Vasculitis and Stroke in the Young

Podcast Transcript

Intro: 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: The incidence of stroke rises steeply with age, but recent trends have shown a rise in stroke in younger patients under the age of 45 years of age. One of the main causes of stroke in the young is vasculitis, which can be devastating in terms of productivity and quality of life.

In today's episode of Neuro Pathways, we're discussing stroke in the young and honing in on identification and management of vasculitis as its cause. I'm your host, Glen Stevens, neurologist neuro oncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to have Dr. Abbas Kharal join me for today's conversation. Dr. Kharal is a cerebrovascular immunologist in the Cerebrovascular Center in Cleveland Clinic's Neurological Institute. Abbas, welcome to Neuro Pathways.

Abbas Kharal, MD, MPH: Thank you so much for having me. It's a pleasure.

Glen Stevens, DO, PhD: So let's get things started. In most young people, the chance of having a stroke seems like an impossibility. Unfortunately, this is not the case. Can you start today's conversation by defining the young stroke population and addressing some of the causes that contribute to stroke in this population.

Abbas Kharal, MD, MPH: Stroke in young adults, there is no specific definition that is agreed upon for what we call young adults. Some stroke registries have taken patients 15 to 45 years of age. Whereas, if you look at the Helsinki Young Adult Stroke Registry, they've studied patients up to 49 years of age. So overall, for clinical purposes, we take patients under the age of 50 as young adults for purposes of ischemic stroke.

Now, as far as causes of stroke in young adults, interestingly, although we think that vascular risk factors are only specific to older adults, there has certainly been a significant rise over the past two to three decades in premature atherosclerotic vascular risk factors in young adults as well. Just like older adults, young adults also have an increase in cardiovascular risk factors, including hypertension, dyslipidemia, diabetes, atrial fibrillation, particularly in the fourth decade of life.

Valvular heart disease is another common cause. Obesity, congenital heart disease and lifestyle risk factors like tobacco use, physical inactivity, sedentary lifestyles, and poor dietary habits, illicit drug use, for example.

Then causes that are more specific to younger adults can be classified as, particularly some gender-specific causes. For example, in females, we see that the use of contraception, particularly estrogen-containing contraception, and pregnancy can be associated with an increased risk of stroke as well. Secondly, patients with migraines are also noted to be at a higher risk of stroke. Then there are causes associated with particularly cryptogenic stroke or anatomical defects of the heart, for example, patent foramen ovale, which is a cause of cryptogenic stroke in patients less than 60 years of age.

Other than that, younger stroke adults are at a higher risk of stroke from inherited thrombophilias and hypercoagulability disorders, including Factor V Leiden mutation, prothrombin gene mutations, antithrombin III, antiphospholipid antibody syndrome, sickle cell disease, hematologic malignancies, metabolic syndrome.

Then last but not least, a very important etiology of stroke in young adults is cerebral arteriopathy or vasculopathy. That includes both inflammatory and noninflammatory arteriopathies, with noninflammatory arteriopathies including things like Moyamoya disease, neck vessel dissections, fibromuscular dysplasia, and then some of the inflammatory vasculitides, including both primary and secondary vasculitides, which are numerous, particularly secondary causes, including Giant cell arteritis, Takayasu's arteritis, radiation-induced arteritis, to mention a few.

Glen Stevens, DO, PhD: So if we move away from ischemic stroke, what about intercerebral hemorrhage, subarachnoid stroke in the young?

Abbas Kharal, MD, MPH: So the two entities that we see subarachnoids hemorrhage in younger adults is aneurysmal subarach and non-aneurysmal subarach. The aneurysmal subarach is subarachnoid hemorrhage particularly seen in patients who have a family history of intracerebral aneurysms or polycystic kidney disease or connective tissue disorders. The other entity in which we see subarachnoid hemorrhage in younger adults is reversible cerebral vasoconstriction syndrome or RCDs, which can present with subarachnoid hemorrhage as well.

Glen Stevens, DO, PhD: Well, I never wanted to be old, but I guess when I'm hearing all this for the young, I feel better being old and that I made it through. As I always tell the residents on service, I always quote the great Canadian strokeologist, C Miller Fisher, who said that, "We learn neurology stroke by stroke."

