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Surgery for cerebral cavernous malformations: a systematic review and meta-analysis

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Abstract

Background

We sought to quantify the risks of neurosurgical excision of cerebral cavernous malformations (CCMs) in a systematic review of cohort studies.

Methods

We updated our previous systematic review by searching OVID Medline, OVID EMBASE, and the Cochrane Library from 1 January 2013 to 30 April 2019. The primary outcome was a composite of death attributed to CCM or surgery, non-fatal symptomatic intracerebral haemorrhage (ICH), or new or worsened persistent non-haemorrhagic focal neurological deficit (FND).

Results

We included 70 cohorts, 67 reporting surgery alone, and three compared surgery to conservative management. A total of 5,089 patients (median age 36 years, 52% female) underwent surgery (total follow-up 19,404 patient-years). The annual rate of the composite outcome was 4.2% (95% CI 2.9 to 5.7; 46 cohorts; I2 = 93%), which was higher in cohorts reporting exclusively brainstem CCM (6.0%, 95% CI 4.1–8.3; 25 cohorts, I2 = 92%) versus predominantly supratentorial CCM (2.4%, 95% CI 1.3–3.8, 21 cohorts, I2 = 86%, phet = 0.001). The annual rate of the composite outcome was higher in cohorts with > 95% presenting with ICH (6.1%, 95% CI 4.2–8.4; 23 cohorts, I2 = 93%) versus others (2.3%, 95% CI 1.2–3.7; 23 cohorts, I2 = 83%, phet = 0.001). The incidence of the composite outcome did not change over time in cohorts of exclusively brainstem CCM (p = 0.7) or predominantly supratentorial CCM (p = 0.5).

Conclusions

The risk of death, ICH, or FND after CCM excision is ~ 4%. This risk is higher for brainstem CCM and CCM that have caused ICH but has not changed over time.

Trial registration

This systematic review was registered (PROSPERO CRD42019131246).

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Data Availability

See Appendix; extra data available on request.

Code availability

Not applicable.

References

  1. Akers A, Al-Shahi Salman R, Awad I, Dahlem K, Flemming K, Hart B, Kim H, Jusue-Torres I, Kondziolka D, Lee C, Morrison L, Rigamonti D, Rebeiz T, Tournier-Lasserve E, Waggoner D, Whtiehead K (2017) 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 80:665–680

    Article  Google Scholar 

  2. Al-Shahi R, Bhattacharya JJ, Currie DG, Papanastassiou V, Ritchie V, Roberts RC, Sellar RJ, Warlow CP (2003) Prospective, population-based detection of intracranial vascular malformations in adults: the Scottish Intracranial Vascular Malformation Study (SIVMS). Stroke 34:1163–1169. https://doi.org/10.1161/01.STR.0000069018.90456.C9

    Article  PubMed  Google Scholar 

  3. Al-Shahi Salman R, Berg M, Morrison L, Awad I (2008) Hemorrhage from cavernous malformations of the brain: definition and reporting standards. Stroke 39:3222–3230. https://doi.org/10.1161/STROKEAHA.108.515544

    Article  PubMed  Google Scholar 

  4. Al-Shahi Salman R, Kitchen N, Thomson J, Ganesan V, Mallucci C, Radatz M, Priority Setting Partnership Steering Group C (2016) Top ten research priorities for brain and spine cavernous malformations. Lancet Neurol 15:354–355. https://doi.org/10.1016/S1474-4422(16)00039-9

    Article  Google Scholar 

  5. Flemming KD, Graff-Radford J, Aakre J, Kantarci K, Lanzino G, Brown RD, Mielke MM, Roberts RO, Kremers W, Knopman DS, Petersen RC, Jack CR (2017) Population-based prevalence of cerebral cavernous malformations in older adults: Mayo Clinic Study of Aging. JAMA Neurol 74:801–805. https://doi.org/10.1001/jamaneurol.2017.0439

    Article  PubMed  PubMed Central  Google Scholar 

  6. Freeman MF, Tukey JW (1950) Transformations related to the angular and the square root. Ann Math Stat 21:607–611

    Article  Google Scholar 

  7. Garner P, Hopewell S, Chandler J, MacLehose H, Schünemann HJ, Akl EA, Beyene J, Chang S, Churchill R, Dearness K, Guyatt G, Lefebvre C, Liles B, Marshall R, Martínez García L, Mavergames C, Nasser M, Qaseem A, Sampson M, Soares-Weiser K, Takwoingi Y, Thabane L, Trivella M, Tugwell P, Welsh E, Wilson EC (2016) When and how to update systematic reviews: consensus and checklist. BMJ 354

  8. Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, Welch V (2019) Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane Collab

