Cerebral Amyloid Angiopathy-Related Inflammation

Podcast Transcript

Neuro Pathways Podcast Series

Release Date: April 1, 2024

Expiration Date: April 1, 2025

Estimated Time of Completion: 30 minutes

Cerebral Amyloid Angiopathy-Related Inflammation

G. Abbas Kharal, MD

Description

Each podcast in the Neurological Institute series provides a brief, review of management strategies related to the topic.

Learning Objectives

• Review up to date and clinically pertinent topics related to neurological disease
• Discuss advances in the field of neurological diseases
• Describe options for the treatment and care of various neurological disease

Target Audience

Physicians and Advanced Practice providers in Family Practice, Internal Medicine & Subspecialties, Neurology, Nursing, Pediatrics, Psychology/Psychiatry, Radiology as well as Professors, Researchers, and Students.

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CREDIT DESIGNATION

• American Medical Association (AMA)

Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Participants claiming CME credit from this activity may submit the credit hours to the American Osteopathic Association for Category 2 credit.

• American Nurses Credentialing Center (ANCC)

Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 ANCC contact hours.

• Certificate of Participation

A certificate of participation will be provided to other health care professionals for requesting credits in accordance with their professional boards and/or associations.

• American Board of Surgery (ABS)

Successful completion of this CME activity enables the learner to earn credit toward the CME requirements of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Credit will be reported within 30 days of claiming credit.

Podcast Series Director

Imad Najm, MD

Epilepsy Center

Additional Planner/Reviewer

Cindy Willis, DNP

Faculty

G. Abbas Kharal, MD

Cerebrovascular Center

Host

Glen Stevens, DO, PhD

Cleveland Clinic Brain Tumor and Neuro-Oncology Center

Agenda

Cerebral Amyloid Angiopathy-Related Inflammation

G. Abbas Kharal, MD

Disclosures

In accordance with the Standards for Integrity and Independence issued by the Accreditation Council for Continuing Medical Education (ACCME), The Cleveland Clinic Center for Continuing Education mitigates all relevant conflicts of interest to ensure CME activities are free of commercial bias.

The following faculty have indicated that they may have a relationship, which in the context of their presentation(s), could be perceived as a potential conflict of interest:

Imad Najm, MD	Eisai Advisor or review panel participant NIH Other activities from which remuneration is received or expected: Research Funding LivaNova, PLC  Advisor or review panel participant SK Life Science Inc Advisor or review panel participant Teaching and Speaking
Glen Stevens, DO, PhD	DynaMed  Consulting

The following faculty have indicated they have no relationship which, in the context of their presentation(s), could be perceived as a potential conflict of interest: Cindy Willis, DNP and G. Abbas Kharal, MD

CME Disclaimer

The information in this educational activity is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options of a specific patient's medical condition. The viewpoints expressed in this CME activity are those of the authors/faculty. They do not represent an endorsement by The Cleveland Clinic Foundation. In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this CME activity.

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Go to: Neuro Pathways Podcast April, 1 2024  to log into myCME and begin the activity evaluation and print your certificate If you need assistance, contact the CME office at myCME@ccf.org

Copyright © 2024 The Cleveland Clinic Foundation. All Rights Reserved.

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: Cerebral amyloid angiopathy is a cerebral vascular disorder characterized by the buildup of amyloid proteins in small sized vessel walls of the brain and leptomeninges. A subset of individuals with this disorder develop an inflammatory reaction to the amyloid deposition known as cerebral amyloid angiopathy-related inflammation, which causes progressive but potentially reversible cognitive decline. However, because cerebral amyloid angiopathy-related inflammation is underrecognized, some patients are misdiagnosed with dementia and thus do not receive appropriate treatment.

In this episode of Neuro Pathways, we're discussing the diagnosis and management of cerebral amyloid, angiopathy-related inflammation and research aimed at determining its true prevalence and improving clinical care. I'm your host Glen Stevens, neurologist neuro-oncologist in Cleveland Clinic's Neurological Institute. And joining me for today's conversation is Dr. Abbas Kharal. Dr. Kharal is a stroke neurologist in the Cerebrovascular Center in Cleveland Clinic's Neurological Institute. Abbas, welcome to Neuro Pathways.

