Arteriovenous Malformation: Examining the Treatment Landscape

Podcast Transcript

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD:

Presence of an intranidal aneurysm, a prior hemorrhage, venous outlet stenosis, deep location, and associated flow related aneurysms are some of the qualitative features that can help classify an arterial venous malformation as high risk. But even after estimating risk based on these factors, management decisions can be difficult. Medical management alone with blood pressure control, high risk behavior reduction, and routine surveillance may not be adequate to prevent an event. At the same time, intervention whether with resection, radiation, embolization, or a combination of these strategies entails potential hazards of its own. In this episode of Neuro Pathways, we're discussing the current methods for managing AVMs, as well as a look at what's on the horizon. I'm your host, Glen Stevens, neurologist neuro-oncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to have Dr. Nina Moore join me for today's conversation. Dr. Moore is a neurosurgeon in Cleveland Clinic's Neurological Institute's cerebral vascular center. Nina, welcome to Neuro Pathways.

Nina Moore, MD:

Thank you for having me.

Glen Stevens, DO, PhD:

So Nina, I know you do a lot of things in neurosurgery but today, we'll sort of stick a little bit to AVMs. But can you start by just telling our audience, because it's not all neuro related folks, what is an AVM?

Nina Moore, MD:

So an arterial venous malformation is an abnormal artery to vein connection. Typically, blood flow goes through a large vessel to a smaller vessel, to an even smaller vessel. And then finally, to small capillaries that feed back into small venous collection areas that feed into larger veins. An arterial venous malformation is actually an abnormal high flow connection between the artery to the vein bypassing some of those smaller pathways. In the brain, this can be particularly dangerous carrying about a 3% rupture risk per year. Sometimes, up to nine to 10%, if some of those high risk features that you mentioned are involved.

Glen Stevens, DO, PhD:

And my understanding is, we can get AVMs in other part of our body, right? Just doesn't have to be in the brain.

Nina Moore, MD:

Correct. Yeah. So oftentimes, we can also see these in the lung for certain sort of genetic mutations and we can also see them within facial AVMs, body AVMs, all the way through pretty much the entire body, you can find one. And the brain in particular, is because it's a fixed space, if something were to bleed, it tends to be a little bit more worrisome.

Glen Stevens, DO, PhD:

Yeah. So I'd like not to have my AVM diagnosed by having a bleed, but I guess how would I know otherwise?

Nina Moore, MD:

Well, sometimes, people present with headaches, can have family history of blood vessel malformations. Another location in the body may trigger an investigation to look into the brain. Seizures can be a source. Even some neurologic impairment may be considered AVM steal phenomenon, where blood is actually shunted away from normal territories due to high flow going to one location.

Glen Stevens, DO, PhD:

AVM complicated area with a lot of potential treatment options. Can you give us the lay of the land for the various types of treatments for this type of disorder?

Nina Moore, MD:

Well, fortunately, we do have a fair amount of treatment options. Typically, these are diagnosed initially with some noninvasive imaging, and then we typically use not like an invasive test, like a cerebral angiogram to better understand what the AVM looks like. Most people's AVMs are not the same as another person's. And so we really tailor treatment options based on the location and whether or not it's amenable to certain types of procedures. Our go-to standard is usually surgical resection. And sometimes, when we do a surgical resection, it can be safer to do preoperative gluing of a vessel or blocking of a vessel called embolization.

Nina Moore, MD:

We do that with catheters and then afterwards, surgical resection to try to take the entire AVM out of the brain. When it comes to other options, there are locations that are trying to embolize these AVMs entirely without surgery. We've found that it can carry a higher risk than surgical resection and sometimes Gamma Knife radiation, or radiosurgery. But there are locations that have successfully done this, it's just a question of, "Is it a safe technique?" And not always is it a safe technique, just because there's a higher risk of potential rupture of the AVM during the treatment.

Glen Stevens, DO, PhD:

So for my training many years ago, I remember the Spetzler-Martin classification for AVMs. Is that still used today or is that out of date? Do you use different systems or it's still helpful?

