Transcript
First of all, I'd like to thank Stefan Vilsmeier, and BrainLab, and the Institute for Medical Education for allowing me to speak. And I'll talk to you a little bit about the role of focal therapy in ARUBA. My disclosures are listed there, none really that pertain to this presentation, though I'm not a radiosurgeon. So I get to work with Doug Kondziolka. So I think that will make up for my lack of knowledge about radiosurgery and AVMs. And obviously, focal therapy, as we know, involves resection, endovascular embolization, and stereotactic radiosurgery in ARUBA-eligible patients, basically unruptured AVMs. I think the important thing about ARUBA, and I think Professor Wurm sort of hinted at that, is ARUBA made us think a lot more about the patients that we were treating and how we would go about treating them. I definitely operate on far fewer AVMs than I did in the past. I also do interventional neuroradiology and I embolize for fewer AVM patients than I did in the past. And so there definitely has been an impact. So even though we all talk about how much we don't like the ARUBA trial, it definitely changed the way we approach the management of these patients, and I think in a good way, ironically.
So for those of you that like Formula 1 racing, this is a picture from the Ferrari store in Rome. Michael Logan and I were there a couple of years ago with our families. And when we were looking over our pictures that we had taken from the trip, both of us had taken a lot of pictures of this exhaust from a Ferrari Formula 1 racecar, which looks a lot like the venous drainage of an AVM, or the arterial supply, depending on how you think about it. But basically with complex vascular malformations in the ARUBA era, we certainly have the ARUBA trial published in Lancet, and then a lot of other trials that have pointed out sort of the flaws or the limitations of the ARUBA trial itself and the fact that we didn't really follow these patients long enough. So I'll summarize ARUBA in a second. But these two main trials, obviously, ARUBA showing us that our interventions in the early part of management of the patients with the AVMs were causing a significant amount of morbidity that eventually resulted in stopping the trial and then some later studies that show that if you start to follow these patients long enough and allow the natural history of the condition to start playing a role, you will see the ruptures and sequelae of having a brain AVM.
So ARUBA in general, as you know, a randomized trial of unruptured brain AVMs. It was prospective, which when you sit on the editorial board of a journal is an important thing because a lot of data that we get is retrospective, not multi-central, parallel design, non-blinded, was funded by the NIH and NIDS. And the big question, which a lot of us had struggled with for years, is medical management alone superior than the interventions that we do? And that can be surgery. It can be radiosurgery. It can be embolization. And there's a cultural factor also. So the way we may manage certain things in the United States may be different than in Europe or other parts of the world. There are definitely places, and I have good friends throughout the world that believe in 100% embolization and cure of AVMs using interventional radiology techniques and they have transvenous approaches. And we've used some of those approaches, but our philosophy is different. And is that right or wrong? I think it remains to be seen.
So then, you know, drilling down on ARUBA, and you've seen a lot of these slides before, 1,740 patients, 18 years of age or older, no previous hemorrhage, no previous treatment, and suitable for complete obliteration. And so that's the other key. When thinking about approaching these patients, and we see them and we're making recommendations to the office, a patient presents with a hemorrhage, that is a completely different paradigm than someone coming in without any history of previous hemorrhage. But when we elect to treat, the goal for us is always complete obliteration. So then back down to ARUBA, only 226 patients were enrolled and randomized, which was only 13% of the screened patients. And this has been one of the main complaints about the trial itself, was the poor recruitment. And that was only 28% of the original goal of 800 patients that they wanted to be in the trial. And so of the 177 screened patients managed outside of the randomized portion of the trial, there was an inherent selection bias. You know, 53 patients did not complete the trial. Twenty patients never even started their treatment. Seven patients crossed over into the intervention group. Three patients were lost for follow-up. And technically, less than one patient randomized by active center per year.
