Advertisement

Could propranolol be beneficial in adult cerebral cavernous malformations?

  • Caroline ApraEmail author
  • Chloé Dumot
  • Pierre Bourdillon
  • Isabelle Pelissou-Guyotat
Short Review

Abstract

Surgery is the only therapeutic option for cerebral cavernous malformations (CCM) and is proposed, whenever possible, after haemorrhagic events, neurological symptoms, or epilepsy, radiosurgery being a controversial alternative in some cases. However, there is no treatment for non-accessible lesions, such as brainstem CCM, multiple CCM, or those located in functional areas. Propranolol, a non-selective beta-blocker used as first-line treatment for infantile haemangiomas, has proved spectacularly effective in a few cases of adult patients with CCM. We herein review the histological, in vitro data and clinical findings that support the idea of propranolol as a potential treatment for CCM. Since one retrospective study has not been conclusive, we support the idea that prospective trials are necessary.

Keywords

Cavernomas Cavernous malformations Cavernous angiomas Cavernous haemangiomas Beta-blocker 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participant or animals and complies with French ethical standards.

Informed consent

This article does not contain any studies with human participants performed by any of the authors. This article has never been published or presented previously.

References

  1. 1.
    Flemming KD, Graff-Radford J, Aakre J, Kantarci K, Lanzino G, Brown RD Jr, Mielke MM, Roberts RO, Kremers W, Knopman DS, Petersen RC, Jack CR Jr (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 CrossRefGoogle Scholar
  2. 2.
    Akers A, Al-Shahi Salman R, A Awad I et al (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.  https://doi.org/10.1093/neuros/nyx091 CrossRefGoogle Scholar
  3. 3.
    Gross BA, Lin N, Du R, Day AL (2011) The natural history of intracranial cavernous malformations. Neurosurg Focus 30:E24.  https://doi.org/10.3171/2011.3.FOCUS1165 CrossRefGoogle Scholar
  4. 4.
    Kondziolka D, Lunsford LD, Kestle JR (1995) The natural history of cerebral cavernous malformations. J Neurosurg 83:820–824.  https://doi.org/10.3171/jns.1995.83.5.0820 CrossRefGoogle Scholar
  5. 5.
    Akers AL, Johnson E, Steinberg GK, Zabramski JM, Marchuk DA (2009) Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum Mol Genet 18:919–930.  https://doi.org/10.1093/hmg/ddn430 CrossRefGoogle Scholar
  6. 6.
    Fischer A, Zalvide J, Faurobert E, Albiges-Rizo C, Tournier-Lasserve E (2013) Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis. Trends Mol Med 19:302–308.  https://doi.org/10.1016/j.molmed.2013.02.004 CrossRefGoogle Scholar
  7. 7.
    Gault J, Shenkar R, Recksiek P, Awad IA (2005) Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion. Stroke 36:872–874.  https://doi.org/10.1161/01.STR.0000157586.20479.fd CrossRefGoogle Scholar
  8. 8.
    Gross BA, Du R (2015) Cerebral cavernous malformations: natural history and clinical management. Expert Rev Neurother 15:771–777.  https://doi.org/10.1586/14737175.2015.1055323 CrossRefGoogle Scholar
  9. 9.
    Taslimi S, Modabbernia A, Amin-Hanjani S, Barker FG II, Macdonald RL (2016) Natural history of cavernous malformation: systematic review and meta-analysis of 25 studies. Neurology 86:1984–1991.  https://doi.org/10.1212/WNL.0000000000002701 CrossRefGoogle Scholar
  10. 10.
    Zabramski JM, Kalani MYS, Filippidis AS, Spetzler RF (2016) Propranolol treatment of cavernous malformations with symptomatic hemorrhage. World Neurosurg 88:631–639.  https://doi.org/10.1016/j.wneu.2015.11.003 CrossRefGoogle Scholar
