EDITORIAL

Improving the Accuracy of PerfusionImaging in Acute Ischemic Stroke

The basic premise underlying acute stroke therapy is

to salvage some portion of the ischemic region from

evolving into infarction, thereby partially or even com-

pletely maintaining brain function and improving out-

come.1 The concept of preserving ischemic brain with

timely intervention(s) and preventing infarction implies

that salvageable tissue is present for a period of time after

ischemic stroke onset and directly relates to the proposal

of Astrup and colleagues in 1981 of the ischemic penum-

bra.2 As proposed by Astrup and colleagues, the ischemic

penumbra was defined as a region of reduced cerebral

blood flow (CBF) with absent electrical activity but pre-

served ion homeostasis and transmembrane electrical

potentials. Many subsequent definitions for the ischemic

penumbra were proposed, but the most clinically relevant

ones are potentially reversible ischemic tissue by Hakim

and the target of acute stroke therapy by Fisher.3,4 The

ischemic penumbra concept envisions not only poten-

tially salvageable or at-risk ischemic tissue but also nonvi-

able tissue also identified as the ischemic core. Initial

imaging of at-risk and nonviable ischemic tissue was

obtained with positron emission tomography (PET) stud-

ies that provide quantitative measurements of CBF, the

metabolic rate of oxygen (CMRO2), and the rate of oxy-

gen extraction by brain tissue. With PET, penumbral

ischemic tissue is characterized by an increase in oxygen

extraction fraction (OEF) with reduced CBF and

CMRO2, whereas the ischemic core has very low CBF

levels and CMRO2 with poor OEF.5 The CBF levels in

the ischemic core were identified to be <12ml/100g/

min, and in the penumbral region the levels were 12 to

25ml/100g/min. A third ischemic tissue type, oligemic or

not at-risk tissue, was also identified by PET and is

defined as a region with reduced CBF, increased OEF,

and normal CMRO2 . PET studies have substantial pre-

cision for distinguishing these 3 ischemic regions, but are

not practical for clinical acute stroke imaging, because

PET scanners are not readily available, and the imaging

and data processing time required is too lengthy.With the advent of diffusion/perfusion MRI in the

1990s, hope arose that a clinically available imaging

modality with a relatively rapid acquisition and dataprocessing time in experienced hands could be useful foridentification of the ischemic penumbra. On diffusion-weighted magnetic resonance imaging (MRI) (diffusion-weighted imaging; DWI), regions of hyperintensity arereadily identified and represent ischemic tissue where ionhomeostasis has been lost and cytotoxic edema hasoccurred.6 This DWI hyperintense region provides anapproximation of the ischemic core, but it must beacknowledged that DWI hyperintensity can be partiallyreversed with early reperfusion.7 Recent data from boththe EPITHET and DEFUSE studies indicate that theamount of DWI reversal is typically very small andunlikely to be clinically relevant.8 Therefore, the acuteDWI lesion appears to provide a very good surrogate foracute irreversible tissue injury. The fact that DWI lesioncan integrate the degree of injury over time provides adistinct advantage over CBF values that may fluctuatedynamically. For example, a single snapshot of brain per-fusion does not provide information regarding the inten-sity and duration of the blood flow disturbance thatoccurred during the previous few hours.

Bolus contrast perfusion MRI (perfusion-weightedimaging; PWI) provides a qualitative picture of thebrain’s microcirculation. Regions of PWI abnormalitythat are normal on DWI, the PWI/DWI mismatch, canapproximate the ischemic penumbra.9 A key unresolvedissue has been how to optimally identify and quantifythe PWI abnormality, and multiple different parametersincluding CBF, mean transit time, time to peak, andTmax (time-to-maximum of the residue function) mapshave been used, as discussed by Dani et al in this issueof Annals of Neurology.10 Furthermore, it has becomeclear that a method for quantitative thresholding of per-fusion maps is extremely important, because mild distur-bances in perfusion, even if persistent, do not result inbrain infarction.11 Recent PET studies have demonstratedthat when optimal parameters and thresholds areemployed, PWI can provide high sensitivity and specific-ity for identification of PET-determined penumbralflow.12,13 For example, in a recent study that imagedacute stroke patients with both PWI and PET, a receiveroperating characteristic analysis yielded an area under thecurve of 0.95 for detection of PET-confirmed CBF

VC 2011 American Neurological Association 347

<20ml/100ml/min with an optimal Tmax threshold of5.5 seconds.13 Although less well studied at present, per-fusion computed tomography (CTP) is another imagingmodality that qualitatively evaluates brain perfusion, andvarious definitions of penumbral tissue and ischemic corehave been proposed for CTP.14

The systematic review by Dani et al in this month’sAnnals of Neurology evaluated the definitions of at-risk,nonviable, and not at-risk ischemic tissue imaged byDWI/PWI or CTP up to 24 hours after ischemic strokeonset, as well as the quality of the studies included.10

