Is Penumbral Imaging Useful for Extendingthe Treatment Window for Intravenous

Tissue Plasminogen Activator?

The results of the DEFUSE study reported in this issueof Annals provide important preliminary informationconcerning the potential utility of magnetic resonanceimaging (MRI)–based imaging of the ischemic penum-bra and the response to intravenous (IV) tissue plas-minogen activator (t-PA) therapy 3 to 6 hours after theonset of ischemic stroke.1 The primary observationprovided by the DEFUSE data set is that patients witha perfusion–diffusion mismatch of moderate size orgreater and early reperfusion documented by perfusion-weighted imaging (PWI) had a significantly greaterlikelihood of a favorable clinical outcome at day 30,especially when adjusted for baseline National Insti-tutes of Health Stroke Scale status and PWI lesion vol-ume. An example of such reperfusion is provided inthe Figure. In addition, it was observed after a pre-specified interim analysis that patients with large(�100ml) baseline diffusion lesion volumes and/orlarge, severe PWI lesions, called malignant mismatch,were at high risk for symptomatic intracerebral hemor-rhage and a poor outcome. When these “malignantmismatch” patients were excluded from the overallpopulation of patients with a PWI/diffusion-weightedimaging (DWI) mismatch, the “target mismatch” pa-tients with early reperfusion were even more likely tohave a favorable 30-day outcome than the overall mis-match population. Surprisingly, patients without a mis-match who did not demonstrate early reperfusion hadthe most favorable outcome profile of all of the imag-ing defined subgroups in the study. Only seven pa-tients had such a profile, and this observation high-lights a major deficiency of the study: the smallnumber of patients included. It is certainly counterin-tuitive to presume that t-PA therapy not inducing earlyreperfusion will be associated with a greater probabilityof a favorable, delayed clinical outcome, because manystudies have found a correlation between early reperfu-sion status and clinical outcome.2,3 Another importantaspect of the DEFUSE study was the observation thatearly recanalization on magnetic resonance angiographycorrelated with a reduction in PWI lesion volume. Pa-tients with small baseline lesions who could not be as-sessed for a PWI/DWI mismatch comprised 26% ofthe population, and not surprisingly, these patients hada high rate of good clinical outcome at day 30.

DEFUSE is an observational study that evaluated

imaging and clinical responses to IV t-PA therapygiven 3 to 6 hours after stroke onset. Patients were notrandomly or blindly assigned to treatment, there wasno placebo group, and therapy decisions were notbased on the imaging pattern observed. As such, itshould be viewed as hypothesis generating that shouldprovide useful information that can be tested in futurerandomized and blinded studies. The results suggestthat stroke patients with a PWI/DWI mismatch and aDWI baseline lesion that is not too large (�100ml) ora PWI lesion that is not too large or with too severe adecline in tissue perfusion are most likely to benefitfrom early reperfusion. Several other preliminary stud-ies support this hypothesis. Two reports of the openuse of IV t-PA in the 3- to 6-hour time window inpatients with at least a 20% greater PWI versus DWIlesion volume demonstrated a rate of favorable clinicaloutcome comparable with that observed with the useof IV t-PA in the 0- to 3-hour window at the centerstreating the patients.4,5 Two small phase II trials withanother thrombolytic drug, desmoteplase, have beenperformed and reported.6,7 In both of these studies,patients were randomly and blindly assigned to activetreatment with desmoteplase or placebo 3 to 9 hoursafter stroke onset, if they demonstrated at least a 20%or greater PWI than DWI lesion volume. The125�g/kg dose was associated with a significant in-crease in early reperfusion on PWI, magnetic resonanceangiography, or both, and this dose also improved clin-ical outcome. The risk for symptomatic intracerebralhemorrhage was very low. The results of these prelim-inary desmoteplase studies were encouraging and pre-cipitated an ongoing larger study that could eventuallylead to regulatory approval of a stroke treatment with a9-hour treatment window based on imaging identifica-tion of the presence of residual ischemic penumbra.Penumbral imaging to identify presumably appropriatepatients for reperfusion therapy is being used in theMR and Recanalization of Stroke Clots Using Embo-lectomy (MR-RESCUE) study (C. Kidwell, personalcommunication). In this study, the clot-retrievingMERCI device is being evaluated in patients undergo-ing DWI/PWI up to 8 hours after stroke onset to de-termine whether successful endovascular therapy ismore likely to improve outcome in stroke patients with

EDITORIALS

© 2006 American Neurological Association 499Published by Wiley-Liss, Inc., through Wiley Subscription Services

an MRI-documented ischemic penumbra than in pa-tients without a penumbra.