G. Abbas Kharal, MD: Thank you so much, Glen. It's a pleasure to be here.

Glen Stevens, DO, PhD: Abbas, I know you, but for our audience out there, tell us a little bit about your background, how you made it to the Cleveland Clinic, and what's your specific area of interest.

G. Abbas Kharal, MD: So originally I’m from Toronto, Canada and my interest particularly later in my medical years was towards cerebrovascular disorders. And during training, I was always drawn towards cerebrovascular inflammation. So I was really interested in research and kind of solving some of the unanswered questions in cerebral amyloid angiopathy and related disorders. And so to that note, after medical school completed a master's in public health with a major in epidemiology and biostatistics and clinical research at the Johns Hopkins Bloomberg School of Public Health. And I stayed in Baltimore for internal medicine training. And then the journey of life took me to the Mass General Brigham Harvard Neurology Residency Program where I completed my neurology residency there and where I had the pleasure and honor to train with various trainees of Dr. C. Miller Fisher himself, particularly including mentors like Dr. Steven Greenberg, Natalia Rost, and Aneesh Singhal, who were very formative in my interest in training.

And there I developed an interest in particularly cerebral amyloid angiopathy, and I've always been drawn towards the overlap of inflammation and cerebrovascular disorders. So to that note, I completed a fellowship in vascular neurology followed by a fellowship in autoimmune neurology. And basically wanted to take that training and both the clinical training and the research training to try to help solve, or at least shed more light and understand better the disorder of cerebral amyloid angiopathy-related inflammation and various other vasculopathies, particularly those that have an inflammatory basis. And cerebral amyloid angiopathy related inflammation is such. So to that note, trying to make my way slowly back to Canada or near Canada. Cleveland Clinic is an institution very well known for cerebrovascular disorders and inflammation. And this was actually a place where mentors used to say, "We want to send you over to Cleveland Clinic to train with those guys and bring it back to Mass General." And then the journey of life happened, and I met great people here and I thought this would be a great place to serve the patient population here and further my career. And so here we are.

Glen Stevens, DO, PhD: Well, we're happy that you're here and I'm really glad that you mentioned C. Miller Fisher. He's actually my favorite neurologist. As you know, I'm Canadian as well, so we're having a Canadian love fest here. But I always would tell the residents when I'm on service, "Read about C. Miller Fisher." And as a stroke vascular neurologist, he's really the father of vascular neurology and we obviously don't have time to go through it today, but his history and his life story is just fascinating and I encourage anybody out there to read about him. It's very fascinating. So I'm looking forward to talking about cerebral. As I'm getting older, I'm more interested in amyloid problems. So I'm looking forward to your talk here about the cerebral amyloid angiopathy-related neuroinflammation, but tell us basically first, what is cerebral amyloid angiopathy?

G. Abbas Kharal, MD: Absolutely. So to break it up, angiopathy is blood vessel disorder, cerebral, obviously brain and amyloid is this protein that abnormally deposits in cortical and leptomeningeal blood vessels and can lead to a very serious hemorrhagic condition, particularly in adults over the age of 50. And it presents as a progressive cause of spontaneous intracerebral hemorrhage. And unfortunately, there's no cure to date. In patients with this disorder, we know that have a progressive risk throughout life. As an amyloid deposition gets more and more with age, their risk of intracerebral hemorrhage increases. And studies show that particularly in the aging population with autopsy studies suggesting that the pathological prevalence ranges anywhere from about 29% in those greater than 50 years of age to about nearly 80% in particularly octogenarians with Alzheimer's disease. So Alzheimer's is also another amyloid disorder and that's why there's a lot of overlap and a lot of interest in this disorder because amyloid when deposits in cortical LGE vessels causes cerebral amyloid angiopathy. But when it deposits in the brain parenchyma itself leading to amyloid plaques, that is thought to be the underlying pathology of Alzheimer's disease. And there's a lot of overlap, we believe. 