  9. Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. Br Med J 327:557–560

    Article  Google Scholar 

  10. Horne MA, Flemming KD, Su IC, Stapf C, Jeon JP, Li D, Maxwell SS, White P, Christianson TJ, Agid R, Cho WS, Oh CW, Wu Z, Zhang JT, Kim JE, ter Brugge K, Willinsky R, Brown RD, Murray GD, Salman RAS, Al-Shahi Salman R, Baird S, Bhattacharya JJ, Counsell CE, St George EJ, White PM, Ritchie V, Roberts RC, Sellar RJ, Warlow CP, Link MJ, Tymianski M, Wallace MC, Hervé D, Riant F, Schneble HM, Chung YS, Oh S, Ahn JH, Son YJ, Bang JS, Kang HS, Sohn CH, Hao SY, Jia GJ, Zhang LW (2016) Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol 15:166–173. https://doi.org/10.1016/S1474-4422(15)00303-8

    Article  PubMed  PubMed Central  Google Scholar 

  11. Josephson CB, Bhattacharya JJ, Counsell CE, Papanastassiou V, Ritchie V, Roberts R, Sellar R, Warlow CP, Al-Shahi Salman R (2012) Seizure risk with AVM treatment or conservative management: prospective, population-based study. Neurology 79:500–507. https://doi.org/10.1212/WNL.0b013e3182635696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kearns KN, Chen CJ, Tvrdik P, Park MS, Kalani YMS (2019) Outcomes of surgery for brainstem cavernous malformations a systematic review. Stroke 50:2964–2966. https://doi.org/10.1161/STROKEAHA.119.026120

    Article  PubMed  Google Scholar 

  13. Magro E, Gentric JC, Darsaut TE, Ziegler D, Bojanowski MW, Raymond J (2017) Responses to ARUBA: a systematic review and critical analysis for the design of future arteriovenous malformation trials. J Neurosurg 126:486–494. https://doi.org/10.3171/2015.6.JNS15619

    Article  PubMed  Google Scholar 

  14. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097. https://doi.org/10.1371/journal.pmed.1000097.s001

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mohr JP, Overbey JR, Hartmann A, von Kummer R, Al-Shahi Salman R, Kim H, van der Worp HB, Parides MK, Stefani MA, Houdart E, Libman R, Pile-Spellman J, Harkness K, Cordonnier C, Moquete E, Biondi A, Klijn CJM, Stapf C, Moskowitz AJ (2020) Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. Lancet Neurol 19:573–581. https://doi.org/10.1016/S1474-4422(20)30181-2

    Article  PubMed  Google Scholar 

  16. Mohr JP, Parides MK, Stapf C, Moquete E, Moy CS, Overbey JR, Salman RAS, Vicaut E, Young WL, Houdart E, Cordonnier C, Stefani MA, Hartmann A, Von Kummer R, Biondi A, Berkefeld J, Klijn CJM, Harkness K, Libman R, Barreau X, Moskowitz AJ (2014) Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 383:614–621. https://doi.org/10.1016/S0140-6736(13)62302-8

    Article  CAS  PubMed  Google Scholar 

  17. Morris Z, Whiteley WN, Longstreth WT, Weber F, Lee YC, Tsushima Y, Alphs H, Ladd SC, Warlow C, Wardlaw JM, Al-Shahi Salman R (2009) Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 339:547–550. https://doi.org/10.1136/bmj.b3016

    Article  Google Scholar 

  18. Moultrie F, Horne MA, Josephson CB, Hall JM, Counsell CE, Bhattacharya JJ, Papanastassiou V, Sellar RJ, Warlow CP, Murray GD, Al-Shahi Salman R, collaborators, SAIVMs collaborators and steering committee (2014) Outcome after surgical or conservative management of cerebral cavernous malformations. Neurology 83:582–589. https://doi.org/10.1212/WNL.0000000000000684

    Article  PubMed  PubMed Central  Google Scholar 

  19. Newcombe RG (1998) Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 17:857–872. https://doi.org/10.1002/(SICI)1097-0258(19980430)17:8%3c857::AID-SIM777%3e3.0.CO;2-E

    Article  CAS  PubMed  Google Scholar 

  20. Poorthuis M, Samarasekera N, Kontoh K, Stuart I, Cope B, Kitchen N, Al-Shahi Salman R (2013) Comparative studies of the diagnosis and treatment of cerebral cavernous malformations in adults: systematic review. Acta Neurochir (Wien) 155:643–649. https://doi.org/10.1007/s00701-013-1621-4

    Article  Google Scholar 

  21. Poorthuis MHF, Klijn CJM, Algra A, Rinkel GJE, Al-Shahi Salman R (2014) Treatment of cerebral cavernous malformations: a systematic review and meta-regression analysis. J Neurol Neurosurg Psychiatry 85:1319–1323. https://doi.org/10.1136/jnnp-2013-307349

