Moyamoya Disease: Management in Patients with Large Artery Intracranial Occlusive Disease

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:

Moyamoya disease is a rare and progressive cerebral vascular disorder that can cause an array of neurologic symptoms ranging from headaches and tingling sensation in the limbs to transient ischemic attacks and stroke. The disorder is often seen in patients with large artery intracranial occlusive disease, but misdiagnosis and delayed treatment are common pitfalls for this patient population. In today's episode of Neuro Pathways, we're discussing the management and treatment of Moyamoya Disease for these patients. I'm your host, Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. I am very pleased to have Dr. Andrew Russman join me for today's conversation. Dr. Russman is medical director of the Comprehensive Stroke Center and head of the stroke program in Cleveland Clinic's Neurological Institute. Andy, welcome to Neuro Pathways.

Andrew Russman, DO:

Thank you. Happy to be here.

Glen Stevens, DO, PhD:

Andy, I always loved the name Moyamoya, I thought it was always interesting. My understanding, it was described about 65 years ago, so it's as old as I am, and I'm sure you're going to define it for us but give us a brief overview of Moyamoya Disease and its mechanisms.

Andrew Russman, DO:

Basically, moyamoya, it's an uncommon cerebral blood vessel disorder, which is characterized by progressive narrowing of the large intracranial arteries, usually the carotid terminus region, the carotid artery, and the initial segments of the anterior cerebral artery or middle cerebral artery. It's associated with the development of small collateral channels, which are small vessels that develop in order to deliver blood flow to an allogenic or ischemic deep brain area. This condition, as you mentioned, was first described in the 1960s and characterized at that time largely in Japan, and as a result when investigations took place at that time, the best technique, still the best technique for visualizing these blood vessels is angiography or conventional angiography. When these small blood vessel channels are visualized on angiogram, it often produces a hazy appearance to the tissue in that area or to the blood vessels, or it looks potentially like a puff of smoke. These terms, in Japanese translated to moyamoya, which is where that phrase came from in describing this clinical condition. It's not one clinical condition in terms of cause. It's a disease process that's characterized by these progressive blood vessel neurons, and there's a number of potential etiologies or implications in terms of the pathology, pathogenesis of how these blood vessels develop.

Glen Stevens, DO, PhD:

You've alluded to it a little bit, but there's a difference between moyamoya disease and moyamoya syndrome. As a neuro oncologist, I used to look after a number of neurofibromatosis patients, and they have a increased instance of it, and certainly patients that have radiation therapy around the skull base, we can see a slight increased incidents of moyamoya in these patients. Can you tell us a little bit of the difference between moyamoya disease and moyamoya syndrome?

Andrew Russman, DO:

Moyamoya disease is characterized by the same angiographic appearance, but it is an idiopathic disorder. It develops, and it develops for a relatively unclear reasons in most patients. In those patients we have the best understanding are those in which there appears to be a genetic basis. There does seem to be some association between a mutation in the ring finger protein 213 gene, which is on chromosome 17, and this does represent a factor that can contribute to the future risk of developing moyamoya disease, which typically has its onset in childhood. That particular disease is characterized by the progressive blood vessel narrowings, yet if we look at the total population among, let's say the Japanese population, only about 10% have this very specific genetic variation in these genes that affect the ring finger 213 gene. Whereas in the US population when we do see this, it's about 3%. The majority of moyamoya disease that we see occurs again for some idiopathic reason, and it's not necessarily associated with a variety of conditions.

Some of the conditions we see in childhood that are associated with moyamoya syndrome are conditions that are like hematologic conditions like sickle cell disease can be associated with it. When we see moyamoya disease, there has been a long term experience in that condition. Again, there have been attempts during procedures or surgical procedures to revascularize patients in which we've tried to look at the blood vessel pathology. Again, there's not one uniform pathology that is associated. It does appear to be some type of fibrotic process or thickening of the blood vessel wall rather than something extrinsic to the vessel. It seems to be intrinsic to the vessel, and that is the characteristic of moyamoya disease.