And the way we're looking at it is more amyloid-related imaging abnormalities that there's a spectrum of amyloid related disorders on one end of the spectrum. Whereas Alzheimer's and the other end is cerebral amyloid angiopathy. And the more we're learning about these amyloid disorders, we're learning that there are perhaps similarities in the way amyloid presents, particularly we know that one of the subtypes or APOE alleles of the amyloid, that is what is not only what causes much of the amyloid, but also in Alzheimer's, but also is more prevalent in those with CAA related inflammation. 

So CAA itself can present with small micro bleeds that can be asymptomatic throughout life. But also can present with macro hemorrhages, which are bigger hemorrhages, greater than five millimeters. And sometimes a manifestation called cortical superficial cirrhosis, which is basically on the layers of the brain of the cortical superficial sort of parts of the brain leading to subarachnoid hemorrhage, which portrays a significantly higher risk of progressive intracerebral hemorrhage throughout life. 

We do know that although there's no cure, but the use of anticoagulants and uncontrolled blood pressure particularly can also increase the risk of spontaneous intracerebral hemorrhage. Now, a subset of these patients go on to develop a T-cell mediated inflammatory reaction where we believe it's like your immune system is trying to attack this amyloid and attempt to get rid of it. But it's so complexly intertwined in the blood vessels that not only is it unsuccessful in getting rid of the amyloid, but it causes so much catastrophic damage and inflammation by invasion of macrophages and basically starts an inflammatory cascade leading to significant cerebral edema.

And now this cerebral edema is what causes the progressive cognitive decline, can lead to seizures, headaches. And oftentimes the most surprising part, but also the most devastating part of this is oftentimes because it coexists in patients with Alzheimer's disease, so patients with Alzheimer's can often also have concomitant cerebral amyloid angiopathy, which is a solely progressive process, but CAA-related inflammation, what happens is more subacute and can lead to much more rapidly progressive cognitive decline. So oftentimes you'll have a patient who has Alzheimer's disease, it's been known for 2, 3, 4 years and is on this slow decline pathway, but then develops cerebral amyloid angiopathy, which may or may not have been picked up, but then they develop alongside cerebral amyloid angiopathy-related inflammation.

Now that causes significant decline very quickly, over weeks to months. And oftentimes I've seen unfortunately that it goes under recognized and the rapidly progressive cognitive decline that happened in these patients is sometimes confused as, "Oh, this patient's dementia that is just terminal and has just rapidly progressed and this is the end." Whereas as devastating as it can be and can even lead to seizures and sometimes coma, it is still fortunately very treatable and reversible. The inflammation is very reversible and treatable with steroids and other immunosuppressive agents. And so the CAA-RI portion is indeed reversible and treatable and we can get patients back to where they were, back on that slowly progressive track of cognitive decline that they had or the natural history of their Alzheimer's. But most importantly, the edema and all that inflammation that's causing the subacute cognitive decline in seizures can be very easily treated within days to weeks.

Glen Stevens, DO, PhD: Now, my understanding, if I remember back to my pathology is that the vessel walls are weakened related to the amyloid and they're more friable. That's why they bleed. And you can see, as I recall, low bar hemorrhages is more common. And I think I remember the exam question was always Congo Red stains.

G. Abbas Kharal, MD: Yes, amyloid. Yeah, the amyloid stain is the positive Congo Red stain.

Glen Stevens, DO, PhD: Now, do you see it in other vessels outside of the CNS? So you do an autopsy study, do you see it in the kidneys? Do you see it elsewhere? Is it really localized to the brain?

