Neurol Sci DOI 10.1007/s10072-014-2020-1
LETTER TO THE EDITOR
Predicting outcomes from radiosurgery for intracranial arteriovenous malformations: effect of embolization, prior hemorrhage, and nidus anatomy Dale Ding
Received: 11 July 2014 / Accepted: 26 November 2014 Ó Springer-Verlag Italia 2014
Dear Editor, The modern management of intracranial arteriovenous malformations (AVM) is a highly controversial topic. The recently published high-profile study, A Randomized Trial of Unruptured Brain AVMs (ARUBA), reported superior outcomes with medical management of unruptured AVMs compared to intervention [1]. The primary endpoint, defined as symptomatic stroke or mortality, was observed in 10 % of the medical arm compared to 31 % of the intervention arm (p \ 0.0001) after a mean follow-up of 33 months. Due to the premature termination of ARUBA, the relatively short follow-up duration, and the heterogeneity of the interventions performed, there remains a considerable debate within the cerebrovascular community regarding the validity and generalizability of the trial’s findings. AVM treatment can be undertaken with surgical resection, endovascular embolization, or stereotactic radiosurgery, alone or in combination. Among the different treatment modalities, radiosurgery is the least invasive but requires a latency period of 2–3 years to achieve AVM obliteration. In the following discussion, we explore the effect of previous interventions, prior hemorrhage, and nidus angioarchitecture on AVM radiosurgery outcomes. The aims of AVM embolization depend on both the anatomy of the nidus and the treatment paradigms endorsed by the neurointerventionalists. Curative embolization is possible for relatively small, compact nidi, although the risk to benefit profile of standalone embolization compared to surgical resection or radiosurgery is controversial. For
D. Ding (&) Department of Neurosurgery, University of Virginia, Charlottesville, P.O. Box 800212, VA 22908, USA e-mail: [email protected]
large or diffuse nidi, embolization can reduce operative blood loss or decrease radiosurgical treatment volume by occluding high-flow feeding arteries or intranidal arteriovenous shunts. As mounting evidence supports the deleterious effect of nidal embolization on radiosurgical obliteration rates, the use of pre-radiosurgery embolization has waned in the multimodality management of AVMs [2]. Furthermore, embolization has not been shown to reduce an AVM’s hemorrhage risk prior radiosurgery or during the latency period between radiosurgical treatment and nidus obliteration. In fact, critical analysis of the interventional outcomes from ARUBA suggests that incomplete AVM occlusion may promote nidal destabilization and predispose them to rupture [1]. The mechanisms underlying embolization-induced alterations to AVM biology have not been fully delineated, and the explanations for lower radiosurgical obliteration rates in previously embolized nidi are not rigorously substantiated. However, for large AVMs, embolization followed by single-session radiosurgery appears to be more effective than staged radiosurgery approaches, although this has not been confirmed by a prospective study. Intracranial hemorrhage is the most common presentation of AVMs, and ruptured AVMs are more prone to hemorrhage than unruptured ones. Whether AVM rupture has the same effect on latency period hemorrhage as it does on the natural hemorrhage risk is unknown. Based on our institutional experience of over 1,000 AVMs treated with radiosurgery, we found the annual post-radiosurgery hemorrhage rates of ruptured and unruptured AVMs to be 2.0 and 1.6 %, respectively [2, 3]. In our analysis of 398 patients with Spetzler–Martin grade III AVMs, multivariate Cox proportional hazards regression analysis identified prior hemorrhage to be an independent predictor of obliteration (p = 0.016) [4]. Additionally, multivariate logistic
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Neurol Sci
regression analysis found unruptured AVMs were significantly more likely to have radiation-induced changes (p \ 0.0001), defined as perinidal T2-weighted hyperintensities on magnetic resonance imaging. Thus, the perinidal gliotic capsule which develops after AVM rupture may protect the surrounding normal parenchyma from the development of radiation-induced changes. Currently, the effect of prior hemorrhage on AVM radiosurgery outcomes has yet to be rigorously defined. Although the original intention of the Spetzler–Martin grading system was to predict AVM surgical outcomes, it has also been shown to correlate with radiosurgery outcomes [2]. In an effort to devise a classification system which could efficiently and reliably predict AVM radiosurgery outcomes, Starke et al. proposed the Virginia Radiosurgery AVM Scale (VRAS), which is comprised of AVM volume (\2 cm3—0 points, 2–4 cm3—1 point, [4 cm3—2 points), prior hemorrhage (1 point), and eloquent location (1 point) [5]. The incidence of favorable outcome, defined as complete AVM obliteration without latency period hemorrhage or permanent radiation-induced symptoms, was 80 % for a VRAS of 0 or 1 point, 70 % for a VRAS of 2 points, and 45 % for a VRAS of 3 or 4 points. External validation of the VRAS with a large, multicenter cohort is presently underway and is necessary to propel it towards widespread utilization. In conclusion, although radiosurgery has been established as an effective therapeutic modality for AVMs, our understanding of the factors which have the most profound impact on obliteration, latency period hemorrhage, and adverse radiation effects
123
continues to evolve. It is crucial that future efforts are undertaken to refine our ability to predict AVM radiosurgery outcomes so that patients can be appropriately selected for treatment and be properly counseled regarding radiosurgical efficacy and morbidity. Conflict of interest
The authors have no conflicts of interest.
