Stroke Alert

On Episode 12 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the January 2022 issue of Stroke: “Efficacy of Intravenous Mesenchymal Stem Cells for Motor Recovery After Ischemic Stroke: A Neuroimaging Study” and “Cumulative Concussion and Odds of Stroke in Former National Football League Players.” She also interviews Dr. Mike Sharma about his article “Frequency and Patterns of Brain Infarction in Patients With Embolic Stroke of Undetermined Source: NAVIGATE ESUS Trial.” Dr. Negar Asdaghi: 1) Can repeated concussions increase the risk of stroke in professional athletes? 2) Does stem cell therapy enhance the recovery from ischemic stroke? 3) ESUS stands for “embolic stroke of unknown source.” Is ESUS just a fancy new term, or is there more to it than meets the eye? These are some of the topics that we will discuss in today's podcast. We're covering the best in Stroke. Stay with us. Dr. Negar Asdaghi:         Welcome to a new year of Stroke podcasts. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The January 2022 issue of Stroke covers a host of topics, from molecular biomarkers and drug targets in brain arteriovenous malformation to examining the role of calcium in atherosclerotic carotid disease, which I encourage you to review in addition to listening to today's podcast. Later in the podcast, I have the honor of interviewing Dr. Mike Sharma from McMaster University in Hamilton, Ontario, on his work with embolic stroke of unknown source and some of the therapies to soon be studied in this population, including the new Factor XI inhibitors. But first with these two articles. Dr. Negar Asdaghi:         Stem cells are truly the new kids on the block of therapies to potentially enhance stroke recovery. There's now four decades worth of experience with preclinical research and studies with animal models to evaluate the safety and efficacy of stem cell therapies and stroke. Now, this is a complex topic, and I will try to simplify it as much as possible. So, what are the things that we need to know about stem cell therapy and ischemic stroke? Well, first, in humans, the bone marrow has emerged as the widely used source of stem cells, primarily because of its long track record of safety profile. In fact, bone marrow derived cell populations, some examples being mesenchymal stem cells, mononuclear cells, endothelial progenitor cells, are the leading candidates for stem cell therapies in ischemic stroke. Number two, stem cells can be practically delivered to the brain through a variety of pathways. Intravenous and intra-arterial treatments have been and are currently being studied, but stem cells can also be delivered intranasally and, of course, surgically transplanted in the brain. Dr. Negar Asdaghi:         So, with these in mind, there are two recently concluded clinical trials of mesenchymal stem cells in adult stroke patients. The STARTING-2 trial, which stands for the Stem Cell Application Researches and Trials in Neurology-2, was one of those two trials. This trial evaluated the safety and efficacy of intravenous autologous, meaning from the same individual, mesenchymal stem cells in patients with moderate to severe neurological deficit originating from the middle cerebral artery territory infarct within 90 days of symptom onset. The primary results of the trial was published in Neurology very recently in February of 2021, and if you missed it, well, luckily, you are listening to the podcast today. So, here's a quick recap of the trial. Fifty-four patients were enrolled in the trial with mean stroke onset to randomization of 20 days. Patients were randomized 2:1 to either receive intravenous mesenchymal stem cell treatment or placebo. Dr. Negar Asdaghi:         Well, in terms of the primary outcome, stem cell therapy did not improve the primary outcome, which was improvement of modified Rankin Scale at 90 days after treatment. So, disappointing, but secondary analysis showed a significant improvement in lower extremity motor function in the stem cell group as compared to the control group. So, in the current issue of the journal, in the study titled "Efficacy of Intravenous Mesenchymal Stem Cells For Motor Recovery After Ischemic Stroke: A Neuroimaging Study," the STARTING-2 collaborators, led by Dr. Jungsoo Lee from the Department of Physical and Rehabilitation Medicine from Sungkyunkwan University School of Medicine in Seoul, South Korea, aimed to look at this improved motor recovery in more detail using advanced neuroimaging. So, of the original 54 patients in the trial, 44 were eligible for the current neuroimaging study. Participants underwent a variety of testings, including diffusion tensor imaging and resting-state functional MRI studies, at the time of enrollment and then 90 days afterwards. Dr. Negar Asdaghi:         So, not surprisingly, at baseline, patients in both the stem cell and control group had comparable demographics, clinical characteristics and infarct volumes, as well as similar motor function, which was measured by the Fugl-Meyer, or the FMA, score. So here's a look at their main findings. So, number one, the FMA scores that were comparable at baseline were significantly higher at follow-up in the stem cell-treated group. Number two is the interesting results; they looked at the motor pathways using diffusion tensor imaging. So, they looked at fractional anisotropy values of the corticospinal pathways and the posterior limb of the internal capsule. Now, just a quick review of a somewhat complex concept of the fractional anisotropy for our listeners. In general, FA is one of the calculated parameters in DTI with a value between zero to one, and what it does is that it defines the degree of diffusion directionality. Dr. Negar Asdaghi:         A value of zero means that the diffusion is isotropic, meaning it is unrestricted or equally restricted in all directions. A value of one means that diffusion occurs only along one axis and is fully restricted along all the other directions. So, it's easy to understand in terms of axons creating white matter tracts. When the tracts are intact, then the FA values would be high because the diffusion is occurring only in one direction as the tract is intending it to do so, whereas if the white matter tracts are damaged, then the uni-directionality of the tract would be disrupted and the molecules would diffuse freely in various directions and the FA values for that white matter tract is then, as expected, reduced. So, in the stroke model, for example, if a neuron in the motor cortex is damaged, the white matter tract related to that region will, over time, degenerate, a process which we know as Wallerian degeneration and, as such, the FA values of that tract is expected to decrease as we go from the acute to the chronic stages of stroke. Dr. Negar Asdaghi:         So, back to the current study. At time zero, FA values for the corticospinal tract and the posterior limb of internal capsule were fairly similar between the two groups, but interestingly, at 90-day follow-up, those in the control group had a significant and expected drop in their FA values, whereas those who had received stem cell therapy did not show a significant drop, meaning that intravenous administration of mesenchymal stem cells did modulate and perhaps prevented degeneration of the motor tracts after stroke. The third and final interesting finding of the study was the findings of the resting-state functional MRI. They used RS, or resting-state, fMRI as a measure of functional motor connectivity and found that stem cell treatment increased the strength of ipsilesional connectivity in the motor network and prevented a drop in the strength of intrahemispheric connectivity, whereas these findings were not seen in the control group. Dr. Negar Asdaghi:         So, what does this all mean? We now have some detailed neuroimaging evidence that indeed stem cell treatment can facilitate motor recovery possibly by reducing degeneration, which is what their DTI data showed, and potentially by leading to positive motor network organization or reorganization, which is what the resting-state fMRI findings showed. So, obviously, lots still to come in this topic and a reminder to our listeners that there are ongoing clinical trials on this topic. So, we will stay tuned as the neuroprotection and regeneration paradigm is truly changing for ischemic stroke with stem cell therapy. Dr. Negar Asdaghi:         Sports-related concussive symptoms typically resolve within a few weeks of the injury, but there is now ample scientific evidence to suggest that repeated concussion can cause long-term neurological disorders extending way beyond the short-term post-concussive period. How can traumatic brain injury, or TBI, be a cause for stroke? Well, in the more severe forms of TBI, it can actually cause damage to the large vessels and cause dissection, but there is more and more research showing that even milder trauma can lead to microvascular disruptions and even alterations in coagulation pathway, which will then increase the risk of stroke. So, how about repeated mild trauma or repeated concussion in professional athletes? Is concussion a risk factor for stroke in this population? Dr. Negar Asdaghi:         Well, in the current issue of the journal, in the study titled "Cumulative Concussion and Odds of Stroke in Former NFL Players," Dr. Benjamin Brett and Zachary Kerr from Department of Neurosurgery, Medical College of Wisconsin, and Department of Exercise and Sports Science, University of North Carolina at Chapel Hill, and colleagues report on a cross-sectional study that included professional football players who had at least played for one year in the National Football