G. Abbas Kharal, MD: So the amyloid beta subtype is particularly we understand is most localized to the central nervous system, particularly the brain. There haven't been really studies looking at spinal cord extension, but we do know that it's mainly cortical parenchymal, low bar predominant blood vessels. Now pathologically as you were mentioning, yes, it starts off as cerebral microbleeds, but can manifest as larger macro hemorrhages and even subarachnoid hemorrhage. And oftentimes in conversations with my mentor, Steve Greenberg, he often says, "What we don't quite understand is some patients are just micro bleeders and they'll just micro bleed all their life. They'll have hundreds and thousands of microbleeds and may not go on to develop a macro hemorrhage. Whereas some patients will have two micro bleeds, and the next thing is a big catastrophic macro hemorrhage." We don't clearly understand why that occurs, but we believe it has something to do with the underlying composition of the amyloid.

Glen Stevens, DO, PhD: So if you do a SWI or a gradient sequence on these people that have a low bar hemorrhage, are you most likely probably going to also see susceptibility changes elsewhere in the brain, they'll have multiple of these because it probably doesn't exist in isolation, right?

G. Abbas Kharal, MD: Exactly, and rather when you see an isolated macro hemorrhage in itself, you should think otherwise and want to look into other things like a low bar macro hemorrhage being caused by a venous sinus thrombosis or underlying vascular malformation or a tumor or an infarct with hemorrhagic conversion. So those are other things that you want to look at. But normally what really should direct us towards a diagnosis of cerebral amyloid angiopathy as a cause of a macro hemorrhage is obviously age greater than 50. They have to meet basically modified Boston criteria for at least possible or probable CAA, which would be evidence of other stigmata, a hemorrhagic stigmata or white matter disease stigmata as well, albeit cerebral hemorrhages or microbleeds, cortical superficial siderosis, along with the macro hemorrhage, other white matter markers as enlarged perivascular spaces, white matter disease, et cetera.

Glen Stevens, DO, PhD: And the role of hypertension in this. So if you're not hypertensive, is it fairly unlikely you're going to bleed or not necessarily?

G. Abbas Kharal, MD: Not necessarily. So the way we're looking at cerebral amyloid angiopathy as a field is that it is a form of small vessel vasculopathy, and when you have one form of small vessel vasculopathy, you're also likely to have others. But hypertension is not considered a risk factor to our knowledge of cerebral amyloid angiopathy. It's mainly a deposition of amyloid.

Glen Stevens, DO, PhD: So you mentioned sort of this T-cell response. So is the brain fighting against itself?

G. Abbas Kharal, MD: It's basically the immune system-

Glen Stevens, DO, PhD: Autoimmune type?

G. Abbas Kharal, MD: Exactly. It's an autoimmune phenomenon where the immune system is fighting against the amyloid. But since the amyloid is so complexly intertwined and roped into the blood vessels, it is very difficult for the amyloid to get rid of.

Glen Stevens, DO, PhD: And what percentage of people that have cerebral amyloid will get the inflammatory?

G. Abbas Kharal, MD: That's an excellent question. And the right answer to that is we don't know. And that is what our research paper tried to explain is we talk about cerebral amyloid, angiopathy-related inflammation as it comes to attention when patients present with rapid cognitive decline, seizures, headaches, or other signs of edema. And we pick it up on imaging and we see, "Oh, behold, this person has either known cerebral amyloid angiopathy before or a new diagnosis and a pattern that fits with edema, that is vasogenic edema or T2 flare hyperintensity in areas of cerebral microbleeds." That is much more than what you'd expect from the microbleeds alone. 

But the true prevalence, I still don't think we understand. So our study tried to look at asymptomatic and symptomatic together. So it was a term that we put out in the literature, a term called radiological cerebral amyloid angiopathy-related inflammation, which basically is cerebral amyloid angiopathy-related inflammation that radiographically meets criteria for CAA-RI that may not manifest symptomatically, may not present with the headaches or the cognitive decline or seizures yet, versus the clinical radiographic CAA-RI, which is clinically manifesting and has radiographic evidence. In our database or in our study we showed that CAA-RI was prevalent about 10.8% of all CAA patients. So we studied about 511 patients with CAA. About 10.8% of those had what we believed, at least radiological CAA-RI, some of which also had clinical radiographic evidence of that as well. But if we looked at specifically the subgroup of CAA with white matter disease of any type, in those patients, the prevalence was as high as 28% who had CAA-related inflammation.