References 1. Mohr JP, Parides MK, Stapf C, Moquete E, Moy CS, Overbey JR, Al-Shahi Salman R, Vicaut E, Young WL, Houdart E, Cordonnier C, Stefani MA, Hartmann A, von Kummer R, Biondi A, Berkefeld J, Klijn CJ, 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(9917):614–621 S0140-6736(13)62302-8101016/S01406736(13)62302-8 2. Ding D, Yen CP, Xu Z, Starke RM, Sheehan JP (2013) Radiosurgery for patients with unruptured intracranial arteriovenous malformations. J Neurosurg 118(5):958–966. doi:10.3171/ 2013.2.JNS121239 3. Ding D, Yen CP, Starke RM, Xu Z, Sheehan JP (2014) Radiosurgery for ruptured intracranial arteriovenous malformations. J Neurosurg. doi:10.3171/2014.2.JNS131605 4. Ding D, Yen CP, Starke RM, Xu Z, Sun X, Sheehan JP (2014) Radiosurgery for Spetzler-Martin Grade III arteriovenous malformations. J Neurosurg 120(4):959–969. doi:10.3171/2013.12. JNS131041 5. Starke RM, Yen CP, Ding D, Sheehan JP (2013) A practical grading scale for predicting outcome after radiosurgery for arteriovenous malformations: analysis of 1012 treated patients. J Neurosurg 119(4):981–987. doi:10.3171/2013.5.JNS1311
LETTER TO THE EDITOR
Predicting outcomes from radiosurgery for intracranial arteriovenous malformations: effect of embolization, prior hemorrhage, and nidus anatomy Dale Ding
Received: 11 July 2014 / Accepted: 26 November 2014 Ó Springer-Verlag Italia 2014
Dear Editor, The modern management of intracranial arteriovenous malformations (AVM) is a highly controversial topic. The recently published high-profile study, A Randomized Trial of Unruptured Brain AVMs (ARUBA), reported superior outcomes with medical management of unruptured AVMs compared to intervention [1]. The primary endpoint, defined as symptomatic stroke or mortality, was observed in 10 % of the medical arm compared to 31 % of the intervention arm (p \ 0.0001) after a mean follow-up of 33 months. Due to the premature termination of ARUBA, the relatively short follow-up duration, and the heterogeneity of the interventions performed, there remains a considerable debate within the cerebrovascular community regarding the validity and generalizability of the trial’s findings. AVM treatment can be undertaken with surgical resection, endovascular embolization, or stereotactic radiosurgery, alone or in combination. Among the different treatment modalities, radiosurgery is the least invasive but requires a latency period of 2–3 years to achieve AVM obliteration. In the following discussion, we explore the effect of previous interventions, prior hemorrhage, and nidus angioarchitecture on AVM radiosurgery outcomes. The aims of AVM embolization depend on both the anatomy of the nidus and the treatment paradigms endorsed by the neurointerventionalists. Curative embolization is possible for relatively small, compact nidi, although the risk to benefit profile of standalone embolization compared to surgical resection or radiosurgery is controversial. For
D. Ding (&) Department of Neurosurgery, University of Virginia, Charlottesville, P.O. Box 800212, VA 22908, USA e-mail: [email protected]
large or diffuse nidi, embolization can reduce operative blood loss or decrease radiosurgical treatment volume by occluding high-flow feeding arteries or intranidal arteriovenous shunts. As mounting evidence supports the deleterious effect of nidal embolization on radiosurgical obliteration rates, the use of pre-radiosurgery embolization has waned in the multimodality management of AVMs [2]. Furthermore, embolization has not been shown to reduce an AVM’s hemorrhage risk prior radiosurgery or during the latency period between radiosurgical treatment and nidus obliteration. In fact, critical analysis of the interventional outcomes from ARUBA suggests that incomplete AVM occlusion may promote nidal destabilization and predispose them to rupture [1]. The mechanisms underlying embolization-induced alterations to AVM biology have not been fully delineated, and the explanations for lower radiosurgical obliteration rates in previously embolized nidi are not