League and were over the age of 50 at the time of the study. Dr. Negar Asdaghi:         Now, before we go over the results, there are a few important definitions from this study to note. Number one, concussion was defined as a blow to the head followed by a variety of neurological symptoms, such as headache, dizziness, loss of balance, etc. Getting knocked out or being unconscious was not necessary to define concussion. For our listeners, this is an important shift from the original definition of concussion that required some alteration of level of consciousness. Number two, the participants were asked as part of the study survey about a history of stroke, which was defined as any health provider giving the participant the diagnosis of stroke at some point in their life. So, there were no mandates of any neuroimaging or particular testings to confirm this diagnosis as part of the study. So, with these in mind, 979 participants met the study inclusion criteria and were included in the study. The mean age was 65 years ranging from 50 to 99, self-reported lifetime concussion history was recorded, and the participants were then divided into five categories of zero, meaning never had experienced concussion, to those with over 10 concussions. Dr. Negar Asdaghi:         So, the first important finding was that over a quarter of their study population actually were in the over 10 concussions category. The second finding was the overall prevalence of stroke was 3.4% amongst the pro-NFL players, which was significantly lower than that expected from age-matched normative population, meaning the prevalence of stroke amongst U.S. men over age of 50. So, in simple words, being athletic is a good thing and not surprisingly is associated with a lower risk of vascular disease. But what they found was that NFL players with a history of 10 or more prior concussions had five times the odds of stroke as compared to those with no prior concussions in the adjusted models. So, what we learned from this study is that traumatic brain injury, specifically repeated TBI, however mild, seems to be an independent risk factor for stroke. Microvascular disruptions and potentially alterations in coagulation pathways have been proposed as potential mechanisms for this association. Dr. Negar Asdaghi:         About a quarter of patients with ischemic stroke do not have a clear cause for the stroke and fall under the cryptogenic or unknown category. In 2014, an international panel of experts developed a criteria to define a group of patients with cryptogenic stroke that are likely to have an embolic, but yet undefined source for their ischemic event and called them ESUS, which stands for "embolic stroke of unknown source." These were operationally defined as non-lacunar brain infarcts without significant proximal arterial stenosis or known cardioembolic sources of infarct. Now, the idea behind the development of this new term, ESUS, was to identify a more homogenous subgroup of cryptogenic stroke patients that would perhaps benefit from preemptive anticoagulation therapy over the standard antiplatelet treatment for secondary prevention of stroke. Dr. Negar Asdaghi:         Indeed, since 2014, ESUS has become a rather commonly used terminology in the stroke literature with multiple ongoing and a few already completed randomized trials examining the efficacy and safety of the newer oral anticoagulants in patients with ESUS over antiplatelet therapy. Similarly, much has been done to further study the clinical and radiographic characteristics of patients with ESUS. In this issue of the journal, in the study titled "Frequency and Patterns of Brain Infarction in Patients With Embolic Stroke of Undetermined Source," the NAVIGATE ESUS randomized control trial investigators set out to examine the radiographic characteristics and infarct patterns of ESUS patients enrolled in the NAVIGATE ESUS randomized trial. Dr. Negar Asdaghi:         Joining me now is the first author of the paper, Dr. Mike Sharma, to discuss the findings of this paper. I always say that my guest needs no introduction, and today's guest is, of course, no exception to that. Dr. Sharma is well known to our Stroke readership. He is a stroke neurologist and a scientist at the Population Health Research Institute at McMaster University in Ontario, Canada. He is truly a leader in the field of clinical epidemiology in secondary stroke prevention with an interest in randomized trials, covert stroke, and economics of stroke care. He holds the Michael G. DeGroote Chair in Stroke Prevention and is the immediate past chair of the Canadian Stroke Consortium and also leads the Hamilton McMaster Stroke Program. Good morning, Mike. It's so good to connect with you after so many years. Thanks for being with us. Dr. Mike Sharma:            Good morning, Negar. It's a pleasure to talk to you again, and thank you for that kind introduction. Dr. Negar Asdaghi:         Well, thank you so much. Can you please start us off with a brief summary of what the NAVIGATE ESUS trial set out to do, and what were the main findings of the trial? Dr. Mike Sharma:            So, in NAVIGATE, we really wanted to advance the care of patients with cryptogenic stroke. Cryptogenic has been a somewhat nebulous term for decades, and care really hasn't advanced beyond using aspirin. The problem with that term is, there is no agreed upon criteria to define cryptogenic stroke. Sometimes it means that the workup is incomplete, where there are multiple competing causes or indeed there is a disagreement as to what the cause is. So, in NAVIGATE, we took a different approach, which was to look for markers which would identify patients who had strokes which were embolic. Our feeling was that they might respond better to anticoagulation than antiplatelet therapy. So that was the main goal in NAVIGATE, was to use this construct of ESUS to test the hypothesis that anticoagulation will be more effective in preventing stroke recurrence than antiplatelet therapy. Dr. Negar Asdaghi:         And what did the trial find? Dr. Mike Sharma:            So, NAVIGATE randomized over 7,000 patients with ESUS, and it was stopped, unfortunately, at the time of the second interim analysis after about 67% of primary events had occurred. At that point in time, our mean follow-up was only about 11 months. It was stopped because there was a difference in the risk of bleeding between the rivaroxaban arm and the aspirin arm and, at that point in time, no evidence of benefit. So, the DMC reasonably halted the trial. So, at that point, we saw an excess of hemorrhage with rivaroxaban without an offsetting benefit in preventing recurrent ischemia. Dr. Negar Asdaghi:         Okay, so to recap for our listeners, NAVIGATE is an early terminated randomized trial that basically looked at the safety and efficacy of rivaroxaban over aspirin in secondary prevention of stroke in ESUS. Now, the dose of rivaroxaban used in NAVIGATE ESUS was slightly lower than the current standard of care for treatment of embolic stroke patients with known atrial fibrillation. So, you used 15 milligrams per day rivaroxaban, whereas the standard is 20 milligrams per day. Was there a reason why a slightly lower dose of rivaroxaban was chosen for the trial? Dr. Mike Sharma:            That's a great question. So, 20 milligrams a day in atrial fibrillation is approved in the U.S. I must say that many guidelines, including the AHA guidelines, suggest 15 milligrams for patients with renal impairment and creatinine clearance that is less than 50. Now, in other countries, as the label is slightly different recommending the lower dose. So, in planning this very large international trial, we had a variability in dosing and the complexity of possibly having to change the dose during the course of the trial if a patient's renal function changed. When we looked at the drug exposure between the 15 and 20 milligrams, it turns out that they were very similar. So, taking 15 milligrams, you get very close to the drug exposure with 20 milligrams. The lower dose, we felt, would eliminate the need for dose adjustments during the course of the trial and make running the trial simpler and possibly have a slightly lower risk of hemorrhage than the 20 milligram dose. So, for all those reasons, 15 milligrams was chosen. Dr. Negar Asdaghi:         Mike, I love these interviews mainly because of these valuable background information we get on trials that is otherwise impossible to easily access. Now, coming back to your current paper, the current paper in the January issue actually is an MRI sub-study of the NAVIGATE ESUS trial. Can you please walk us through the details of the current study? Dr. Mike Sharma:            Sure. You know, in NAVIGATE, in the parent trial, we included people who had embolic strokes of uncertain source, and those were operationally defined as either visible on imaging, the majority were, or having symptoms that lasted greater than 24 hours. You couldn't have atrial fibrillation, and we required at least 20 hours of monitoring. Now, 20 hours sounds like a funny time period to request. Originally, we asked for 24 hours, but it turns out that when you put a monitor on for 24 hours, it's never exactly 24 hours. It's often just slightly less. So, we had to make a practical decision as to how much was enough, and in addition, you had to have less than 50% extracranial stenosis. We didn't require imaging of the intracranial vasculature; however, if it was imaged, the stenosis had to be less than 50% to the affected area. Dr. Mike Sharma:            You needed an echocardiogram. We didn't specify a transesophageal echo. Most were transthoracic, which excluded left ventricular thrombus