Whereas Moyamoya syndrome is a much more heterogeneous disorder and is characterized by a variety of circumstances. You mentioned one of them, Glen, or a couple of them, this exposure to skull base radiation can be seen as a delayed complication. The development of a vasculopathy that affects these areas of the brain that were irradiated, can be seen in certain tumor types. It can be seen in patients with history of meningitis. We see it in sickle cell disease. That's something that we might see a little bit more often than the other hematologic conditions. We've seen this in polycythemia vera. We see it in conditions in which people have an early onset of more accelerated atherosclerosis. Sometimes you see this in systemic lupus erythematosus. You see this characteristically in Graves disease, especially with thyroiditis. It's been reported in type one diabetes. We certainly do see that condition developing and we speculate on the reasons we can see it in conditions like sarcoidosis and a whole host of other conditions in which it has even a more rare occurrence.

Again, we can see it in conditions like Sturge-Weber or tuberous sclerosis. We see it in Marfan syndrome or other disorders like Sjogren's syndrome. These causes of moyamoya syndrome are particularly important when compared to moyamoya disease. When moyamoya disease from an investigational perspective, we're looking for some of these other conditions, for instance, systemic erythematosis, lupus erythematosis, or type one diabetes that may have an onset as a result in childhood and have some appearance to affect these vessels. But for the most part, we don't often find the occurrence of these conditions. Whereas in the adult population, much of the focus on understanding the pathogenesis is related to the treatment for that associated condition with the hope that by treating that underlying condition, we could abate further progression of the disease. Whether it's sarcoidosis or glycemic control in diabetes or control or treatment of systemic lupus erythematosis and some of these other conditions that we mentioned, aggressive treatment of the underlying disorder is critically important in combination with any understanding about revascularization.

Glen Stevens, DO, PhD:

Andy, in your practice, what's the typical presentation for these patients? Are they presenting with TIAs, strokes, seizures, non-specific neurologic symptoms?

Andrew Russman, DO:

Yeah. In general, 80% or more of these patients are going to present with ischemic symptoms. Some of that can be in the context of ischemia, potentially inducing more migraine headache activity as headache is not an uncommon presentation, but it's typically ischemia more often than not. A subset of patients may have a hemorrhagic presentation and intraparenchymal hemorrhage that is part of the initial presentation. Those are the two presentations we typically see.

Glen Stevens, DO, PhD:

I don't want to get too far ahead of myself, but you mentioned the angiogram, and I know that routinely when we see patients that we think have had a TIA, a vascular event, when I'm on service, everybody gets a CTA. Can you visualize this on a CTA, or do they need to have an angio?

Andrew Russman, DO:

Well, both. Certainly, we can visualize some of these small blood vessel channels on CT angiography; however, the precision and understanding how blood flow is being delivered to a specific area of the brain, it's really necessary to have diagnostic cerebral angiography. Essentially, every patient with moyamoya will end up getting diagnostic cerebral angiography as part of an understanding of how they are perfusing the ischemic brain or what has led to the hemorrhagic occurrence in a specific location.

Glen Stevens, DO, PhD:

Just give us a little more detail on your diagnostic workup. I mean, you mentioned a little bit ruling out some of these various disorders, but go through some of the diagnostic workup force.

Andrew Russman, DO:

Typically, someone who presents let's say in early adulthood, in their 20s or 30s, we will investigate these potential causes by looking initially at the cerebral blood vessels, which blood vessels are involved. Is this only one internal carotid artery or middle cerebral artery or carotid terminus, or are both involved? That initial approach is going to trigger okay, was this a hemorrhagic or ischemic presentation? MRI imaging of the brain, and sometimes it could be helpful to have contrast imaging in the circumstance to look and see whether there are changes in the leptinmeninges. For instance, associated disorders may have a pachymeningeal presentation, and seeing this is going to be important to understanding the disorder, so MRI of the brain with and without contrast.

Initially, if we have CT angiography, which we often do as you mentioned in the emergency department who patients present, we're going to have that basic understanding of where these blood vessel abnormalities are. Then we are going to embark an understanding of what's going on with the blood vessel walls. Does it have characteristic changes that we would think you see in more of an atherosclerotic picture, or is this something that you might see in something that looks more, let's say concentric in terms of the degree of enhancement of the blood vessel wall on specialized imaging? We're typically doing MR angiography with and without contrast, using at least a three or seven Tesla magnet to visualize whether there's enhancement of the vessel wall and what's the characteristic of that enhancement within the vessel wall, again, to have an understanding of which category of disorder this puts it in.