Glen Stevens, DO, PhD: And maybe I'm getting ahead and maybe you don't know the answer, but could you give an immunosuppressant to those patients?

G. Abbas Kharal, MD: That's another great question, and that's what we're trying to study now in the future is that what should we be doing with these patients who have radiological CAA-RI but do not yet have symptoms from that? Are those patients who we should just monitor radiographically or are those patients who we should start on treatment? And what are their chances of developing further edema? What are their chances of relapsing and getting worse and manifesting? So those are all questions that we are trying to answer because right now it is not standard practice to serially image patients with cerebral amyloid angiopathy alone. It is not standard of care or common practice at most centers where you take patients with cerebral amyloid angiopathy, who have known CAA at least once or present with a hemorrhage to serially image them every year or six months to see if they are going to develop CAA-related inflammation. Now, as we understand this more, that's another question that we're trying to answer. And I think a lot of other colleagues and collaborators we're discussing as to how will this change practice?

Should we be serially imaging patients with cerebral amyloid angiopathy? At least yearly, maybe. I don't know what the right answer is to see if they are to go on to develop cerebral amyloid angiopathy-related inflammation. And the question is, well, obviously if they present clinically, of course we treat them, but if they present with just radiographic sort of isolated inflammation, is that something worth watching or should we then start monitoring them once they have radiographic CAA-RI? I do so in my practice, I've started to serially image patients with cerebral amyloid angiopathy, but I think we don't have enough data yet to say whether or not that's cost-effective and feasible, and also should these patients be treated or not. And I think as more studies on CAA-RI and also sort of allow us to understand better the prevalence of CAA-RI, maybe we'll be able to know better as if the prevalence is truly high enough, then maybe we should be serially imaging these patients.

Glen Stevens, DO, PhD: So let's go to the edema. As a vascular neurologist, I'm sure there's lots of vascular neurologists out, they're salivating when they look at someone that has a stroke and you see edema and you go, "Boy, steroids should help this." But it doesn't because it's cytotoxic edema. So the edema here must be vasogenic, is that right?

G. Abbas Kharal, MD: It is vasogenic. Absolutely, yes, vasogenic edema.

Glen Stevens, DO, PhD: Secondly, what percentage of patients do you have to go in and do something surgically with the hemorrhage or is that uncommon with these types of bleeds?

G. Abbas Kharal, MD: So again, depends on particularly what type of hemorrhage they have. So we do know that most patients will have just progressive cerebral microbleeds. A small percentage of them may go on to have a larger macro hemorrhage. We do know that the progressive risk of recurrent macro hemorrhages is about 10% based on studies from Mass General from Dr. Greenberg and Edip Gurol's work and Dr. Schmahmann work as well. But as far as surgical evacuation for macro hemorrhage, so we do know from previous data from STITCH trial that was not standard of practice. It did not improve functional outcomes. However, the recent ENRICH trial with minimally invasive surgery did show that there was benefit of minimally invasive surgery in patients with low bar macro hemorrhages who had basically signs of clinical radiographic deterioration.

It was an adaptive design trial and basically during the trial showed that low bar hemorrhages benefited basal ganglia hemorrhages or deep hemorrhages did not. And so based on adaptive design, they excluded patients with deeper hemorrhages. So that has certainly changed practice. We are now taking patients who progress with neurologic deterioration with macro hemorrhages who meet criteria of ENRICH trial for evacuation. And there are talks about further expanding that or doing a sub study of ENRICH for basal ganglia hemorrhages as well. But cerebral amyloid angiopathy for purposes of CAA, we know that that's a low bar predominant. So yes, if you have patients who have large macro hemorrhages with neurologic deterioration who meet criteria per ENRICH, I think with the data that we have now at least minimally invasive surgery for evacuation will be a topic of discussion for those patients.

