Let's initially discuss the natural history of artilovenous malformations, at least what we understand to be the natural history. There is thought to be a risk of about 3% per year of hemorrhage from an artilovenous malformation. This very much has been shown to be dependent upon AVM size, obviously whether or not they present with hemorrhage versus, for instance, epilepsy, when they present in terms of childhood versus adulthood. And certainly that risk of bleeding is increased if you've had a previous hemorrhage. There is, most studies will show, about a 10% risk of severe morbidity or mortality associated with each hemorrhage from an artilovenous malformation, even in a contemporary era. There are different ways we talk about artilovenous malformations, and I have a colleague here from the Barron Neurological Institute, Dr. Spetzler, has developed what is the most widespread grading system for artilovenous malformations shown here. It breaks down into three different categories, size of the AVM, in this case linear dimension of the AVM, eloquent or non-eloquent cortex, and superficial or deep drainage from the AVM. And sometimes you can have both, of course, but if it were deep, it would fall into, if there were a deep component, you would get a one point in this category. Obviously the greater the number of this category, the greater the risk, but that risk is associated with resection. There are at least two other grading systems that are out there. We've proposed one, and University of Pittsburgh, where Bruce Pollack and John Flickinger developed this, this grading system, basically they are in many ways similar. This involves an equation factoring in volume, age, and location. Sparse factors in volume, history of previous hemorrhage, which we found to be more important, and eloquent location. If you will, you'll see, though, that there are a number of different factors that are all sort of permeating these three different grading systems. These grading systems shown on this slide are really validated for radius surgical outcomes, not for microsurgical outcomes. So what are the goals with the management of AVMs? The goals are really elimination of the hemorrhagic risk in the future, obviously to preserve neurological function whenever possible, and then to minimize the treatment-related risks associated with dealing with this AVM. And there are, in the modern era, at least three viable treatment approaches for many of these patients, microsurgery, radius surgery, and endovascular, and these are not mutually exclusive as you can, as depicted here by this Venn diagram. Certainly embolization is having an increasing role in the management of patients with AVMs. Surgical resection has been a mainstay of treatment. Radius surgery, there have been more than 80,000 AVM patients treated with radius surgery alone. And then conservative management for those who have had an AVM picked up incidentally or who may have epilepsy associated with their AVM but no prior hemorrhage. Sometimes we'll simply follow these patients because either the risk is too great of treating them or the perceived benefit is too little. For radius surgery, I think that the role of radius surgery is most valuable in managing AVMs that are small and deep-seated. And those that are small and accessible could go either the route of resection or radius surgery. Those that are larger and deep-seated are reasonably well-suited for radius surgery. Those that are larger and accessible are probably going to be either managed through a combination of embolization or resection. Just in brief, the radius surgical technique for AVMs is a little bit different than it is for acoustic neuromas or brain metastasis or skull-based tumors. This is, in general, what's done in my institution with a little bit of mild sedation, placement of some kind of a frame. Certainly one could use a frameless device like a mask where penetration and rigid fixation may not be required. We still do biplanar angiography on all of our AVM cases. We do couple it with MR and MRA, or one can do CT, CTA. And then there's the dose planning phase and then the radiation delivery. With these patients who do have a history of seizures, we're careful to check their anticonvulsant level and to make sure that they're therapeutic before the procedure. And we usually give a single dose of steroids around the time of radius surgery. The AVM cases are the single case with any regularity that we'll use angiographic guidance. And it is a little different than typical tomographic guidance. You can appreciate that using biplanar angiography here, you can see a lateral projection, AP projection. One can't exclusively target off this, but I do think, particularly for small AVMs, that angiographic guidance is critical. For the larger AVMs, it may not be quite as critical. I do think that angiographic confirmation of obliteration remains the gold standard. Dr. Friedman published a paper just a short while ago. We have one working its way through that continues to confirm that even with using fairly sophisticated MRI, MRA, or CTA, that some AVMs that appear obliterated may in fact not be, and that it's worth following these patients up with angiographic confirmation of obliteration over time. Just in thinking about radiosurgical dose planning, if one looks at and has an AVM like this, which we targeted, certainly one wants to consider the volume of the AVM, the location, critical structures that may be near their prior hemorrhage. I'm a bit more aggressive with my dose selection, and for that matter, recommending radiosurgery if someone's had a previous hemorrhage versus someone who may not have had one but may have other associated symptoms. Whether or not they've had any embolic material that may obscure the view of the ninus, that can be difficult, especially with onyx. Whether or not there's an area of encephalomalacia that may be close by. For instance, if there is, one might dump dose, and it's a bit of a crude term, but be less conformal near an area of encephalomalacia and more conformal near