Vasileios-Arsenios Lioutas, MD

The goal of all our interventions in acute ischemic stroke is salvaging as much hypoperfused tissue as possible, with the hope that this will improve clinical outcomes. Although clinically intuitive, the idea that targeting the penumbra would lead to better outcomes was not rigorously tested until the last few years when several studies, including DEFUSE 1 (published in 2006) and DEFUSE 2 (published in 2012) studied the use of MRI diffusion and perfusion imaging to select patients for treatment. The underlying idea is that following an ischemic insult, a “core” infarct of irreparably damaged tissue ensues, corresponding to increased intensity signal in the Diffusion Weighted MRI sequences. This is surrounded by hypoperfused, “stunned” tissue that is potentially salvageable, widely known as ischemic penumbra. Its imaging correlate is thought to be altered signal in perfusion weighted images that exceed the extent of the core infarction in DWI sequences; that is the penumbra is represented by the “mismatch” between PWI and DWI sequences.

Starting with broad definitions, the investigators identified imaging mismatch patterns that were thought to predict better outcome if reperfusion was achieved. This mismatch pattern was termed “target mismatch” and its main feature was defined as a ratio of critically hypoperfused tissue and ischemic core of ≥1.8. The leading hypothesis was that achieving reperfusion of the ischemic penumbra would translate into meaningful clinical outcome in patients with target mismatch profile (TMM), whereas no such relation exists in patients with no target mismatch (no TMM).

As already reported in each of the 2 studies individually, the findings support the primary hypothesis: Reperfusion correlates with favorable clinical outcome in TMM patients, whereas no TMM patients do not seem to benefit. Furthermore, increasing degree of reperfusion was associated with improved clinical outcome in TMM patients, with those within the highest quartile (94-100% reperfusion ) benefitting significantly more compared to those in the lower three quartiles. After adjusting for other independent outcome predictors (DWI lesion volume and age), each 10% increase in the degree of reperfusion had an OR of 1.3 (95% CI: 1.13-1.49) for favorable clinical response and 1.31 for good functional outcome (95% CI: 1.14-1.50).

The data is interesting, but it should be kept in mind that the total number of patients is relatively small (121 patients in total analyzed in this substudy) and especially the number of no TMM patients was limited (23 patients only), not allowing for detailed analysis in this subgroup. Also, all patients included in the two studies received either intravenous tPA or endovascular treatment (in the extended time window of >3hrs from symptom onset), essentially not including a control group.

From one point of view, the two trials could be viewed as proof-of-principle studies: they provide convincing evidence that perfusion is a reliable marker of underlying cerebral dysfunction/ischemia and that reperfusion correlates well with clinical improvement and functional outcome in a patient subgroup with a certain neuroimaging profile. Whether perfusion imaging should become routine and affect our management options (essentially classifying patients as “responders” vs “non-responders”) needs to be more extensively investigated, perhaps including patients within the 3 hour treatment window.