I mean, these are significant drawbacks. And I wonder if it was submitted to, you know, some other journals now in this day and age with the limited number of patient participation, if it would be even be accepted. Five patients treated with surgery, 4%, 30 patients treated with embolization, 32%, and 31 patients treated with radiosurgery. These are very, very low numbers. The study is very, very limited by the small patient cohort, the data that is generated. These are very small numbers to make some major conclusions or draw major conclusions. And only 28 patients had multimodal therapy, which at least the way we manage AVMs, we like to use multimodal management of these lesions. And as you know the results, there was an unprecedented complication rate in the treatment arm of 30.7%. But there were no standardized protocols. In radiosurgery, the type and dosing wasn't specified. In embolization, was it single-stage embolization? Was it multiple stages? Did you use Onyx? Did you use the acrylic adhesives that we had from years ago?
And so, you know, there were a lot of questions about that. And that made people start to think about, "Well, we need to look at this some more." And so I think that's really, really the benefit of ARUBA. And it got us thinking about what we were doing and how we were managing these patients. And so certainly the study that came from the Scottish group published in JAMA in 2014, 204 patients, not randomized, but all the interventions were in one group. And the actual type or number of interventions were unknown. But there was less morbidity in the conservative group within the first four years. But then it became similar. And so as the natural history of the lesion starts to play a role, we see a change. And then sort of after about four years, you start to see the benefits of some of these interventions that we do. So observation seemed here early on to do worse over time. And that's what we kind of start to know is that if you have a young patient with many, many years of life ahead of them, you're going to have a lot of time to see some of these detrimental effects of having the brain AVM.
And so many people had issues with ARUBA. And Professor Wurm had a lot of these slides. You're gonna see a lot of similar slides. But certainly, the group, this multicenter group involving people from Yale and Philadelphia basically took exception to ARUBA and looking at really evidence-based ways of criticizing it. But there were other ways of looking at it and being more critical of AVMs in the ARUBA trial. And so radiosurgery for AVMs in a randomized trial for ARUBA, the multicenter study that Sheehan looked at, radiosurgery beat observation in patients that live more than 15 years. So again, as you followed the patients out further, some of the interventions had an impact of decreasing the morbidity and mortality associated with having the lesion, so over the natural history.
Again, a randomized trial looking at surgery. So microsurgery, out of the group in Toronto, basically showing that you could do microsurgery in select patients. And again, patients selection is very important. But doing microsurgery in select patients could have a certain advantage with or without embolization here. You see, embolization, and this is kind of what we do, is that if we see we're going to take something to the operating room, the role for us, for embolization or interventional neuroradiology, is to decrease the morbidity associated with the open procedure, so embolization of the AVM before resection. The other for us, the other role of embolization is if someone presents with a hemorrhage and we see a feature that we don't like, we'll embolize that feature minimally. So we'll close that portion of the AVM that has the abnormality and then maybe consider radiosurgery.
This is looking at the type of embolic material that we'd use, so here, using Onyx embolization. Remember, when...you might not know, but when I started my training in interventional over 25 years ago, we used the acrylic glues. We used the n-BCA, which was a wonderful material. But in the United States, we didn't have n-BCA legally. We had to drive to Canada to get the n-BCA and then bring it into the United States to use it in our patients for embolization. We refer to it as the magic elixir to our embolizations. Onyx, a very different type of material that you could inject. You could stop injecting, do angiographic runs, see how the penetration of the material was occurring, and then start injecting again. You could do very, very long injections, over 40 or 50 minutes plus. We couldn't do that with the acrylic glues. With the acrylic glues, you would inject them and have to pull the microcatheter out so that it didn't get glued into the AVM. And if it did get glued into the AVM, we would cut it off the catheter sheath at the groin. I don't think we do that very much anymore. But these were some of the things that we did early on in the treatment of AVM. So the agent, the agent used and the tools available are evolving and are different.
And then the same slide that also Professor Wurm showed from the Pittsburgh group, looking at radiosurgery for ARUBA-eligible. So the big thing is ARUBA-eligible patients and analysis over an appropriate follow-up period. The longer you follow these patients, just like the group in Virginia said, the group in Pittsburgh, Doug Kondziolka, our own radiosurgeon who was obviously in Pittsburgh for many, many years, if you follow these patients long enough, some of these interventions will impact the natural history of the lesions. So basically, this is from another group. This is from the Cleveland Clinic group, also showing the same thing. I keep giving you more and more of the data and the publications over the last few years looking at how interventions when done on ARUBA-eligible patients and followed using here microsurgery and Gamma Knife radiosurgery are appropriate in the treatment of unruptured brain AVMs.