Glen Stevens, DO, PhD: Let's say I'm your patient and I have some history of cerebral amyloid and I've had a decline. So go through a few things with me. One, let's say you scan me and you see some edema and you decide I should have a lumbar puncture done. What's the likelihood the spinal tap is going to be abnormal with this inflammatory process? Is it inflammatory or non-inflammatory?

G. Abbas Kharal, MD: First of all, I never wish you have that, but the most important thing is recognizing the entity of cerebral amyloid angiopathy-related inflammation and how it's a very treatable entity if picked up earlier and treated appropriately. So if a patient with known cerebral amyloid angiopathy or even a patient with Alzheimer's disease who could have concomitant CAA, if that patient presents with say, a seizure or rapid cognitive decline or headaches, that is a patient I want to image. At least if you don't have an MRI available, getting at least a CT brain to look for the possibility of an angiogenic edema. But then obviously an MRI brain, because CAA-RI is a clinical radiographic diagnosis, you do not need CSF to make the diagnosis for that. And that is again from data from mentors at Mass General who've shown that it's more of a clinical radiographic diagnosis. 

Now, we do know that the pathogenesis involves anti-amyloid antibodies. And so there are patients who oftentimes I will go on to do CSF, particularly those patients who I'm concerned who may have amyloid beta related angiitis, which is more of a transmural CNS vasculitis caused by amyloid and is the much more aggressive vasculitic form caused by amyloid. But if we were to do CSF studies in these patients, we often see some CSF inflammation, and that's usually some elevated CSF protein. We don't often see CSF pleocytosis because it's not an infective process, but even by way of... since it's more sort of perivascular inflammation, you may see some elevated protein and if any cells, a few cells with lymphocytic pleocytosis, but mainly CSF protein elevation, which is nonspecific. Oftentimes you'll see normal CSF completely. 

The testing of anti-amyloid antibodies in CSF is not commercially available. Dr. Piazza in Milan is a scientist who has been doing that in his lab under research and is a collaborator on that, but this is not something that's commercially readily available. So when the diagnosis is in question, that is when I do perform CSF analysis on these patients. Recently I had a patient who presented with cognitive decline, not so much so progressive/rapid, but a very kind of subacute to late cognitive decline. And I was worried about concomitant Alzheimer's in that patient. So I did pursue CSF in that patient, particularly also not just to look at their CSF profile, but also to look at amyloid and tau markers. And behold, it did show that they met the diagnosis of Alzheimer's disease. And so yes, if you're gathering other information or you really are questioning the diagnosis to rule out an infectious or other inflammatory process, I think it's reasonable. But is it necessary to make a diagnosis? Not necessarily.

Glen Stevens, DO, PhD: If you feel that I need to go on some steroids, what's your steroid of choice, IV or oral?

G. Abbas Kharal, MD: So initially, I've approached this and I think I've learned a lot over the years on how to treat cerebral amyloid angiopathy-related inflammation. And I still think that our regimen is not perfect. We can always improve, but if the patients are inpatient, if they present inpatient, particularly if they're presenting with seizures or in status epilepticus or comatose, those are patients who since we're able to, will start them on IV methylprednisone a gram daily for five days, followed by a long prednisone taper.

Glen Stevens, DO, PhD: How long do people need to be on steroids? Is this a week thing? Is this a month thing? Is this-

G. Abbas Kharal, MD: No. Normally, it's a few months. So the inflammation starts to reverse in about a few weeks, but I normally keep these patients on about three to four months of prednisone on a slow taper, starting at about one mg per kg, roughly about 60 to 80 milligrams, and then tapering by about five milligrams every other week. And then serially imaging these patients. And in the outpatient setting, however, kind of from what we learned from the optic neuritis trials, that IV steroids may give you a head start, but at the end of the race, both oral prednisone and IV prednisone or those who got IV plus oral at the end ultimately did the same.

