The exact time of symptom onset cannot be determined for up to a fourth of acute stroke patients. In such cases, clinicians often use magnetic resonance imaging (MRI), in particular a difference of signal intensities between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) sequences to approximate the age of a lesion.  Cytotoxic edema appears minutes after stroke onset and can be visualized using DWI.  Comparing this to FLAIR, which can demonstrate the vasogenic edema that appears hours after stroke onset, the so-called DWI/FLAIR mismatch has been proposed as a predictor with regards to the 4.5h window for intravenous thrombolysis. However, the sensitivity of DWI/FLAIR mismatch between studies. These variations are in part explained by imaging techniques, but it is likely that pathophysiological variables such as collateral circulation significantly contribute as well. Wouters et al. sought to investigate the association between timing of DWI/FLAIR mismatch and collateral circulation using hypoperfusion intensity ratio (HIR), a measurement of perfusion weighted imaging (PWI) severity that has been shown to be a good predictor for poor collaterals.

The authors utilized clinical and neuroimaging data from the AXIS 2 trial, a multicenter Phase IIb placebo-controlled, randomized and double blinded trial investigating recombinant Granulocyte Colony Stimulating Factor in acute stroke. A total of 141 patients were included for analysis, excluding patients with incomplete imaging sequences, severe FLAIR lesions overlapping the acute lesion or in the contralateral hemisphere (as the contralateral hemisphere was used for FLAIR intensity measurement), or reperfused core. Quantitative relative FLAIR maps (rFLAIR) were calculated in a voxel-based manner using in house software. Collateral status assessed by HIR was dichotomized into “good” (n= 87, 61.7%) and “poor” (n= 54, 38.3%). Patients with poor collaterals had more severe stroke symptoms at baseline (NIHSS 14 vs NIHSS 11, p= 0.01), larger DWI lesion volumes (47.2 mL vs 14.6 mL, p= <0.01), and larger TMax > 6s perfusion volumes (91.5 mL vs 45.8 mL, p=0.01). 

The predictive value of time for rFLAIR intensity was moderate in patients with poor collateral circulation (R2 = 0.28), but poor in patients with good collateral circulation (R2 = 0.03). The relationship between time from onset to rFLAIR signal intensity was stronger in patients with poor collaterals compared to those with good collaterals (p for interaction = 0.04). In addition, a strong interaction between increased Tmax in the region of perfusion deficit (a measurement of hypoperfusion severity) on the association between time and rFLAIR intensity was identified (p=0.001).

This study reinforces the concept that the development of DWI/FLAIR mismatch as a marker for ischemia is dependent on the severity of hypoperfusion. The authors’ omission of digital subtraction angiography (DSA) in the study precludes a definitive association with collateral status, but as the authors note, the HIR technique that was utilized has shown to have good correlation with DSA-assessed collateral circulation. These findings also provide valuable insight into the relationship between collateral status and the timing of DWI/FLAIR mismatch which will prove useful for clinical trials using this assessment as a substitute for last known well in cases where this is unable to be determined from history. Based on these results, patients with good collateral circulation may be misidentified as having lesions <4.5h old. Whether these patients would receive the same benefit from intravenous thrombolysis as compared to patients with poor collaterals and younger lesions presents an interesting avenue for future research, as DWI/FLAIR mismatch may emerge as a viable alternative to time of last known well in determining progression of ischemia in the context of thrombolysis eligibility.