And so we get to the point where now everyone's thinking about, "Well, what did ARUBA really, really mean?" And so we've poked holes in the study. We know that if you follow the patients long enough, you see the impact. We know that some of the therapies that we use when you think about them and you analyze them effectively and utilize them effectively, they can be used by minimizing the complication rate. And so now we're starting to think, "Well, with ARUBA, maybe we should start considering some of these more proactive ways of treating patients." And so that gets us to, how do we select patients? So this is Doug and I from several years ago when Doug first came to NYU. And working closely together with Doug Kondziolka really changed the way that I approached the management of brain AVMs. And so certainly, a patient coming in with a ruptured AVM, we know the treatment options, certainly, observation and what started this conversation with ARUBA versus microsurgery, radiosurgery, and embolizations and combinations thereof.
And so I'm going to show you several examples of some of the different AVMs that we've treated. But again, the way that I managed these lesions in the past changed dramatically after ARUBA. But I think we're getting a better management paradigm presented to our patients now than we did in the past. So this is a right frontal AVM grade-two lesion that was treated with radiosurgery in June of 2013 with complete obliteration at three months. I think this patient came in with a seizure during the follow-up period that made us get the follow-up imaging study that demonstrated the obliteration. And we have had several of these very, very rapid AVM obliterations following radiosurgery. And it's not completely clear what features are associated with this rapid shutdown. It could be the venous drainage and catching the portion of the nidus right at the area of shunting that may result where the radiosurgery having an effect and causing a complete closure in that area at the same time. When we think about embolization and cure of AVMs and this whole concept on transvenous embolization, the idea is to get right at the area of shunting and closing the shunt. And it may be that the radiosurgery is doing something similarly and why a lesion like this would close more quickly. I think I'm running out of time. But I'll pick up the pace.
Here is a 12-year-old girl with intraventricular hemorrhage with a full recovery, 6 months asymptomatic. And at 12 months, you can see the area where she was treated. And of course, the follow-up angiogram at one year demonstrating obliteration. So you can give a very structured and basically targeted dose of radiation to these lesions and result with, you know, complete obliteration and excellent, you know, outcomes for the patients. What do we do with some of these abnormal features? If a patient comes in and has a feature that we don't like, just like when they come in and they have a hemorrhage, we look for areas of abnormality such as flow-related aneurysms. And we all know from and we've known for quite some time, if you treat the aneurysm, many times, the flow-related lesion will go away. Now, it doesn't necessarily have to. Now, certainly, if the aneurysm presented with rupture, you would want to secure the rupture. But if they don't, oftentimes they will disappear.
AVMs with venous varices, it's the same thing. Here's a left temporal lobe AVM with an associated varix, and then 18 months with complete disappearance and obviously disappearance of the varix. As the high flow state disappears, the alterations and normalization of the angiographic features occur. And so the concept for large AVM treatment, do we observe and manage the symptoms only or do we consider a different treatment paradigm? And certainly, you know, if you look at, and we have looked at stereotactic radiosurgery alone versus embolization plus radiosurgery, in embolization, it seems to interfere with the targeting. And that's sort of the philosophy that we have at our place right now. And so that unless we see abnormal features or there's been a feature that is associated with hemorrhage, we'll do radiosurgery before upfront we do any type of embolization so that we don't interfere with the targeting. Here, a 26-year-old male with headaches and two-stage radiosurgery, and obviously, you've heard a little bit already about staging of some of the larger legions and complete obliteration in three years.