And that's what I've seen in my practice that the inflammation gets better regardless with steroids, IV or oral. IV might work a little quicker, but ultimately as you treat them even in the outpatient setting with just oral prednisone alone, they will start to get better. 

I think there are several unanswered questions, and these are questions that have come in my mind as I've treated these patients. And particularly I think we have one of the largest CAA-RI population here at the Cleveland Clinic that I've been able to gather over the past few years. Now, the questions in my mind were always, well, how long do these patients really need to be on steroids for? And not only that, previous literature had shown that about one-third of these patients will relapse once steroids are stopped and need things like mycophenolate or cyclophosphamide.

Glen Stevens, DO, PhD: Do you guys use Rituxan? It seems like Rituxan is being used for everything.

G. Abbas Kharal, MD: Yeah. Given that it's more of a T-cell mediated response, not so much rituximab, but more T-cell directed therapies. So the question in my mind was one, what truly is the percentage of patients who do relapse and why do those relapse, relapse? Are there predictors that can help us predict who's going to relapse and who's not? And so that's kind of a small prospective study that we did. And what our study shows was I tried to look at imaging predictors. Can I pick up on MRI upfront on a first MRI of a patient? Can I predict if this person has a high chance of relapse or not? And maybe those are the patients who I want to upfront have that conversation of steroid sparing therapy, particularly mycophenolate with those patients. So our data did show that those who relapse were more likely to relapse if they had on imaging either a diffuse pattern of edema or had also temporal lobe involvement. And temporal lobe involvement patients are the ones who are going to seize more. Those are the patients often present in status epilepticus. So those patients, particularly with a diffuse pattern of edema, are the ones who are going to relapse. And the time to relapse in our data was at a median of about five and a half months after their steroids were stopped. So we'll treat them for with steroids for about four months on a slow taper. But once their steroids are stopped, those who had a diffuse pattern of edema relapsed at about a median of about five and a half months. 

And rather than me waiting to see these patients relapse and then have a conversation about mycophenolate, my practice has changed to when I see a diffuse pattern of edema on imaging, that's a patient who upfront I will have a conversation that based on our study, there was a tenfold higher risk of relapse if you had a diffuse pattern of edema. So I tell them that based on our data, although it's a small patient population, it's still probably the largest study that has been done so far looking at imaging predictors of relapse in this patient population. So those are the patients who I will start on mycophenolate upfront along with the prednisone, and so we taper them as we ramp down the prednisone, we ramp up the cyclophosphamide, and then ultimately they're on mycophenolate. 

And then the other thing I'll say is a bit different. I think that has been really one of the benefits of being a cerebrovascular neurologist and immunologist as well. I mean, I've learned so much from, even in my training from colleagues in rheumatology who treat a much younger patient population. That patient with psoriasis who comes in at the age of 25 or 30, they can probably tolerate or take a lot more immunosuppression. But I've realized along the initial years of my career that these patients that I'm treating are 70, 80 years old, more prevalent in females than men. And so these 80-year-old females with cerebral amyloid angiopathy-related inflammation, whom I'm putting on immunosuppression, may not be the strongest substrate to tolerate three grams of mycophenolate or a lot of cyclophosphamide, for example. So I have an approach where I ramp up their mycophenolate a lot slower and try to use the lowest dose of immunosuppression that gets the job done, and then serially follow and image these patients at about three to six month intervals. And as long as we've established remission, then continuing them on immunosuppression. And I think the question that still remains is, how long should we treat these patients with immunosuppression? Are they going to stay on it for the rest of their lives? If we look at what we've learned from the MS field, that early aggressive treatment and most often lifelong is probably the way to go. But I think those are still several questions we have.

Glen Stevens, DO, PhD: Well, Abbas, I appreciate your being here today. It's very informative. I always learn things, and I know our audience as well. And appreciate your being here today.

G. Abbas Kharal, MD: It has been my utmost pleasure, and I always enjoy our conversations.

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 @CleClinicMD, all one word. And thank you for listening.