Perfusion imaging in Acute ischemic stroke: Let Us Improve the ...

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Perfusion Imaging in Acute Ischemic Stroke: Let Us Improve the Science before Changing Clinical Practice1 Mayank Goyal, MD, FRCPC Bijoy K. Menon, MD, DM Colin P. Derdeyn, MD

Published online 10.1148/radiol.12112134 Content codes: Radiology 2013; 266:16–21 1

From the Departments of Radiology and Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada (M.G., B.K.M.); and Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (C.P.D.). Received March 24, 2012; revision requested April 16; final revision received July 12; accepted August 3; final version accepted August 25. Address correspondence to M.G., Department of Radiology, Foothills Medical Centre, 1403 29th St NW, Calgary, AB, Canada T2N 2T9 (e-mail: [email protected]). Conflicts of interest are listed at the end of this article. See also the article by Lev in this issue. RSNA, 2013

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eperfusion is the only proved effective therapy for patients with acute ischemic stroke (1). There is an urgent need for improvement in acute stroke care, as only 15%–20% of patients, at best, are eligible for intravenous tissue plasminogen activator (tPA), and many patients so treated do not achieve good clinical outcome (2,3). This need has resulted in an enormous amount of research about developing better methods of revascularization and neuroprotection and designing better imaging paradigms for patient selection. A key element of these advanced imaging paradigms is perfusion imaging. We intend to bring focus on the extent of our current knowledge on the imaging triaging of acute ischemic stroke patients by using perfusion imaging and to make recommendations for practice and clinical research. Our position is that perfusion imaging should not be used outside of clinical studies seeking to establish the utility of these measurements. We do not intend to focus on the utility of perfusion imaging in other relevant clinical scenarios where this imaging modality has defined its role, and neither do we intend to go into detail on the mathematic constructs behind these techniques.

Definitions of Core, Penumbra, and Benign Oligemia The core is tissue that is already dead at the time of imaging. For our purpose, we shall define penumbra as ischemic, nonfunctioning but living brain tissue that will die unless blood flow is restored. Benign oligemia is tissue that is underperfused but functioning normally and that will survive irrespective of improvement in blood supply (4–6). The first indication of the presence of penumbra in ischemic brain tissue came from electrophysiologic studies

in animals. In a series of experiments in cats, Hossman et al (7) reported the restoration of electrical activity in individual neurons with the restoration of cerebral blood flow. They also found that the longer the duration and the greater the depth of ischemia, the less likely that electrical function would return. The threshold level for neuronal dysfunction in these studies was a cerebral blood flow (CBF) of approximately 20 mL/100 g/min. Tissue with a value above this CBF threshold level never infarcts; this region was defined as benign oligemia. These animal experiments also demonstrated the dynamic nature of the ischemic penumbra: Without reperfusion, the infarct core expands into the penumbra over time (4,8).

Imaging of Core, Penumbra, and Benign Oligemia Over the past 20 years, we have developed good imaging methods to delineate core with some certainty. These include low attenuation on nonenhanced head computed tomography (CT) and on CT angiographic source images, low cerebral blood volume or low CBF at perfusion CT, and restricted diffusion by using magnetic resonance (MR) imaging (9–15). These imaging modalities are used to identify core by allowing a comparison of baseline imaging parameters mentioned above with final infarct in early reperfusers, unlike positron emission tomographic (PET) studies in which pathophysiological constructs such as oxygen extraction fraction or flumazenil binding are used (16,17). Studies validating imaging measures of core at nonenhanced CT (hypoattenuation) or MR diffusion-weighted imaging with PET have been impossible to perform early enough and close enough to PET such that the core infarct measurements are accurate (18,19). With

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CONTROVERSIES: Perfusion Imaging in Acute Ischemic Stroke Is Promising

current advances in endovascular treatment, the imaging definition of what is core at perfusion CT or MR imaging is constantly changing as the benchmark for “early successful reperfusion” reduces. It is, however, our opinion that the current definition of core is reliable enough for clinical decision making (20–22). The accurate separation of penumbra from benign oligemia is a challenge (23). In addition, there is very likely tissue within imaging-defined penumbra that is not dead yet, but may be doomed to die even if reperfused (because of apoptosis or other mechanisms) (24). A single measurement of CBF or other related perfusion estimates made at a single point in time is not a reliable indicator of whether that tissue will live if left alone or survive if reperfused. Our ability to identify core, penumbra, and benign oligemia by using blood flow measures is affected by conceptual and technical flaws.