The goal if we're going to approach these lesions should be towards obliteration. If we're going to offer treatment, unless there's a feature that we've seen that caused a hemorrhage, we want to secure that feature and then proceed. So this is our algorithm right now. And so I apologize that I went over. But in conclusion, the lifetime risk of ruptured and unruptured AVM warrants treatment in patients that have more than 10 years of life expectancy. We often do diagnostic angiography to understand the angioarchitecture of a lesion and surgery for low Spetzler-Martin AVMs. We still do, but we also present radiosurgery to patients. So if I see a patient in the office that has an AVM, I have them get a consultation from Dr. Kondziolka often at the same setting. We do radiosurgery for higher grade, deep-seated, or eloquent lesions, also with deep venous drainage that we know have propensities to bleed and then embolize intra-nidal abnormalities, aneurysms, bleeding sites or areas of outflow obstruction as an adjunct to surgical resection. So thank you, and I apologize again for running over.
So for those of you that like Formula 1 racing, this is a picture from the Ferrari store in Rome. Michael Logan and I were there a couple of years ago with our families. And when we were looking over our pictures that we had taken from the trip, both of us had taken a lot of pictures of this exhaust from a Ferrari Formula 1 racecar, which looks a lot like the venous drainage of an AVM, or the arterial supply, depending on how you think about it. But basically with complex vascular malformations in the ARUBA era, we certainly have the ARUBA trial published in Lancet, and then a lot of other trials that have pointed out sort of the flaws or the limitations of the ARUBA trial itself and the fact that we didn't really follow these patients long enough. So I'll summarize ARUBA in a second. But these two main trials, obviously, ARUBA showing us that our interventions in the early part of management of the patients with the AVMs were causing a significant amount of morbidity that eventually resulted in stopping the trial and then some later studies that show that if you start to follow these patients long enough and allow the natural history of the condition to start playing a role, you will see the ruptures and sequelae of having a brain AVM.
So ARUBA in general, as you know, a randomized trial of unruptured brain AVMs. It was prospective, which when you sit on the editorial board of a journal is an important thing because a lot of data that we get is retrospective, not multi-central, parallel design, non-blinded, was funded by the NIH and NIDS. And the big question, which a lot of us had struggled with for years, is medical management alone superior than the interventions that we do? And that can be surgery. It can be radiosurgery. It can be embolization. And there's a cultural factor also. So the way we may manage certain things in the United States may be different than in Europe or other parts of the world. There are definitely places, and I have good friends throughout the world that believe in 100% embolization and cure of AVMs using interventional radiology techniques and they have transvenous approaches. And we've used some of those approaches, but our philosophy is different. And is that right or wrong? I think it remains to be seen.
So then, you know, drilling down on ARUBA, and you've seen a lot of these slides before, 1,740 patients, 18 years of age or older, no previous hemorrhage, no previous treatment, and suitable for complete obliteration. And so that's the other key. When thinking about approaching these patients, and we see them and we're making recommendations to the office, a patient presents with a hemorrhage, that is a completely different paradigm than someone coming in without any history of previous hemorrhage. But when we elect to treat, the goal for us is always complete obliteration. So then back down to ARUBA, only 226 patients were enrolled and randomized, which was only 13% of the screened patients. And this has been one of the main complaints about the trial itself, was the poor recruitment. And that was only 28% of the original goal of 800 patients that they wanted to be in the trial. And so of the 177 screened patients managed outside of the randomized portion of the trial, there was an inherent selection bias. You know, 53 patients did not complete the trial. Twenty patients never even started their treatment. Seven patients crossed over into the intervention group. Three patients were lost for follow-up. And technically, less than one patient randomized by active center per year.
I mean, these are significant drawbacks. And I wonder if it was submitted to, you know, some other journals now in this day and age with the limited number of patient participation, if it would be even be accepted. Five patients treated with surgery, 4%, 30 patients treated with embolization, 32%, and 31 patients treated with radiosurgery. These are very, very low numbers. The study is very, very limited by the small patient cohort, the data that is generated. These are very small numbers to make some major conclusions or draw major conclusions. And only 28 patients had multimodal therapy, which at least the way we manage AVMs, we like to use multimodal management of these lesions. And as you know the results, there was an unprecedented complication rate in the treatment arm of 30.7%. But there were no standardized protocols. In radiosurgery, the type and dosing wasn't specified. In embolization, was it single-stage embolization? Was it multiple stages? Did you use Onyx? Did you use the acrylic adhesives that we had from years ago?
