Introduction: Ruptured intracranial arteriovenous malformations (AVM) are at a significantly greater risk for future hemorrhage than unruptured lesions thereby necessitating treatment in the majority of cases. We describe the radiosurgical outcomes for a large cohort of ruptured AVMs.

Methods: From an institutional AVM radiosurgery database, we identified all patients with a history of AVM rupture. Those with less than 2 years radiologic follow-up were excluded except those with obliteration resulting in 565 ruptured AVM patients for analysis with a median radiologic follow-up of 57 months. The patients’ median age was 29 years, and 21% underwent pre-radiosurgery embolization. The median volume and prescription dose were 2.1 cc and 22 Gy, respectively. The Spetzler-Martin grade was III or higher in 56% of patients, the median radiosurgery-based AVM score was 1.08, and the Virginia Radiosurgery AVM Scale (RAS) was 3 to 4 points in 44%.

Results: The cumulative obliteration rate was 76%, and the actuarial obliteration rates were 41% and 64% at 3 and 5 years, respectively. Multivariate analysis identified no pre-radiosurgery embolization (P<0.001), increased prescription dose (P=0.001), single draining vein (P=0.046), no post-radiosurgery hemorrhage (P=0.007), and lower Virginia RAS (P=0.020) as independent predictors of obliteration. The annual risk of latency period hemorrhage was 2.0% with a 1.6% rate of hemorrhage-related morbidity and mortality. Decreased prescription dose (P<0.001) and multiple draining veins (P=0.003) were independent predictors of post-radiosurgery hemorrhage based on multivariate analysis. The rates of symptomatic and permanent radiation-induced changes (RIC) were 8% and 2.7%, respectively. From multivariate analysis, single draining vein (P<0.001) and higher Virginia RAS (P=0.005) were independent predictors of RIC following radiosurgery.

Conclusions: Radiosurgery effectively treats ruptured AVMs with an acceptably low risk to benefit ratio. For ruptured AVMs, favorable outcomes are more likely when pre-radiosurgical embolization is avoided and a higher prescription dose can be delivered.

Patient Care: AVM rupture is the most devastating and feared and complication associated with this cerebrovascular pathology. Our retrospective analysis demonstrates that Gamma Knife radiosurgery affords a favorable risk to benefit profile for ruptured AVMs and identifies independent predictors of successful outcomes and complications.

Learning Objectives: By the conclusion of this session, participants should be able to 1) Describe the outcomes of Gamma Knife radiosurgery as a treatment approach for ruptured intracranial arteriovenous malformations, 2) Discuss, in small groups the patient, arteriovenous malformation and treatment characteristics which predict obliteration and radiation-induced changes following radiosurgery, and 3) Identify an effective treatment for ruptured arteriovenous malformations.

References: 1. Achrol AS, Guzman R, Varga M, Adler JR, Steinberg GK, and Chang SD: Pathogenesis and radiobiology of brain arteriovenous malformations: implications for risk stratification in natural history and posttreatment course. Neurosurg Focus 26: E9, 2009. 2. Andrade-Souza YM, Ramani M, Scora D, Tsao MN, terBrugge K, and Schwartz ML: Embolization before radiosurgery reduces the obliteration rate of arteriovenous malformations. Neurosurgery 60: 443-51; discussion 451-2, 2007. 3. Bing F, Doucet R, Lacroix F, Bahary JP, Darsaut T, Roy D, Guilbert F, Raymond J, and Weill A: Liquid embolization material reduces the delivered radiation dose: clinical myth or reality? AJNR Am J Neuroradiol 33: 320-2, 2012. 