Infratentorial Cerebral Cavernous Malformation May be a Risk Factor for Symptomatic Bleeding and Precocity of Symptoms: A Multicenter, Propensity Score Matched, Case-Control Study


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Abstract

Background::Cerebral Cavernous Malformation (CCM) is one of the most common types of vascular malformation of the central nervous system. Intracerebral hemorrhage, seizures, and lesional growth are the main clinical manifestations. Natural history studies have tried to identify many risk factors; however, the clinical course remains highly unpredictable.

Objective::Here, we have analyzed a multicenter CCM cohort looking for the differential clinical data regarding the patients harboring supra and/or infratentorial cavernous malformations in order to better understand risk factors involved in the anatomical location of the unique neurosurgical disease.

Methods::We have presented a multicenter, Propensity Score Matched (PSM), case-control study including 149 consecutive CCM cases clinically evaluated from May 2017 to December 2022 from three different neurosurgical centers. Epidemiological data were defined at each clinical assessment. Logistic regression was used to identify the independent contribution of each possible risk factor to the bleeding risk. To balance baseline covariates between patients with and without symptoms, and specifically between those with and without symptomatic bleeding, we used a PSM strategy. The Kaplan-Meier curve was drawn to evaluate if patients with infratentorial lesions had a greater chance of bleeding earlier in their life.

Results::The presence of infratentorial lesions was a risk factor in the multivariate analysis comparing the bleeding risk with pure asymptomatic individuals (OR: 3.23, 95% CI 1.43 – 7.26, P = 0.005). Also, having an infratentorial CCM was a risk factor after PSM (OR: 4.56, 95% CI 1.47 - 14.10, P = 0.008). The presence of an infratentorial lesion was related to precocity of symptoms when the time to first bleed was compared to all other clinical presentations in the overall cohort (P = 0.0328) and in the PSM group (P = 0.03).

Conclusion::Here, we have provided some evidence that infratentorial cerebral cavernous malformation may have a more aggressive clinical course, being a risk factor for symptomatic haemorrhage and precocity of bleeding.

About the authors

Gustavo Galvão

Department of de Neurosurgery,, Federal University of Rio de Janeiro, University Hospital Clementino Fraga Filho,

Author for correspondence.
Email: info@benthamscience.net

Ricardo Filho

Department of de Neurosurgery, Federal University of Rio de Janeiro, University Hospital Clementino Fraga Filho

Email: info@benthamscience.net

Alexandre Cunha

Department of de Neurosurgery, Federal University of Rio de Janeiro, University Hospital Clementino Fraga Filho

Email: info@benthamscience.net

Andre Soares

Department of Neurosurgery, Santa Casa de Belo Horizonte

Email: info@benthamscience.net

Marcos Filho

Department of Neurosurgery,, Santa Casa de Belo Horizonte,

Email: info@benthamscience.net

Jorge de Souza

Department of de Neurosurgery, Federal University of Rio de Janeiro, University Hospital Clementino Fraga Filho,