Then we're doing other imaging of the brain to understand how on MRI imaging the brain is responding to blood flow changes. At our institution, we've developed a protocol using pre and post perfusion maps using a technique to look and see whether there is appropriate augmentation to flow after acetazolamide administration or challenge in terms of looking at a perfusion imaging or perfusion abnormality. This helps us to understand is there an adequate cerebrovascular reserve within the affected blood vessels in order to be able to tolerate disruptions in cerebral blood flow that occur in everyday life.

The other considerations of things that we are going to do in investigations are an extensive blood work evaluation. We're looking for inflammatory disorders, rheumatologic disorders, autoimmune disorders, typically looking at not only at an ANA panel, but an extractable nuclear antigen, looking at a variety of different rheumatologic factors, looking for causes of vasculitis like anca. We're going to look at rheumatoid factor or cyclic citrullinated peptide in the occurrence of this, we are going to look for potential infectious causes, so we can see the appearance of blood vessels mimicked in patients who have varicella vasculopathy. We can see this in a herpes simplex vasculopathy. We're doing some blood work to attain that, but critically important is the next stage of doing then a lumbar puncture in those patients.

Lumbar puncture is going to help us to understand what's the immune activity, is there a relative intrathecal concentration of IgG synthesis with an elevated IgG index, and then what makes up that relative intrathecal increase in production? Is that due to something like an infectious cause like you could see in varicella, or with herpes simplex, or is it from an autoimmune ideology, which you can see in patients who have Sjogren's or sarcoidosis or a variety of other conditions in which you'll see that type of autoimmune development.

In addition, we're doing blood work, as I mentioned, looking for thyroid diseases. Sometimes if we're concerned about the occurrence or possible occurrence within the blood work of some indicators, let's say of sarcoidosis, we want to at least have a chest x-ray. We might want to observe whether there's acetylcholinesterase level that's abnormal within the blood, but sometimes we're see to CT of the chest or abdomen-pelvis looking for whether there's lymph adenopathy. Again, as we've seen patients who have these conditions do have different responses to revascularization and critically important to know this information in advance. I think, sorry, I elucidated blood work and lumbar puncture, detailed MRI imaging, and obviously most importantly as well, diagnostic cerebral angiography, which not only tells us how the patient gets blood flow, but how we might revascularize them if that's necessary.

Glen Stevens, DO, PhD:

Sounds like an extensive workup for these patients. The moyamoya disease, as I think you alluded to, tends to be more bilateral and affect the internal carotid artery area. Do you see much disease in the posterior fossa in these guys in the basler or they don't?

Andrew Russman, DO:

Traditionally, the disorder was not described that way, but certainly we can, especially at some of the genetic disorders. We have a number of patients we follow in which their specific genetic polymorphism is associated with a vasculopathy that's more extensive. We often hear the description, and when Suzuki first described the stages of the moyamoya vasculopathy in the late 1960s, they focused on the anterior circulation, looking at the internal PR arteries, but there can be involvement of other blood vessels. In moyamoya disease, this is less common. Outside of the genetic subtypes.

Glen Stevens, DO, PhD:

Let's say we have the diagnosis of moyamoya, let's look at treatment options. What percentage of patients can we just treat medically, what percent do we have to do some type of revascularization to increase blood flow, and what are the medical and then surgical options?

Andrew Russman, DO:

In general, the investigations that you and I talked about are going to help us to characterize. If we look at patients what we think was moyamoya disease, in some cases is this is a progressive disorder and slowly develops over a long period of time. We can see that patients will adapt and develop new vascular channels and create their own extracranial to intracranial connections. Sometimes, we refer to this as auto bypass. What will happen is that let's say the middle meningial artery will feed through the skull and provide additional blood flow, the cerebral circulation, patients will get collateral flow from the posterior circulation, feeding flow into the anterior circulation, and this can happen to a degree that produces either relatively minimal or little profusion abnormalities. In patients who present in which we've incidentally identified this, sometimes this happens in patients let's say with headache or migraine in which we do MRI imaging and find, "Oh, they have this moyamoya vasculopathy," we might actually discover that they've already made either their own auto bypasses progressively over time, or they have adequate cerebral blood flow that they have no abnormality in cerebral perfusion that is significant. Patients who are already getting adequate cerebral blood flow are people that we're going to treat medically.