And so, you know, there were a lot of questions about that. And that made people start to think about, "Well, we need to look at this some more." And so I think that's really, really the benefit of ARUBA. And it got us thinking about what we were doing and how we were managing these patients. And so certainly the study that came from the Scottish group published in JAMA in 2014, 204 patients, not randomized, but all the interventions were in one group. And the actual type or number of interventions were unknown. But there was less morbidity in the conservative group within the first four years. But then it became similar. And so as the natural history of the lesion starts to play a role, we see a change. And then sort of after about four years, you start to see the benefits of some of these interventions that we do. So observation seemed here early on to do worse over time. And that's what we kind of start to know is that if you have a young patient with many, many years of life ahead of them, you're going to have a lot of time to see some of these detrimental effects of having the brain AVM.
And so many people had issues with ARUBA. And Professor Wurm had a lot of these slides. You're gonna see a lot of similar slides. But certainly, the group, this multicenter group involving people from Yale and Philadelphia basically took exception to ARUBA and looking at really evidence-based ways of criticizing it. But there were other ways of looking at it and being more critical of AVMs in the ARUBA trial. And so radiosurgery for AVMs in a randomized trial for ARUBA, the multicenter study that Sheehan looked at, radiosurgery beat observation in patients that live more than 15 years. So again, as you followed the patients out further, some of the interventions had an impact of decreasing the morbidity and mortality associated with having the lesion, so over the natural history.
Again, a randomized trial looking at surgery. So microsurgery, out of the group in Toronto, basically showing that you could do microsurgery in select patients. And again, patients selection is very important. But doing microsurgery in select patients could have a certain advantage with or without embolization here. You see, embolization, and this is kind of what we do, is that if we see we're going to take something to the operating room, the role for us, for embolization or interventional neuroradiology, is to decrease the morbidity associated with the open procedure, so embolization of the AVM before resection. The other for us, the other role of embolization is if someone presents with a hemorrhage and we see a feature that we don't like, we'll embolize that feature minimally. So we'll close that portion of the AVM that has the abnormality and then maybe consider radiosurgery.
This is looking at the type of embolic material that we'd use, so here, using Onyx embolization. Remember, when...you might not know, but when I started my training in interventional over 25 years ago, we used the acrylic glues. We used the n-BCA, which was a wonderful material. But in the United States, we didn't have n-BCA legally. We had to drive to Canada to get the n-BCA and then bring it into the United States to use it in our patients for embolization. We refer to it as the magic elixir to our embolizations. Onyx, a very different type of material that you could inject. You could stop injecting, do angiographic runs, see how the penetration of the material was occurring, and then start injecting again. You could do very, very long injections, over 40 or 50 minutes plus. We couldn't do that with the acrylic glues. With the acrylic glues, you would inject them and have to pull the microcatheter out so that it didn't get glued into the AVM. And if it did get glued into the AVM, we would cut it off the catheter sheath at the groin. I don't think we do that very much anymore. But these were some of the things that we did early on in the treatment of AVM. So the agent, the agent used and the tools available are evolving and are different.
And then the same slide that also Professor Wurm showed from the Pittsburgh group, looking at radiosurgery for ARUBA-eligible. So the big thing is ARUBA-eligible patients and analysis over an appropriate follow-up period. The longer you follow these patients, just like the group in Virginia said, the group in Pittsburgh, Doug Kondziolka, our own radiosurgeon who was obviously in Pittsburgh for many, many years, if you follow these patients long enough, some of these interventions will impact the natural history of the lesions. So basically, this is from another group. This is from the Cleveland Clinic group, also showing the same thing. I keep giving you more and more of the data and the publications over the last few years looking at how interventions when done on ARUBA-eligible patients and followed using here microsurgery and Gamma Knife radiosurgery are appropriate in the treatment of unruptured brain AVMs.
