Towards a histological diagnosis of childhood small vessel CNS vasculitis.

Background: Primary small vessel CNS vasculitis (sv-cPACNS) is a challenging inflammatory brain disease in children. Brain biopsy is mandatory to confirm the diagnosis. This study aims to develop and validate a histological scoring tool for diagnosing small vessel CNS vasculitis.

Methods: A standardized brain biopsy scoring instrument was developed and applied to consecutive full-thickness brain biopsies of pediatric cases and controls at a single center. Stains included immunohistochemistry and Hematoxylin & Eosin. Nine North American neuropathologists, blinded to patients' presentation, diagnosis, and therapy, scored de-identified biopsies independently.

Results: A total of 31 brain biopsy specimens from children with sv-cPACNS, 11 with epilepsy, and 11 with non-vasculitic inflammatory brain disease controls were included. Angiocentric inflammation in the cortex or white matter increases the likelihood of sv-cPACNS, with odds ratios (ORs) of 3.231 (95CI: 0.914-11.420, p = 0.067) and 3.923 (95CI: 1.13-13.6, p = 0.031). Moderate to severe inflammation in these regions is associated with a higher probability of sv-cPACNS, with ORs of 5.56 (95CI: 1.02-29.47, p = 0.046) in the cortex and 6.76 (95CI: 1.26-36.11, p = 0.025) in white matter. CD3, CD4, CD8, and CD20 cells predominated the inflammatory infiltrate. Reactive endothelium was strongly associated with sv-cPACNS, with an OR of 8.93 (p = 0.001). Features reported in adult sv-PACNS, including granulomas, necrosis, or fibrin deposits, were absent in all biopsies. The presence of leptomeningeal inflammation in isolation was non-diagnostic.

Conclusion: Distinct histological features were identified in sv-cPACNS biopsies, including moderate to severe angiocentric inflammatory infiltrates in the cortex or white matter, consisting of CD3, CD4, CD8, and CD20 cells, alongside reactive endothelium with specificity of 95%. In the first study of its kind proposing histological criteria for evaluating brain biopsies, we aim to precisely characterize the type and severity of the inflammatory response in patients with sv-cPACNS; this can enable consolidation of this population to assess outcomes and treatment methodologies comprehensively.