Brainstem cerebral cavernous malformations (CCM) are clinically more aggressive compared to superficial CCMs. Due to their location, resection can be challenging, making stereotactic radiosurgery (SRS) an attractive alternative for symptomatic patient. Brainstem CCM patients (n = 170) were treated with Gamma Knife SRS at 11 radiosurgical centers. Hemorrhagic risk reduction, risk factors of post-SRS hemorrhage, and clinical outcomes were retrospectively analyzed. Most patients had a single (165/170 patients) brainstem CCMs treated; the majority of CCMs (165/181) presented with bleeding. Single-session SRS decreased the risk of repeat hemorrhage in patients with hemorrhagic brainstem CCM (HR: 0.17, p < 0.001) using recurrent multivariate analysis. The annual hemorrhage rate decreased from 14.8 per 100 CCM-years before SRS to 2.3 after treatment. Using univariate Cox-analysis, the probability of a new hemorrhages after SRS was reduced for patient older than 35 years (HR = 0.21, p = 0.002) and increased with a margin dose > 13 Gy (HR = 2.57, p = 0.044). Adverse radiation effect (ARE) occurred in 9 patients (5.3%) and was symptomatic in four (2.4%). At a median follow-up of 3.4 years (Inter-quartile range: 5.4), 13 patients (8.0%) had a worsened clinical status, with the treated CCM being the cause in 5.6% (10) of the patients. Single-session SRS decreased the risk of repeat hemorrhage in patients with hemorrhagic brainstem CCM and conveyed this benefit with a low risk of advrse radiation effects (ARE) and worsening clinical status.

Department of Clinical Oncology Ain Shams University Cairo Egypt

Department of Neurological Surgery Hospices Civils de Lyon Lyon France

Department of Neurological Surgery University of Virginia Box 800212 Charlottesville VA 22908 USA

Department of Neurosurgery Ain Shams University Cairo Egypt

Department of Neurosurgery and Department of Oncology University of Alberta Edmonton AB Canada

Department of Neurosurgery Koc University School of Medicine Istanbul Turkey

Department of Neurosurgery NYU Langone New York City NY USA

Department of Neurosurgery Postgraduate Institute of Medical Education and Research Chandigarh India

Department of Neurosurgery Scientific Institute for Research Hospitalization and Healthcare IRCCS Humanitas Research Hospital Milan Italy

Department of Radiation Oncology National Cancer Institute Cairo University Cairo Egypt

Department of Radiation Therapy Postgraduate Institute of Medical Education and Research Chandigarh India

Department of Radiosurgery Rúber Internacional Hospital Madrid Spain

Department of Stereotactic and Radiation Neurosurgery Na Homolce Hospital Prague Czech Republic

Division of Neurosurgery Université de Sherbrooke Centre de Recherche du CHUS Sherbrooke QC Canada

Division of Radiation Oncology Department of Oncology University of Alberta Edmonton AB Canada

Dominican Gamma Knife Center and Radiology Department CEDIMAT Santo Domingo Dominican Republic

Extended Modular Program Faculty of Medicine Ain Shams University Cairo Egypt

Gamma Knife Center Cairo Nasser Institute Hospital Cairo Egypt

Gamma Knife Center Jewish Hospital Mayfield Clinic Cincinnati OH USA

Neurosurgery Department Faculty of Medicine Benha University Qalubya Egypt

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Gross, B. A., Batjer, H. H., Awad, I. A., Bendok, B. R. & Du, R. Brainstem cavernous malformations: 1390 surgical cases from the literature. World Neurosurg.80(1–2), 89–93. 10.1016/j.wneu.2012.04.002 (2013). PubMed

Porter, R. W. et al. Cavernous malformations of the brainstem: Experience with 100 patients. J. Neurosurg.90(1), 50–58. 10.3171/jns.1999.90.1.0050 (1999). PubMed

Horne, M. A. et al. Clinical course of untreated cerebral cavernous malformations: A meta-analysis of individual patient data. Lancet Neurol.Bold">15(2), 166–173. 10.1016/S1474-4422(15)00303-8 (2016). PubMed PMC

Garcia R.M., Ivan M.E., & Lawton, M.T. Brainstem cavernous malformations: Surgical results in 104 patients and a proposed grading system to predict neurological outcomes. Neurosurgery. 76(3), 265–277. 10.1227/NEU.0000000000000602 (2015). discussion 277–278. PubMed

Fritschi, J. A., Reulen, H. J., Spetzler, R. F. & Zabramski, J. M. Cavernous malformations of the brain stem. A review of 139 cases. Acta Neurochir. (Wien). 130(1–4), 35–46. 10.1007/BF01405501 (1994). PubMed

Pandey, P., Westbroek, E., Gooderham, P. & Steinberg, G. Cavernous malformation of Brainstem, Thalamus, and basal ganglia: A series of 176 patients. NEUROSURGERY. 72(4), 573–588. 10.1227/NEU.0b013e318283c9c2 (2013). PubMed

Kondziolka, D., Lunsford, L. D., Coffey, R. J., Bissonette, D. J. & Flickinger, J. C. Stereotactic radiosurgery of angiographically occult vascular malformations: indications and preliminary experience. Neurosurgery. 27(6), 892–900. 10.1097/00006123-199012000-00006 (1990). PubMed

