{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:51:34Z","timestamp":1791726694714,"version":"4.3.4"},"reference-count":31,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T00:00:00Z","timestamp":1758931200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Open Access Publication Fund of the University of Duisburg-Essen"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cells"],"abstract":"<jats:p>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\u20133.07 cm3). There were significantly more NLRP3-positive cells (32.56% to 91.98%; mean: 65.82%, median: 68.34%; SD: \u00b117.70%), compared to COX-2-positive cells (1.82% to 79.69%; mean: 45.87%, median: 49.06%; SD: \u00b122.56%). No correlation was shown between the volume of CCMs and a hemorrhage event (p = 0.13, 95% CI: 0.99\u20131.02). Symptomatic brain hemorrhage showed a significantly increased inflammatory enzyme upregulation from both COX-2 (p &lt; 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.<\/jats:p>","DOI":"10.3390\/cells14191510","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T10:49:34Z","timestamp":1759142974000},"page":"1510","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Inflammation in Cerebral Cavernous Malformations: Differences Between Malformation Related Epilepsy vs. Symptomatic Hemorrhage"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3185-2391","authenticated-orcid":false,"given":"Jan","family":"Rodemerk","sequence":"first","affiliation":[{"name":"Department of Neurosurgery and Spine Surgery, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6328-2066","authenticated-orcid":false,"given":"Adrian","family":"Engel","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Spine Surgery, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julius L. H.","family":"Horstmann","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Spine Surgery, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8348-4298","authenticated-orcid":false,"given":"Laur\u00e8l","family":"Rauschenbach","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Spine Surgery, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin","family":"Darkwah Oppong","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Spine Surgery, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6616-5313","authenticated-orcid":false,"given":"Alejandro N.","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Spine Surgery, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8063-9765","authenticated-orcid":false,"given":"Andreas","family":"Junker","sequence":"additional","affiliation":[{"name":"Department for Neuropathology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9262-7289","authenticated-orcid":false,"given":"Cornelius","family":"Deuschl","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5584-9824","authenticated-orcid":false,"given":"Michael","family":"Forsting","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Spine Surgery, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8356-6629","authenticated-orcid":false,"given":"Ramazan","family":"Jabbarli","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Spine Surgery, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7076-3503","authenticated-orcid":false,"given":"Karsten H.","family":"Wrede","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Spine Surgery, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00f6rge","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9073-1821","authenticated-orcid":false,"given":"Ulrich","family":"Sure","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Spine Surgery, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Dammann","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Spine Surgery, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,27]]},"reference":[{"key":"ref_1","unstructured":"Caton, M.T., Karsonovich, T., and Shenoy, V.S. 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