Abbas Kharal, MD, MPH: Absolutely.

Glen Stevens, DO, PhD: As time goes on. So let's move on more specifically. You discussed it very briefly, but let's hone in a little bit on vasculitis. Can you take us through the etiologies? Again, I know you mentioned it briefly, on primary versus secondary vasculitis.

Abbas Kharal, MD, MPH: Absolutely. The way I describe classification of cerebral vasculitis is I think the best way to understand it is to classify it both based on firstly, inflammatory versus noninflammatory arteriopathies. And then further, particularly in the inflammatory arteriopathies, whether or not it's a primary versus a secondary vasculopathy. When a vasculopathy is inflammatory, we call it vasculitis or arteritis. Vasculitis can be classified as primary versus secondary, and then further classified based on vessel involvement to either large vessel versus small or medium vessel disease.

Probably the most important classification, once you classify a vasculopathy as inflammatory, then further defining whether or not its primary versus secondary is the most important thing. Secondary vasculitides are numerous. Basically when you see a patient with a suspected vasculitis, really the workup that you're going to do is primarily looking for secondary causes because primary CNS vasculitis by default is a diagnosis of exclusion once you've excluded all secondary causes.

So the most important question to ask is how do we go about thinking about vasculitis? When should we suspect vasculitis? It's important to note when we have the right clinical presentation, a younger patient with say headaches, subacute encephalopathy, a subacute decline, and recurrent ischemic strokes that really don't fit in one specific cerebrovascular territory and you have other constitutional symptoms, that is when to think that there's something inflammatory going on.

The initial diagnostic tests of choice that leads us to making the diagnosis of a vasculopathy first is an MRI brain showing that there are new ischemic infarcts and then some sort of vessel imaging, be it a CTA or MRA that can demonstrate if there is a vasculopathy at all. Oftentimes large and medium sized vessels, you'll be able to identify on a CT or MRA. However, smaller vessels, particularly vessel calibers that are a couple of hundred micro meters in diameter, the tertiary and quaternary branches, are better visualized on cerebral angiography or DSA.

Once you have vessel imaging showing that there are vessel irregularities and CT or MRI evidence of new acute infarcts, what you've established thus far is that there is some sort of vasculopathy. You still have not diagnosed whether or not this is inflammatory or not. That's a common mistake I see clinicians making. Someone will do an angiogram on someone and see vascular irregularities and say, "This is suggestive of vasculitis." All we can tell on an angiogram or any vessel imaging is whether or not there is a vasculopathy or not.

The presence of vasculitis requires either a presence of an inflammatory CSF or tissue diagnosis to support that there is some inflammation going on. Or other than that, if particularly in secondary causes, elevated inflammatory markers, other evidence of inflammatory signs and symptoms. Basically once you've established a diagnosis that now what we're dealing with is an inflammatory vasculitis, that is when you want to further decide whether or not this is now a primary versus a secondary vasculitis.

Glen Stevens, DO, PhD: When should we refer a patient to see a specific cerebrovascular immunologist like yourself?

Abbas Kharal, MD, MPH: Great question, I think particularly when we're suspecting strokes of unknown etiology, when we have vascular irregularities. Again, we're not specifically asking you must obtain CSF or demonstrate that there is inflammation. Obviously any arteriopathy, you should start thinking of whether or not this is inflammatory or not. Particularly when you have evidence of inflammatory CSF and vascular irregularities in a somewhat young person who otherwise does not fit in any of the TOS criteria of either large vessel athero or cardioembolic cause, those are the patients you should highly consider referring to a vasculitis specialist further.

Glen Stevens, DO, PhD: What percentage of these patients do you think end up getting a biopsy or requiring a biopsy?

Abbas Kharal, MD, MPH: That's an excellent question. A brain biopsy still remains the gold standard of diagnosis for cerebral vasculitis. However, to be very specific, we try to get a brain biopsy in every patient we can. However, in patients where a biopsy's either not possible or we think that the vessels involved are very focal or deep and not approachable by a brain biopsy or we may have an inconclusive brain biopsy, in those settings we try to use other adjunct diagnostic tests.

