See the corresponding article in this issue, pp 113–119.
J Neurosurg 120:111–112, 2014 ©AANS, 2014
Editorial
Arteriovenous malformations Jason Sheehan, M.D., Ph.D. Department of Neurological Surgery, University of Virginia Health System, Charlottesville Virginia
Years ago, my late colleague Ladislau Steiner expressed disappointment to me about the lack of substantial improvement in radiosurgical obliteration of arteriovenous malformations (AVMs) during the more than 4 decades after his seminal work.8,9 Certainly, with the advent of tomographic imaging to enable a planned treatment volume that more closely conformed to the 3-dimensional shape of the nidus, the complication rate for radiosurgery had decreased. More appropriate dose selection has also led to decreased complications. Arguably, with the increase in partial embolization of AVMs, obliteration rates for some patients may actually have decreased in the modern era of neurosurgery.2,5,7 Obliteration, after all, is the ultimate goal for AVM radiosurgery. Although radiosurgery for AVMs seems to have become safer, we have largely failed to improve the obliteration rate or shorten the latency period after radiosurgery. In the current study by Reddy et al., the authors use a preclinical AVM model to study a novel vascular-targeting strategy for AVM thrombosis.6 Using a lipopolysaccharide (LPS) and soluble tissue factor (sTF) conjugate, they compellingly demonstrate augmentation of stereotactic radiosurgery–induced vessel thrombosis. Thrombosis induced by LPS/sTF and radiosurgery proved durable and fairly specific to vessels within the targeted volume. Moreover, the phenomenon of thrombosis increased for up to 3 months after treatment. Reddy et al. temper their enthusiasm by noting potential safety concerns for nonligand-targeted approaches such as LPS in humans. Ligand-based techniques may obviate some of these risks. We have been exploring the use of MR-guided focused ultrasonography and microbubbles to effectuate favorable changes on microvasculature; others have explored the direct occlusive properties of MR-guided focused ultrasonography.1,3,4 Although much more study of MR-guided focused ultrasonography for AVMs is needed, this technique could have the target specificity of radiosurgery without the latency period. Ever since the Data Safety and Monitoring Board closed the ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) trial early, there has J Neurosurg / Volume 120 / January 2014
been a keen awareness of the need to improve the safety and efficacy of AVM treatment options. Proponents of ARUBA may contend that treatment of a patient with an unruptured AVM is not warranted. A broader discussion about ARUBA and the optimal management of patients with AVM seems best left for another day. Nevertheless, although it remains clear that stereotactic radiosurgery will continue to play an important role in AVM treatment, improvements in the benefit-to-risk profile for stereotactic radiosurgery can and should be made. The current study provides one avenue for augmenting the extent of stereotactic radiosurgery–induced AVM obliteration. I look forward to future research in this field by Reddy and colleagues.
(http://thejns.org/doi/abs/10.3171/2013.6.JNS131080) Disclosure The author reports no conflict of interest. References
1. Burke CW, Klibanov AL, Sheehan JP, Price RJ: Inhibition of glioma growth by microbubble activation in a subcutaneous model using low duty cycle ultrasound without significant heating. Laboratory investigation. J Neurosurg 114:1654–1656, 2011 2. Cheng CH, Crowley RW, Yen CP, Schlesinger D, Shaffrey ME, Sheehan JP: Gamma Knife surgery for basal ganglia and thalamic arteriovenous malformations. Clinical article. J Neurosurg 116:899–908, 2012 3. Hynynen K, Colucci V, Chung A, Jolesz F: Noninvasive arterial occlusion using MRI-guided ultrasound. Ultrasound Med Biol 22:1071–1077, 1996 4. Jolesz, FA: Intraoperative imaging in neurosurgery: where will the future take us? Acta Neurochir Suppl 109:21–25, 2011 5. Kano H, Kondziolka D, Flickinger JC, Park KJ, Iyer A, Yang HC, et al: Stereotactic radiosurgery for arteriovenous malformations after embolization: a case-control study. Clinical article. J Neurosurg 117:265–275, 2012 6. Reddy R, Duong TTH, Fairhall JM, Smee RI, Stoodley MA: Durable thrombosis in a rat model of arteriovenous malformation treated with radiosurgery and vascular targeting. Laboratory investigation. J Neurosurg [epub ahead of print November 1, 2013. DOI: 10.3171/2013.9.JNS122056] 7. Schwyzer L, Yen CP, Evans A, Zavoian S, Steiner L: Long-term results of gamma knife surgery for partially embolized arteriovenous malformations. Neurosurgery 71:1139–1148, 2012 8. Sheehan J, Steiner L: A perspective on radiosurgery: creativity, elegance, simplicity, and flexibility to change. World Neurosurg 80:83–86, 2013 9. Steiner L, Leksell L, Greitz T, Forster DM, Backlund EO: Stereotaxic radiosurgery for cerebral arteriovenous malformations. Report of a case. Acta Chir Scand 138:459–464, 1972
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Editorial