rigorously substantiated. However, for large AVMs, embolization followed by single-session radiosurgery appears to be more effective than staged radiosurgery approaches, although this has not been confirmed by a prospective study. Intracranial hemorrhage is the most common presentation of AVMs, and ruptured AVMs are more prone to hemorrhage than unruptured ones. Whether AVM rupture has the same effect on latency period hemorrhage as it does on the natural hemorrhage risk is unknown. Based on our institutional experience of over 1,000 AVMs treated with radiosurgery, we found the annual post-radiosurgery hemorrhage rates of ruptured and unruptured AVMs to be 2.0 and 1.6 %, respectively [2, 3]. In our analysis of 398 patients with Spetzler–Martin grade III AVMs, multivariate Cox proportional hazards regression analysis identified prior hemorrhage to be an independent predictor of obliteration (p = 0.016) [4]. Additionally, multivariate logistic
123
Neurol Sci
regression analysis found unruptured AVMs were significantly more likely to have radiation-induced changes (p \ 0.0001), defined as perinidal T2-weighted hyperintensities on magnetic resonance imaging. Thus, the perinidal gliotic capsule which develops after AVM rupture may protect the surrounding normal parenchyma from the development of radiation-induced changes. Currently, the effect of prior hemorrhage on AVM radiosurgery outcomes has yet to be rigorously defined. Although the original intention of the Spetzler–Martin grading system was to predict AVM surgical outcomes, it has also been shown to correlate with radiosurgery outcomes [2]. In an effort to devise a classification system which could efficiently and reliably predict AVM radiosurgery outcomes, Starke et al. proposed the Virginia Radiosurgery AVM Scale (VRAS), which is comprised of AVM volume (\2 cm3—0 points, 2–4 cm3—1 point, [4 cm3—2 points), prior hemorrhage (1 point), and eloquent location (1 point) [5]. The incidence of favorable outcome, defined as complete AVM obliteration without latency period hemorrhage or permanent radiation-induced symptoms, was 80 % for a VRAS of 0 or 1 point, 70 % for a VRAS of 2 points, and 45 % for a VRAS of 3 or 4 points. External validation of the VRAS with a large, multicenter cohort is presently underway and is necessary to propel it towards widespread utilization. In conclusion, although radiosurgery has been established as an effective therapeutic modality for AVMs, our understanding of the factors which have the most profound impact on obliteration, latency period hemorrhage, and adverse radiation effects
123
continues to evolve. It is crucial that future efforts are undertaken to refine our ability to predict AVM radiosurgery outcomes so that patients can be appropriately selected for treatment and be properly counseled regarding radiosurgical efficacy and morbidity. Conflict of interest
The authors have no conflicts of interest.
References 1. Mohr JP, Parides MK, Stapf C, Moquete E, Moy CS, Overbey JR, Al-Shahi Salman R, Vicaut E, Young WL, Houdart E, Cordonnier C, Stefani MA, Hartmann A, von Kummer R, Biondi A, Berkefeld J, Klijn CJ, 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(9917):614–621 S0140-6736(13)62302-8101016/S01406736(13)62302-8 2. Ding D, Yen CP, Xu Z, Starke RM, Sheehan JP (2013) Radiosurgery for patients with unruptured intracranial arteriovenous malformations. J Neurosurg 118(5):958–966. doi:10.3171/ 2013.2.JNS121239 3. Ding D, Yen CP, Starke RM, Xu Z, Sheehan JP (2014) Radiosurgery for ruptured intracranial arteriovenous malformations. J Neurosurg. doi:10.3171/2014.2.JNS131605 4. Ding D, Yen CP, Starke RM, Xu Z, Sun X, Sheehan JP (2014) Radiosurgery for Spetzler-Martin Grade III arteriovenous malformations. J Neurosurg 120(4):959–969. doi:10.3171/2013.12. JNS131041 5. Starke RM, Yen CP, Ding D, Sheehan JP (2013) A practical grading scale for predicting outcome after radiosurgery for arteriovenous malformations: analysis of 1012 treated patients. J Neurosurg 119(4):981–987. doi:10.3171/2013.5.JNS1311