Email: info@benthamscience.net

References

  1. Al-Shahi Salman R, Hall JM, Horne MA, Moultrie F, Josephson CB, Bhattacharya JJ, et al. Untreated clinical course of cerebral cavernous malformations: A prospective, population-based cohort study. Lancet Neurol 2012; 11(3): 150-6. doi: 10.1016/S1474-4422(12)70004-2
  2. Akers A, Al-Shahi Salman R. A Awad I, et al. 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 2017; 80(5): 665-80. doi: 10.1093/neuros/nyx091 PMID: 28387823
  3. de Souza JM, Domingues RC, Cruz LCH Jr, Domingues FS, Iasbeck T, Gasparetto EL. Susceptibility-weighted imaging for the evaluation of patients with familial cerebral cavernous malformations: A comparison with t2-weighted fast spin-echo and gradient-echo sequences. AJNR Am J Neuroradiol 2008; 29(1): 154-8. doi: 10.3174/ajnr.A0748 PMID: 17947370
  4. Dammann P, Wrede KH, Maderwald S, et al. The venous angioarchitecture of sporadic cerebral cavernous malformations: A susceptibility weighted imaging study at 7 T MRI. J Neurol Neurosurg Psychiatry 2013; 84(2): 194-200. doi: 10.1136/jnnp-2012-302599 PMID: 23085932
  5. Dammann P, Wrede K, Zhu Y, et al. Correlation of the venous angioarchitecture of multiple cerebral cavernous malformations with familial or sporadic disease: A susceptibility-weighted imaging study with 7-Tesla MRI. J Neurosurg 2017; 126(2): 570-7. doi: 10.3171/2016.2.JNS152322 PMID: 27153162
  6. Labauge P, Denier C, Bergametti F, Tournier-Lasserve E. Genetics of cavernous angiomas. Lancet Neurol 2007; 6(3): 237-44. doi: 10.1016/S1474-4422(07)70053-4 PMID: 17303530
  7. Gault J, Sain S, Hu LJ, Awad IA. Spectrum of genotype and clinical manifestations in cerebral cavernous malformations. Neurosurgery 2006; 59(6): 1278-85. doi: 10.1227/01.NEU.0000249188.38409.03 PMID: 17277691
  8. Denier C, Goutagny S, Labauge P, et al. Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet 2004; 74(2): 326-37. doi: 10.1086/381718 PMID: 14740320
  9. Bergametti F, Denier C, Labauge P, et al. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 2005; 76(1): 42-51. doi: 10.1086/426952 PMID: 15543491
  10. Fontes-Dantas FL, da Fontoura Galvão G, Veloso da Silva E, et al. Novel CCM1 (KRIT1) mutation detection in brazilian familial cerebral cavernous malformation: Different genetic variants in inflammation, oxidative stress and drug metabolism genes affect disease aggressiveness. World Neurosurg 2020; 138: 535-540.e8. doi: 10.1016/j.wneu.2020.02.119 PMID: 32113992
  11. Awad IA, Polster SP. Cavernous angiomas: Deconstructing a neurosurgical disease. J Neurosurg 2019; 131(1): 1-13. doi: 10.3171/2019.3.JNS181724 PMID: 31261134
  12. Taslimi S, Modabbernia A, Amin-Hanjani S, Barker FG II, Macdonald RL. Natural history of cavernous malformation. Neurology 2016; 86(21): 1984-91. doi: 10.1212/WNL.0000000000002701 PMID: 27164680
  13. Batra S, Lin D, Recinos PF, Zhang J, Rigamonti D. Cavernous malformations: Natural history, diagnosis and treatment. Nat Rev Neurol 2009; 5(12): 659-70. doi: 10.1038/nrneurol.2009.177 PMID: 19953116
  14. Girard R, Li Y, Stadnik A, et al. A roadmap for developing plasma diagnostic and prognostic biomarkers of cerebral cavernous angioma with symptomatic hemorrhage (CASH). Neurosurgery 2021; 88(3): 686-97. doi: 10.1093/neuros/nyaa478 PMID: 33469662
  15. Lyne SB, Girard R, Koskimäki J, et al. Biomarkers of cavernous angioma with symptomatic hemorrhage. JCI Insight 2019; 4(12): e128577. doi: 10.1172/jci.insight.128577 PMID: 31217347
  16. Abdulrauf SI, Kaynar MY, Awad IA. A comparison of the clinical profile of cavernous malformations with and without associated venous malformations. Neurosurgery 1999; 44(1): 41-6. doi: 10.1097/00006123-199901000-00020 PMID: 9894962
  17. Girard R, Zeineddine HA, Koskimäki J, et al. Plasma biomarkers of inflammation and angiogenesis predict cerebral cavernous malformation symptomatic hemorrhage or lesional growth. Circ Res 2018; 122(12): 1716-21. doi: 10.1161/CIRCRESAHA.118.312680 PMID: 29720384
  18. Zhang D, Kinloch AJ, Srinath A, et al. Antibodies in cerebral cavernous malformations react with cytoskeleton autoantigens in the lesional milieu. J Autoimmun 2020; 113: 102469. doi: 10.1016/j.jaut.2020.102469 PMID: 32362501
  19. Gao X, Yue K, Sun J, et al. Microsurgery vs. Gamma knife radiosurgery for the treatment of brainstem cavernous malformations: A systematic review and meta-analysis. Front Neurol 2021; 12: 600461. doi: 10.3389/fneur.2021.600461 PMID: 33574793
  20. El Ahmadieh TY, Aoun SG, Bendok BR, Batjer HH. Management of brainstem cavernous malformations. Curr Treat Options Cardiovasc Med 2012; 14(3): 237-51. doi: 10.1007/s11936-012-0181-x PMID: 22555447
  21. Abla AA, Lekovic GP, Turner JD, de Oliveira JG, Porter R, Spetzler RF. Advances in the treatment and outcome of brainstem cavernous malformation surgery: A single-center case series of 300 surgically treated patients. Neurosurgery 2011; 68(2): 403-15. doi: 10.1227/NEU.0b013e3181ff9cde PMID: 21654575
