Identification of Reversible Disruption of the Human Blood-Brain Barrier Following Acute Ischemia

Abstract

Background and purpose: Animal models of acute cerebral ischemia have demonstrated that diffuse blood-brain barrier (BBB) disruption can be reversible after early reperfusion. However, irreversible, focal BBB disruption in humans is associated with hemorrhagic transformation in patients receiving intravenous thrombolytic therapy. The goal of this study was to use a magnetic resonance imaging biomarker of BBB permeability to differentiate these 2 forms of BBB disruption.

Methods: Acute stroke patients imaged with magnetic resonance imaging before, 2 hours after, and 24 hours after treatment with intravenous tissue-type plasminogen activator were included. The average BBB permeability of the acute ischemic region before and 2 hours after treatment was calculated using a T2* perfusion-weighted source images. Change in average permeability was compared with percent reperfusion using linear regression. Focal regions of maximal BBB permeability from the pretreatment magnetic resonance imaging were compared with the occurrence of parenchymal hematoma (PH) formation on the 24-hour magnetic resonance imaging scan using logistic regression.

Results: Signals indicating reversible BBB permeability were detected in 18/36 patients. Change in average BBB permeability correlated inversely with percent reperfusion (P=0.006), indicating that early reperfusion is associated with decreased BBB permeability, whereas sustained ischemia is associated with increased BBB disruption. Focal regions of maximal BBB permeability were significantly associated with subsequent formation of PH (P=0.013).

Conclusions: This study demonstrates that diffuse, mild BBB disruption in the acutely ischemic human brain is reversible with reperfusion. This study also confirms prior findings that focal severe BBB disruption confers an increased risk of hemorrhagic transformation in patients treated with intravenous tissue-type plasminogen activator.

Keywords: acute stroke; blood–brain barrier; hemorrhagic transformation; magnetic resonance imaging; permeability imaging.

Figure 1

Panel A shows a scatter plot of the average permeability prior to treatment on the x-axis and the average permeability 2 hours after treatment on the y-axis. Dots falling on the blue line showed no change, while those below the line showed reversal of BBB permeability and those above the blue line show an increase in BBB permeability. Panel B shows a scatter plot of the change in average BBB permeability vs. the percent reperfusion. The red curve fit line demonstrates that when there was a high percent of reperfusion there was a decrease in BBB permeability, whereas in the absence of reperfusion, BBB permeability was more likely to increase. The p-value reflects the significance of this association from their linear regression.

Figure 2

An example of a patient with severe focal BBB disruption who went on to suffer a parenchymal hematoma is shown. Panels A, B and C are from the pre-treatment scan and panel D is from the 24 hour scan. Panel A shows the diffusion weighted image with early ischemic changes. Panel B shows the ischemic lesion on the time-to-peak map of the perfusion-weighted imaging (PWI). Panel C shows the blood-brain permeability map overlain on the source image from the PWI acquisition; the color code represents increasing blood-brain barrier (BBB) permeability going from green, to yellow, to orange, to red (greatest). Panel D shows the gradient echo images 24 hours later with a large parenchymal hematoma centered on the area of focal BBB disruption.