4. Chang SD, Shuster DL, Steinberg GK, Levy RP, and Frankel K: Stereotactic radiosurgery of arteriovenous malformations: pathologic changes in resected tissue. Clin Neuropathol 16: 111-6, 1997. 5. Choi JH and Mohr JP: Brain arteriovenous malformations in adults. Lancet Neurol 4: 299-308, 2005. 6. Choi JH, Mast H, Sciacca RR, Hartmann A, Khaw AV, Mohr JP, Sacco RL, and Stapf C: Clinical outcome after first and recurrent hemorrhage in patients with untreated brain arteriovenous malformation. Stroke 37: 1243-7, 2006. 7. Cockroft KM: Unruptured brain arteriovenous malformations should be treated conservatively: no. Stroke 38: 3310-1, 2007. 8. da Costa L, Wallace MC, Ter Brugge KG, O'Kelly C, Willinsky RA, and Tymianski M: The natural history and predictive features of hemorrhage from brain arteriovenous malformations. Stroke 40: 100-5, 2009. 9. Davis SM and Donnan GA: Unruptured brain arteriovenous malformations: another asymptomatic conundrum. Stroke 38: 3312, 2007. 10. Ding D, Yen CP, Xu Z, Starke RM, and Sheehan JP: Radiosurgery for patients with unruptured intracranial arteriovenous malformations. J Neurosurg 2013. 11. Fiehler J and Stapf C: ARUBA--beating natural history in unruptured brain AVMs by intervention. Neuroradiology 50: 465-7, 2008. 12. Graf CJ, Perret GE, and Torner JC: Bleeding from cerebral arteriovenous malformations as part of their natural history. J Neurosurg 58: 331-7, 1983. 13. Gross BA and Du R: Natural history of cerebral arteriovenous malformations: a meta-analysis. J Neurosurg 118: 437-43, 2013. 14. Hamilton MG and Spetzler RF: The prospective application of a grading system for arteriovenous malformations. Neurosurgery 34: 2-6; discussion 6-7, 1994. 15. Han PP, Ponce FA, and Spetzler RF: Intention-to-treat analysis of Spetzler-Martin grades IV and V arteriovenous malformations: natural history and treatment paradigm. J Neurosurg 98: 3-7, 2003. 16. Hartmann A, Mast H, Mohr JP, Koennecke HC, Osipov A, Pile-Spellman J, Duong DH, and Young WL: Morbidity of intracranial hemorrhage in patients with cerebral arteriovenous malformation. Stroke 29: 931-4, 1998. 17. Heros RC, Korosue K, and Diebold PM: Surgical excision of cerebral arteriovenous malformations: late results. Neurosurgery 26: 570-7; discussion 577-8, 1990. 18. Kano H, Kondziolka D, Flickinger JC, Park KJ, Parry PV, Yang HC, Sirin S, Niranjan A, Novotny J, Jr., and Lunsford LD: Stereotactic radiosurgery for arteriovenous malformations, Part 6: multistaged volumetric management of large arteriovenous malformations. J Neurosurg 116: 54-65, 2012. 19. Kano H, Kondziolka D, Flickinger JC, Park KJ, Iyer A, Yang HC, Liu X, Monaco EA, 3rd, Niranjan A, and Lunsford LD: Stereotactic radiosurgery after embolization for arteriovenous malformations. Prog Neurol Surg 27: 89-96, 2013. 20. Kano H, Kondziolka D, Flickinger JC, Yang HC, Flannery TJ, Niranjan A, Novotny J, Jr., and Lunsford LD: Stereotactic radiosurgery for arteriovenous malformations, Part 5: management of brainstem arteriovenous malformations. J Neurosurg 116: 44-53, 2012. 21. Kano H, Kondziolka D, Flickinger JC, Yang HC, Flannery TJ, Niranjan A, Novotny J, Jr., and Lunsford LD: Stereotactic radiosurgery for arteriovenous malformations, Part 4: management of basal ganglia and thalamus arteriovenous malformations. J Neurosurg 116: 33-43, 2012. 22. Kano H, Kondziolka D, Flickinger JC, Yang HC, Flannery TJ, Awan NR, Niranjan A, Novotny J, and Lunsford LD: Stereotactic radiosurgery for arteriovenous malformations, part 2: management of pediatric patients. J Neurosurg Pediatr 9: 1-10, 2012. 