J Korean Neurosurg Soc.  2024 May;67(3):326-332. 10.3340/jkns.2024.0011.

Pediatric Cerebral Vascular Malformations : Current and Future Perspectives

• Smith ER

• KMID: 2554870
• DOI: http://doi.org/10.3340/jkns.2024.0011

Abstract

Intracranial vascular malformations typically encountered by pediatric neurosurgeons include arteriovenous malformations, vein of Galen malformations and cavernous malformations. While these remain amongst some of the most challenging lesions faced by patients and caregivers, the past decade has produced marked advances in the understanding of the pathophysiology of these conditions, with concomitant innovations in treatment. This article will highlight present and future perspectives relevant to these diseases, with a focus on an emerging approach utilizing disease-specific mutations to develop a novel taxonomy for these conditions.

Keyword

Arteriovenous malformations; Stroke; Pediatrics

Reference

References

1. Alexander MD, Cooke DL, Hallam DK, Kim H, Hetts SW, Ghodke BV. Less can be more: targeted embolization of aneurysms associated with arteriovenous malformations unsuitable for surgical resection. Interv Neuroradiol. 22:445–451. 2016.

2. Baxter PA, Su JM, Onar-Thomas A, Billups CA, Li XN, Poussaint TY, et al. A phase I/II study of veliparib (ABT-888) with radiation and temozolomide in newly diagnosed diffuse pontine glioma: a Pediatric Brain Tumor Consortium study. Neuro Oncol. 22:875–885. 2020.

3. Copelan A, Drocton G, Caton MT, Smith ER, Cooke DL, Nelson J, et al. Brain arteriovenous malformation recurrence after apparent microsurgical cure: increased risk in children who present with arteriovenous malformation rupture. Stroke. 51:2990–2996. 2020.

4. De Leacy R, Ansari SA, Schirmer CM, Cooke DL, Prestigiacomo CJ, Bulsara KR, et al. Endovascular treatment in the multimodality management of brain arteriovenous malformations: report of the Society of NeuroInterventional Surgery Standards and Guidelines Committee. J Neurointerv Surg. 14:1118–1124. 2022.

5. De Witt ME, Almaguer-Ascencio M, Petropoulou K, Tovar-Spinoza Z. The use of stereotactic MRI-guided laser interstitial thermal therapy for the treatment of pediatric cavernous malformations: the SUNY Upstate Golisano Children’s Hospital experience. Childs Nerv Syst. 39:417–424. 2023.

6. Duran D, Karschnia P, Gaillard JR, Karimy JK, Youngblood MW, DiLuna ML, et al. Human genetics and molecular mechanisms of vein of Galen malformation. J Neurosurg Pediatr. 21:367–374. 2018.

7. Duran D, Zeng X, Jin SC, Choi J, Nelson-Williams C, Yatsula B, et al. Mutations in chromatin modifier and ephrin signaling genes in vein of Galen malformation. Neuron. 101:429–443.e4. 2019.

8. Fehnel KP, Penn DL, Duggins-Warf M, Gruber M, Pineda S, Sesen J, et al. Dysregulation of the EphrinB2-EphB4 ratio in pediatric cerebral arteriovenous malformations is associated with endothelial cell dysfunction in vitro and functions as a novel noninvasive biomarker in patients. Exp Mol Med. 52:658–671. 2020.

9. Fellner F, Blank M, Fellner C, Böhm-Jurkovic H, Bautz W, Kalender WA. Virtual cisternoscopy of intracranial vessels: a novel visualization technique using virtual reality. Magn Reson Imaging. 16:1013–1022. 1998.

10. Ferriero DM, Fullerton HJ, Bernard TJ, Billinghurst L, Daniels SR, DeBaun MR, et al. Management of stroke in neonates and children: a scientific statement from the American Heart Association/American Stroke Association. Stroke. 50:e51–e96. 2019.

11. Fish JE, Flores Suarez CP, Boudreau E, Herman AM, Gutierrez MC, Gustafson D, et al. Somatic gain of KRAS function in the endothelium is sufficient to cause vascular malformations that require MEK but not PI3K signaling. Circ Res. 127:727–743. 2020.

12. Flemming KD, Smith E, Marchuk D, Derry WB. Familial Cerebral Cavernous Malformations. Seattle: University of Washington;2023.

13. Flores BC, See AP, Weiner GM, Jankowitz BT, Ducruet AF, Albuquerque FC. Use of the Apollo detachable-tip microcatheter for endovascular embolization of arteriovenous malformations and arteriovenous fistulas. J Neurosurg. 130:963–971. 2018.

