Understanding the Importance of Blood-Brain Barrier Alterations in Brain Arteriovenous Malformations and Implications for Treatment: A Dynamic Contrast-Enhanced-MRI-Based Prospective Study

Abstract

Background and objectives: The major clinical implication of brain arteriovenous malformations (bAVMs) is spontaneous intracranial hemorrhage. There is a growing body of experimental evidence proving that inflammation and blood-brain barrier (BBB) dysfunction are involved in both the clinical course of the disease and the risk of bleeding. However, how bAVM treatment affects perilesional BBB disturbances is yet unclear.

Methods: We assessed the permeability changes of the BBB using dynamic contrast-enhanced MRI (DCE-MRI) in a series of bAVMs (n = 35), before and at a mean of 5 (±2) days after treatment. A set of cerebral cavernous malformations (CCMs) (n = 16) was used as a control group for the assessment of the surgical-related collateral changes. The extended Tofts pharmacokinetic model was used to extract permeability (K trans ) values in the lesional, perilesional, and normal brain tissues.

Results: In patients with bAVM, the permeability of BBB was higher in the perilesional of bAVM tissue compared with the rest of the brain parenchyma (mean K trans 0.145 ± 0.104 vs 0.084 ± 0.035, P = .004). Meanwhile, no significant changes were seen in the perilesional brain of CCM cases (mean K trans 0.055 ± 0.056 vs 0.061 ± 0.026, P = .96). A significant decrease in BBB permeability was evident in the perilesional area of bAVM after surgical resection (mean K trans 0.145 ± 0.104 vs 0.096 ± 0.059, P = .037). This benefit in BBB permeability reduction after surgery seemed to surpass the relative increase in permeability inherent to the surgical manipulation.

Conclusion: In contrast to CCMs, BBB permeability in patients with bAVM is increased in the perilesional parenchyma, as assessed using DCE-MRI. However, bAVM surgical resection seems to reduce BBB permeability in the perilesional tissue. No evidence of the so-called breakthrough phenomenon was detected in our series. DCE-MRI could become a valuable tool to follow the longitudinal course of BBB damage throughout the natural history and clinical course of bAVMs.

FIGURE 1.

Evolution of Blood-Brain Barrier permeability, assessed using Dynamic Contrast-Enhanced-MRI before and after treatment of an unruptured bAVM and CCM. The first row corresponds to an unruptured left temporal bAVM case. The second row corresponds to an unruptured left frontal CCM. In both settings, the first column corresponds to the T1-weighed imaging and the manual segmentation of the lesion (red) and perilesional (green) areas of interest. The second and third columns correspond to the K_trans color maps before (second column) and after (third column) surgical treatment. The last row corresponds to the superposition of the pre and post-treatment color maps. Regions that appear in reddish tones show higher K_trans values before treatment, and regions in bluish tones show higher K_trans values after treatment. bAVM, brain arteriovenous malformation; CCM, cerebral cavernous malformation.

FIGURE 2.

Boxplot showing the basal (before treatment) values of K_trans in bAVMs and controls (CCMs), according to the Ex-Tofts model. On the left, a significant increase in BBB permeability is evident in the perilesional area of the bAVM, compared with the rest of the brain parenchyma (GM + WM). On the right, CCM does not show such an alteration of BBB. AVM, arteriovenous malformation; bAVM, brain AVM; BBB, Blood-Brain Barrier; CCM, cerebral cavernous malformation; GM, gray matter; WM, white matter.

FIGURE 3.

Boxplot showing the evolution of K_trans values before (T0) and after (T1) treatment of bAVMs and controls (CCMs), according to the Ex-Tofts model. On the left, a significant decrease in BBB permeability is seen in the perilesional area of bAVMs after surgical resection (T1), compared with the pretreatment values (T0). On the right, CCMs show a nonsignificant increase in BBB permeability after surgical resection (T1). This figure is original to this submission, so no credit or license is needed. AVM, arteriovenous malformation; bAVM, brain AVM; BBB, Blood-Brain Barrier; CCM, cerebral cavernous malformation.

FIGURE 4.

Boxplots showing the evolution of K_trans values, in the perilesional area, before (T0) and after (T1) treatment of bAVMs (top) and controls (CCMs) (bottom), according to the rupture status. In bAVMs (top), the decrease in BBB permeability after surgical treatment (T1) is seen in both ruptured (left) and unruptured (right) cases; these differences between pre- (T0) and post- (T1) K_trans values did not reach statistical significance in the stratified analysis. In CCMs, a nonsignificant increase in BBB permeability after surgical resection (T1) was seen in both ruptured (left) and unruptured (right) cases. bAVM, brain AVM; BBB, Blood-Brain Barrier; CCM, cerebral cavernous malformation.