The current use of a PWI/DWI mismatch to iden-tify purported ischemic penumbra must be acknowl-edged as an approximation.8 The mismatch is depen-dent on how the region of abnormality is identified onMRI modalities, and the accuracy of identifying abnor-malities is more problematic for PWI. Defining DWIregions of abnormality by hyperintensity is relativelystraightforward either by a trained observer or in asemiautomated manner. However, it must be acknowl-edged that early after the onset of focal ischemia, DWIabnormalities can be partially reversed with timelyreperfusion, especially when the decline in apparentdiffusion coefficient values are not severe.9 Definingabnormality on PWI is more problematic and less stan-dardized. In the DEFUSE study, Tmax values with adelay of 2 seconds or more were used to identify thePWI lesion and its volume. Other PWI/DWI studieshave used delayed mean transit time or time to peak ofvarying degrees to identify the abnormality on PWI.10

How PWI abnormality is defined and used to calculatethe PWI lesion volume is critical for quantifying thePWI/DWI mismatch, and no gold standard currentlyexists. It must also be recognized that bolus contrastPWI as currently used in clinical practice only provides

an approximation of absolute tissue perfusion, andhence cerebral blood flow. With more accurate mea-surements of these parameters provided by arterial spinlabeling PWI, it is likely that better predictive modelsof tissue fate will evolve. In animal models, it was ob-served that using arterial spin-labeling perfusion andabsolute diffusion coefficient maps can predict tissueresponses to reperfusion on a pixel-by-pixel basis with ahigh degree of probability.11 The somewhat imprecisenature of penumbral identification used in the DE-FUSE study must be acknowledged.

In the future, more temporally precise and spatiallyelegant methods for identifying the ischemic penumbraearly after stroke onset will become available, leading tomore accurate predictions of tissue and clinical out-come after successful reperfusion and with neuropro-tection. Penumbral imaging can also be performedwith perfusion computed tomography, but many of thesame concerns raised for PWI/DWI are present withthis approach as well.12 Physicians who care for strokepatients need to be aware that penumbral imaging withMRI or computed tomography is in its infancy andwill evolve rapidly over the next few years. Studies suchas DEFUSE will pave the way for such advances, be-cause they provide novel data and pose challengingquestions to be answered by future investigations

Fig. Baseline diffusion/perfusion magnetic resonance imaging demonstrates a large left middle cerebral artery perfusion lesion andsmall diffusion lesion with a proximal occlusion on magnetic resonance angiography (MRA). At 24 hours, the perfusion lesion haslargely resolved, the diffusion lesion has not enlarged, and the proximal middle cerebral artery occlusion has resolved. The patienthad an excellent clinical outcome. DWI � diffusion-weighted imaging; MTT � mean transit time. (Courtesy Dr Italo Linfante)

500 Annals of Neurology Vol 60 No 5 November 2006

driven by hypotheses generated by well-conceived, im-plemented, and analyzed clinical studies, as exemplifiedby DEFUSE.

Marc Fisher, MD

Department of NeurologyUniversity of Massachusetts Medical SchoolWorcester, MA

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11. Shen Q, Fisher M, Sotak CH, Duong TQ. Effects of reperfu-sion on ADC and CBF pixel-by-pixel dynamics in stroke: char-acterizing tissue fates using quantitative diffusion and perfusionimaging. J Cereb Blood Flow Metab 2004;24:280–290.

12. Wintermark M, Flanders AE, Velthius B, et al. Perfusion-CTassessment of infarct core and penumbra: receiver operatingcharacteristic curve analysis in 130 patients suspected of hemi-spheric stroke. Stroke 2006;37:1771–1777.

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