Conceptual Issues with Defining Tissue State by Using Perfusion Measures The concept of defining the size and extent of penumbra and distinguishing it from infarct core and benign oligemia by using perfusion threshold levels (CBF, cerebral blood volume, time to maximum, and mean transit time, or summary parameters such as time to peak) has several major problems. First, these perfusion threshold levels are time dependent. Tissue with a CBF of less than 10 mL/100 g/min may survive for 30 minutes, but probably not for 3 hours. Perfusion threshold levels that separate core from penumbra could therefore depend on when tissue was imaged after ischemia onset (25). Second, perfusion measurements do not reflect metabolic activity of brain tissue. Dead, dying, or doomed tissue may have normal flow. Perfusion threshold levels for infarction may be different in various regions of the brain (26). It is also important to note that the penumbra is a dynamic state. Any attempt to determine the status of ischemic and oligemic tissue is a snapshot in time (6). We do not know the factors that determine the rate of transformation of

the penumbra into core. If leptomeningeal collateral vessels fail (Figure) or CBF varies with time because of as yet unknown factors, defining penumbra by using perfusion imaging at a single time will be error prone (27). The dynamic nature of the penumbra is reflected in variable infarct growth rates over time. The transformation of penumbra into core in the infarct “border zone” is dependent on many complex and interrelated factors, including leptomeningeal collateral supply (Figure), ischemic tissue susceptibility to necrosis, and peri-infarct depolarization (6,25). These same factors lead to variable growth of penumbra into regions of oligemia and result in clinical worsening (28). In addition, in vitro studies hint at the possibility of selective neuronal death in the penumbra and protein dysfunction in the region with benign oligemia (29). The use of blood flow threshold levels to define irreversibility and salvageability of brain tissue and to predict infarct growth rates is affected conceptually by these physiologic issues.

Technical Limitations of Current Perfusion Techniques Present perfusion techniques (either deconvolution or nondeconvolution based)

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make certain assumptions. One source of error is with the choice and measurement of the arterial input function (AIF) (30). Perfusion techniques rely on the assumption that the AIF is from an artery that is the sole blood supply to the region where blood flow is measured. This assumption is not always true. Variability in the choice of AIF can lead to variability in blood flow measurements caused by varying delay and/or dispersion (31,32). Singular-value decomposition techniques correct for these errors; however, not all available perfusion software uses these techniques (33,34). Partial volume averaging of the AIF can lead to errors in measuring blood flow (35). These errors can be corrected by appropriate scaling techniques by using the venous output function. MR perfusion techniques are affected because of low spatial resolution, orientation of the vessel with respect to the direction of the magnetic field, and the mixing of tissue signal intensity with signal from the artery. Additional assumptions that are not always accurate are in determining the proportionality constant K, an integral part of deconvolution algorithms and dependent on capillary hematocrit levels that can vary in ischemic tissue (36,37). To overcome this drawback and to achieve a means of comparison between estimated CBF

Schematic shows regions beyond an arterial occlusion with border zones among core, penumbra, and benign oligemia. These regions may change over time owing to possible change in leptomeningeal collateral vessels and other toxic metabolic or physiologic processes, including periinfarct depolarization.

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values from different patients, crosscalibration is used by some researchers in conjunction with deconvolution-based approaches (36,37). Although absolute quantification may indeed vary, we do agree that the use of relative threshold levels could help in unilateral ischemic stroke evaluation. Nonetheless, white matter disease, age-related changes and previous infarcts can compromise the validity of cross-calibration. In addition, discriminating between perfusion threshold levels for ischemia in the gray and white matter is prone to errors (38,39). The use of parameters such as mean transit time and time to maximum are confounded by reliability and by issues of dispersion and delay (40). There is a distinct lack of standardization of postprocessing tools in perfusion imaging not only across modalities (CT vs MR imaging) but also across vendors and laboratories (41,42). Lack of standardization of postprocessing tools is, in our opinion, a major limitation. Efforts toward increasing the speed of postprocessing have led to automated postprocessing tools that could further worsen these measurement errors, although this idea is debatable (43,44).

The Issue of Time Taken for Perfusion Imaging There seems to be a misconception that perfusion imaging in real time only takes a few minutes. This may be true for image acquisition time (45,46) but not for time from entry into the imaging suite to making a treatment decision. For CT perfusion, this time includes setting up the imaging unit and injector, acquiring and transferring images, postprocessing, and finally interpreting the data. For MR perfusion, other additional steps are required: making sure the patient is MR safe, patient positioning, motion, claustrophobia, and obtaining localizing images. These steps may easily extend the total imaging time by 30 minutes (47). Perfusion imaging–based paradigms may not be practical in a real world scenario unless ongoing efforts at reducing image postprocessing time succeed (48). 18

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Other Limitations of Perfusion Imaging Limited coverage of perfusion imaging and the need for a different sequence to image neck vessels and the arch of aorta for planning endovascular treatment are also disadvantages. This limitation can be addressed by newer-generation whole-brain CT scanners or MR imaging units; however, not all centers have access to these tools. Additional radiation and contrast agent dose given to patients is also a concern and must be justified by potential benefits obtained when making clinical decisions.