14. Gao X, Liang G, Li Z, Wang X, Yu C, Cao P, et al. Transarterial coilaugmented Onyx embolization for brain arteriovenous malformation. Technique and experience in 22 consecutive patients. Interv Neuroradiol. 20:83–90. 2014.

15. Ghorbani M, Griessenauer CJ, Wipplinger C, Jabbour P, Asl MK, Rahbarian F, et al. Adenosine-induced transient circulatory arrest in transvenous embolization of cerebral arteriovenous malformations. Neuroradiol J. 34:509–516. 2021.

16. Goss JA, Huang AY, Smith E, Konczyk DJ, Smits PJ, Sudduth CL, et al. Somatic mutations in intracranial arteriovenous malformations. PLoS One. 14:e0226852. 2019.

17. Graffeo CS, Bhandarkar AR, Carlstrom LP, Perry A, Nguyen B, Daniels DJ, et al. That which is unseen: 3D printing for pediatric cerebrovascular education. Childs Nerv Syst. 39:2449–2457. 2023.

18. Groff MW, Adams DC, Kahn RA, Kumbar UM, Yang BY, Bederson JB. Adenosine-induced transient asystole for management of a basilar artery aneurysm. Case report. J Neurosurg. 91:687–690. 1999.

19. Gross BA, Du R, Orbach DB, Scott RM, Smith ER. The natural history of cerebral cavernous malformations in children. J Neurosurg Pediatr. 17:123–128. 2016.

20. Gross BA, Scott RM, Smith ER. Management of brain arteriovenous malformations. Lancet. 383:1635. 2014.

21. Gross BA, Storey A, Orbach DB, Scott RM, Smith ER. Microsurgical treatment of arteriovenous malformations in pediatric patients: the Boston Children’s Hospital experience. J Neurosurg Pediatr. 15:71–77. 2015.

22. Hak JF, Boulouis G, Kerleroux B, Benichi S, Stricker S, Gariel F, et al. Pediatric brain arteriovenous malformation recurrence: a cohort study, systematic review and meta-analysis. J Neurointerv Surg. 14:611–617. 2022.

23. Hamilton MG, Spetzler RF. The prospective application of a grading system for arteriovenous malformations. Neurosurgery. 34:2–6. discussion 6-7. 1994.

24. Iosif C, Mendes GA, Saleme S, Ponomarjova S, Silveira EP, Caire F, et al. Endovascular transvenous cure for ruptured brain arteriovenous malformations in complex cases with high Spetzler-Martin grades. J Neurosurg. 122:1229–1238. 2015.

25. Kahle KT, Duran D, Smith ER. Increasing precision in the management of pediatric neurosurgical cerebrovascular diseases with molecular genetics. J Neurosurg Pediatr. 31:228–237. 2023.

26. Kapadia M, Walwema M, Smith TR, Bellinski I, Batjer H, Getch C, et al. Seizure outcome in patients with cavernous malformation after early surgery. Epilepsy Behav. 115:107662. 2021.

27. Killer-Oberpfalzer M, Chapot R, Orion D, Barr JD, Cabiri O, Berenstein A. Clinical experience with the Bendit steerable microcatheter: a new paradigm for endovascular treatment. J Neurointerv Surg. 15:771–775. 2023.

28. Koyanagi M, Mosimann PJ, Nordmeyer H, Heddier M, Krause J, Narata AP, et al. The transvenous retrograde pressure cooker technique for the curative embolization of high-grade brain arteriovenous malformations. J Neurointerv Surg. 13:637–641. 2021.

29. Li CR, Shen CC, Yang MY, Tsuei YS, Lee CH. Intraoperative augmented reality in microsurgery for intracranial arteriovenous malformation: a case report and literature review. Brain Sci. 13:653. 2023.

30. Lin N, Smith ER, Scott RM, Orbach DB. Safety of neuroangiography and embolization in children: complication analysis of 697 consecutive procedures in 394 patients. J Neurosurg Pediatr. 16:432–438. 2015.

31. Litts C, Jasper P, Wessell JE, Eskandari R. 3-dimensional exoscope for far lateral approach to pontomedullary cavernous malformation. World Neurosurg. 166:88. 2022.

32. Maimon S, Strauss I, Frolov V, Margalit N, Ram Z. Brain arteriovenous malformation treatment using a combination of Onyx and a new detachable tip microcatheter, SONIC: short-term results. AJNR Am J Neuroradiol. 31:947–954. 2010.