Nina Moore, MD:

So we still use the Robert Spetzler's grading scale. I think there have been modifications, Dr. Lawton modified his grading skill in the recent past but for the most part, is one of the standard ways we evaluate AVMs.

Glen Stevens, DO, PhD:

And what about risk factors for bleeding?

Nina Moore, MD:

Well, aneurysms located inside the AVM can be a higher risk of bleeding. If there's narrowing of the draining veins, which are already taking on more fluid flow and pressure than they're used to, if that vessel narrows, it's kind of like obstructing a pipe. You expect there's going to be backup of the fluid. And in that case, that can cause a rupture. There are things that we do ourselves that can cause AVMs to rupture more likely. Smoking unfortunately does increase people's vascular risks of bleeding either from an aneurysm or an AVM, and then blood pressure being out of control can be a contributor as well.

Glen Stevens, DO, PhD:

And I'm just curious in your practice with patients that have AVMs, do they quit smoking or they don't?

Nina Moore, MD:

For the most part, we're pretty aggressive about treating the vascular malformations when we find one. There was a recent study called the ARUBA trial, where there was a debate whether or not it was an important thing to try to surgically or endovascularly or with radiosurgery treat these AVMs or to let natural history kind of play out. In our own research here, we found that our results were safer. And so typically, we're pretty aggressive about taking out the AVM than letting it kind of rupture on its own.

Glen Stevens, DO, PhD:

So what about medical management for AVMs?

Nina Moore, MD:

That's a new, interesting area of research that's been ongoing. We've found out, especially in a more recent New England Journal of Medicine paper, that brain AVMs do carry possibly a 50% rate of genetic mutation, including the KRAS mutations. And you may be interested, and maybe have talked with some of my colleagues about this, but there may be some new applications for some of these currently used oncologic medications that target KRAS mutations for potentially trying to shrink AVMs. In Europe, there's been a fair amount of interest in looking at body AVMs and face AVMs, and using some medications that we've previously either abandoned or considered not applicable.

Nina Moore, MD:

Thalidomide as being used in some facial AVMs to shrink the AVM, because it's thought that it's pruning some of the smaller vessels. And it has been shown to maybe potentially, with bolus administration and then lower maintenance rates, potentially be able to be safe to continue. And it decreases the rate of bleeding among facial AVMs. This and the use of Propranolol, Doxycycline, some of those are thought to potentially help in some of the vasculogenic properties that happen with the AVM, and even ischemia that's induced from either AVM changes. If we can impair that ischemia from happening with Propranolol, potentially you can prevent it from rupturing, at least in body and facial AVMs. So this is kind of an area of interest for us looking at brain AVMs that potentially, those could be applicable.

Glen Stevens, DO, PhD:

Well, very interesting about the KRAS. As you know, mutation abnormalities in lung cancer now is very target driven and KRAS mutations are not uncommon in lung cancer patients. And it provides a very nice target to treat those patients. We did a study with Thalidomide years ago with NF patients. As you know, the Thalidomide is an anti-angiogenic type drug and it was being looked at... It was given initially to young women that were pregnant to help with nausea. And of course, it's an anti-angiogenic drug so it turned out to be the worst drug to give to somebody who was pregnant. So you had then had all these children born without limbs, caused a massive problem. But it still has a utility and I see that it's still slinging around and shows up again.

Nina Moore, MD:

Yeah, it is interesting. I don't know if any of these drugs have been able to completely reduce the AVM to nothing, but I think even if you could potentially shrink an AVM to a surgically manageable size, that may be of interest. We don't know how these will interact with the endothelium of the cerebral circulation. The vessels in the head are significantly smaller and thinner than the rest of the body. So, that's going to be an area that we have to be very cautious about when we start administering some of these medications in patients. And so that's a very interesting area of research coming up.

Glen Stevens, DO, PhD:

When I first started for multiple sclerosis, there was steroids and there was steroids and there was steroids. And now, there's probably 30 drugs they can use to treat patients with MS. And I always kind of wonder when a patient comes in, how do they really decide which of these medications? And of course, I come to see you with my AVM and is it, leave it alone? Is it do surgery on it? Is it glue it, coil it, embolize it, Gamma Knife it, give you a drug otherwise? How do I decide? I'm sure it's difficult and you use some of these grading systems that tell you where the risk is, but patient preferences well. How are you deciding? It must be some long conversations.

