MR Mismatch Is Useful for Patient Selection for Thrombolysis
The clinical constellation of a large MCA stroke with a substantial mismatch between DWI and PWI in the 3- to 6-hour time window is for many stroke neurologists an indication for the off-label use of intravenous t-PA. Clinical practice, however, frequently shows that a significant mismatch can persist for days and that such patients typically improve without any recanalizing therapy. Mismatch imaging may thus not only identify patients with a salvageable penumbra eligible for thrombolysis but also those who may simply recover on their own. To equate the mismatch in a stroke patient with a treatment indication may therefore not be inappropriate.
The mismatch or the penumbra imaging concept was developed by experimental studies and translated into human stroke almost a decade ago. Until today several hundred patients were investigated mainly in smaller unblinded and nonrandomized studies. These data suggested that in patients with a mismatch in the 3- to 6-hour time window thrombolysis may hasten recanalization and reperfusion, possibly reducing infarct growth and improving clinical outcome.1 Unfortunately, in the recently published first-ever randomized controlled study in this context (EPITHET),2 neither the primary end point—geometric mean relative infarct growth—nor clinical outcome was positive. One explanation might be that sponaneously recovering subjects selected by mismatch MRI dilute the patient samples, a factor at least in part responsible for the negative results in the DIAS 2 trial.
For acute MRI lesions that recover without recanalizing therapy, collateral blood supply probably reflects the most important cause for longterm persistance of penumbral tissue and the opportunity for endogenous repair. It is well known that patients with good collaterals have relatively large areas of mild hypoperfused tissue than those with poor collaterals.3 Infarct growth within the penumbral zone is typically smaller when collaterals are better. Infarct growth, on the other hand, occurs even in absence of a mismatch.4 Poor collateral flow is known as an important determinant of tissue fate, particularly in the setting of poor or partial recanalization after treatment and extensive mismatch on the pretreatment MRI. The largest enlargement of DWI lesion volumes were observed with an increase in mismatch volume in patients with poor collaterals, compared with patients with good collaterals.3 Another important point is certainly the location of the infarction. Infarcts attributable to proximal MCA occlusion sparing the insula but involving the subcortical gray and white matter indicate good pial collateral flow, whereas a MCA occlusion with an infarct including the insula can be a harbinger of insufficient cortical collaterals and thus infarct growth.5
Another problematic point derives from technical issues. There is no existing gold standard as to how MRI perfusion images should be obtained and what imaging thresholds are used to define the hypoperfused area. In fact, perfusion lesions can have at least a 50% variation depending on the processing method.6 This technical problem is reflected by the EPITHET trial which allowed, because of the complexity of the exact mismatch assessment in the acute stroke situation, no randomization based on the initial mismatch itself. These unsettled technical issues make it certainly unacceptable to base treatment decisions routinely on presence of a MR mismatch.
The mismatch concept is certainly a pathophysiologically established concept indicating salvageable tissue in the direct vicinity of a cerebral infarction. The concept is, however, more complex than the previously propagated idea that existence of a mismatch equals by all means patient responders requiring treatment, eg, thrombolysis. Every mismatch is presumably crucially determined by collateral blood flow depending on the size and the location of the infarction, a factum which was neglected so far. Collateral blood flow should therefore be assessed in patients presenting with a mismatch, representing, however, a major technical challenge. Collateral flow is typically assessed by conventional angiography, a method certainly not available for the majority of acute stroke patients. This indicates the need of new tomography based methods for visualization of collateral blood flow. Other technical obstacles include the need for internationalized standards for the perfusion processing methods. Until these requirements are fulfilled, the use of mismatch imaging as a basis for further therapeutic decisions should be reserved for experts in specialized stroke centers.
- Received March 17, 2009.
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