33. Manjila S, Karhade A, Phi JH, Scott RM, Smith ER. Real-time ultrasound-guided catheter navigation for approaching deep-seated brain lesions: role of intraoperative neurosonography with and without fusion with magnetic resonance imaging. Pediatr Neurosurg. 52:80–86. 2017.

34. Mohr JP, Parides MK, Stapf C, Moquete E, Moy CS, Overbey JR, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, nonblinded, randomised trial. Lancet. 383:614–621. 2014.

35. Ogasawara C, Watanabe G, Young K, Kwon R, Conching A, Palmisciano P, et al. Laser interstitial thermal therapy for cerebral cavernous malformations: a systematic review of indications, safety, and outcomes. World Neurosurg. 166:279–287.e1. 2022.

36. Orbach DB, Wilkins-Haug LE, Benson CB, Rangwala SD, Pak C, Saffarzadeh M, et al. Overcoming roadblocks in clinical innovation via high fidelity simulation: use of a phantom simulator to achieve FDA and IRB approval of a clinical trial of fetal embolization of vein of Galen malformations. J Neurointerv Surg. 15:1218–1223. 2023.

37. Orbach DB, Wilkins-Haug LE, Benson CB, Tworetzky W, Rangwala SD, Guseh SH, et al. Transuterine ultrasound-guided fetal embolization of vein of galen malformation, eliminating postnatal pathophysiology. Stroke. 54:e231–e232. 2023.

38. Paramasivam S, Niimi Y, Fifi J, Berenstein A. Onyx embolization using dual-lumen balloon catheter: initial experience and technical note. J Neuroradiol. 40:294–302. 2013.

39. Park KY, Kim JW, Kim BM, Kim DJ, Chung J, Jang CK, et al. Coil-protected technique for liquid embolization in neurovascular malformations. Korean J Radiol. 20:1285–1292. 2019.

40. Pile-Spellman J, Young WL, Joshi S, Duong H, Vang MC, Hartmann A, et al. Adenosine-induced cardiac pause for endovascular embolization of cerebral arteriovenous malformations: technical case report. Neurosurgery. 44:881–886. discussion 886-887. 1999.

41. Pinkiewicz M, Pinkiewicz M, Walecki J, Zawadzki M. State of the art in the role of endovascular embolization in the management of brain arteriovenous malformations-a systematic review. J Clin Med. 11:7208. 2022.

42. Qi C, Bujaroski RS, Baell J, Zheng X. Kinases in cerebral cavernous malformations: Pathogenesis and therapeutic targets. Biochim Biophys Acta Mol Cell Res. 1870:119488. 2023.

43. Rangwala SD, Albanese JS, Slingerland AL, Papadakis JE, Weber DS, Smith ER, et al. External validation of the R2eD AVM scoring system to assess rupture risk in pediatric AVM patients. J Neurosurg Pediatr. 31:469–475. 2023.

44. Rangwala SD, Johnson K, See AP, Smith ER, Orbach DB. Direct transverse sinus puncture for transvenous coil embolization of vein of galen malformations: innovating existing techniques. Oper Neurosurg (Hagerstown). 25:e352–e358. 2023.

45. Ravindra VM, Bollo RJ, Eli IM, Griauzde J, Lanpher A, Klein J, et al. A study of pediatric cerebral arteriovenous malformations: clinical presentation, radiological features, and long-term functional and educational outcomes with predictors of sustained neurological deficits. J Neurosurg Pediatr. 24:1–8. 2019.

46. Ravindra VM, Karsy M, Lanpher A, Bollo RJ, Griauzde J, Scott RM, et al. A national analysis of 9655 pediatric cerebrovascular malformations: effect of hospital volume on outcomes. J Neurosurg Pediatr. 24:397–406. 2019.

47. Razavi SAS, Mirbolouk MH, Gorji R, Ebrahimnia F, Sasannejad P, Zabihyan S, et al. Endovascular treatment as the first-line approach for cure of low-grade brain arteriovenous malformation. Neurosurg Focus. 53:E8. 2022.

48. Rodriguez-Calienes A, Vivanco-Suarez J, Borjas-Calderón NF, Chavez-Ecos FA, Fernández DEM, Malaga M, et al. Curative embolization of ruptured pediatric cerebral arteriovenous malformations. Clin Neurol Neurosurg. 227:107663. 2023.

49. Sarica C, Erdogan O, Sahin Y, Dagcinar A, Baltacioglu F. Endoscopic third ventriculostomy in an untreated vein of Galen malformation presenting lately with acute obstructive hydrocephalus. World Neurosurg. 138:35–38. 2020.