Response Marcus A. Stoodley, Ph.D., F.R.A.C.S. Australian School of Advanced Medicine, Macquarie University, Sydney, Australia
The comments by Dr. Sheehan are acknowledged and appreciated. He notes the findings of the ARUBA study, and although we agree that an in-depth analysis is beyond the scope of this discussion, our view is that comparing the results of intervention to the short-term natural history of AVMs is not a valid comparison. Regardless, our work is aimed at developing a new treatment for AVMs that are currently untreatable without unacceptable risks. The LPS/sTF approach is intended to be a proof-ofconcept study. The goal, rather than to enhance the normal biological response to radiosurgery, is to use radiosurgery to alter the AVM endothelium so that it can be targeted with biological therapies delivered into the systemic vasculature. We are currently working on ligand-based treat-
112
ments, which we expect will be more specific and more effective than the non-ligand LPS/sTF approach. Dr. Sheehan suggests that MR-guided focused ultrasonography might have a role in AVM treatment. We also have been exploring this technique as an alternative to radiosurgery for altering AVM endothelial characteristics. In this context, focused ultrasonography would work by heating the vessel wall and inducing molecular expression changes that could be targeted in the same way that we proposed with the radiosurgery and vascular-targeting approach. Some concerns with this technique are the ability of the focused ultrasonography to heat the endothelium while there is high blood flow adjacent to the endothelial surface and the possibility that heating thin vessel walls could lead to rupture. However, we agree that the technique has much promise and is worthy of further exploration. Please include this information when citing this paper: published online November 1, 2013; DOI: 10.3171/2013.6.JNS131080.
J Neurosurg / Volume 120 / January 2014
J Neurosurg 120:111–112, 2014 ©AANS, 2014
Editorial
Arteriovenous malformations Jason Sheehan, M.D., Ph.D. Department of Neurological Surgery, University of Virginia Health System, Charlottesville Virginia
Years ago, my late colleague Ladislau Steiner expressed disappointment to me about the lack of substantial improvement in radiosurgical obliteration of arteriovenous malformations (AVMs) during the more than 4 decades after his seminal work.8,9 Certainly, with the advent of tomographic imaging to enable a planned treatment volume that more closely conformed to the 3-dimensional shape of the nidus, the complication rate for radiosurgery had decreased. More appropriate dose selection has also led to decreased complications. Arguably, with the increase in partial embolization of AVMs, obliteration rates for some patients may actually have decreased in the modern era of neurosurgery.2,5,7 Obliteration, after all, is the ultimate goal for AVM radiosurgery. Although radiosurgery for AVMs seems to have become safer, we have largely failed to improve the obliteration rate or shorten the latency period after radiosurgery. In the current study by Reddy et al., the authors use a preclinical AVM model to study a novel vascular-targeting strategy for AVM thrombosis.6 Using a lipopolysaccharide (LPS) and soluble tissue factor (sTF) conjugate, they compellingly demonstrate augmentation of stereotactic radiosurgery–induced vessel thrombosis. Thrombosis induced by LPS/sTF and radiosurgery proved durable and fairly specific to vessels within the targeted volume. Moreover, the phenomenon of thrombosis increased for up to 3 months after treatment. Reddy et al. temper their enthusiasm by noting potential safety concerns for nonligand-targeted approaches such as LPS in humans. Ligand-based techniques may obviate some of these risks. We have been exploring the use of MR-guided focused ultrasonography and microbubbles to effectuate favorable changes on microvasculature; others have explored the direct occlusive properties of MR-guided focused ultrasonography.1,3,4 Although much more study of MR-guided focused ultrasonography for AVMs is needed, this technique could have the target specificity of radiosurgery without the latency period. Ever since the Data Safety and Monitoring Board closed the ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) trial early, there has J Neurosurg / Volume 120 / January 2014
been a keen awareness of the need to improve the safety and efficacy of AVM treatment options. Proponents of ARUBA may contend that treatment of a patient with an unruptured AVM is not warranted. A broader discussion about ARUBA and the optimal management of patients with AVM seems best left for another day. Nevertheless, although it remains clear that stereotactic radiosurgery will continue to play an important role in AVM treatment, improvements in the benefit-to-risk profile for stereotactic radiosurgery can and should be made. The current study provides one avenue for augmenting the extent of stereotactic radiosurgery–induced AVM obliteration. I look forward to future research in this field by Reddy and colleagues.