Akers, A., Al-Shahi Salman, R. & Awad, A. Synopsis of guidelines for the Clinical Management of Cerebral cavernous malformations: Consensus recommendations based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel. Neurosurgery. 80(5), 665. 10.1093/neuros/nyx091 (2017). PubMed PMC

von Elm, E. et al. The strengthening the reporting of Observational studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. J. Clin. Epidemiol.61(4), 344–349. 10.1016/j.jclinepi.2007.11.008 (2008). PubMed

Al-Shahi Salman, R., Berg, M. J., Morrison, L., Awad, I. A. & Angioma Alliance Scientific Advisory Board. Hemorrhage from cavernous malformations of the brain: definition and reporting standards. Angioma Alliance Sci. Advisory Board. Stroke. 39(12), 3222–3230. 10.1161/STROKEAHA.108.515544 (2008). PubMed

Zabramski, J. M. et al. The natural history of familial cavernous malformations: Results of an ongoing study. J. Neurosurg.80(3), 422–432. 10.3171/jns.1994.80.3.0422 (1994). PubMed

Dumot, C. et al. Stereotactic radiosurgery for haemorrhagic cerebral cavernous malformation: A multi-institutional, retrospective study. Stroke Vasc Neurol. Published online. doi: (2023). 10.1136/svn-2023-002380 PubMed PMC

R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL (2020). https://www.R-project.org/

RStudio, T. & RStudio RStudio: Integrated Development Environment for R. PBC, Boston, MA URL http://www.rstudio.com/. (2020).

Sahai, H. & Khurshid, A. Statistics in Epidemiology: Methods, Techniques, and Applications (CRC, 1996).

Amorim, L. D. A. F. & Cai, J. Modelling recurrent events: a tutorial for analysis in epidemiology. Int. J. Epidemiol.44(1), 324–333. 10.1093/ije/dyu222 (2015). PubMed PMC

Moeller, B. J., Cao, Y., Li, C. Y. & Dewhirst, M. W. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell.5(5), 429–441. 10.1016/s1535-6108(04)00115-1 (2004). PubMed

Park, C. M. et al. Ionizing radiation enhances matrix metalloproteinase-2 secretion and invasion of glioma cells through Src/epidermal growth factor receptor-mediated p38/Akt and phosphatidylinositol 3-kinase/Akt signaling pathways. Cancer Res.66(17), 8511–8519. 10.1158/0008-5472.CAN-05-4340 (2006). PubMed

Hlatky, L., Tsionou, C., Hahnfeldt, P. & Coleman, C. N. Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res.54(23), 6083–6086 (1994). PubMed

Gross, B. A. & Du, R. Hemorrhage from cerebral cavernous malformations: a systematic pooled analysis. J. Neurosurg.126(4), 1079–1087. 10.3171/2016.3.JNS152419 (2017). PubMed

Grunewald, M. et al. Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span. Science. 373(6554), eabc8479. 10.1126/science.abc8479 (2021). PubMed

Pollock, B. E. et al. Stereotactic radiosurgery for cavernous malformations. J. Neurosurg.93(6), 987–991. 10.3171/jns.2000.93.6.0987 (2000). PubMed

Lunsford, L. D., Niranjan, A., Kano, H., Monaco Iii, E. A. & Flickinger, J. C. Leksell Stereotactic Radiosurgery for cavernous malformations. Prog Neurol. Surg.34, 260–266. 10.1159/000493072 (2019). PubMed

Nagy, G. et al. Contemporary radiosurgery of cerebral cavernous malformations: Part 1. Treatment outcome for critically located hemorrhagic lesions. J. Neurosurg.1306(6), 1817–1825. 10.3171/2017.5.JNS17776 (2019). PubMed

Karaaslan, B. et al. Stereotactic radiosurgery for cerebral cavernous malformation: Comparison of hemorrhage rates before and after stereotactic radiosurgery. J. Neurosurg.136(3), 655–661. 10.3171/2021.2.JNS21138 (2022). PubMed

Xu, X. Y. et al. Nomogram for predicting an individual prospective hemorrhage risk in untreated brainstem cavernous malformations. J. Neurosurg.138(4), 910–921. 10.3171/2022.8.JNS221228 (2023). PubMed

Hori, T. et al. Long-term outcomes after surgery for brainstem cavernous malformations: Analysis of 46 consecutive cases. J. Neurosurg.138(4), 900–909. 10.3171/2022.7.JNS22314 (2023). PubMed

Walcott, B. P., Choudhri, O. & Lawton, M. T. Brainstem cavernous malformations: Natural history versus surgical management. J. Clin. Neurosci.32, 164–165. 10.1016/j.jocn.2016.03.021 (2016). PubMed PMC

Niranjan, A. & Lunsford, L. D. Stereotactic radiosurgery guidelines for the management of patients with intracranial cavernous malformations. Prog Neurol. Surg.27, 166–175. 10.1159/000341792 (2013). PubMed

Li, D. et al. Neurological outcomes of untreated brainstem cavernous malformations in a prospective observational cohort and literature review. Stroke Vasc Neurol.6(4), 501–510. 10.1136/svn-2020-000608 (2021). PubMed PMC

Li, D. et al. Natural history of brainstem cavernous malformations: Prospective hemorrhage rate and adverse factors in a consecutive prospective cohort. J. Neurosurg.134(3), 917–928. 10.3171/2019.12.JNS192856 (2021). PubMed