  22. Garcia RM, Ivan ME, Lawton MT. Brainstem cavernous malformations: Surgical results in 104 patients and a proposed grading system to predict neurological outcomes. Neurosurgery 2015; 76(3): 265-78. doi: 10.1227/NEU.0000000000000602 PMID: 25599205
  23. Gross BA, Batjer HH, Awad IA, Bendok BR, Du R. Brainstem cavernous malformations: 1390 surgical cases from the literature. World Neurosurg 2013; 80(1-2): 89-93. doi: 10.1016/j.wneu.2012.04.002 PMID: 22484766
  24. Flores BC, Whittemore AR, Samson DS, Barnett SL. The utility of preoperative diffusion tensor imaging in the surgical management of brainstem cavernous malformations. J Neurosurg 2015; 122(3): 653-62. doi: 10.3171/2014.11.JNS13680 PMID: 25574568
  25. Garcia RM, Oh T, Cole TS, Hendricks BK, Lawton MT. Recurrent brainstem cavernous malformations following primary resection: Blind spots, fine lines, and the right-angle method. J Neurosurg 2021; 135(3): 671-82. doi: 10.3171/2020.6.JNS201555 PMID: 33254145
  26. Polster SP, Stadnik A, Akers AL, et al. Atorvastatin treatment of cavernous angiomas with symptomatic hemorrhage exploratory proof of concept (AT CASH EPOC) trial. Neurosurgery 2019; 85(6): 843-53. doi: 10.1093/neuros/nyy539 PMID: 30476251
  27. Kupersmith MJ, Kalish H, Epstein F, et al. Natural history of brainstem cavernous malformations. Neurosurgery 2001; 48(1): 47-54. doi: 10.1097/00006123-200101000-00007 PMID: 11152360
  28. Gross BA, Lin N, Du R, Day AL. The natural history of intracranial cavernous malformations. Neurosurg Focus 2011; 30(6): E24. doi: 10.3171/2011.3.FOCUS1165 PMID: 21631226
  29. Weinsheimer S, Nelson J, Abla AA, et al. Intracranial hemorrhage rate and lesion burden in patients with familial cerebral cavernous malformation. J Am Heart Assoc 2023; 12(3): e027572. doi: 10.1161/JAHA.122.027572 PMID: 36695309
  30. Alalfi MO, Lanzino G, Flemming KD. Clinical presentation, hemorrhage risk, and outcome in patients with familial cavernous malformations: A pragmatic prospective analysis of 75 patients. J Neurosurg 2023; 139(4): 1-7. doi: 10.3171/2023.1.JNS222434 PMID: 36933254
  31. Shenkar R, Shi C, Rebeiz T, et al. Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations. Genet Med 2015; 17(3): 188-96. doi: 10.1038/gim.2014.97 PMID: 25122144
  32. Kumar S, Lanzino G, Brinjikji W, Hocquard KW, Flemming KD. Infratentorial developmental venous abnormalities and inflammation increase odds of sporadic cavernous malformation. J Stroke Cerebrovasc Dis 2019; 28(6): 1662-7. doi: 10.1016/j.jstrokecerebrovasdis.2019.02.025 PMID: 30878367
  33. Cogswell PM, Pillai JJ, Lanzino G, Flemming KD. Prevalence of developmental venous anomalies in association with sporadic cavernous malformations on 7T MRI. AJNR Am J Neuroradiol 2024; 45(1): 72-5. Epub ahead of print doi: 10.3174/ajnr.A8072 PMID: 38123913
  34. Brinjikji W, El-Masri AER, Wald JT, Flemming KD, Lanzino G. Prevalence of cerebral cavernous malformations associated with developmental venous anomalies increases with age. Childs Nerv Syst 2017; 33(9): 1539-43. doi: 10.1007/s00381-017-3484-0 PMID: 28643038
  35. Kumar S, Lanzino G, Flemming KD. Affected health domains in patients with brainstem cavernous malformations. Acta Neurochir 2019; 161(12): 2521-6. doi: 10.1007/s00701-019-04075-0 PMID: 31641860
  36. Lashkarivand A, Ringstad G, Eide PK. Surgery for brainstem cavernous malformations: Association between preoperative grade and postoperative quality of life. Oper Neurosurg 2020; 18(6): 590-8. doi: 10.1093/ons/opz337 PMID: 31768544
  37. Cornelius JF, Kürten K, Fischer I, Hänggi D, Steiger HJ. Quality of life after surgery for cerebral cavernoma: Brainstemversus nonbrainstem location. World Neurosurg 2016; 95: 315-21. doi: 10.1016/j.wneu.2016.08.014 PMID: 27542564
  38. Dukatz T, Sarnthein J, Sitter H, et al. Quality of life after brainstem cavernoma surgery in 71 patients. Neurosurgery 2011; 69(3): 689-95. doi: 10.1227/NEU.0b013e31821d31b7 PMID: 21508880
  39. Bicalho VC, Bergmann A, Domingues F, Frossard JT, de Souza JPBM. Cerebral cavernous malformations: Patient-reported outcome validates conservative management. Cerebrovasc Dis 2017; 44(5-6): 313-9. doi: 10.1159/000480125 PMID: 28968597
  40. Hage S, Kinkade S, Girard R, et al. Trial readiness of cavernous malformations with symptomatic hemorrhage, part II: Biomarkers and trial modeling. Stroke 2024; 55(1): 31-9. doi: 10.1161/STROKEAHA.123.044083 PMID: 38134265
  41. Srinath A, Xie B, Li Y, et al. Plasma metabolites with mechanistic and clinical links to the neurovascular disease cavernous angioma. Commun Med 2023; 3(1): 35. doi: 10.1038/s43856-023-00265-1 PMID: 36869161
  42. Flemming KD, Kim H, Hage S, et al. Trial readiness of cavernous malformations with symptomatic hemorrhage, Part I: Event rates and clinical outcome. Stroke 2024; 55(1): 22-30. doi: 10.1161/STROKEAHA.123.044068 PMID: 38134268

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