(http://thejns.org/doi/abs/10.3171/2013.6.JNS131080) Disclosure The author reports no conflict of interest. References
1. Burke CW, Klibanov AL, Sheehan JP, Price RJ: Inhibition of glioma growth by microbubble activation in a subcutaneous model using low duty cycle ultrasound without significant heating. Laboratory investigation. J Neurosurg 114:1654–1656, 2011 2. Cheng CH, Crowley RW, Yen CP, Schlesinger D, Shaffrey ME, Sheehan JP: Gamma Knife surgery for basal ganglia and thalamic arteriovenous malformations. Clinical article. J Neurosurg 116:899–908, 2012 3. Hynynen K, Colucci V, Chung A, Jolesz F: Noninvasive arterial occlusion using MRI-guided ultrasound. Ultrasound Med Biol 22:1071–1077, 1996 4. Jolesz, FA: Intraoperative imaging in neurosurgery: where will the future take us? Acta Neurochir Suppl 109:21–25, 2011 5. Kano H, Kondziolka D, Flickinger JC, Park KJ, Iyer A, Yang HC, et al: Stereotactic radiosurgery for arteriovenous malformations after embolization: a case-control study. Clinical article. J Neurosurg 117:265–275, 2012 6. Reddy R, Duong TTH, Fairhall JM, Smee RI, Stoodley MA: Durable thrombosis in a rat model of arteriovenous malformation treated with radiosurgery and vascular targeting. Laboratory investigation. J Neurosurg [epub ahead of print November 1, 2013. DOI: 10.3171/2013.9.JNS122056] 7. Schwyzer L, Yen CP, Evans A, Zavoian S, Steiner L: Long-term results of gamma knife surgery for partially embolized arteriovenous malformations. Neurosurgery 71:1139–1148, 2012 8. Sheehan J, Steiner L: A perspective on radiosurgery: creativity, elegance, simplicity, and flexibility to change. World Neurosurg 80:83–86, 2013 9. Steiner L, Leksell L, Greitz T, Forster DM, Backlund EO: Stereotaxic radiosurgery for cerebral arteriovenous malformations. Report of a case. Acta Chir Scand 138:459–464, 1972
111
Editorial
Response Marcus A. Stoodley, Ph.D., F.R.A.C.S. Australian School of Advanced Medicine, Macquarie University, Sydney, Australia
The comments by Dr. Sheehan are acknowledged and appreciated. He notes the findings of the ARUBA study, and although we agree that an in-depth analysis is beyond the scope of this discussion, our view is that comparing the results of intervention to the short-term natural history of AVMs is not a valid comparison. Regardless, our work is aimed at developing a new treatment for AVMs that are currently untreatable without unacceptable risks. The LPS/sTF approach is intended to be a proof-ofconcept study. The goal, rather than to enhance the normal biological response to radiosurgery, is to use radiosurgery to alter the AVM endothelium so that it can be targeted with biological therapies delivered into the systemic vasculature. We are currently working on ligand-based treat-
112
ments, which we expect will be more specific and more effective than the non-ligand LPS/sTF approach. Dr. Sheehan suggests that MR-guided focused ultrasonography might have a role in AVM treatment. We also have been exploring this technique as an alternative to radiosurgery for altering AVM endothelial characteristics. In this context, focused ultrasonography would work by heating the vessel wall and inducing molecular expression changes that could be targeted in the same way that we proposed with the radiosurgery and vascular-targeting approach. Some concerns with this technique are the ability of the focused ultrasonography to heat the endothelium while there is high blood flow adjacent to the endothelial surface and the possibility that heating thin vessel walls could lead to rupture. However, we agree that the technique has much promise and is worthy of further exploration. Please include this information when citing this paper: published online November 1, 2013; DOI: 10.3171/2013.6.JNS131080.
J Neurosurg / Volume 120 / January 2014