an area that doesn't have changes that may be associated with a prior hemorrhage or stroke. And certainly then the conformality, the gradient index, and then I don't think we've heard quite about this before in the two previous talks, but this V12 is something that we look at pretty extensively with our AVMs and do look at for some other cases as well. And that's been shown to be relevant in terms of predicting complications associated with radiosurgery for AVMs. So in outcomes for radiosurgery with AVMs, we're really looking first and foremost at obliteration rates. And by obliteration, I mean that the AVM is occluded on post-radiosurgical angiographic testing. Certainly MRI, MRA can be used to confirm obliteration, but there may be a false negative test with MRI, MRA. And then we certainly look at other secondary outcomes in terms of symptomatic control in terms of seizures in patients who've had previous epilepsy associated with their AVMs, headaches and other neurological deficits, for instance, vascular steel that may occur with an AVM. It's been pretty well documented, and as a footnote in history, my predecessor at UVA provided and published what I believe to be the first successful radiosurgical case of an AVM that was obliterated. And hearing him tell the story about how he arrived at the dose, first, you know, I showed you pictures before where we cover the entire AVM nidus with the prescription isodose line. He found what he determined to be the fistulas communication in the nidus and just targeted a single spot in a large AVM. And then he looked at some of the radiation therapy literature and found that some had had success using fraction of radiation therapy delivering 50 gray and being not wanting to do any harm in a procedure that hadn't been validated. He said, well, let's half the dose. And either I tend to think through incredible intelligence, but maybe he played it off as serendipity that that half the dose, the 50 to 25 reduction, that the 25 gray seemed to be the optimal dose and has been borne out to be a fairly optimal dose in terms of achieving obliteration as is depicted here. So against plotting dose versus obliteration rate. So you can see that it plateaus at about 25 gray, that you don't get much more bang for your buck by going above and you actually do get substantially greater complication rate and that most AVMs are treated with a dose of somewhere between 16 to 18 gray up to 25 gray to the prescription or the edge of the nidus. And you can see what in these histological studies in an animal model that were done at the University of Virginia, how there's intimal hyperproliferation and that these AVMs gradually go on to occlude. It's clear that unlike the argument that may be brewing with acoustic neuromas and other things that fractionation really doesn't give great value in these cases. Actually it probably works against you and substantially so in terms of achieving obliteration with the exception of AVMs that may be too large to treat in a single session. So what are the types of outcomes one might see? Well this is one, certainly partial obliteration where it takes an AVM that looks like this prior to radiosurgery and at three years out, which is when the obliteration is usually assessed, that one sees a smaller nidus but it's not all gone. So this has been pretty well described to not reduce the risk of hemorrhage. So that hemorrhage risk still hovers around two to three or maybe four percent. Maybe a slight reduction but not much. But it does certainly give some benefits for those who have had seizures. You don't have to have obliteration to achieve improvements in epilepsy associated with an AVM. So there are some benefits but we would treat this patient again. Treatment may be repeat radiosurgery for the remaining nidus. It may be resection or embolization but this patient probably warrants additional treatment. Subtotal obliteration is something that is a bit confusing. It is in fact absence of the AVM nidus but persistence of a draining vein. And we saw this in about 10% of patients that we treated with radiosurgery at UVA and published a few experiences. So the Stockholm group, Christopher Lindquist and others have published about this. But in essence you take a complex AVM shown here and then what you're left with is no discernible nidus which is marvelous in something like this which one wouldn't be able to easily resect much less embolize and cure. But you see an early draining vein here and we found pretty convincingly that this is likely a safe and good result. That we have not seen any incidences of hemorrhage and we just tend to follow these patients. And in fact many of the times with another angiogram in a year that this early draining vein disappears. So it's likely a stage on the obliteration spectrum and it's probably not worth retreating. And then of course what we would hope to see is an instance like this where one takes a very surgically difficult to access AVM from posterior circulation basilar and in fact achieve a complete angiographically confirmed obliteration at about three years out. When we looked at a series of greater than 1,000 AVMs that were treated and helped to derive that scoring system that I had shown you earlier. We're hopping at about 75 to 80 percent long term obliteration not at three years but usually about four or five. Ten percent that had subtotal obliteration, 5% that had some degree of partial obliteration, 5% that had no angiographic change at three years out. So these patients that have no angiographic change or that have a partial obliteration really weren't repeat treatment. But you could see that we're having some substantial benefits in terms of risk reduction in terms of future hemorrhage in 90% or more patients long-term with radiosurgery. This very much depends upon the volume. The smaller the AVM volume at the time of initial radiosurgery, the more likely we'll achieve obliteration so that a three CC or smaller AVM-9 has a very high chance of success. Whereas when one gets above that, our success rate was