or left atrial appendage thrombus. People who had prosthetic mitral valves were excluded as well. So, from that population of about 7,000, our aim was to select 1,000 patients who met those criteria, but in addition had no contraindication to MRI, and the plan in the MRI sub-study was to look at what happened to covert infarcts, infarcts we didn't identify clinically during the course of the trial, if there was a treatment effect on those and also with MRI, a very sensitive, I would say, exquisite measure of hemorrhage that occurs in the brain. Because the trial was closed early, we ended up at baseline having 918 usable images and participants from 87 sites across the world, less than our original target. You know, our goal really was to see what would happen to these MRI lesions and if treatment affected them. Dr. Negar Asdaghi:         Okay. So we are talking about baseline MRIs of a subpopulation of the patients who were enrolled in NAVIGATE ESUS, and I think we are ready now to hear about your main results. Dr. Mike Sharma:            Thanks very much. I'm bursting to talk about them. You know, in spite of the fact that this was a subset of the whole ESUS population, 918 out of 7,000, roughly 13%, the characteristics of these patients was very similar to the main trial. So, I think that with the usual caveats of the subgroup, I think it's reasonable to think that what we found is representative of the ESUS population in general. The most exciting finding for us was that, so we set out to define clinically a group that would be embolic. The majority of the MRIs that we had first off had visible infarcts, and secondly, 70% of these were multiple infarcts often in multiple vascular territories. So, the clinical construct, I would say, worked. We did identify a group of patients who have embolic lesions and often proximal sources, as we see with these multiple vascular territories affected. Dr. Mike Sharma:            So, this clinical construct works really very well in identifying them. The second thing we found, which shouldn't have been overly surprising but really stood out, were the number of lesions that these people had. The ones with multiple lesions, on average, had four infarcts visible on their MRI, and these were present even in patients who did not have a previous history of TIA or stroke. So, this was their first symptomatic event, and I think that tells us a lot about what's happening in this condition. It's an embolic disease with multiple events, which seems to be very active over time, even when these lesions aren't identified symptomatically. Dr. Negar Asdaghi:         So, Mike, you've already alluded to what I was going to ask you in this question, but I want to recap and repeat for our listeners again, some very pretty impressive findings you have in the study, 93% of ESUS patients with evidence of infarcts, 70% in multiple vascular territories. What I find very interesting is that two-thirds of your patients without even a history of TIA or stroke had multiple infarcts on their neuroimaging. Does that represent to you this clinical radiographic dissociation in the ESUS population? Dr. Mike Sharma:            You know, I think that's a really great question. So, it certainly does. What we know in the number of other covert studies and some other work that colleagues have done epidemiologically is the proportion of covert infarcts. These are infarcts without clinical symptoms that have been identified as stroke, is roughly 5 to 10 times symptomatic events. And we are seeing this recapitulated in this population. Dr. Mike Sharma:            In looking across literature, I suspect that some of these and perhaps a majority had symptoms which were transient, which they didn't appreciate the significance of, or were not identified as stroke at the time. So, this is similar to what's been seen in other populations, just more striking, I think, because of the embolic nature of this condition. You know, I think this really points to the significance of identifying these patients. We expect them to continue to have these covert infarcts, and I prefer the term "covert" to "silent." Silent means it's not really having any manifestation, whereas covert indicates a hidden and nefarious purpose. So, these things do detract from cognition, from motor function, they correlate with disability and recurrent stroke. So, this condition seems to us to be very dynamic and really needs to be addressed. Dr. Negar Asdaghi:         So, striking indeed and definitely concerning findings, Mike, as you pointed out. I think it goes along with all the continuous efforts of increasing public awareness about mild or transient neurological symptomatology along the lines of what you were mentioning. For our listeners, what should be the top two takeaway messages from your study? Dr. Mike Sharma:            So, you know, I think from this study, the really important things are when you identify one of these patients where there is an infarct that you cannot comfortably identify the etiology of, please know that it is likely to be embolic often from a proximal source, but not exclusively, and that patient has an ongoing risk of recurrent infarcts, which may not present symptomatically. So, I think that what this underscores is the need to pay a very serious attention to these patients, look carefully for underlying causes, and we really do need a better treatment. Dr. Negar Asdaghi:         Fair enough. Now I want to end by something that I derived from your study, and I wanted your opinion on that. ESUS is truly proving to encompass a more heterogeneous group of ischemic stroke patients than I think previously recognized. Can you please tell us what's the future for the ESUS trials? Are you going to more elaborate on the etiology of ESUS, again truly cardioembolic versus others, and can you please share with our listeners some of the work that you are currently doing in this field? Dr. Mike Sharma:            Very exciting future, I think, for this. If you consider where we are with this condition, it's similar to where we were with mechanical thrombectomy with the early trials, which were negative but taught us a lot, and so has this one. Our approach with mechanical thrombectomy, we did two things. First, we honed in on the patient population that was likely to respond, and secondly, we improved the treatments, and I think our approach to ESUS, and this goes along with what we are doing currently, is along the same lines. So, in terms of honing down on the population likely to respond, there is now a number of interesting trials being done. One of these is ARCADIA, and I would encourage everybody to refer patients for this trial. In a post hoc analysis of NAVIGATE, we found that patients with markers of atrial myopathy, particularly a large left atrial diameter, seemed to respond to anticoagulation. Dr. Mike Sharma:            So, in ARCADIA, which is being run from Columbia University through NIH StrokeNet, is looking for patients with ESUS who have markers of atrial myopathy, randomizing to anticoagulation or aspirin. So, really honing in on a population likely to respond. The other thing that we are working on are better treatments. So, at the same time NAVIGATE was being done at our institute, we were doing COMPASS. Now, COMPASS used low dose rivaroxaban 2.5 milligrams BID with aspirin, and one of the startling findings in COMPASS was a 50% reduction in ischemic stroke occurrence in that trial. And if you think about it, emboli can be fibrin rich or platelet rich or some combination and we really don't know. So, if there is a safe dose to combine aspirin with an anticoagulant, that is a promising approach. So, currently what we are doing is a trial using Factor XI inhibitors. Dr. Mike Sharma:            Now, you know, if you think broadly across stroke prevention, we have made advances using dual antiplatelet therapy, but they seem to be hitting a ceiling in terms of efficacy with some risk of hemorrhage, and it certainly seems to be the case from NAVIGATE and also RE-SPECT ESUS, which used dabigatran, that anticoagulation by itself won't work. So, from COMPASS, we have this dual pathway approach combining anticoagulation and antiplatelet agents. The novelty here that we are pursuing is using anticoagulants, which have a much lower risk of hemorrhage. So, Factor XI, unlike Factor X, which is affected by rivaroxaban, is not involved in hemostasis, but rather amplifies thrombi, and we know that Factor XI-deficient patients have a low rate of stroke, lower than matched controls, and really no significant spontaneous hemorrhage. Dr. Mike Sharma:            So, there's a number of trials currently in DVT. We are running really the first trial ever done in stroke at phase two to develop an appropriate dose of anticoagulation for these patients. So, I think the future is going to be combining anticoagulants with antiplatelet agents to reduce these patterns of embolic stroke. Holds a lot of promise after what we saw in COMPASS, and indeed we did a similar MRI study in COMPASS, which taught us a lot about how to do these trials. So, currently, we are working on those, and the first results from two trials using Factor XI inhibition. This approach should be available to us next year. Dr. Negar Asdaghi:         So, wow, a lot of information, and we look forward to reading about all of this and perhaps collaborating with you on this. Now, Mike, one question that came up along the lines of what you were mentioning is that, what about the duration of therapy? Do you think that much like CHANCE and POINT, where dual antiplatelet therapy is beneficial for shorter period of time and not for long period of time, that