  11. 11.
    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, The Surgical Task Force, Commission on Therapeutic Strategies of the ILAE (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.  https://doi.org/10.1111/epi.12402 CrossRefGoogle Scholar
  12. 12.
    Abla AA, Lekovic GP, Turner JD, de Oliveira JG, Porter R, Spetzler RF (2011) Advances in the treatment and outcome of brainstem cavernous malformation surgery: a single-center case series of 300 surgically treated patients. Neurosurgery 68:403–414; discussion 414-415.  https://doi.org/10.1227/NEU.0b013e3181ff9cde CrossRefGoogle Scholar
  13. 13.
    Gross BA, Batjer HH, Awad IA, Bendok BR, du R (2013) Brainstem cavernous malformations: 1390 surgical cases from the literature. World Neurosurg 80:89–93.  https://doi.org/10.1016/j.wneu.2012.04.002 CrossRefGoogle Scholar
  14. 14.
    Gibson CC, Zhu W, Davis CT, Bowman-Kirigin JA, Chan AC, Ling J, Walker AE, Goitre L, Delle Monache S, Retta SF, Shiu YTE, Grossmann AH, Thomas KR, Donato AJ, Lesniewski LA, Whitehead KJ, Li DY (2015) Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation 131:289–299.  https://doi.org/10.1161/CIRCULATIONAHA.114.010403 CrossRefGoogle Scholar
  15. 15.
    Leblanc GG, Golanov E, Awad IA, Young WL (2009) Biology of vascular malformations of the brain. Stroke 40:e694–e702.  https://doi.org/10.1161/STROKEAHA.109.563692 CrossRefGoogle Scholar
  16. 16.
    Shenkar R, Shi C, Austin C, Moore T, Lightle R, Cao Y, Zhang L, Wu M, Zeineddine HA, Girard R, McDonald DA, Rorrer A, Gallione C, Pytel P, Liao JK, Marchuk DA, Awad IA (2017) RhoA kinase inhibition with fasudil versus simvastatin in murine models of cerebral cavernous malformations. Stroke 48:187–194.  https://doi.org/10.1161/STROKEAHA.116.015013 CrossRefGoogle Scholar
  17. 17.
    Wüstehube J, Bartol A, Liebler SS, Brütsch R, Zhu Y, Felbor U, Sure U, Augustin HG, Fischer A (2010) Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling. Proc Natl Acad Sci U S A 107:12640–12645.  https://doi.org/10.1073/pnas.1000132107 CrossRefGoogle Scholar
  18. 18.
    Filippidis AS, Fountas KN, Kalani MYS, Zabramski JM, Spetzler RF (2011) Letter by Filippidis et al regarding article, “Evaluating strategies for the treatment of cerebral cavernous malformations.”. Stroke 42:e373–e373.  https://doi.org/10.1161/STROKEAHA.110.606251 CrossRefGoogle Scholar
  19. 19.
    Strahle J, Odden AJ, Maher CO, Garton HJL (2013) Letter to the editor: hemangiomas and propranolol. J Neurosurg Pediatr 12:418.  https://doi.org/10.3171/2013.6.PEDS13284 CrossRefGoogle Scholar
  20. 20.
    Léauté-Labrèze C, Dumas de la Roque E, Hubiche T et al (2008) Propranolol for severe hemangiomas of infancy. N Engl J Med 358:2649–2651.  https://doi.org/10.1056/NEJMc0708819 CrossRefGoogle Scholar
  21. 21.
    Smithson SL, Rademaker M, Adams S, Bade S, Bekhor P, Davidson S, Dore A, Drummond C, Fischer G, Gin A, Grills C, Halbert A, Lokmic Z, McCahon E, Morgan VA, Murrell DF, Orchard D, Penington A, Purvis D, Relic J, Robertson S, Robinson AJ, Scardamaglia L, Su J, Tan S, Wargon O, Warren L, Wong LC, Zappala T, Phillips R (2017) Consensus statement for the treatment of infantile haemangiomas with propranolol. Australas J Dermatol 58:155–159.  https://doi.org/10.1111/ajd.12600 CrossRefGoogle Scholar
  22. 22.