50. See AP, Smith ER. Evolution of clinical and translational advances in the management of pediatric arteriovenous malformations. Childs Nerv Syst. 39:2807–2818. 2023.

51. See AP, Wilkins-Haug LE, Benson CB, Tworetzky W, Orbach DB. Percutaneous transuterine fetal cerebral embolisation to treat vein of Galen malformations at risk of urgent neonatal decompensation: study protocol for a clinical trial of safety and feasibility. BMJ Open. 12:e058147. 2022.

52. Sesen J, Driscoll J, Moses-Gardner A, Orbach DB, Zurakowski D, Smith ER. Non-invasive urinary biomarkers in Moyamoya disease. Front Neurol. 12:661952. 2021.

53. Sesen J, Ghalali A, Driscoll J, Martinez T, Lupieri A, Zurakowski D, et al. Discovery and characterization of ephrin B2 and EphB4 dysregulation and novel mutations in cerebral cavernous malformations: in vitro and patient-derived evidence of ephrin-mediated endothelial cell pathophysiology. Cell Mol Neurobiol. 44:12. 2023.

54. Shoubash L, Nowak S, Greisert S, Al Menabbawy A, Rathmann E, von Podewils F, et al. Cavernoma-related epilepsy: postoperative epilepsy outcome and analysis of the predictive factors, case series. World Neurosurg. 172:e499–e507. 2023.

55. Signorelli F, Gory B, Pelissou-Guyotat I, Guyotat J, Riva R, Dailler F, et al. Ruptured brain arteriovenous malformations associated with aneurysms: safety and efficacy of selective embolization in the acute phase of hemorrhage. Neuroradiology. 56:763–769. 2014.

56. Smith ER, Manfredi M, Scott RM, Black PM, Moses MA. A recurrent craniopharyngioma illustrates the potential usefulness of urinary matrix metalloproteinases as noninvasive biomarkers: case report. Neurosurgery. 60:E1148–E1149. discussion E1149. 2007.

57. Smith ER, Zurakowski D, Saad A, Scott RM, Moses MA. Urinary biomarkers predict brain tumor presence and response to therapy. Clin Cancer Res. 14:2378–2386. 2008.

58. Snellings DA, Hong CC, Ren AA, Lopez-Ramirez MA, Girard R, Srinath A, et al. Cerebral cavernous malformation: from mechanism to therapy. Circ Res. 129:195–215. 2021.

59. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 65:476–483. 1986.

60. Taki W, Yonekawa Y, Iwata H, Uno A, Yamashita K, Amemiya H. A new liquid material for embolization of arteriovenous malformations. AJNR Am J Neuroradiol. 11:163–168. 1990.

61. Thiex R, Williams A, Smith E, Scott RM, Orbach DB. The use of Onyx for embolization of central nervous system arteriovenous lesions in pediatric patients. AJNR Am J Neuroradiol. 31:112–120. 2010.

62. van Rooij WJ, Jacobs S, Sluzewski M, van der Pol B, Beute GN, Sprengers ME. Curative embolization of brain arteriovenous malformations with onyx: patient selection, embolization technique, and results. AJNR Am J Neuroradiol. 33:1299–1304. 2012.

63. Weinstock P, Prabhu SP, Flynn K, Orbach DB, Smith E. Optimizing cerebrovascular surgical and endovascular procedures in children via personalized 3D printing. J Neurosurg Pediatr. 16:584–589. 2015.

64. Yousefi O, Sabahi M, Malcolm J, Adada B, Borghei-Razavi H. Laser interstitial thermal therapy for cavernous malformations: a systematic review. Front Surg. 9:887329. 2022.

65. Zeng X, Hunt A, Jin SC, Duran D, Gaillard J, Kahle KT. EphrinB2-EphB4-RASA1 signaling in human cerebrovascular development and disease. Trends Mol Med. 25:265–286. 2019.

66. Zhang P, Zhang H, Shi C, Zhou J, Dong J, Liang M, et al. Clinical characteristics and risk factors of cerebral cavernous malformation-related epilepsy. Epilepsy Behav. 139:109064. 2023.

67. Zhao S, Mekbib KY, van der Ent MA, Allington G, Prendergast A, Chau JE, et al. Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations. Nat Commun. 14:7452. 2023.

68. Zhao S, Mekbib KY, van der Ent MA, Allington G, Prendergast A, Chau JE, et al. Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations. Available at : https://doi.org/10.1101/2023.03.18.532837.