you might choose that as well for ESUS patients, that a short period of anticoagulation or combined anticoagulation and antiplatelet therapy might be beneficial and then not continuing them indefinitely for this population? Dr. Mike Sharma:            You know, it's an entirely reasonable approach to consider. The problem really is what we found in the MRI study, which is that infarcts continue to occur over the long period. We have data now for about a year. But, in other trials and COMPASS, we saw it over many, many years. So, I think that if we focus on the short term, we will have success in reducing the recurrence rate, and the payoff might be a lower risk of hemorrhage, but at the cost of leaving patients vulnerable to recurrences over the long term, you know, and NAVIGATE, we saw recurrence rate of about 5% per year. So quite a significant recurrence rate of symptomatic stroke, and we won't have touched the occurrence of covert infarcts and all that means for the brain. Dr. Negar Asdaghi:         Dr. Mike Sharma, thank you so much for joining us on the podcast this morning. We look forward to covering more of your work in the future. Dr. Mike Sharma:            It's a pleasure, Negar, very nice to talk to you. Dr. Negar Asdaghi:         And this concludes our podcast for the January 2022 issue of Stroke. Please be sure to check out this month's table of contents for a full list of publications, including an organizational update from the European Stroke Conference, which highlights some of the top science presented as part of the plenary sessions at this year's meeting to give us that extra motivation to start the year. Now, speaking of motivation, starting the year, in my view, is much like running a long distance race. Anyone who has done it would tell you that this is as much about mental fitness as it is about physical fitness. So, I think it's only fitting to end the beginning of this year's podcast remembering one of America's inspirational distance runners, Steve Prefontaine. Dr. Negar Asdaghi:         As a kid, he was told that he's too short and perhaps too slow to be played in any of his school's sport teams. Later, when he became a runner, people would say that they had never seen anyone run like him, a runner who never slowed down nor paced himself. And he famously said "to give anything less than your best is to sacrifice a gift." All of 2022 is now ahead of us. Let's not sacrifice the gift. There is no time to pace ourselves, and what better way to do this than staying alert with Stroke Alert? Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org

On Episode 11 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the December 2021 issue of Stroke: “Baseline Cognitive Impairment in Patients With Asymptomatic Carotid Stenosis in the CREST-2 Trial” and “Serious Adverse Events and Their Impact on Functional Outcome in Acute Ischemic Stroke in the WAKE-UP Trial.” She also interviews Dr. Mark Parsons about his article “Stroke Patients With Faster Core Growth Have Greater Benefit From Endovascular Therapy.” Dr. Negar Asdaghi:         1) Can the presence of a high-grade asymptomatic carotid stenosis result in development of early dementia? 2) Have you ever wondered if a random poststroke urinary tract infection or hospital-acquired pneumonia can impact the 90-day poststroke outcome? 3) When it comes to the beneficial effect of endovascular thrombectomy, what is the concept of late window paradox, and why do we need to know about this and its relation with the speed of infarct growth? These are the questions that we will tackle in our December podcast. We're covering the best in Stroke. Stay with us. Dr. Negar Asdaghi:         Welcome back to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the December 2021 issue of Stroke, we have a large selection of topics, from whether adjusting antiplatelet therapies after stenting for intercranial aneurysms can potentially reduce ischemic events, to studying the outcomes of patients with reversible cerebral vasoconstriction syndrome and analysis from a nationwide study in the United States, which I encourage you to review in addition to listening to our podcast today. Later in the podcast, I have the pleasure of interviewing Dr. Mark Parsons, from the University of New South Wales in Sydney, Australia, on his work suggesting that the beneficial effect of endovascular thrombectomy may be modified based on the speed of infarct growth, from the time of symptom onset to the time when the patient is being considered for reperfusion therapies. But first with these two articles. Dr. Negar Asdaghi:         It has been suggested that the presence of chronic high-grade carotid stenosis can result in early cognitive decline, even in the absence of ischemic stroke secondary to the carotid disease. Multiple mechanisms for this decline have been proposed, including an alteration of cerebrovascular reactivity and ipsilateral hemispheric hypoperfusion. Now, if this is true, then asymptomatic patients harboring a high-grade carotid stenosis would have a lower cognitive status than their age and risk factor in matched counterparts. And this is the exact topic that Dr. Ronald Lazar from the Department of Neurology at the University of Alabama and colleagues studied in this issue of the journal, in their article titled “Baseline Cognitive Impairment in Patients With Asymptomatic Carotid Stenosis in the CREST-2 Trial.” Dr. Negar Asdaghi:         Now, a very quick recap of the CREST-2 Trial. You will recall that CREST-2 is an ongoing randomized trial of patients over 35 years of age with asymptomatic carotid disease of equal or greater than 70%. Asymptomatic is defined as absence of ipsilateral stroke or TIA symptoms within 180 days prior to randomization. Also, a reminder, that to be able to be enrolled in the CREST-2 Trial, patients had to be independent, with no diagnosis of dementia, and they were then randomized to either intensive medical management versus carotid artery stenting, or intensive medical management alone versus carotid endarterectomy. It's important to keep in mind that a secondary outcome of CREST-2 is to see whether carotid intervention over intensive medical management is better in reducing cognitive decline over time in this patient population. Dr. Negar Asdaghi:         Obviously, we'll have these results after the completion of the CREST-2 trial and its follow-up completion, but in the current study, the authors were interested to compare the baseline cognitive function of the CREST-2 candidates, and they were able to compare this baseline cognitive status to participants of the REGARDS population-based study. Now, the acronym for REGARDS stands for "Reasons for Geographic and Racial Differences in Stroke." This was a population-based study in the United States that included over 30,000 community-dwelling White and Black adults over the age of 45. So, think about the REGARDS cohort as the stroke-free participants without the high-grade carotid stenosis. Dr. Negar Asdaghi:         So, to match the two populations, the authors included only CREST-2 participants that were older than 45 years of age and did not have any prior strokes. So, that gave them a sample size of 786 patients for the current analysis with a complete neurocognitive battery of four tests administered over the phone, in the same order in both studies. So, let's go over these cognitive tests. The test included the Word List Learning Sum, assessing the cognitive domain of learning; the Word List Recall, which is a test of memory; and the two tests for executive function, Word Fluency for animal names and fluency for the single letter 'F'; and a brief screen for depression. Dr. Negar Asdaghi:         So, simply put, we have four cognitive tests assessing the three cognitive domains of learning, memory, and executive function. And depending on how the person did on each test, it gave the investigators Z scores for each participant in each category and then they compiled the Z scores in a percentile tabulation for the CREST-2 population and compared these percentiles to the normative data obtained for the REGARDS population. Dr. Negar Asdaghi:         So, what they found was that, well, not surprisingly, the population of CREST-2 had a higher prevalence of cardiovascular risk factors, things like hypertension, elevated lipids, smoking and diabetes. Slightly more than half, exactly 52% of the CREST-2 patients, had a target carotid stenosis vessel on the right side. And then they did some complex statistical models, adjusting for age, race and educational level, and then further adjusting for some vascular risk factors, such as hypertension, diabetes, dyslipidemia, and smoking, for each cognitive test, and they found that the overall Z score for patients in CREST-2 was significantly below expected for higher percentiles and marginally below expected for the 25th percentile for all four cognitive tests, as compared to the normative population. Dr. Negar Asdaghi:         For example, if they were expecting that 90% of the CREST-2 population would score in the 75th percentile for a particular test, or at 95th percentile on a different test, these percentages were significantly lower in the CREST-2 candidates. The greatest cognitive differences were detected for Word List Delay, which is a test of memory, followed with the Word List Learning, which is a test for learning. And the results really did not change when they adjusted for the vascular risk factors, and importantly, unchanged when they adjusted for right- or left-sided stenosis of the carotid, which is important, as language plays an important role in assessment of memory function. Dr. Negar Asdaghi:         