Extent of FLAIR Hyperintense Vessels May Modify Treatment Effect of Thrombolysis: A Post hoc Analysis of the WAKE-UP Trial

Abstract

Background and Aims: Fluid-attenuated inversion recovery (FLAIR) hyperintense vessels (FHVs) on MRI are a radiological marker of vessel occlusion and indirect sign of collateral circulation. However, the clinical relevance is uncertain. We explored whether the extent of FHVs is associated with outcome and how FHVs modify treatment effect of thrombolysis in a subgroup of patients with confirmed unilateral vessel occlusion from the randomized controlled WAKE-UP trial. Methods: One hundred sixty-five patients were analyzed. Two blinded raters independently assessed the presence and extent of FHVs (defined as the number of slices with visible FHV multiplied by FLAIR slice thickness). Patients were then separated into two groups to distinguish between few and extensive FHVs (dichotomization at the median <30 or ≥30). Results: Here, 85% of all patients (n = 140) and 95% of middle cerebral artery (MCA) occlusion patients (n = 127) showed FHVs at baseline. Between MCA occlusion patients with few and extensive FHVs, no differences were identified in relative lesion growth (p = 0.971) and short-term [follow-up National Institutes of Health Stroke Scale (NIHSS) score; p = 0.342] or long-term functional recovery [modified Rankin Scale (mRS) <2 at 90 days poststroke; p = 0.607]. In linear regression analysis, baseline extent of FHV (defined as a continuous variable) was highly associated with volume of hypoperfused tissue (β = 2.161; 95% CI 0.96-3.36; p = 0.001). In multivariable regression analysis adjusted for treatment group, stroke severity, lesion volume, occlusion site, and recanalization, FHV did not modify functional recovery. However, in patients with few FHVs, the odds for good functional outcome (mRS) were increased in recombinant tissue plasminogen activator (rtPA) patients compared to those who received placebo [odds ratio (OR) = 5.3; 95% CI 1.2-24.0], whereas no apparent benefit was observed in patients with extensive FHVs (OR = 1.1; 95% CI 0.3-3.8), p-value for interaction was 0.11. Conclusion: While the extent of FHVs on baseline did not alter the evolution of stroke in terms of lesion progression or functional recovery, it may modify treatment effect and should therefore be considered relevant additional information in those patients who are eligible for intravenous thrombolysis. Clinical Trial Registration: Main trial (WAKE-UP): ClinicalTrials.gov, NCT01525290; and EudraCT, 2011-005906-32. Registered February 2, 2012.

Keywords: FLAIR hyperintensities; MRI; hyperintense vessel; ischemic stroke; prognosis; thrombolysis; wake-up stroke.

Figure 1

Patient A and Patient B represent two cases at different ends of the spectrum of the extent of FLAIR hyperintense vessels (FHVs). Patient A is a 69-year-old female with a left-sided M2 branch occlusion and baseline FHV extent of 60 (multiple linear and serpentine vessels visible surrounding the operculum and temporal lobe on all three images). Patient B is a 70-year-old male with a right-sided occlusion in the M2 branch of the middle cerebral artery whose initial extent of FHVs at baseline was 13 (a single serpentine vessel is visible between the operculum and the temporal lobe on the middle image). Both were treated with placebo; the modified Rankin Scale (mRS) at 90 days was 0 for patient A and 3 for patient B. Patients C and D represent cases with comparable FHV patterns but different stroke extent and severity at baseline. A comparison of two patients, one a 44-year-old male (patient C) and the other a 46-year-old female (patient D), both with a left-sided occlusion of the mainstem middle cerebral artery (MCA). The baseline extent of FHVs was 30 for both cases with a comparable distribution of vessels, yet the stroke volumes and distributions were different. Patient C showed only small scattered lesions in the insula, tip of the putamen, as well as the temporal and parietal lobes (total volume of 3 ml), while patient D showed an infarction encompassing the entire putamen and nucleus caudatus as well as portions of the insula and operculum, with additionally some scattered lesions in the frontal and parietal lobes (total volume of 15 ml). Their baseline National Institutes of Health Stroke Scale (NIHSS) score was also different (6 for patient C and 20 for patient D). At follow-up, both patients recanalized [patient C received recombinant tissue plasminogen activator (rtPA) and patient D received placebo]. They had a similar dynamics of FHVs showing a reduction in their extent (a complete reduction to zero in patient C and a partial reduction to 12 in patient D). Their mRS outcome at 90 days was 1 for patient C and 3 for patient D.

Figure 2

Predicted probability of good clinical outcome [modified Rankin Scale (mRS) <2] in patients grouped according to treatment, plotted against the extent of FLAIR hyperintense vessels (FHVs) on baseline imaging. The continuous blue line represents recombinant tissue plasminogen activator (rtPA)-treated patients, and the dotted red line stands for patients who received placebo.

Figure 3

Patients A and B represent cases with comparable stroke evolution yet differing evolution of FLAIR hyperintense vessels (FHVs) between baseline and follow-up imaging. Both 64-year-old males with a right-sided M1 occlusion. Patient A additionally had an occlusion of the ipsilateral internal carotid artery (ICA). The baseline lesions were comparable in terms of volume and pattern (predominantly basal ganglia involvement and lesion size up to 20 ml). Their baseline National Institutes of Health Stroke Scale (NIHSS) score was also comparable (15 for patient A and 14 for patient B). The baseline extent of FHVs was different between the patients (30 in patient A and 50 in patient B). Both patients received placebo, and neither of them experienced a recanalization by the time of follow-up. There was a pronounced difference in the dynamics of FHVs between the patients, with patient A showing no more visible FHVs at follow-up, whereas the extent of FHVs in patient B actually increased from 50 to 55. Their outcome, however, was the same (both had a 90-day mRS of 4), and their final lesion volumes were almost identical (patient A 52 ml and patient B 59 ml).