Using Mismatch on MRI to Select Thrombolytic Responders
An Attractive Hypothesis Awaiting Confirmation
Our ability to image the ischemic penumbra in vivo raises the attractive possibility of individualized selection of acute therapy, particularly with thrombolytic agents. In other words, clinicians could potentially use magnetic resonance (MR) mismatch as a physiological tissue clock in acute stroke and allow selection of therapy beyond the accepted time windows. Indeed, this was foreshadowed nearly 25 years ago by the originators of the penumbral concept.1 As indicated by Schellinger and Fiebach, there is a body of evidence from small phase II studies to support this approach.2–4 However, prospective trials are still in progress to more rigorously test this hypothesis, and there remain significant uncertainties about the precise MRI definition of the penumbra. These include the optimal measure of perfusion (eg, mean transit time, Tmax, or time to peak), the issues of thresholding of perfusion because of benign oligemia, and the relationship between recanalization on MR angiography and reperfusion on perfusion-weighted imaging.
A further critical question that remains unanswered is the potential for diffusion-weighted imaging reversibility with thrombolysis.5 Hence, it is plausible that some nonmismatch patients might be recombinant tissue plasminogen activator (rtPA) responders. Therefore, when we designed the Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) (testing the hypothesis that using mismatch, treatment responders to rtPA can be selected in the 3- to 6-hour window), we elected not to use this as an entry criterion.4 Only by including patients without mismatch in a prospective study can this hypothesis be adequately tested. Interestingly, in the Desmoteplase in Acute Ischemic Stroke trial6 of desmoteplase 3 to 9 hours, MR mismatch was used as an entry criterion. Conversely, in the nonrandomized Diffusion-weighted imaging Evaluation for Understanding Stroke Evolution study,7 entry criteria are similar to EPITHET to enable the identification of MR patterns that predict response.
In selecting patients for thrombolysis beyond 3 hours, prediction of risk is as important as prediction of benefit. Hence, additional information required from these prospective trials will include the risk of hemorrhagic transformation in relation to the size of baseline perfusion and diffusion deficits. This emphasizes the uncertainties that exist and that it is premature to use MR treatment algorithms as a selection tool at present.
Hence, although not as skeptical as Zivin, we share his view that a higher level of evidence is required before MR mismatch can be used as a routine clinical tool. However, the concept is so attractive that it seems likely to be useful in some form or other.
“You may say I’m a dreamer, but I’m not the only one.”
— John Lennon, “Imagine,” 1977
- Received October 21, 2004.
- Accepted October 22, 2004.
Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia—the ischemic penumbra. Stroke. 1981; 12: 723–725.
Rother J, Schellinger PD, Gass A, Siebler M, Villringer A, Fiebach JB, Fiehler J, Jansen O, Kucinski T, Schoder V, Szabo K, Junge-Hulsing GJ, Hennerici M, Zeumer H, Sartor K, Weiller C, Hacke W. Effect of intravenous thrombolysis on MRI parameters and functional outcome in acute stroke ≈6 hours. Stroke. 2002; 33: 2438–2445.
Chalela JA, Kang DW, Luby M, Ezzeddine M, Latour LL, Todd JW, Dunn B, Warach S. Early magnetic resonance imaging findings in patients receiving tissue plasminogen activator predict outcome: insights into the pathophysiology of acute stroke in the thrombolysis era. Ann Neurol. 2004; 55: 105–112.
Kidwell CS, Alger JR, Saver JL. Beyond mismatch: evolving paradigms in imaging the ischemic penumbra with multimodal magnetic resonance imaging. Stroke. 2003; 34: 2729–2735.
Hacke W. The DIAS study: results of a phase II, MRI-based dose finding study of desmoteplase and acute stroke. 29th International Stroke Conference. San Diego, Calif; February 5–7, 2004.
Wechsler LR. Can DWI/PWI identify patients who are likely to benefit from thrombolytic therapy? Thrombolysis and Acute Stroke Therapy—Satellite Symposium of the 5th World Stroke Conference. Whistler, BC; June 19–22, 2004.