So, what did we learn from this study? Well, number one, poor cognition is associated with harboring high-grade asymptomatic carotid occlusive disease, an effect that was only modestly attenuated by further adjustment for other risk factors. Number two, patients with high-grade carotid stenosis showed a significantly lower cognitive performance in the learning and memory domains. This profile of cognitive decline is different than what was typically expected to be seen in the case of vascular dementia, where abnormalities are predominately seen in the test of executive function. Number three, though we don't know the precise mechanism for cognitive impairment in the setting of carotid stenosis, cerebral hypoperfusion seemed to be the leading plausible cause as hippocampus and amygdala are known to be susceptible to hypoperfusion, and the findings of the current study show that the predominant impairment seen in patients with carotid disease seemed to be involving memory and learning. So, really important findings, and lots to still learn on this topic. Dr. Negar Asdaghi:         The occurrence of adverse events during acute treatment and within the first few weeks of acute ischemic stroke are common and can negatively influence the course and clinical outcomes of stroke patients. Serious adverse events, or SAEs, are defined as life-threatening events resulting in death or requiring hospitalization, prolongation of hospitalization, or resulting in significant disability, and they can be either neurological, such as recurrent ischemic events, hemorrhagic complications, seizure disorders, but also can include a myriad of systemic complications, including, but not limited to, occurrence of deep vein thrombosis, pulmonary emboli, cardiac arrhythmias, various infections, GI bleeds, to name a few. Dr. Negar Asdaghi:         In a setting of a clinical trial, patients are regularly and systematically monitored for SAEs, and from these studies we know that, indeed, both adverse events, or AEs, and SAEs are quite common poststroke and are reported in up to 95% of participants of prior randomized trials. Intravenous thrombolysis increased the risk of symptomatic intracerebral hemorrhage, but in general, the rate of SAEs are similar in thrombolyzed and non-thrombolyzed patients. Which clinical characteristics prone stroke patients to what type of side effects is, of course, an intriguing subject for a stroke neurologist. Similarly, it's important to know how, for example, a seemingly indirect complication of ischemic stroke, such as a hospital-acquired urinary tract infection, can potentially affect the stroke outcomes. Dr. Negar Asdaghi:         So, in this issue of the journal, Dr. Iris Lettow from University Medical Center in Hamburg, Germany, and colleagues looked at the subject in the paper titled “Serious Adverse Events and Their Impact on Functional Outcome in Acute Ischemic Stroke in the WAKE-UP Trial.” This was a post-hoc analysis of the WAKE-UP Trial, which was a multicenter randomized trial of MR-guided intravenous thrombolysis with alteplase in ischemic stroke patients with unknown time of onset. The WAKE-UP Trial included 503 patients, and they had 199 SAEs reported for 110 patients, meaning that one in five patients had at least one serious adverse event in the trial. Of those patients who did suffer an SAE, 20 patients, which was 10%, had a fatal outcome. Dr. Negar Asdaghi:         The rate of SAEs were not different between thrombolyzed and non-thrombolyzed patients. But, when they categorized the patients based on who did and who did not experience an SAE, they found that those who experienced an SAE were older, presented with more severe strokes, and were more likely to have a large vessel occlusion. But only higher age and male sex were independent predictors of development of an SAE poststroke. So, let's pause and think about these findings. This was in contrast to the previous studies, where traditionally, the severity of stroke was a predictor of complications, and importantly, the first study to identify male sex as an independent predictor of SAE, whereas, traditionally, female sex had been identified as a risk factor for development of adverse events poststroke. Dr. Negar Asdaghi:         Perhaps what we're seeing with a paradigm shift in improvement in poststroke quality of care. Now, another important finding of this study was that the presence of any SAE, whether neurological or non-neurological, resulted in reduction of favorable outcome by half and almost quadrupled the odds of poor outcome, defined as modified Rankin Scale of four to six at 90 days, even after accounting for all the known confounders. Now, the authors also looked at some interesting details. The organ most effected by serious adverse events poststroke was indeed the nervous system. Almost 50% of all SAEs were neurological in nature. This was then followed by cardiac events. Some examples would include an acute coronary syndrome, MI, various arrhythmias. And the surgical and medical procedures were the third most common category of serious adverse events in this study. Dr. Negar Asdaghi:         And what they found was that SAEs by organ of involvement had a significant association with 90-day outcomes, where any neurological serious adverse events significantly affected 90-day functional outcome poststroke. When adjusting and accounting for important variables, such as age, sex, LVO, this still remained true in terms of a predictor of outcome. In contrast, cardiac serious adverse events, infectious serious adverse events, did not have any effect on the 90-day functional outcome. Dr. Negar Asdaghi:         So, what are the top takeaway messages from this study? Number one, SAEs occur commonly poststroke, and in this particular study, occurred in one in five ischemic stroke patients. Number two, 10% of those who suffer from an SAE had a fatal outcome. Number three, nervous system disorders and cardiac disorders were the most frequent classes of side effects poststroke. And finally, patients suffering from at least one serious adverse event had a lower odds of reaching favorable outcome at 90 days. These findings emphasize the importance of dedicated stroke care, neurointensive care units, and all poststroke efforts to reduce preventable adverse events poststroke. Dr. Negar Asdaghi:         Time is an exceedingly important concept in treatment of patients with acute ischemic stroke. As an example, in a typical stroke related to a proximal large vessel occlusion, the ischemic brain loses an average of two million neurons per minute. Now, endovascular therapy is the standard reperfusion treatment for patients with acute ischemic stroke secondary to a large vessel occlusion. It is an effective treatment to restore blood flow and reperfusion to the brain and had been shown to improve outcomes in stroke patients. Dr. Negar Asdaghi:         Therefore, one would naturally anticipate that the benefits of endovascular therapy would be dramatically reduced with treatment so late. If this is true, then why is it that the beneficial treatment effect from endovascular therapy was even larger in patients treated in the late time window trials, and you will recall that these were patients included from 6 to 16 hours, or 6 to 24 hours, from their symptom onset time. This compared to treatment effects noted in patients enrolled in the early time window trials. This concept is known as the "late window paradox" and does not mean that we have to wait to provide reperfusion therapies to patients. It actually refers to those fortunate few that have robust collaterals and, as a result, have slow infarct growth, which will afford them that extra precious time to remain eligible to receive this life-saving treatment. Dr. Negar Asdaghi:         Joining me now on the podcast is Dr. Mark Parsons from the University of New South Wales in Sydney, Australia, to talk to us about the concept of infarct growth. Dr. Parsons is one of the senior authors of the study published in the current issue of the journal titled “Stroke Patients With Faster Core Growth Have Greater Benefit From Endovascular Therapy,” and will discuss how the beneficial effect of endovascular treatment may be modified by the speed of infarct growth in the early time window after symptom onset. As in every podcast, when I have the pleasure of interviewing a pioneer in the field of stroke, that my guest needs no introduction, but truly Dr. Parsons needs no introduction to our listeners. He's a Professor of Neurology at the University of New South Wales in southwestern Sydney. He's an internationally recognized leader in the field of stroke, stroke clinical trials, and brain imaging whose research has helped improve patient selection for acute stroke reperfusion therapies. It's truly an honor to have him on the podcast today. Welcome, Mark. Thank you so much for joining us all the way in Sydney on a Saturday morning. Dr. Mark Parsons:           Yes, thank you, Negar. It's OK, I have been up for a little while. So, yes, lovely to chat with you, and we haven't chatted in person for quite a long time, and I think I actually remember the last time was in Hamburg, in Germany, at a big stroke conference. I remember it quite well. We had a very pleasant evening with a group of Canadians and Australians, and I had to present a major tenecteplase study finding the next day, and I was a little bit off my game, some of my friends said, and I think that's probably your fault, Negar. Dr. Negar Asdaghi:         Mark, you did really great, and we really, truly, look forward to getting back to in-person meetings. So, let's start with the study here. Can you please tell us about the INSPIRE