23. Kano H, Lunsford LD, Flickinger JC, Yang HC, Flannery TJ, Awan NR, Niranjan A, Novotny J, Jr., and Kondziolka D: Stereotactic radiosurgery for arteriovenous malformations, Part 1: management of Spetzler-Martin Grade I and II arteriovenous malformations. J Neurosurg 116: 11-20, 2012. 24. Kano H, Kondziolka D, Flickinger JC, Yang HC, Flannery TJ, Awan NR, Niranjan A, Novotny J, Jr., and Lunsford LD: Stereotactic radiosurgery for arteriovenous malformations, Part 3: outcome predictors and risks after repeat radiosurgery. J Neurosurg 116: 21-32, 2012. 25. Katsaridis V, Papagiannaki C, and Aimar E: Curative embolization of cerebral arteriovenous malformations (AVMs) with Onyx in 101 patients. Neuroradiology 50: 589-97, 2008. 26. Kilic K, Konya D, Kurtkaya O, Sav A, Pamir MN, and Kilic T: Inhibition of angiogenesis induced by cerebral arteriovenous malformations using gamma knife irradiation. J Neurosurg 106: 463-9, 2007. 27. Lawton MT, Du R, Tran MN, Achrol AS, McCulloch CE, Johnston SC, Quinnine NJ, and Young WL: Effect of presenting hemorrhage on outcome after microsurgical resection of brain arteriovenous malformations. Neurosurgery 56: 485-93; discussion 485-93, 2005. 28. Lawton MT, Kim H, McCulloch CE, Mikhak B, and Young WL: A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery 66: 702-13; discussion 713, 2010. 29. Mast H, Young WL, Koennecke HC, Sciacca RR, Osipov A, Pile-Spellman J, Hacein-Bey L, Duong H, Stein BM, and Mohr JP: Risk of spontaneous haemorrhage after diagnosis of cerebral arteriovenous malformation. Lancet 350: 1065-8, 1997. 30. Miller RA and Jankowitz B: Endovascular embolization in combination with radiosurgery for treatment of arteriovenous malformations. Prog Neurol Surg 27: 81-8, 2013. 31. Mohr JP, Moskowitz AJ, Stapf C, Hartmann A, Lord K, Marshall SM, Mast H, Moquete E, Moy CS, Parides M, Pile-Spellman J, Al-Shahi Salman R, Weinberg A, Young WL, Estevez A, Kureshi I, and Brisman JL: The ARUBA trial: current status, future hopes. Stroke 41: e537-40, 2010. 32. Morgenstern LB, Hemphill JC, 3rd, Anderson C, Becker K, Broderick JP, Connolly ES, Jr., Greenberg SM, Huang JN, MacDonald RL, Messe SR, Mitchell PH, Selim M, and Tamargo RJ: Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 41: 2108-29, 2010. 33. Mounayer C, Hammami N, Piotin M, Spelle L, Benndorf G, Kessler I, and Moret J: Nidal embolization of brain arteriovenous malformations using Onyx in 94 patients. AJNR Am J Neuroradiol 28: 518-23, 2007. 34. Natarajan SK, Ghodke B, Britz GW, Born DE, and Sekhar LN: Multimodality treatment of brain arteriovenous malformations with microsurgery after embolization with onyx: single-center experience and technical nuances. Neurosurgery 62: 1213-25; discussion 1225-6, 2008. 35. Ondra SL, Troupp H, George ED, and Schwab K: The natural history of symptomatic arteriovenous malformations of the brain: a 24-year follow-up assessment. J Neurosurg 73: 387-91, 1990. 36. Panagiotopoulos V, Gizewski E, Asgari S, Regel J, Forsting M, and Wanke I: Embolization of intracranial arteriovenous malformations with ethylene-vinyl alcohol copolymer (Onyx). AJNR Am J Neuroradiol 30: 99-106, 2009. 37. Pandey P, Marks MP, Harraher CD, Westbroek EM, Chang SD, Do HM, Levy RP, Dodd RL, and Steinberg GK: Multimodality management of Spetzler-Martin Grade III arteriovenous malformations. J Neurosurg 116: 1279-88, 2012. 38. Pollock BE, Flickinger JC, Lunsford LD, Maitz A, and Kondziolka D: Factors associated with successful arteriovenous malformation radiosurgery. Neurosurgery 42: 1239-44; discussion 1244-7, 1998. 39. Pollock BE, Flickinger JC, Lunsford LD, Bissonette DJ, and Kondziolka D: Factors that predict the bleeding risk of cerebral arteriovenous malformations. Stroke 27: 1-6, 1996. 