left corona radiata. An MTT map (b) shows a much larger region of impaired perfusion, theoretically representing tissue at risk. However, a follow-up T2-weighted FLAIR image (c) shows that the infarct has not grown substantially. Preservation of penumbral tissue, as demonstrated by this case, is the goal of acute stroke therapy.

In most cases, the ultimate volume of an infarct is larger than that seen in initial

DWI images, , - encompassing both initially DWI-abnormal tissue and other tissue into which the infarct extends. The ultimate volume of an infarct also is

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