registry? Dr. Mark Parsons:           So, the INSPIRE registry, that's an acronym. So, it's best to spell out this acronym, so that stands for the "International Stroke Perfusion Imaging Registry." So, that was something we set up quite a while ago when perfusion CT was quite considered advanced or novel. We set that up, I think, in about 2010, and because that was obviously one of my areas of interest, perfusion imaging, we started collecting perfusion CT and CT angiography , and noncontract CT, for that matter, from our stroke patients from a number of centers in several countries. And over time, that built up to over 20 centers around the world, so predominantly Australia and China, because of the close connections that we've got there, but also one site in Canada, actually two sites now. We have so many sites that I sometimes overlook a few. Dr. Mark Parsons:           So, it is international. And what we do is, we collect prospective data from stroke patients, both clinical and their acute imaging, follow-up imaging, follow-up clinical information, and in the majority of patients, we also get three-month Rankin. So, there's now over 3,000 patients in that database with complete datasets from acute baseline imaging through to three months. And that was the dataset that we used for this current study. Dr. Negar Asdaghi:         So, Mark, this is truly an impressive registry. It is not easy to do large-scale imaging-based registries, and this is really impressive to have so many centers involved. Can you tell us about the current study population? Who did you include in the current study paper? Dr. Mark Parsons:           Firstly, we specifically looked at patients that had a large vessel occlusion, or LVO. Of course, the definition of large vessel occlusion varies a bit from place to place, but essentially, that means a clot in a proximal artery to the brain that's potentially retrievable via endovascular thrombectomy. I guess the beauty of the INSPIRE registry is, we started collecting stroke patient data well before endovascular thrombectomy was a routine treatment. We had quite a large number of large vessel occlusion patients in this study who didn't receive endovascular thrombectomy because it simply wasn't available at the time. And then, of course, with all of those big trials that came out in 2015, as you know, and beyond, with thrombectomy becoming routine at all of our INSPIRE sites and many other places around the world, we then had a, I guess, a historical cohort comparison of large vessel occlusion patients that were not given EVT and then, more recently, a cohort of large vessel occlusion patients who were treated with thrombectomy. Dr. Mark Parsons:           The non-thrombectomy patients, in the vast majority, received intravenous thrombolysis because they were in the 4.5-hour time window. I guess the only other thing, the main other inclusion criteria, was we specified that patients in this particular study needed to have a relatively small infarct core, less than 70 mL, and we can talk more about that later, if you like, and a significant area of tissue that's potentially salvageable with reperfusion, the so-called penumbra. Dr. Negar Asdaghi:         Thank you. Just to recap for our listeners, so your current study population included patients presenting early on, within 4.5 hours from symptom onset, with a large vessel occlusion, and because, as you mentioned, the study had been ongoing even before endovascular therapy became a standard of care, you have a group of patients in whom endovascular therapy was offered and you have the comparison to this group to those patients who had an LVO, large vessel occlusion, but simply received intravenous thrombolysis only. Can you now tell us about these two groups, basically, IV thrombolysis versus endovascular therapy group. What were the differences between the two groups, and what were the main clinical outcomes in your study? Dr. Mark Parsons:           Yes. We had about 400 patients in each arm. And though reasonably well matched, I mean, of course, registry, it's not randomized, so you can't have perfectly matched groups, and indeed, in the more recent era where most patients with large vessel occlusion, particularly with this small core, big penumbra on imaging, would go to thrombectomy because they had the so-called ideal target population. So, in the modern era, if patients don't receive EVT, then there's probably a good reason for that. But, essentially, they are around 70 years of age. Their NIH Stroke score was around 15, or the median score, so that's reasonably consistent with large vessel occlusion. And then if you look at the perfusion imaging, so this was all with perfusion CT in our studies, so the core volume was quite small, 15 mL, but there was quite a large range. And the median penumbra volume was actually a bit bigger in the EVT group; it was 80 versus 65 in the penumbral group. Dr. Mark Parsons:           We probably don't need to go into the details of how those core penumbral volumes are calculated, but that might be a bit over-technical for our audience, but happy to elucidate further if you want. Dr. Negar Asdaghi:         Actually, I think it's important to, just briefly, talk about how those values were measured. Dr. Mark Parsons:           Yes, OK. The other thing I should say is that, interestingly enough, we specified the 4.5-hour time window, but in fact, the median time from stroke onset to imaging was just under two hours in both groups, which is quite short. Dr. Mark Parsons:           And indeed, some of the people that are less enthusiastic about perfusion CT than I am would say, "Well, maybe measures of core are not so reliable in that early time window with perfusion CT." I would probably debate that to some degree. But, if we talked to the technicalities, there's quite a lot of data to suggest that the cerebral blood flow threshold is probably the most robust for identifying core, or at least tissue that's destined to infarct. It may not actually be infarcted at the time we measure it, particularly at two hours, but there's quite a lot of data now showing that with perfusion CT with a cerebral blood flow threshold of 30%, depending on software variations, that's a pretty accurate estimate of the final infarct in people that have rapid reperfusion fairly quickly after the perfusion CT. Dr. Mark Parsons:           So, all of these figures that we use are based on, for example, the core threshold on perfusion CT relates to, we validate that from patients, particularly that have had thrombectomy, so we know when they've reperfused. And the theory should be that if the CT perfusion core is an accurate measure of the final infarct, that there should not be much change from the baseline CT perfusion core to the follow-up infarct because there's been reperfusion not long after the perfusion scan. Now, with the penumbral volume, we use software that measures a delay time. Other software, particularly in North America, you would use a Tmax, but they're both basically direct measures of collateral flow. Dr. Mark Parsons:           So, as you know, when you have a large vessel occlusion, say, of a middle cerebral artery and in one segment, the way that blood gets to the cortex, it's typically supplied from the middle cerebral, is via retrograde flow from the anterior cerebral and the posterior cerebral via leptomeningeal collateral, so you actually get blood coming back retrograde bypassing the occlusion. And these measures on perfusion CT delay time in Tmax, actually, give you a measurement in seconds of how long it takes the blood to travel to that part of the brain. And, obviously, the longer the delay in seconds means the poorer the collateral flow. And then, typically, that means the poorer the collaterals, the less time you've got to salvage the penumbra, and the quicker the infarct core will expand. Dr. Negar Asdaghi:         Right. So, in your study, using these perfusion parameters. First, before even we come to the perfusion parameters, you found that overall, when you adjusted for all confounders, endovascular-treated patients had a better, or higher, odds of achieving good 90-day outcomes. This was not a surprising finding when you compare this population of endovascularly-treated patients to those treated with intravenous thrombolysis alone. But what was interesting was, indeed, those analyses related to infarct growth rate. Can you tell us a little bit about this concept of infarct growth rate, and you already mentioned how you measured infarct growth by perfusion imaging. Dr. Mark Parsons:           Thanks, Negar. I guess that's the novel part in it. I guess it would have been quite surprising if we didn't show that EVT was superior to IVT in the early time window. So, that certainly wasn't unexpected, that finding. But I guess the novel part of this study is this relatively new concept of infarct core growth rate. I'm not saying we're the first that's described it because, as you know, there are a number of papers in the literature and talking about the concept of slow infarct core growers versus fast infarct core growers. And you mentioned the late time window thrombectomy studies, DAWN and DEFUSE 3, which actually showed a dramatic benefit in the later time window, up to 24 hours after stroke, in patients who had evidence of perfusion core mismatch. And the concept then was suggested that the reason that these people benefited so much in that late time window was that they had very slow infarct core growth because they had great collaterals. Dr. Mark Parsons:           The treatment effect was bigger in those late time window studies than it was in the early time window thrombectomy