40. Pollock BE, Kondziolka D, Flickinger JC, Patel AK, Bissonette DJ, and Lunsford LD: Magnetic resonance imaging: an accurate method to evaluate arteriovenous malformations after stereotactic radiosurgery. J Neurosurg 85: 1044-9, 1996. 41. Saatci I, Geyik S, Yavuz K, and Cekirge HS: Endovascular treatment of brain arteriovenous malformations with prolonged intranidal Onyx injection technique: long-term results in 350 consecutive patients with completed endovascular treatment course. J Neurosurg 115: 78-88, 2011. 42. Schneider BF, Eberhard DA, and Steiner LE: Histopathology of arteriovenous malformations after gamma knife radiosurgery. J Neurosurg 87: 352-7, 1997. 43. Schwyzer L, Yen CP, Evans A, Zavoian S, and Steiner L: Long-term Results of Gamma Knife Surgery for Partially Embolized Arteriovenous Malformations. Neurosurgery 71: 1139-48, 2012. 44. Spetzler RF and Martin NA: A proposed grading system for arteriovenous malformations. J Neurosurg 65: 476-83, 1986. 45. St George EJ, Perks J, and Plowman PN: Stereotactic radiosurgery XIV: The role of the haemosiderin 'ring' in the development of adverse reactions following radiosurgery for intracranial cavernous malformations: a sustainable hypothesis. Br J Neurosurg 16: 385-91, 2002. 46. Stapf C and Mohr JP: Unruptured brain arteriovenous malformations should be treated conservatively: yes. Stroke 38: 3308-9, 2007. 47. Stapf C, Mohr JP, Choi JH, Hartmann A, and Mast H: Invasive treatment of unruptured brain arteriovenous malformations is experimental therapy. Curr Opin Neurol 19: 63-8, 2006. 48. Stapf C, Mast H, Sciacca RR, Choi JH, Khaw AV, Connolly ES, Pile-Spellman J, and Mohr JP: Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology 66: 1350-5, 2006. 49. Starke RM, Yen CP, Ding D, and Sheehan JP: A practical grading scale for predicting outcome after radiosurgery for arteriovenous malformations: analysis of 1012 treated patients. J Neurosurg 2013. 50. Starke RM, Yen CP, Ding D, and Sheehan JP: A Practical Grading Scale to Predict Radiosurgery Outcome in Arteriovenous Malformations: Analysis of 1,012 Treated Patients. J Neurosurg In press: 2013. 51. Steiner L, Lindquist C, Adler JR, Torner JC, Alves W, and Steiner M: Clinical outcome of radiosurgery for cerebral arteriovenous malformations. J Neurosurg 77: 1-8, 1992. 52. Stemer AB, Bank WO, Armonda RA, Liu AH, Herzig DW, and Bell RS: Acute embolization of ruptured brain arteriovenous malformations. J Neurointerv Surg 5: 196-200, 2013. 53. Sure U, Battenberg E, Dempfle A, Tirakotai W, Bien S, and Bertalanffy H: Hypoxia-inducible factor and vascular endothelial growth factor are expressed more frequently in embolized than in nonembolized cerebral arteriovenous malformations. Neurosurgery 55: 663-9; discussion 669-70, 2004. 54. Valle RD, Zenteno M, Jaramillo J, Lee A, and De Anda S: Definition of the key target volume in radiosurgical management of arteriovenous malformations: a new dynamic concept based on angiographic circulation time. J Neurosurg 109 Suppl: 41-50, 2008. 55. van Rooij WJ, Sluzewski M, and Beute GN: Brain AVM embolization with Onyx. AJNR Am J Neuroradiol 28: 172-7; discussion 178, 2007. 56. Wegner RE, Oysul K, Pollock BE, Sirin S, Kondziolka D, Niranjan A, Lunsford LD, and Flickinger JC: A modified radiosurgery-based arteriovenous malformation grading scale and its correlation with outcomes. Int J Radiat Oncol Biol Phys 79: 1147-50, 2011. 57. Yen CP, Monteith SJ, Nguyen JH, Rainey J, Schlesinger DJ, and Sheehan JP: Gamma Knife surgery for arteriovenous malformations in children. J Neurosurg Pediatr 6: 426-34, 2010.