Neutrophil extracellular trap-related pathology in sporadic brain arteriovenous malformations after radiosurgery: An...

Brain arteriovenous malformations (bAVMs) shunt arterial blood directly into veins, bypassing capillaries and predisposing young patients to hemorrhagic stroke. Stereotactic radiosurgery (SRS) can result in curative bAVM obliteration through delayed thrombosis, yet hemorrhage risk persists during the latency period. The mechanisms underlying this delayed response remain unclear. Neutrophil extracellular traps (NETs), web-like structures of chromatin DNA and granule proteins, have been identified in bAVMs. We investigated whether citrullinated histone H3 (CitH3)-positive cells, used as a surrogate marker of NET-related activity, are associated with post-radiosurgical vascular remodeling in bAVMs.

We analyzed the expression of CitH3 in surgical specimens from patients with bAVMs without prior SRS (n = 6), with prior SRS (n = 6), and with epilepsy as controls (n = 2). CitH3 localization in the vessel wall and endoluminal space was examined by immunohistochemistry.

CitH3-positive cells were more abundant in both the vessel wall and endoluminal regions of SRS-treated bAVMs compared with untreated bAVMs and controls. In the vessel wall, the mean percentage of CitH3-positive cells was 1.73% in SRS-treated bAVMs, 0.86% in untreated bAVMs, and 0.25% in controls, with a significant increase following SRS compared with control vessels (p = 0.04). In the endoluminal area, the mean percentage was 1.01% in SRS-treated bAVMs, 0.14% in untreated bAVMs, and 0.01% in controls, with SRS-treated bAVMs showing significantly higher levels than both untreated bAVMs (p = 0.02) and controls (p = 0.02).

CitH3-positive cells were increased in surgically resected post-SRS bAVMs, with localization in both vessel walls and endoluminal compartments. These findings support a possible association between NET-related pathology and radiosurgery-associated vascular remodeling. Given the small sample size, selected post-SRS surgical cohort, and surrogate nature of CitH3 staining, these results should be interpreted as hypothesis-generating and require validation in further mechanistic and longitudinal studies.