Nina Moore, MD:

It is. I think there are certain locations in the brain that make AVMs very amenable to surgery. If an AVM's located deep within a vital structure like the brain stem, surgical resection can be very damaging to the surrounding area. And so something like radiosurgery, like here, we use Gamma Knife, can be a very eloquent way of taking care of the AVM. It doesn't give you a definitive cure right away, but over the course of three years, it has a decently high success rate in curing the AVM. Sometimes, for large AVMs that are not resectable, we can do staged Gamma Knife, we can do staged embolization to try to take down some of the more dangerous feeders. Obviously, if it's a very large AVM, sometimes we unfortunately can't do a whole lot. And so hopefully, some of these new medications coming down the line will be able to give us some more options.

Nina Moore, MD:

From a planning standpoint, we are trying to determine ways of more accurately predicting who will need an AVM resection or treatment. My lab is working on doing fluid structure modeling, where we look at AVM mechanics, both fluid flow and the actual mechanical properties of these vessels, to see if we can take a patient's specific anatomy, do a mechanical model of it, where we import based on their own kind of characteristics, what the mechanical properties are for those vessels. And also, look at the fluid flow based off preoperative imaging to see if we can predict if they're potentially going to rupture and over what timeframe.

Glen Stevens, DO, PhD:

My best friend growing up as a hydrogeologist and he's all into fluid flow dynamics. He does soil science, he's a hydrogeologist. Maybe I need to have him give you a call, you guys can do some fluid dynamics.

Nina Moore, MD:

That would be great.

Glen Stevens, DO, PhD:

That's what he's looking at all the time, right?

Nina Moore, MD:

Yes. Yeah.

Glen Stevens, DO, PhD:

How would you determine that in a patient? Would you do an angiogram, inject something in and look at the flow, or how would you determine the dynamics?

Nina Moore, MD:

Well, that's an interesting question and it's kind of a complicated question because of the current limitations we have with some of the technology we have. So we've been creating 3D printed AVM models of a patient specific AVM, that's something that we've kind of recently done here. And we're hooking that into a fluid flow model and trying to see what the best imaging modality is for being able to predict fluid flow. We might only need the inlet parameters for a fluid structure model. And so being able to take something from one of the arteries that's feeding into the AVM, may be enough. But from a standpoint, the ultimate goal is to be able to take a patient's pre-operative imaging, whether it be 4D MRA, 4D diagnostics cerebral angiography, or even just 3D angiography or 2D films, and be able to see if we can predict what that fluid flow is for that patient, with pressure measurements in the 3D printed model and import that into the fluid structure model.

Glen Stevens, DO, PhD:

Well, I have had the odd patient that has come to see me that's an engineer, that will bring a model of their brain. They'll get their imaging structure and they'll actually make a model and bring it into me. There's a lot of interest out there. Surgical techniques. Is there anything revolutionary on the border or is surgery right now kind of where it is for these? Or is there anything new?

Nina Moore, MD:

Well, we are using more image guidance in AVM surgery. There's more techniques that are becoming useful in some of the microscopes that we're using. Obviously, as we improve it and the ability to evaluate flow through an AVM within surgery, that's helpful. Image navigation being incorporated into the microscope has been in advance. Being able to identify which vessels are going through the AVM, but not involved in the AVM, is also helpful. And so there are new imaging, like fluorescence imaging techniques, within the microscopic world that we're able to kind of improve our technique.

Glen Stevens, DO, PhD:

And what about interventional, anything new there? Do you have any new devices that you're putting in or new glue or something?

Nina Moore, MD:

So the glue has stayed relatively similar. There are always people working on trying to get the right concentration of glue. There are different techniques that are being used around the world, as far as how to embolize an AVM. If they're going to try to treat it completely, sometimes they stick multiple catheters in. There are new or smaller catheters that have balloons on them, to allow a little bit more direction of the embolization material than there were before. And so there are techniques that are being developed from an embolization standpoint to try to do this. Even cardiac arrest with fast pacing of the heart in order to inject the AVM to try to prevent the risk of bleeding, is an option. So there are new advances in embolization. I don't know if we're quite there yet, to say it's as safe as some of the other options, but it's certainly a field that's progressing.