studies, which was hypothesized might have included a lot of patients with fast infarct core growth rate, which wasn't really measured in a number of the thrombectomy studies in the early time window. We wanted to look more at, does the rate of infarct core growth have an influence on the effective treatment, with both IV and endovascular treatment? Dr. Mark Parsons:           So, the way we measured infarct core growth was pretty simple, actually. It's basically, we excluded patients with uncertain time of stroke onset because we had more than double this total number of LVO stroke patients with target mismatch, but we had to exclude the patients with uncertain time of onset, which included wake-up stroke and others. So, in this group, where there was a defined time of onset, basically, the infarct core growth rate was simply measured from the volume of the infarct core measured on perfusion CT divided by the time from stroke onset. So, just simplistically, if you've got a core of 50 mL, and it's two hours after stroke onset, then the infarct core growth rate is 25 mL per hour. That's simple, but that obviously assumes a linear core growth rate. And we based that linear model on previous studies of repeated diffusion MR imaging, which is another measure of core, that showed that the core growth rate was linear. Dr. Mark Parsons:           Now, of course, you could criticize that because I suspect, in some patients, the core growth rate is not linear. This is an estimate of core growth rate. Dr. Negar Asdaghi:         Right. So, your study actually found something quite interesting, which I really want you to go over for us and for our listeners, and that's that the beneficial effect of endovascular therapy is superior in those with a fast infarct growth rate, and was not superior, in fact not any different, in those patients who had a slow infarct growth rate. Can you walk us through that, and also tell us how that does not contradict what we've found as part of DAWN and DEFUSE with the slow infarct growers? Dr. Mark Parsons:           Thanks, Negar. It is slightly complicated, so we'll go one step at a time. So, first of all, the core growth rate varied quite a bit in this population. A number of patients, and this is because you saw that the median core in this group was 15 mL, so there was quite a large population of patients that had a core growth rate of less than 15 mL per hour. So, they're your traditional slow growers, slow core growers, who have really great collateral flow. You probably have a number of hours to save the penumbra. Now, I'm not saying that you should waste time in this group of patients, but it might be particularly relevant, for example, if you're transferring from a primary stroke center to a comprehensive stroke center. You know that you're going to have time to save that penumbra because the infarct core is going to grow slowly. Dr. Mark Parsons:           In, for example, in Australia, at least half of our thrombectomy patients come from regional or out of metro centers, where there is a significant transfer time from the primary stroke center to the comprehensive center. So, that may be a particularly important finding to look at in the future for longer transfer times from primary to comprehensive stroke centers. So, then, at the other end of the scale, we had a proportion of patients who had what we call a fast core growth rate of more than 25 mL per hour. And then there were people in the middle between 15 and 25 who we called sort of moderate core growth. So greater than 25 mL per hour was a fast core growth. Dr. Mark Parsons:           We categorized it into those sort of three categories. Again, that's a bit arbitrary, but the reason we did that was that if you look at the IVT group alone, those who had slow core growth rate, less than 15 mL per hour, their rates of good outcome, so a Rankin 0 to 2, so getting back to close to normal function at three months, their rates of a good outcome were almost 60% in the slow core growth rate with IVT. Then, if you go to the other end of the scale with fast core growth with intravenous therapy, the rates of good outcome in that group were only 30%. So, there was a clear decline in terms of three-month good outcomes with intravenous thrombolysis versus core growth rate. So, as the core growth rate increased, the chances of good outcome with intravenous thrombolysis decreased. Dr. Mark Parsons:           Then, if you looked at the EVT group, it was quite interesting that this core growth rate effect had minimal impact on the outcome of the EVT patients. So, in the EVT patients with slow core growth rate, less than 15 mL, the rates of good outcome at three months were, again, close to 60% and identical to the IV therapy group. But, at the other end of the scale, with fast core growth rate above 25 mL with the EVT group, they had a much higher rate of good outcome compared to the IVT group. Their rates of good outcome were around 45%. So, they are a little bit lower than the slow core growers with EVT, but there wasn't much drop-off with core growth rate, and there was a significant increase in good outcomes in the EVT group who had fast core growth compared to the IVT group. Dr. Negar Asdaghi:         So, I just want to summarize this so that I understand it and, of course, want to make sure that it's simplified also for our listeners. So, you found that those people, and it should be noted these are all within the first 4.5 hours. Dr. Mark Parsons:           Yes. Dr. Negar Asdaghi:         So, we understood in that time frame. Those people who had a fast growth rate, they had the greatest benefit from endovascular therapy in this time frame. And those people who had the slow growth rate, that is defined in your study as less than 15 cc per hour, they actually had a similar benefit from endovascular therapy as they did with intravenous thrombolysis. Did I summarize that? Dr. Mark Parsons:           Yes. That's correct. Dr. Negar Asdaghi:         So, Mark, how do you explain this from a pathophysiological standpoint? Dr. Mark Parsons:           Fortunately, there's a relatively simple explanation. So, because of the way that we set up INSPIRE, we collected follow-up infarct volumes as well. From the time window for follow-up infarct measurement was a little bit variable, but it was around 48 hours after stroke onset. In this group of patients, we actually were able to measure final infarct volume and essentially, in the slow core group, so less than 15 cc growth per hour, in that group, with both IVT and EVT, there was minimal infarct growth by the time we measured it at 48 hours. So, both therapies basically led to minimal infarct growth after the treatment, whereas in the fast core growth group, more than 25 cc per hour, the IVT group had much greater infarct growth by 48 hours, about 40 or 50 mL more, on average, than the EVT group. Dr. Mark Parsons:           I guess also, to explain that a touch more, if you look at the slow core growth EVT group versus the fast core growth EVT group, there was still more infarct growth in the fast core growth rate. And this is because you measure the core at a certain time on the CT or the MR. And then, even with the very best system, you're not going to get reperfusion with EVT for at least 30 minutes after that because you have got to get into the angio lab, you have to puncture the groin, and you have got to get up there, and you have got to pull the clot. So, even if you get complete perfect circumstances, it's still usually at least a 30- to 60-minute delay between the perfusion CT and when you're fully reperfused. Dr. Mark Parsons:           But the theory should be, if there's a minimal delay from the perfusion CT to reperfusion, the core at that time should be identical to the follow-up, final infarct volume. And that's what we actually found in the slow core group. It was almost the same. The interesting thing was, it was the same in both IVT and EVT, which basically, we don't know for sure, because we don't know exactly when the IVT group reperfused, but it probably means that because the core growth is so slow in this group, even if you reperfuse later with IV therapy, which we know is the case, often with IV thrombolysis the recanalization is a bit slower than with EVT, so even if you've got delayed reperfusion, if you've got slow core growth rate, you may not get much infarct expansion at all, whereas if you've got fast core growth rate, getting reperfusion as quickly as possible after your CT is crucial to limit subsequent infarct growth before reperfusion. And that's exactly what we found in the fast core growers, that EVT substantially limited that subsequent infarct growth and led to better clinical outcomes as well. Sorry, again, that was a long explanation. Dr. Negar Asdaghi:         Mark, but these are really important findings, and as you alluded to earlier, I believe that they have major implications in how the systems of care are organized and our transfers are going to be decided upon in the future. We have a few minutes before we end the podcast here, and I want to ask you, do you think it's fair to have a similar concept that's studying the infarct growth rate in the late time window, especially in the sort of past 12 hours time window in the future? Dr. Mark Parsons:           Yeah, it's a fascinating question, Negar. In fact, we do have a paper somewhere under review. I think Stroke might have knocked it back. Anyway, but it's actually looking exactly at this concept, but the fascinating thing is, in the late time window, you see very few true fast growers because they actually present early. This is what the paper under review is talking about. So, in