Those include particularly, in the case of a secondary systemic vasculitis, other systemic inflammatory markers, a PET CT to diagnose or assess for other systemic inflammatory stigmata. One diagnostic imaging tool that I've become a really big fan of in my clinical practice and research is vessel wall imaging. It's a great adjunct tool. Again, not something that is 100% specific, or can be used as a gold standard yet, but it is a great adjunct tool when added on to your clinical findings, your MRI brain and your vascular irregularities on whatever vessel imaging you have. When you're able to correlate that with vessel wall imaging and demonstrate inflammatory changes or concentric vessel wall enhancement in vessels that you coincidingly see focal stenotic disease in the setting of inflammatory CSF, that can really help increase the sensitivity and specificity of diagnosing a vasculitis. Again, it won't help you differentiate primary versus secondary, but it will help you establish inflammatory from noninflammatory causes.

Glen Stevens, DO, PhD: Is there a go-to area in the brain that you biopsy? Or what is required with the tissue? What do you need to get? Do you need blood vessels? You need leptomeninges? What do you need?

Abbas Kharal, MD, MPH: Yeah. So the best possible diagnostic sample would be an area where there is inflammatory arterial involvement without an established infarct yet, because oftentimes people make the mistake of getting a biopsy from an area that has already an established infarct around an inflamed vessel. Most of the time all you do is come back with just necrotic tissue. So the most ideal sample would be a non-infarcted tissue where there is vessel wall inflammation.

There have been studies showing that if you target sites with established vessel wall enhancement, you can increase the yield of your biopsy. The sample that you're looking for is a good one centimeter thick slice of tissue, which should include the meninges and the brain pragma and also contain arterial vessels as well.

Now, when we see particularly that there is mostly involvement of eloquent cortex, and we cannot biopsy that site, then if the process is seemingly diffused, particularly if you have a floridly diffused inflammatory process, then an alternative site can be the non-dominant hemisphere temporal tip biopsy, which can also be helpful in some cases.

Glen Stevens, DO, PhD: So we've made the diagnosis of vasculitis. How do we treat them?

Abbas Kharal, MD, MPH: Just like any inflammatory condition, an inflammatory vasculitis is treated with anti-inflammatories. So the first thing, once we've ruled out a secondary cause either we're treating primary CNS vasculitis, or we've identified the secondary cause and we're treating that specific secondary cause, steroids are often the first mainstay of treatment. We oftentimes start pulse dose steroids up front for three to five days, followed by an oral prednisone taper.

Once we've established that this is an inflammatory vasculitis and is responsive to anti-inflammatory treatment, then beyond that, it really depends on what the underlying cause is. So for example, primary CNS vasculitis, the most studied therapeutic approach is the use of cyclophosphamide. So we basically use, after pulse dose steroids, we induce with cyclophosphamide and continue oral prednisone along the induction of cyclophosphamide. Once we've passed through the maintenance phase, that's when we start other steroid-sparing agents.

So again, there's a little bit of difference in practices, but technically my approach is steroids and Cytoxan up front, and then once you finished the maintenance of Cytoxan, you switch over to oral steroid sparing agents like Mycophenolate, for example, and then you continue those as you've tampered off steroids. Whereas some secondary causes, for example, Giant cell arteritis, some recent literature published out of Mass General basically showed that the use of secondary hematologic agents, particularly tocilizumab for Giant cell arteritis, which is an IL-6 inhibitor, was associated with a significant reduction in relapse in Giant cell arteritis and a lower cumulative dose of steroids used over time.

Depending on basically what you're treating, sometimes there are specific agents, for example, neurosarcoid associated vasculopathy or vasculitis, steroids plus infliximab is a mainstay of choice. So steroids up front, and then depending on whether primary or secondary and what secondary cause, there are targeted therapies for several of the vasculitides.

Glen Stevens, DO, PhD: So just a couple of quick follow-up questions. If I'm going to put somebody on steroids for primary vasculitis, do I give them a gram of IV methylprednisolone or 60 of pred is fine to start for pulsing?