    Kaneko T, Sasaki S, Baba N, Koh K, Matsui K, Ohjimi H, Hayashi N, Nakano A, Ohki K, Kuwano Y, Morimoto A, Tamaki Z, Kakazu M, Kishi K, Oyama T, Sato A, Kato R, Higuchi T (2017) Efficacy and safety of oral propranolol for infantile hemangioma in Japan. Pediatr Int 59:869–877.  https://doi.org/10.1111/ped.13318 CrossRefGoogle Scholar
  23. 23.
    Mosnier J-F, Brunon J, Nuti C (2007) Histopathology of central nervous system cavernomas. Neurochirurgie 53:131–135.  https://doi.org/10.1016/j.neuchi.2007.02.004 CrossRefGoogle Scholar
  24. 24.
    Seidmann L, Anspach L, Roth W (2016) The embryo-placental CD15-positive “vasculogenic zones” as a source of propranolol-sensitive pediatric vascular tumors. Placenta 38:93–99.  https://doi.org/10.1016/j.placenta.2015.12.013 CrossRefGoogle Scholar
  25. 25.
    Annabi B, Lachambre M-P, Plouffe K, Moumdjian R, Béliveau R (2009) Propranolol adrenergic blockade inhibits human brain endothelial cells tubulogenesis and matrix metalloproteinase-9 secretion. Pharmacol Res 60:438–445.  https://doi.org/10.1016/j.phrs.2009.05.005 CrossRefGoogle Scholar
  26. 26.
    Lamy S, Lachambre M-P, Lord-Dufour S, Béliveau R (2010) Propranolol suppresses angiogenesis in vitro: inhibition of proliferation, migration, and differentiation of endothelial cells. Vasc Pharmacol 53:200–208.  https://doi.org/10.1016/j.vph.2010.08.002 CrossRefGoogle Scholar
  27. 27.
    Moschovi M, Alexiou GA, Stefanaki K, Tourkantoni N, Prodromou N (2010) Propranolol treatment for a giant infantile brain cavernoma. J Child Neurol 25:653–655.  https://doi.org/10.1177/0883073810363917 CrossRefGoogle Scholar
  28. 28.
    PROPRANOLOL TEVA gélule - EurekaSanté par VIDAL. In: EurekaSanté. https://eurekasante.vidal.fr/medicaments/vidal-famille/medicament-opropa01-PROPRANOLOL-TEVA-gelule.html. Accessed 7 Apr 2018
  29. 29.
    Berti I, Marchetti F, Skabar A, Zennaro F, Zanon D, Ventura A (2014) Propranolol for cerebral cavernous angiomatosis: a magic bullet. Clin Pediatr (Phila) 53:189–190.  https://doi.org/10.1177/0009922813492885 CrossRefGoogle Scholar
  30. 30.
    Cavalheiro S, Campos HG do A, Silva da Costa MD (2016) A case of giant fetal intracranial capillary hemangioma cured with propranolol. J Neurosurg Pediatr 17:711–716.  https://doi.org/10.3171/2015.11.PEDS15469 CrossRefGoogle Scholar
  31. 31.
    Dotan M, Lorber A (2013) Congestive heart failure with diffuse neonatal hemangiomatosis--case report and literature review. Acta Paediatr (Oslo, Norway: 1992) 102:e232–e238.  https://doi.org/10.1111/apa.12184 CrossRefGoogle Scholar
  32. 32.
    Miquel J, Bruneau B, Dupuy A (2014) Successful treatment of multifocal intracerebral and spinal hemangiomas with propranolol. J Am Acad Dermatol 70:e83–e84.  https://doi.org/10.1016/j.jaad.2013.11.006 CrossRefGoogle Scholar
  33. 33.
    Reinhard M, Schuchardt F, Meckel S, Heinz J, Felbor U, Sure U, Geisen U (2016) Propranolol stops progressive multiple cerebral cavernoma in an adult patient. J Neurol Sci 367:15–17.  https://doi.org/10.1016/j.jns.2016.04.053 CrossRefGoogle Scholar
  34. 34.
    Goldberg J, Jaeggi C, Schoeni D, Mordasini P, Raabe A, Bervini D (2018) Bleeding risk of cerebral cavernous malformations in patients on β-blocker medication: a cohort study. J Neurosurg:1–6.  https://doi.org/10.3171/2017.12.JNS172404

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Sorbonne Université, Université Pierre et Marie CurieParisFrance
  2. 2.Brain and Spine Institute, INSERM U1127, CNRS, UMR7225ParisFrance
  3. 3.Hospices Civils de Lyon, Neurology & Neurosurgery Hospital Pierre Wertheimer, Department of NeurosurgeryLyonFrance
  4. 4.University of Lyon, Université Claude BernardLyonFrance

Personalised recommendations