They identified 21 MRI and 10 CTP papers that mettheir inclusion/exclusion criteria and provided adequatetissue definitions. Despite the small number of studies,the authors found that both the MRI and the computedtomography (CT) studies provided multiple differentdefinitions of nonviable versus penumbral tissue versusnot at-risk tissue. Overall study quality was judged tobe poor, with incomplete descriptions of patient selec-tion criteria, assessment of final outcome, and howimages were acquired/analyzed. A key issue in determin-ing the accuracy of tissue thresholds is how the earlyimaging study is evaluated in relationship to finalinfarct size or coregistered with established PET param-eters. Only 3 MRI studies were evaluated in relationshipto PET studies, whereas 18 were evaluated in relation-ship to follow-up MRI or CT studies, as were all 10CTP studies, but at varying delayed imaging timepoints. The studies included were relatively small, rang-ing from 5 to 101 patients, with a wide range of base-line stroke severity and initial median imaging timesfrom 90 to 978 minutes after stroke onset. The authorscorrectly point out that few studies evaluated gray andwhite matter thresholds separately, despite increasinginformation supporting that these 2 tissue types havediffering perfusion thresholds of nonviability and poten-tial salvage.

The systematic review by Dani et al provides ampleevidence of the current confusion and uncertainty sur-rounding the capability of both PWI and CTP for distin-guishing the various ischemic tissue subtypes. Theauthors appropriately warn that nonvalidated perfusionimaging thresholds should not be used to make routineclinical decisions. The article also highlights a number ofissues that should motivate researchers in this field towork more collaboratively. Standardization of perfusionacquisition and analysis techniques are the most funda-mental challenges.

Dani and colleagues reviewed articles published upto August 2009. Since that time, substantial progress hasoccurred. One example is the DEFUSE/EPITHET datapooling project. This collaboration includes 174 prospec-tively collected acute stroke patients from the DEFUSEand EPITHET studies. Both PWI/DWI and magneticresonance angiography were performed between 3 and 6hours after symptom onset and again following treatment

with either tissue plasminogen activator or placebo, toallow assessment of both reperfusion and recanalization.A full assessment of clinical outcomes and final infarctvolumes was included. This collaboration has directlyaddressed many of the issues raised in the Dani paper. Forexample, although DEFUSE and EPITHET both usedTmax as the PWI parameter of choice for identificationof critical hypoperfusion, the software programs used todetermine Tmax volumes differed, leading to significantvariance in the volumes of hypoperfusion reported ineach study.15 For the pooled DEFUSE/EPITHET analy-sis, both PWI and DWI data from each study were ana-lyzed by the same software (RAPID) to standardize theresults.15,16 Analysis of this standardized data set demon-strated that Tmax was superior to mean transit time fordifferentiating critical hypoperfusion from benign olige-mia in patients who did not reperfuse.17 The optimalTmax threshold was 5 seconds, which is nearly identicalto the 5.5-second threshold determined to be optimal fordetecting penumbral flow in the recent PET studydescribed above.13 Using the RAPID threshold that mostclosely approximates this optimal PWI threshold (Tmax> 6 seconds) and a PWI/DWI mismatch ratio of 1.2 todifferentiate the Target Mismatch profile from the NoMismatch profile, the pooled DEFUSE/EPITHET data-base demonstrated a potent association between reperfu-sion and favorable 90-day clinical outcomes (odds ratio,5.6; 95% confidence interval, 2.1–15.3) and attenuationof infarct growth (10 6 23ml with reperfusion vs 40 6

44ml without reperfusion p < 0.001) in Target Mis-match patients.15 In contrast, there was no associationbetween reperfusion and favorable outcomes or attenua-tion of lesion growth in the No Mismatch profilepatients. Furthermore, using an optimized threshold(Tmax > 8-second delay with a PWI volume > 85ml) toidentify the Malignant Profile, such patients who experi-enced reperfusion had a higher incidence of both paren-chymal hematomas (67% vs 11%, p < 0.01) and verypoor clinical outcomes (modified Rankin 5–6 at 90 days;89% vs 39%, p ¼ 0.02) compared with nonreperfusers.18

It is important to acknowledge that these analyses of thepooled DEFUSE/EPITHET studies were post hoc andrequire validation in prospective trials. The ongoingDEFUSE 2 and EXTEND studies are currently attempt-ing validation using fully automated real-time DWI andPWI analysis with the RAPID imaging analysis softwareprogram at all sites.

In conclusion, we congratulate Dani et al forhighlighting many of the current limitations of perfu-sion imaging for assessment of acute stroke. They haveproposed criteria that investigators in this field shouldstrive to achieve. We believe the paradigm for acutestroke treatment in the future will move away fromarbitrary time windows. Identification of salvageablebrain tissue and determining the site of vascularobstruction will become the focus of acute imaging.

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348 Volume 70, No. 3

Treatment strategies can then be individualized to max-imize reperfusion of viable tissue.

Potential Conflicts of Interest

G.W.A.: consultant, Lundbeck; grants/grants pending,NIH. M.F.: board membership, Servier, CoAxia, Photo-thera; consultancy, Olea Medical, Ferrer, Sygnis, Mitsu-bishi Pharma USA, Bioclinica; expert testimony, Masspro;grants/grants pending, Sygnis; compensated by AmericanHeart Association as Editor-in-Chief of Stroke.

Gregory W. Albers, MD1

Marc Fisher, MD2

1Department of Neurology

Neurological Sciences and the Stanford Stroke Center

Stanford University Medical Center

Stanford, CA2Department of Neurology

University of Massachusetts Medical School

Worcester, MA

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DOI: 10.1002/ana.22524

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