Glen Stevens, DO, PhD:

So if I have a bleed, do I have to let it cool down before I can do something or do I do something right away?

Nina Moore, MD:

That's a good question. I think we found that if an AVM is ruptured, we try to take care of the high risk feature if there's an aneurysm associated with it pretty quickly, either through embolization or surgery. But if it's a lot of blood around the AVM, we may operate it on it sooner. But if you let it cool off for a little while, while the clot reabsorbs, it may create a nice plane for a resection, which allows you to kind of protect normal brain without having to get into that as much.

Glen Stevens, DO, PhD:

Do you see vasospasm in these?

Nina Moore, MD:

We see vasospasm in a lot of things that we typically wouldn't imagine we see spasm in. Not as often, if there's a flow related aneurysm associated and that ruptures, you can see more of a typical subarachnoid hemorrhage vasospasm appearance. We do have some dysregulation of the brain's vasoregulatory response when you do resect an AVM or even after a rupture potentially, where the brain is not responding as it used to blood flow. Because this area is getting such high blood flow, that when there is some change in the regulation, the brain may not respond as normally as it would otherwise.

Glen Stevens, DO, PhD:

Other areas of research going on with AVMs, or have we kind of covered the...

Nina Moore, MD:

Well, that's a good question. I think we still don't understand necessarily some of the more cellular level changes that these AVMs undergo. So I think besides understanding the endothelium and what the genetics are within that tissue, as well as the mechanics, there is still... Like in the in between, there's definitely a lot of important information that's going to be gathered from looking at inflammatory markers and things like that from AVMs.

Glen Stevens, DO, PhD:

And is this congenital, or can I get one later in life?

Nina Moore, MD:

That is a good, interesting question. There was a recent study, I think it was out of South Korea, where they were looking at whether or not this annual risk of rupture indicated whether or not people actually had a congenital AVM. The current thought amongst majority of people, is that it is a congenital

problem. But there have been patients that perhaps get de novo AVMs later in life, because it potentially explains better the annual risk of rupture. And so I guess we're still kind of a little bit in the woods as far as understanding exactly how AVMs start. It could be the genetic mutations need another hit before it occurs, or they're small enough and start growing and you don't identify them early.

Glen Stevens, DO, PhD:

So we see someone has a brain metastasis, we do a CT of the chest, abdomen, and pelvis. Someone has an AVM, maybe the incidence is too low, it doesn't make sense to look in other organ systems. Should we, or is the incidence too low unless there's some underlying family history?

Nina Moore, MD:

I think a lot of AVMs present a little later in life. So perhaps, this is the last one that's found or it's incidentally found. If it's seen in a younger patient, I think it's probably worthwhile to evaluate them pretty extensively. If there's other family history or there's other symptoms that seem like they may be related, I always err on the side of safety and try to screen my patients a little more thoroughly if I think there may be something else going on.

Glen Stevens, DO, PhD:

I look at the brain obviously, as a high risk area. Management of AVMs in other parts of the body, a completely different disease?

Nina Moore, MD:

Well, I think we're finding out there's more similarities than we maybe know. I think we tend to treat with endovascular care a little bit more aggressively, some of the body and the facial AVMs. You can potentially surgically resect things, but I think those areas tend to be embolization and like radiosurgery as good options. If it is small enough to be resected and it's in a location that can easily be resected, potentially it will be. But for the most part, I don't know if the fear of rupture is as bad as it is for in the brain.

Glen Stevens, DO, PhD:

Well, Nina, it seems like a real exciting time in the field. I do some Gamma Knife, I don't treat any AVMs, but I do get to see some AVMs being treated at times. Although, I don't get to see all the others that are being managed. But I love your passion and your interest in the things that you're doing. I'm sure it makes for a very rewarding career. And we're glad you joined us today. Thank you.

Nina Moore, MD:

Thank you very much. I appreciate it.

Conclusion: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word. And thank you for listening.