Appropriate Imaging for Patient Selection in Clinical Practice In the next few paragraphs, we explore the questions that clinicians need answers for when making treatment decisions in patients with acute ischemic stroke (49). Our effort is to explore whether these questions can be answered satisfactorily without using perfusion imaging. The questions are as follows: (a) Is there an arterial occlusion? (b) What is the extent of core within or relative to the hypoperfused arterial territory? (c) Can the core so defined possibly explain the patient’s clinical deficits? (d)What is the rate of growth infarct? CT angiography is a reliable, safe, quick, and widely available tool to determine the presence of an arterial occlusion. Tools like diffusion-weighted imaging and apparent diffusion coefficient in MR imaging define core as well as or even better than perfusion measurements (20). Hypoattenuation on a good-quality nonenhanced CT image unless very early is also fairly reliable in estimating core (9,50,51). We agree that perfusion imaging also identifies core (15,52). At our centers, with reasonable training, patients with large early ischemic changes (corresponding to an Alberta Stroke Program Early CT Score of four or lower) are reliably identified and excluded from thrombolytic treatment unless their disease manifests very early (53,54). Proponents of perfusion imaging use their technique to do exactly the same.

A lack of attention to improving the quality of nonenhanced CT and to training in interpretation of early ischemic changes on nonenhanced CT images results in underutilization of this easily available and rapid tool (55). This lack of attention to nonenhanced CT has developed to such an extent that no attention is paid to change in hypoattenuation over time, a marker of time from stroke onset (56). We would like to remind the readers that perfusion imaging and the mismatch paradigm gives a sense of extent of “core” and “salvageable brain tissue” but does not provide a sense of “time from stroke onset to imaging.” In our opinion, information similar to that obtained from perfusion imaging can be gleaned from nonenhanced CT and CT angiography by assessing extent of early ischemic changes and degree of leptomeningeal collateral vessels. In addition, assessment of hypoattenuation on nonenhanced CT images can provide us with a sense of time from stroke symptom onset to imaging. Diffusion-weighted imaging fluid-attenuated inversion-recovery mismatch does provide a sense of this “image time” conceptually, but that paradigm is not an argument for perfusion imaging. Clinicians have a fairly good idea of the presence or absence of clinical-imaging mismatch (57). This point merits some discussion, as there is contradictory literature on the accuracy and relevance of clinical-imaging mismatch (58,59). A careful look at this literature reveals that the use of a volume threshold level for small core rather than clinical judgment on the basis of anatomy and eloquence could be responsible for the lower specificity of clinical-imaging (CT or MR) mismatch when compared with perfusion-diffusion mismatch in predicting clinical outcome (60). Predicting infarct growth rate by using perfusion estimates is possible on the basis of an assessment of severity of ischemia within penumbra; nonetheless, other factors such as change in leptomeningeal collateral vessel status, susceptibility of brain tissue to ischemia and peri-infarct depolarization could confound this assessment. In summary,



if a clinician has knowledge of where the occlusion is and of how complex the arterial access is and is able to glean from imaging information on whether the core is relatively small or large when compared with a potentially hypoperfused brain region, we believe he or she is able to make a decision in favor or against thrombolytic therapy either intravenous or endovascular. We request our readers to question whether perfusion imaging answers any of the above questions better than a small core–occlusion–based paradigm by using good quality nonenhanced CT or CT angiography. We also request them to note the fact that clinicians in many centers where perfusion imaging is used make the decision to use thrombolytic therapy even before perfusion imaging is available. On the basis of this argument, we therefore suggest imaging strategies classified in two groups as follows: 0–4.5-hour time window or longer than 4.5 hours from onset or unknown time of onset.

0–4.5-Hour Time Window In this time window, there is level 1 evidence for the use of intravenous tPA (61). Perfusion imaging has a limited role in determination of appropriate patients for intravenous thrombolysis (20,21). The rationale for endovascular treatment in this time window is based on the low revascularization rates and poor outcomes with intravenous tPA in proximal occlusions. A patient with moderate to severe stroke symptoms with a small core identified at CT and large-vessel occlusion identified at CT angiography is most likely to benefit from endovascular treatment (62). In our opinion, a CT and CT angiography– based imaging paradigm is quick and easy within this time window without prolonging door-to-needle time. Longer than 4.5 Hours from Onset or Unknown Time of Onset Major clinical trials in which perfusion imaging and a mismatch paradigm (Desmoteplase in Acute Ischemic Stroke 2 trial, Echoplanar Imaging Thrombolytic Evaluation Trial) were used have not shown level 1 evidence

