Inflammation in Cerebral Cavernous Malformations: Differences Between Malformation Related Epilepsy vs. Symptomatic Hemorrhage

TL;DR

This study finds that inflammation in brain vascular malformations differs between patients with seizures and those with hemorrhages, with hemorrhage cases showing higher inflammatory enzyme activity.

Contribution

The study reveals that symptomatic hemorrhage in CCM patients shows upregulated inflammatory enzyme activity compared to CCM-related epilepsy.

Findings

NLRP3-positive cells were significantly more prevalent than COX-2-positive cells in CCM tissue samples.

Patients with symptomatic hemorrhage showed increased COX-2 and NLRP3 upregulation compared to those with CCM-related epilepsy.

No correlation was found between CCM volume and hemorrhage events.

Abstract

Background and Objective: Cerebral cavernous malformation (CCM) is a vascular disorder causing seizures, neurological deficits, and hemorrhagic stroke. It can be sporadic or inherited via CCM1, CCM2, or CCM3 gene mutations. Inflammation is broadly recognized as a promoter of cerebral vascular malformations. This study explores inflammatory mechanisms and differences behind CCM-related hemorrhage and epilepsy. Material and Methods: The study group comprised 28 patients, ten patients with CCM-related epilepsy, and 18 patients who clinically presented with a cerebral hemorrhage at diagnosis. All patients underwent microsurgical resection of the CCMs. Formaldehyde-fixed, paraffin-embedded tissue samples were immunohistochemically stained using a monoclonal antibody against Cyclooxygenase 2 (COX-2) (Dako, Santa Clara, CA; Clone: CX-294) and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) (ABCAM, Cambridge, MA, USA; ab214185). MRI and clinical data were correlated with immunohistochemical findings, and the analysis was conducted utilizing the Trainable Weka Segmentation algorithm. Results: Median CCM volume was 1.68 cm3 (IQR: 0.85–3.07 cm3). There were significantly more NLRP3-positive cells (32.56% to 91.98%; mean: 65.82%, median: 68.34%; SD: ±17.70%), compared to COX-2-positive cells (1.82% to 79.69%; mean: 45.87%, median: 49.06%; SD: ±22.56%). No correlation was shown between the volume of CCMs and a hemorrhage event (p = 0.13, 95% CI: 0.99–1.02). Symptomatic brain hemorrhage showed a significantly increased inflammatory enzyme upregulation from both COX-2 (p < 0.001) and NLRP3 (p = 0.009) versus patients with symptomatic CCM-related epilepsy at first diagnosis. Conclusions: Inflammatory processes in CCMs seem to be driven by broad and multiple pathways because both COX-2 and NLRP3-driven inflammatory pathways are consistently activated. As a novelty, this study showed that patients with symptomatic hemorrhage showed upregulated inflammatory enzyme activity compared to patients with CCM-related epilepsy. No direct links between NLRP3, COX-2 expression, and radiological, pathological, or preexisting patient conditions were found.

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