about 60%. Again, optimal prescription dose is about 18 to 25 gray. Going above that doesn't seem to give much benefit and actually increases complications pretty substantially. We have a couple papers working their way through, but this was from a, that look at this in greater detail with the help of Mark Quigg, one of our epileptologists at UVA. But this was from a previous work. We're seeing about 77% that had seizure control after AVM radiosurgery. And in fact, very few have an increase in risk of seizures. Typically, if that does happen, it's a transient risk and oftentimes associated with adverse radiation effect in the surrounding brain parenchyma. There are complications with radiosurgery. We're throwing around a pretty high dose, oftentimes more than we would give to most lesions with the exception of brain metastasis. And we see about a six to 9% risk throughout the literature of adverse radiation changes and about a one through 3%, depending upon the location, risk of permanent adverse radiation effects. This again depends, this is some work from John Flickinger in the Pittsburgh group. It depends upon location, deeper seated. AVMs are more risk prone and more superficially located ones in the parietal region, for instance, are far less risk prone. Complications are more associated with larger volumes, previous embolization, those that had no previous hemorrhage and had AVM situated in eloquent locations. When you see something like this though, and this is obviously a very challenging case to deal with in the sense that you've got a nice compact nidus, you've treated it, you thought it was gonna have a marvelous result. It's a small volume. The patient had had a previous hemorrhage. You can see the pronounced T2-weighted signal changes around this. You first turn to steroids. You may turn to vitamin E and Trentol. There's some literature to support this. Occasionally you use hyperbaric oxygen. We've had on a few instances used Avastin to try to reduce this. And certainly I would, if the patient were not on anticonvulsants, I would have put them on them as I try to ride the patient through this situation. Every once in a while you're forced to resect. So I'm gonna spend the rest of, or the better part of the rest of this talk just mentioning a trial that's come even into the lay press and probably affects what we're gonna do more than anything that I've shown you just before about management of patients with unruptured AVMs. This trial and another one that was done in Scotland have both been published in the last year. This was a trial that was intended to accrue 400 patients and they were intended to be followed for five to 10 years. It was randomized between medical treatment and surgery. By surgery they talk about embolization, radiosurgery, or resection. The trial was halted, this Aruba trial, with a mean fall of 33 months. Just about half the participants that they had intended to enroll were actually enrolled and they were originating from 39 sites. And what they found was that the Data Safety Monitoring Board stopped the trial because there was a threefold greater risk of adverse events in the treatment arm than the medical management, conservative management arm. So this is gonna continue to be followed but you can appreciate here again the fact that lower risk in the medical treatment but a very short follow-up. If I've just told you that radiosurgery doesn't usually achieve success for at least three years, most of these patients aren't even at that three-year time point. In fact, the standard deviation of the follow-up was 19.7 months. There are some issues with this. There have been a number of letters that have come out criticizing this but this is, in fact, the highest level of evidence we have right now about management of unruptured AVMs. But some of the issues that have arisen are issues with equipoise. A high rate, a high percentage of these patients who were placed into the intervention arm were treated with embolization alone, which for most neurosurgeons is usually not a standalone treatment except for very small AVMs but is usually a treatment that's done in advance of a resection. And there have been some issues with the short follow-up and then, to an extent, a degree of clinical proficiency, particularly with the high rate of complications associated with the embolization arm in this study. They're gonna continue to be followed out but this has really caused a good bit of controversy within how we should manage these patients because, in part, we thought we understood what these patients' risks were and that we thought that they were high. So here are a number of the studies that are out there that looked at the natural history of AVMs and the broken lines are those from the series that have no previous hemorrhage. The solid lines are those from the same series that have had previous hemorrhage and their likelihood of developing a second hemorrhage. And you can see that within a five to 10-year period of time that the natural history studies suggest that there's at least a 15, if not a 29 or greater percent risk of repeat hemorrhage within five to 20 years. Unfortunately, with the mean fall in the ARUBA trial of only 33 months, we're not gonna see most of those patients have a hemorrhage yet but I do think over time, we might actually see some beginnings of complications in the management arm that we haven't seen given this natural history data but we'll have to wait and see. Maybe, in fact, the pendulum will swing towards a bit more aggressive intervention. What we did in advance of this study and this has been published was to really look at our cohort of 440 patients who had unruptured AVMs that were treated with radiosurgery alone. And we found, not surprisingly, a pretty high rate of obliteration. Again, if one looks out to about four and a half to five years, about a 60% rate of obliteration, all comers of more than 400 patients. So that's twice the ARUBA power. And when we looked at, in the latency period leading up to obliteration, the risk in this group of