Abbas Kharal, MD, MPH: Yeah. So for pulsing, we usually do one gram of IV Solu-Medrol particularly these are patients who are admitted to the hospital and they're in the inpatient setting, so it's a lot easier to give them pulse dose steroids. So yes, we start off with a gram of IV Solu-Medrol for three to five days, followed by 60 of pred, and then taper them gradually by about five milligrams, every one to two weeks,

Glen Stevens, DO, PhD: Your Giant cell arteritis, do you have a lower age cutoff of where you really just don't see that anymore? Or everything's a possibility?

Abbas Kharal, MD, MPH: Normally Giant cell arteritis is rare less than 50 years of age, but again, nothing's impossible. I've seen in GCA in patients 48 years of age, but more so, more commonly, less than 50, you should really think and look at other causes first.

Glen Stevens, DO, PhD: How was your year of COVID with this group of patients? Anything new for them, change your practice, change the type of diseases you saw?

Abbas Kharal, MD, MPH: That's an excellent question. With COVID we certainly saw a rise in COVID-related hypercoagulability and associated stroke, particularly in younger patients. As you know, COVID can cause stroke by multiple different mechanisms as we know now, including COVID-induced hypercoagulability as a result of the post-COVID inflammatory response that is mounted. In addition to that, COVID also causes cytokine release as an immune response and also endothelial dysfunction as well.

So a combination of these factors certainly has led to an increase of hypercoagulability-related stroke in patients with COVID. I've also seen venous sinus thrombosis in about three patients now as a result of COVID. When we talk about patients with autoimmune diseases or inflammatory conditions with COVID, obviously being put on any of these immunosuppressive medications does automatically put you in a high risk category for catching any sort of infection, especially COVID.

So yes, my practice has really become slightly modified as to when I see someone who has not been vaccinated yet, particularly when I am thinking about starting immunosuppression on them, the goal is to try to get them vaccinated before long-term immunosuppression has started and/or at least these people who are on immunosuppression, make sure that they're taking extra precautions to try to prevent getting infected with COVID at all.

Glen Stevens, DO, PhD: So lastly, let's talk about your team and the collaborative approach. I'm sure it takes a village to look after stroke in the young with all the varied etiologies that you list. Talk a little bit about the other folks involved with treatment of stroke in the young, not just vasculitis.

Abbas Kharal, MD, MPH: Certainly. Thank you for asking that. I feel very honored and very privileged. I can say the work that I do and the ability to help patients, particularly the very complex young stroke patients that I do, I could not have done it without the support of colleagues. Particularly one, within the Cerebrovascular Center. Mentors like Dr. Hussain and Dr. Russman and others who have really showed me the ways and helped me build collaborations. Particularly what really makes my job and taking care of these patients so enjoyable is these very strong collaborations we have.

So for example, we see a lot of patients with noninflammatory arteriopathy, particularly patients who develop Moyamoya disease and ultimately require STA-MCA bypasses. Our collaboration with neurosurgery colleagues is significant on that with Mark Bain and Peter Rasmussen, and also involving the neurocritical care folks, particularly Joao Gomes in that as well.

I also see a lot of patients, obviously under the realm of young adult stroke for paradoxical embolism who require PFO closure, and we have a great relationship with cardiothoracic surgeons here at the Cleveland Clinic. We're the best in the world when it comes to cardiothoracic procedures. We have a great collaboration where before any patient undergoes PFO closure, they see both a cerebrovascular neurologist and a cardiothoracic surgeon who both agree upon whether or not that patient meets criteria for PFO closure.

As far as cerebral vasculitis, I couldn't do the work that I do without collaborations with Dr. Leo Calabrese, Rula Hajj-Ali and other colleagues in rheumatology, Adam Brown and others as well in the department. And then infectious disease colleagues also play a significant role in collaborating with us as well, particularly for infectious vasculitides and particularly also patients with neuro rheumatological diseases, patients who we see together with the sarcoidosis clinic, the SLE clinic. So as you said, it really does take a village. It takes an institution, and it takes a great team of collaborators who really have been a great part of this entire collaboration and allow us to provide the excellent clinical care and the services that we provide to our patients.

Glen Stevens, DO, PhD: Well, Abbas, thank you for joining me today. This has been most insightful. Thank you very much.

Abbas Kharal, MD, MPH: My pleasure. Thank you again.

Outro: 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.