Glen Stevens, DO, PhD:

You mentioned that these patients can hemorrhage, so how nervous are you about antiplatelets, Coumadin, those types of things?

Andrew Russman, DO:

Yeah. In general, if someone has presented with an ischemic presentation, antiplatelet therapy is indicated, but we are more anxious about anticoagulation. There are certainly no evidence that anticoagulation is helpful in the population of patients with Moyamoya, potentially it produces a greater risk, as you alluded to with hemorrhage. Because hemorrhage can make up these presentations, one of those questions is often if you do present with a hemorrhage, is there a benefit to surgical revascularization? As we get into our discussion and we talk about the available data in medical treatment, you'll see that both patients with hemorrhagic and ischemic disease may benefit from the same approaches to revascularization.

Glen Stevens, DO, PhD:

What percentage of these patients present with headache? Is it common?

Andrew Russman, DO:

It is pretty common. I would say more than half of the patients have headache as part of their presentation, but it may not be the predominant presenting symptom.

Glen Stevens, DO, PhD:

I would be pretty concerned if he used calcium channel blockers that their blood pressure could drop, which would then affect their blood flow and worsen their conditions. Use of calcium channel blockers in these patients?

Andrew Russman, DO:

Well, I think it depends on the subtype of patients. Sometimes when patients present and they do have ischemia-induced migraine process, their most disabling symptom can be these migraine auras that they experience, and sometimes drugs like verapamil as a calcium channel blocker can be very helpful for these auras, either visual or sensory, or even language auras that they may get in ischemia-induced migraine. The advantage of verapamil is it's really a pretty weak blood pressure medication. It doesn't typically significantly reduce blood pressure. It's more of a chronotropic issue. It may slow the heart rate down a little, and we need to keep an eye out for that.

Glen Stevens, DO, PhD:

Can you stent these patients or are the segments too long or not in a location you can usually stent?

Andrew Russman, DO:

Yeah, so both. It depends on the clinical presentation. We certainly have, in patients in which we think it's more of an accelerated atherosclerotic picture, we have certainly tried to stent these patients. Although if you look at the experience intracranial atherosclerosis, many of these patients are going to have that involvement of the distal internal carotid artery segments. The experience of intracranial stenting in that population has very high rates of recurrent race stenosis, even in patients who don't have this more moyamoya type changes. As it's progressing, the early stages in the vasculopathy, there may be a small blood vessel channel, and so the thinking is, well, maybe we should try and keep that channel open. But in my experience, when this process occurs, we're not as successful in being able to keep the blood vessel open. Even though they may stent and then temporarily be open, the vessel will still progressively occlude.

Glen Stevens, DO, PhD:

Let's move to revascularization, direct or indirect revascularization. Can you discuss those?

Andrew Russman, DO:

Sure. If we look at the majority of patients who present with moyamoya vasculopathy, whether it's ischemic or hemorrhagic, if they have adequate cerebrovascular reserve on perfusion imaging and they're already either auto bypassing and they have excellent collateral circulation, this population of patients generally doesn't go undergo revascularization. However, the subset of patients, the much larger subset, let's say 80% or more of the patients who present who have a cerebral profusion problem or they have an inadequate of the cerebral vascular reserve, we're going to offer extracranial to intracranial bypass using either a direct technique or an indirect technique.

Direct technique is typically connecting a surface blood vessel like the superficial temporal artery to the middle cerebral artery, and the surgeons who perform that need to be experienced and perform a large number of procedures in completing that technique. There are a variety of different approaches surgically to actually making the bypass in from a direct perspective, and that is the typical approach to treating most patients who are adults. If you said "What about children?" I say most children who have moyamoya disease more often are going to undergo an indirect technique. That indirect technique involves a technique where the branches of the superficial temporal artery and some associated tissue, dura, muscle are laid upon the brain tissue. Basically, they dissect out this area of the scalp tissues, they open a craniotomy and they introduce the extracranial tissues by laying and tacking them to the surface of the brain.