previously unruptured AVMs was 1.6% across the entire patient population. Symptomatically, again, we saw patients largely improve with regard to presenting symptoms which are oftentimes seizures. We did see seizure improvement in nearly 52% of patients. New onset seizures associated with radiosurgery in less than 1% of this series of 444 patients. So in large part, a pretty successful outcome. Symptomatic improvement in the vast majority. Now, granted this was a retrospective study, not a prospective one, and there's selection bias. Obviously, it was one that we seem to think, though, that treating select cases with unruptured AVMs may be warranted despite the ARUBA trial data. So let me just touch upon large AVMs and there are different techniques. I mentioned earlier that I think that fractionation for AVM radiosurgery is counterproductive and the literature would support that in large part, with the exception of large AVMs where there are different approaches that can be taken. So one considers a special Martin grade four or five AVM, which would be very challenging to resect but where there's been a previous hemorrhage, and considering partially embolizing it, especially high risk features, such as a perinatal aneurysm, and then you can do different things. There are two different approaches, volume staging it, breaking the anitis up into maybe half or thirds. So as you've seen here, we've taken this large AVM and treated the upper portion and then the lower portion second. Actually, I think we did it the opposite, treating the deeper portion first and the superficial part second. Or you can, or Tony and his group have done this and not volume stage it, but dose stage it. So treating this with a, treating the entire anitis with a lower dose and then going back and giving a similar dose a second time. There's certainly advantages and disadvantages to both. I tend to gravitate towards a volume stage approach, but I see merits to both. And that we know that the obliteration rates are not gonna be as great that 80% long-term obliteration rate, but it's probably on the order of 50% or lower, but partial obliteration for these patients can lead to substantial improvements. Especially, I've had some patients who had substantial vascular steel, had a guy who worked in the Harley Davidson bike factory, and by partially obliterating his AVM, he was able to get back to doing the kind of manual work, fine manual work that he wanted to do with his job. Repeat radius surgery is sometimes done in these cases, again, where there's partial obliteration, where we found that going back a second time confers very low risk. And in fact, that the risk seems to be just about on par with an initial risk if one waits at least three years to retreat the patients. There are a number of other radiosurgical series out there by a number of members in the audience here, Dr. Friedman included, that show that these results all hover around reasonable success rates of at least 50 to sometimes as high as 90% obliteration rates, again, depending upon the patient cohorts. I do think that embolization has a role. Preoperative embolization, however, likely reduces the long-term rate of obliteration if one controls for the volume of either pre or post embolization volume. This may have to do with some degree of obscuring of the targeting at the time of radius surgery, or even some recanalization through the embolized nidus. And certainly, though, we do embolize patients' AVMs when they're too large to treat with single-session radius surgery where there may be high-risk features. And this work that I believe came out of the Toronto group shows pretty nicely a difference in the obliteration rates between the previously embolized AVMs and the non-embolized AVMs. And then one final example in terms of getting out of jail free, we've gotten a couple of instances of T2-weighted signal changes that have been pretty pronounced. I touched upon this before. And we've gone to using, and Dr. Hsu mentioned this earlier yesterday, about the use of Avastin. And we've gotten ourselves out of trouble with the use of Avastin. In some instances, pretty pronounced perinatal edema around an AVM that was proceeding to obliteration, and a nice response even two weeks out after. And thus far, we haven't had a hemorrhage associated with the administration of Avastin in the few instances we've used it, either in the setting of AVMs or tumors. So just in conclusion, I'll say that in large part, I think AVM radius surgery, hearkening back to Dr. Steiner's successful treatment in 1971, has changed the way we manage patients. It has consistent long-term improvement in patients with AVMs. Certainly MR and angiographic planning is necessary. Careful dose selection for all the factors I've mentioned are important. Multiple procedures sometimes require for large AVMs, and that we can really make a substantial difference in their natural history. Certainly those that have had previous hemorrhage, and even I would submit to you those that haven't had previous hemorrhage associated with their AVMs. Embolization should be reserved for those cases where the AVM notice is too large to treat, or where there may be high-risk features. I think it's a treatment of choice in 2014 for Spetzer-Martin grade III AVMs. Certainly not everyone will agree, but in large part, I think the literature supports this pretty nicely. It's a reasonable treatment option for grade IV Spetzer-Martin AVMs, and I think it competes nicely for grade I and II AVMs, and has some value for even Spetzer-Martin grade V AVMs. And for asymptomatic lesions, we really have to weigh the natural history, the RUBA trial and others, and payers will make us think about this, but I do think that over time, and as the RUBA trial patients are followed longer term, that there will be, in fact, more events in the medical treatment arm than in the actual surgically, or radiosurgically treated arm. Time will tell. Thank you.

arteriovenous malformations

AVMs

treatment approaches

radiosurgery

hemorrhage risk

AVM management goals