And so we get to the point where now everyone's thinking about, "Well, what did ARUBA really, really mean?" And so we've poked holes in the study. We know that if you follow the patients long enough, you see the impact. We know that some of the therapies that we use when you think about them and you analyze them effectively and utilize them effectively, they can be used by minimizing the complication rate. And so now we're starting to think, "Well, with ARUBA, maybe we should start considering some of these more proactive ways of treating patients." And so that gets us to, how do we select patients? So this is Doug and I from several years ago when Doug first came to NYU. And working closely together with Doug Kondziolka really changed the way that I approached the management of brain AVMs. And so certainly, a patient coming in with a ruptured AVM, we know the treatment options, certainly, observation and what started this conversation with ARUBA versus microsurgery, radiosurgery, and embolizations and combinations thereof.
And so I'm going to show you several examples of some of the different AVMs that we've treated. But again, the way that I managed these lesions in the past changed dramatically after ARUBA. But I think we're getting a better management paradigm presented to our patients now than we did in the past. So this is a right frontal AVM grade-two lesion that was treated with radiosurgery in June of 2013 with complete obliteration at three months. I think this patient came in with a seizure during the follow-up period that made us get the follow-up imaging study that demonstrated the obliteration. And we have had several of these very, very rapid AVM obliterations following radiosurgery. And it's not completely clear what features are associated with this rapid shutdown. It could be the venous drainage and catching the portion of the nidus right at the area of shunting that may result where the radiosurgery having an effect and causing a complete closure in that area at the same time. When we think about embolization and cure of AVMs and this whole concept on transvenous embolization, the idea is to get right at the area of shunting and closing the shunt. And it may be that the radiosurgery is doing something similarly and why a lesion like this would close more quickly. I think I'm running out of time. But I'll pick up the pace.
Here is a 12-year-old girl with intraventricular hemorrhage with a full recovery, 6 months asymptomatic. And at 12 months, you can see the area where she was treated. And of course, the follow-up angiogram at one year demonstrating obliteration. So you can give a very structured and basically targeted dose of radiation to these lesions and result with, you know, complete obliteration and excellent, you know, outcomes for the patients. What do we do with some of these abnormal features? If a patient comes in and has a feature that we don't like, just like when they come in and they have a hemorrhage, we look for areas of abnormality such as flow-related aneurysms. And we all know from and we've known for quite some time, if you treat the aneurysm, many times, the flow-related lesion will go away. Now, it doesn't necessarily have to. Now, certainly, if the aneurysm presented with rupture, you would want to secure the rupture. But if they don't, oftentimes they will disappear.
AVMs with venous varices, it's the same thing. Here's a left temporal lobe AVM with an associated varix, and then 18 months with complete disappearance and obviously disappearance of the varix. As the high flow state disappears, the alterations and normalization of the angiographic features occur. And so the concept for large AVM treatment, do we observe and manage the symptoms only or do we consider a different treatment paradigm? And certainly, you know, if you look at, and we have looked at stereotactic radiosurgery alone versus embolization plus radiosurgery, in embolization, it seems to interfere with the targeting. And that's sort of the philosophy that we have at our place right now. And so that unless we see abnormal features or there's been a feature that is associated with hemorrhage, we'll do radiosurgery before upfront we do any type of embolization so that we don't interfere with the targeting. Here, a 26-year-old male with headaches and two-stage radiosurgery, and obviously, you've heard a little bit already about staging of some of the larger legions and complete obliteration in three years.
The goal if we're going to approach these lesions should be towards obliteration. If we're going to offer treatment, unless there's a feature that we've seen that caused a hemorrhage, we want to secure that feature and then proceed. So this is our algorithm right now. And so I apologize that I went over. But in conclusion, the lifetime risk of ruptured and unruptured AVM warrants treatment in patients that have more than 10 years of life expectancy. We often do diagnostic angiography to understand the angioarchitecture of a lesion and surgery for low Spetzler-Martin AVMs. We still do, but we also present radiosurgery to patients. So if I see a patient in the office that has an AVM, I have them get a consultation from Dr. Kondziolka often at the same setting. We do radiosurgery for higher grade, deep-seated, or eloquent lesions, also with deep venous drainage that we know have propensities to bleed and then embolize intra-nidal abnormalities, aneurysms, bleeding sites or areas of outflow obstruction as an adjunct to surgical resection. So thank you, and I apologize again for running over.