of treatment effect with intravenous tPA in the time window of greater than 3 hours (20,63–65). In addition to the many reasons mentioned for the lack of substantial treatment effect of these trials (65), the lack of a treatment endovascular arm resulting in faster reperfusion may also be a reason. Faster reperfusion is imperative. Prolyse in Acute Cerebral Thromboembolism II supports the use of endovascular therapy for proximal occlusions in this time window (66). Post hoc analysis of data from Prolyse in Acute Cerebral Thromboembolism II and Echoplanar Imaging Thrombolytic Evaluation Trial shows treatment effects with small cores identified by using either nonenhanced CT or diffusion-weighted imaging (67,68). In the absence of compelling evidence for the use of intravenous tPA with or without perfusion imaging in this time window (20,21) and the need for identifying a proximal occlusion before initiating endovascular therapy, the use of nonenhanced CT and CT angiography preferably or diffusionweighted imaging and MR angiography and the small-core–occlusion imaging paradigm could be faster and more clinically relevant.

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these studies are accomplished, designing randomized acute stroke trials by using perfusion imaging for patient selection should be attempted. Only then should a clinician use this technology in the real world to make clinical decisions. We do believe that the alternative CT-based paradigm that we propose, a small-core–occlusion paradigm should also go through the same hierarchy of steps mentioned above. Finally, we point out that perfusion imaging helps in detecting the presence of distal occlusions that may be missed at CT angiography, albeit not changing a decision to use thrombolytic therapy. It has the potential to identify hemorrhagic transformation better than nonenhanced CT hypoattenuation or diffusion-weighted imaging fluid-attenuated inversion recovery, although that has to be tested (69). It also identifies stroke mimics. However, even when faced with the possibility of stroke mimics such as seizures, by identifying the presence or absence of an occlusion, CT angiography helps in identifying patients who are candidates for thrombolysis (70). CT angiography is also as good, if not better, at identifying worsening in patients with a transient ischemic attack (71).

Conclusion Future Directions We advocate a hierarchy of steps toward the use of perfusion imaging in clinical decision making that is, in our opinion, appropriate: (a) First, standardization of imaging protocols and image processing tools (CT vs MR imaging, what algorithm to use, differences across vendors) and data acquisition (rate of contrast agent injection, amount of contrast agent, toggling table vs static table) should be performed. These issues are easier to solve and require a cooperative effort between the scientific community and industry. In addition, rapid postprocessing software (possibly automated) that gives good-quality data to treating physicians in real time needs to be designed. (b) Next, carefully designed studies addressing some of the conceptual issues highlighted above are needed. (c) Once


The patient’s clinical stroke severity at presentation gives a fairly good estimate of dysfunctional brain tissue. The clinician is able to determine with reasonable certainty whether the patient’s clinical deficits are explained by tissue that is defined as core on a good-quality nonenhanced CT scan. CT angiography reveals the presence of an occlusion and also allows for assessment of collateral vessels. This small-core– proximal occlusion paradigm with clinical-imaging mismatch is a very good surrogate for information that can be obtained by the penumbra-core mismatch paradigm at perfusion imaging and takes less imaging time. Although no one disputes the value of the concept of penumbra and mismatch in acute ischemic stroke treatment, current perfusion techniques lack robust evidence validating their use in reliably 19


identifying the penumbra and, in addition, are affected by nonstandardized nomenclature, conceptual issues, and measurement errors. In our opinion, therefore, the use of perfusion imaging in clinical practice is premature when seen in the context of other imaging paradigms currently available that do not use this tool. Perfusion imaging in acute ischemic stroke is a promising technique; we have a responsibility to design research studies that try to increase the understanding of the role of this tool in acute ischemic stroke treatment by enrolling more patients in research studies rather than jumping the gun and using the tool as a clinical aid. We believe that a tool such as perfusion imaging that can potentially give rich information about cerebral hemodynamics deserves this approach to realize its true potential. Seen this way, we are proponents of this technique. Disclosures of Conflicts of Interest: M.G. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: received less than $10 000 as consultant to help design a stroke trial from ev3, institution received $16 900 as primary investigator for study to study carotid plaque using MR imaging from Bayer, received less than $5000 for speaking engagements from Penumbra and ev3, holds stock from Calgary Scientific and NONo. Other relationships: none to disclose. B.K.M. No relevant conflicts of interest to disclose. C.P.D. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: received consultancy fees from W. L. Gore and Associates (medical device company), holds stock in nFocus for aneurysm treatment device and Pulse Therapeutics for acute stroke treatment device. Other relationships: none to disclose.

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