    Article  PubMed  Google Scholar 

  22. Poorthuis MHF, Rinkel LA, Lammy S, Al-Shahi Salman R (2019) Stereotactic radiosurgery for cerebral cavernous malformations: a systematic review. Neurology 93:E1971–E1979. https://doi.org/10.1212/WNL.0000000000008521

    Article  PubMed  Google Scholar 

  23. Qiao N, Ma Z, Song J, Wang Y, Shou X, Zhang X, Shen M, Qiu H, Ye Z, He W, Li S, Fu C, Zhao Y (2015) A systematic review and meta-analysis of surgeries performed for treating deep-seated cerebral cavernous malformations. Br J Neurosurg 29:493–499. https://doi.org/10.3109/02688697.2015.1023773

    Article  PubMed  Google Scholar 

  24. Rosenow F, Alonso-Vanegas MA, Baumgartner C, Blümcke I, Carreño M, Gizewski ER, Hamer HM, Knake S, Kahane P, Lüders HO, Mathern GW, Menzler K, Miller J, Otsuki T, Özkara C, Pitkänen A, Roper SN, Sakamoto AC, Sure U, Walker MC, Steinhoff BJ (2013) Cavernoma-related epilepsy: review and recommendations for management - report of the surgical task force of the ILAE Commission on therapeutic strategies. Epilepsia 54:2025–2035

    Article  Google Scholar 

  25. Rothwell PM (2020) Extended short-term follow-up for a trial of treatment of unruptured arteriovenous malformations. Lancet Neurol 19:558–559

    Article  Google Scholar 

  26. Ruan D, Yu XB, Shrestha S, Wang L, Chen G (2015) The role of hemosiderin excision in seizure outcome in cerebral cavernous malformation surgery: a systematic review and meta-analysis. PLoS One 10

  27. Samarasekera N, Poorthuis M, Kontoh K, Stuart I, Respinger C, Berg J, Kitchen N, Al-Shahi Salman R (2012) Guidelines for the management of cerebral cavernous malformations in adults. Genetic Alliance UK & Cavernoma Alliance UK

  28. Schuss P, Marx J, Borger V, Brandecker S, Güresir Á, Hadjiathanasiou A, Hamed M, Schneider M, Surges R, Vatter H, Güresir E (2020) Cavernoma-related epilepsy in cavernous malformations located within the temporal lobe: surgical management and seizure outcome. Neurosurg Focus 48:E6. https://doi.org/10.3171/2020.1.FOCUS19920

    Article  PubMed  Google Scholar 

  29. Tarnaris A, Fernandes RP, Kitchen ND (2008) Does conservative management for brain stem cavernomas have better long-term outcome? Br J Neurosurg 22:748–757. https://doi.org/10.1080/02688690802354210

    Article  CAS  PubMed  Google Scholar 

  30. Wieser HG, Ortega M, Friedman A, Yonekawa Y (2003) Long-term seizure outcomes following amygdalohippocampectomy. J Neurosurg 98:751–763. https://doi.org/10.3171/jns.2003.98.4.0751

    Article  PubMed  Google Scholar 

  31. Cavernomas a randomised effectiveness (CARE) pilot trial, to address the effectiveness of active treatment (with neurosurgery or stereotactic radiosurgery) versus conservative management in people with symptomatic brain cavernoma. https://www.journalslibrary.nihr.ac.uk/programmes/hta/NIHR128694/#/.

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Authors and Affiliations

  1. Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK

    Lauren Harris, Patrick Grover & Neil Kitchen

  2. Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands

    Michiel H. F. Poorthuis

  3. Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK

    Rustam Al-Shahi Salman

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  1. Lauren Harris
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  2. Michiel H. F. Poorthuis
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  3. Patrick Grover
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  5. Rustam Al-Shahi Salman
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Contributions

All authors (LH, MP, PG, NK, RAS) contributed to this manuscript.

Corresponding authors

Correspondence to Lauren Harris or Rustam Al-Shahi Salman.

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Conflict of interest

RASS reports funding paid to his employer for a consultancy with Recursion Pharmaceuticals and funding from the National Institute for Health Research (NIHR128694) for the Cavernomas A Randomised Effectiveness (CARE) pilot trial. Other authors report no disclosures or conflict of interests.

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Lauren Harris and Michiel H.F Poorthuis share first authorship to this work.

All statistical analysis was performed by MP University Medical Centre Utrecht

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Harris, L., Poorthuis, M.H.F., Grover, P. et al. Surgery for cerebral cavernous malformations: a systematic review and meta-analysis. Neurosurg Rev 45, 231–241 (2022). https://doi.org/10.1007/s10143-021-01591-5

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  • DOI: https://doi.org/10.1007/s10143-021-01591-5

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