Silent intralesional microhemorrhage as a risk factor for brain arteriovenous malformation rupture

Abstract

Background and purpose: We investigated whether brain arteriovenous malformation silent intralesional microhemorrhage, that is, asymptomatic bleeding in the nidal compartment, might serve as a marker for increased risk of symptomatic intracranial hemorrhage (ICH). We evaluated 2 markers to assess the occurrence of silent intralesional microhemorrhage: neuroradiological assessment of evidence of old hemorrhage-imaging evidence of bleeding before the outcome events-and hemosiderin positivity in hematoxylin and eosin-stained paraffin block sections.

Methods: We identified cases from our brain arteriovenous malformation database with recorded neuroradiological data or available surgical paraffin blocks. Using 2 end points, index ICH or new ICH after diagnosis (censored at treatment, loss to follow-up, or death), we performed logistic or Cox regression to assess evidence of old hemorrhage and hemosiderin positivity adjusting for age, sex, deep-only venous drainage, maximal brain arteriovenous malformation size, deep location, and associated arterial aneurysms.

Results: Evidence of old hemorrhage was present in 6.5% (n=975) of patients and highly predictive of index ICH (P<0.001; OR, 3.97; 95% CI, 2.1-7.5) adjusting for other risk factors. In a multivariable model (n=643), evidence of old hemorrhage was an independent predictor of new ICH (hazard ratio, 3.53; 95% CI, 1.35-9.23; P=0.010). Hemosiderin positivity was found in 36.2% (29.6% in unruptured; 47.8% in ruptured; P=0.04) and associated with index ICH in univariate (OR, 2.18; 95% CI, 1.03-4.61; P=0.042; n=127) and multivariable models (OR, 3.64; 95% CI, 1.11-12.00; P=0.034; n=79).

Conclusions: The prevalence of silent intralesional microhemorrhage is high and there is evidence for an association with both index and subsequent ICH. Further development of means to detect silent intralesional microhemorrhage during brain arteriovenous malformation evaluation may present an opportunity to improve risk stratification, especially for unruptured brain arteriovenous malformations.

Figure 1

Representative case scored positive for “evidence of old hemorrhage (EOOH)”. Cerebellar AVM with evidence of prior hemorrhage. A 42 year old woman was diagnosed with an asymptomatic AVM of the cerebellum. MRI demonstrates encephalomalacia of the inferior vermis and medial and inferior left cerebellar hemisphere. Axial T2 weighted fast spin echo (A, C) and coronal gradient echo (B) images reveal low signal consistent with hemosiderin (white arrowheads) staining the brain surrounding the AVM. The AVM itself is evident as a linear focus of enhancement (compare panel D axial T1 spin echo to panel E axial T1 spin echo post gadolinium) between black arrowheads in the center of the hemosiderin stained brain parenchyma.

Figure 2

Survival analysis of new ICH after diagnosis by EOOH.

Figure 3. Conceptual overview

Panel A: The biological event, Silent Intralesional Microhemorrhage (SIM), can be assessed using biomarkers. In this study, we used standard tomographic imaging (relatively insensitive) and histopathology (impractical), but future studies can leverage newer iron-sensitive MR imaging to develop risk stratification tools. Panel B: Mediational analysis. EOOH was associated with both Index ICH and new ICH after diagnosis, and appears to lie at least partially in the same causal pathway (arrows A and B). Hemosiderin Positivity was associated with index ICH (arrow A). Future studies with iron-sensitive imaging (ISI) may improve prediction as more sensitive than EOOH and be applicable before treatment.