This technique in which they use the branches of the superficial temporal artery, it's most often was described as an encephaloduroateriosynangiosis, and many variations involve use of some of the muscle tissue. When the muscle tissue's used, then it's called an encephaloduraarteromyosynangiosis. These techniques are the predominant indirect techniques that are used. Now, there are variations on this that my colleague experts such as Dr. Mark Bain, or Dr. Peter Rasmussen, or Dr. Unimore, techniques that they use that are variations on these techniques depending on the area of persistent ischemia for the patient or area that the patient has had prior hemorrhage or predominance of these moyamoya vessels.

Glen Stevens, DO, PhD:

Andy, you gave me some great Scrabble words there. I don't know how many points some of those terms would be for the revascularization. Since the disease is bilateral commonly in patients that have moyamoya disease, how often do patients need to have bilateral revascularization?

Andrew Russman, DO:

If you present with bilateral disease, you are likely going to go on to have bilateral revascularization. Typically, we take the most symptomatic side first, and that's the first technique, and there are variations on this. But then after the patient is adapted to that, within a few weeks they undergo treatment on the other side. Sometimes the patient presents and one side is symptomatic and very involved and the other side is not only not yet symptomatic, but there is still a blood vessel channel there and it's not clear that there's a failure of the cerebrovascular reserve, so we may do serial imaging and follow that area. This is akin to how you follow the patient who has unilateral disease. If we have a patient with unilateral disease who gets bypassed, there's an experience that up to 40% of the patients with unilateral bypass will go on to develop disease on the opposite side, on the contralateral side. It's important to do follow up serial imaging in this population, especially those with unilateral disease because they do often develop disease on the contralateral side.

Glen Stevens, DO, PhD:

It's interesting, and good for you that the external carotid artery is not significantly affected. Do we have any idea why that is? Is the muscular wall characteristic different?

Andrew Russman, DO:

Yeah. I think we don't know those answers to that question, but I do think that in terms of how the tissues are being supplied, obviously it's very different, and resistance to flow is very different within the external carotid circulation versus the internal carotid circulation.

Glen Stevens, DO, PhD:

Any active research going on that you can shed any light on this?

Andrew Russman, DO:

Yeah. I think, again, if you look at randomized studies, there isn't a lot of randomized studies in populations of patients with moyamoya, and I think it's because most clinicians, treating clinicians, don't have clinical equipoise for not performing revascularization and somebody who presents with ischemia and a very clear moyamoya vasculopathy. However, we have a lot of uncertainties about the approach toward more probably the moyamoya syndrome patients where we see such a heterogeneous group of patients and different conditions that are associated with the vasculopathathies. I think some of the important work that has to be done over time is to characterize this population more appropriately in terms of applying a standard evaluation to all these patients and then understanding which and what are the likelihoods of detecting this within a large center such as the Cleveland Clinic.

That's an effort that's underway on our part. Now, others have looked at this and found variable percentages of these presentations of the subtypes. From a treatment perspective, it still comes down to if the patient is having recurrent ischemia and they can't provide that own adequate flow for themselves, then revascularization is critically important to preventing future events. Whether it's disease or it's the syndrome of moyamoya, revascularization or surgical revascularization is the mainstay of therapy, and we'd like to better understand how we combine medical treatments with surgical treatments, especially those with the moyamoya syndrome.

Glen Stevens, DO, PhD:

Any final words of advice for our audience listening today?

Andrew Russman, DO:

I think if you have a patient that has a moyamoya vasculopathy, you need to broaden your understanding of the investigations that need be done. I think there tends to be a focus more on this patient has a blood vessel problem and we need to revascularize, to we need to take a step back and say the majority of the patients we have at least some adequate period of time to investigate the underlying etiologies that may contribute. Especially within the adult population, it's critically important to have the patient seen by an experienced center, such as the Cleveland Clinic, that does revascularization and investigations as well for moyamoya vasculopathy. Again, taking this comprehensive approach is critically important to managing the long term course of those who have moyamoya disease or vasculopathy.

Glen Stevens, DO, PhD:

Well, Andy, thank you very much for joining me today. You can be sure that any of our radiation-induced moyamoyas, or NF related will come directly to your center to help manage these patients. Been very insightful and always appreciate learning some new information. I appreciate your time today.

Andrew Russman, DO:

Thank you, Glen. Thank you for having us.

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.