fact, most people that you see with a favorable imaging pattern in the late time window, such as DAWN and DEFUSE 3, the core is relatively small. In patients with fast core growth, by the time you get to six hours, you've got a massive core and no penumbra, so they are typically not offered endovascular therapy because there's no salvageable tissue and there's already lots of damage, even on the non-con CT. Dr. Mark Parsons:           So, it would be actually really interesting to look just at the late time window, and I'm sure others are doing that, too, but I suspect what we'll find is that the distribution of core growth is pretty narrow. It's mostly the slower core growers, and it's very clear that most of the really fast, and we're actually looking at this now in people with large infarct core over 70 mL, in fact, they present, the ones that we've got at least, present very early. So, it'll be a fascinating area to look at, for sure. Dr. Negar Asdaghi:         Mark, it is definitely fascinating. We look forward to covering that paper, hopefully in our future podcast. But I want to leave you, reminding you that I'm a mild stroke person, so I am definitely interested in looking at these slow grow rate infarct patients because there are also, as you know, some studies suggesting that the slow growth infarct actually can happen sub-clinically on only a radiographic basis, and especially important in the mild group patients. But, we are out of time. Professor Mark Parsons, thank you so much for joining us all the way from Sydney, and it's been a pleasure interviewing you. Dr. Mark Parsons:           Thank you, Negar. Lovely to chat and hope to see you very soon in person. Dr. Negar Asdaghi:         Thank you. Dr. Negar Asdaghi:         And with that, we end our podcast for the December 2021 issue and close the first year of the Stroke podcast. A year ago, Dr. Ralph Sacco, the Editor-in-Chief of Stroke, approached me to talk about the importance of starting a podcast for Stroke as an accessible means to highlight the great work published in the journal, and also introduce me to the amazing Stroke editorial staff. Dr. Negar Asdaghi:         One year, hundreds of reviewed papers, and 11 podcasts later, from missed deadlines to late night emails, early morning texts, and weekend recordings, our podcast has become a bit more than just a quick review of the literature. It has truly become our podcast family. Overcoming the time differences and impossible schedules, you made time to interview with us, listen to us, and work with us as we reached out to researchers across the globe who contributed to this journal and to the podcast. Lots of laughter and a few tears. Like every family, ending the year reminds us of some good times and, of course, the difficult times. Dr. Negar Asdaghi:         So, I want to end our final podcast of the year with a topic that we haven't really covered in our journal, but I think may sprinkle some magic on your holiday season, and that's the topic of quantum biology. Wrapped in mysticism with a pseudoscientific flavor, physicists, neurologists, anesthesiologists, and philosophers have been hard at work deciphering whether consciousness may have similar properties to quantum particles. From superposition to entanglement and coherence, is it possible that your mind may have something to do with the epigenetics, up and down regulation of genes and presentation treatment and, importantly, outcome of various medical or neurological disorders? Now, even if this was proved to have a low scientific validity, as a stroke scientist, isn't it amazing to be working in the one field that ensures the brain, which is the home of consciousness, remains healthy? So, let's think about the power of consciousness in altering the outcome of medical conditions with our ever-excitement to stay alert with Stroke Alert. Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 10 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the November 2021 issue of Stroke: “Biomarkers of Coagulation and Inflammation in COVID-19–Associated Ischemic Stroke” and “Treatment-Associated Stroke in Patients Undergoing Endovascular Therapy in the ARUBA Trial.” She also interviews Dr. S. Claiborne Johnston about “Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack.” Dr. Negar Asdaghi: 1) What is the net ischemic benefit derived from combination of ticagrelor and aspirin treatment in patients with mild ischemic stroke or transient ischemic attack? 2) Is the ischemic stroke in patients hospitalized with COVID-19 associated with the rise in biomarkers of inflammation and coagulopathy? 3) What are the characteristics associated with periprocedural stroke in patients treated endovascularly for an unruptured AVM? We'll discuss these topics and much more at today's podcast. Stay with us. Dr. Negar Asdaghi:                        Welcome back to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the November 2021 issue of Stroke, we have a large selection of topics, from peanut consumption reducing the risk of ischemic stroke, and the decline in the rate of progression of coronary atherosclerosis in patients on a Mediterranean diet, to how the efficacy of endovascular thrombectomy diminishes in patients with more pervious thrombus composition, which I encourage you to review in addition to our podcast today. Dr. Negar Asdaghi:                        Later in the podcast, I have the distinct honor of interviewing Dr. Claiborne Johnston from Dell Medical School at UT Austin on his latest work with data from the THALES trial to clarify the net ischemic benefits derived from a combination of ticagrelor and aspirin therapy in comparison with the risks of hemorrhage associated with this treatment in patients with mild and moderate stroke and TIA. But first with these two articles. Dr. Negar Asdaghi:                        COVID-19–associated ischemic stroke, or CAIS, is a new term that, unfortunately, stroke physicians need to be familiar with. While acute ischemic stroke can occur in parallel from, say, traditional causes of stroke in patients infected with coronavirus, ischemic stroke and other thrombotic events, such as myocardial infarction, pulmonary embolism, deep vein thrombosis, and acute limb thrombosis, can occur in the setting of overt hyperinflammation and subsequent coagulopathy that is observed in patients hospitalized with severe COVID-19 illness. Dr. Negar Asdaghi:                        Elevated D-dimer, although quite non-specific, has emerged as a marker of COVID-19–associated coagulopathy, but whether an elevated D-dimer in isolation or in combination with various other inflammatory and coagulation markers is associated with development of acute in-hospital ischemic stroke in those hospitalized with COVID is not known. Dr. Negar Asdaghi:                        So, in the current issue of the journal, in the article titled "Biomarkers of Coagulation and Inflammation in COVID-19–Associated Ischemic Stroke,” Dr. Charles Esenwa from the Department of Neurology at Montefiore Medical Center and colleagues did an interesting analysis of over 5,000 patients with COVID-19 who were admitted to one of the Montefiore Health System hospitals between March 1, 2020 and May 8, 2020. This was a retrospective analysis, so they had to work with the available biomarkers for each patient and use a machine learning cluster analysis of these biomarkers to divide the patients basically based on five biomarkers to four clusters. Dr. Negar Asdaghi:                        The following five biomarkers were chosen by this machine learning cluster analysis. These included CRP, D-dimer, LDH, white BC, and PTT. So, they had to come up with some arbitrary rules to exclude biomarkers that were either missing in over 30% of their population, and they also excluded those patients that were hospitalized for a long period of time, and they chose a 30-day hospitalization and over. And they also only used the first reading for each biomarker. Again, these were arbitrary rules that were set forth by the authors, and they found some alarming findings. When they clustered patients based on similarities in these biomarkers, they came up with predicted models for combined thrombotic events and acute ischemic stroke. Dr. Negar Asdaghi:                        For example, in the cluster where the patients had the highest mean values for CRP, D-dimer, LDH, and white BC, and a relatively low PTT, these patients had the highest prevalence of acute ischemic stroke. They had the highest prevalence of in-hospital strokes and severe strokes and highest percentage of total thrombotic events. In contrast, the cluster with the lowest mean of all of these five biomarkers had no cases of in-hospital acute ischemic strokes; they had the lowest prevalence of composite, all thrombotic events, and patients had the least severe complications. Dr. Negar Asdaghi:                        So, they also tested the effects of biomarkers individually for prediction of acute ischemic stroke. And it turns out that when they used a lone marker, only D-dimer again was associated with acute ischemic stroke. Very interestingly, D-dimer was specifically elevated in those COVID-19 patients in whom the stroke was ultimately classified as cryptogenic. Dr. Negar Asdaghi:                        So, what does that mean? That means that it's more likely that a stroke had occurred in the setting of severe COVID-19 hyperinflammatory response, and less likely associated with other classical causes of stroke. Dr. Negar Asdaghi:                        So, what did we learn overall from this study? Well, hospitalized COVID-19 patients with a combination of high CRP, D-dimer, LDH, and white BC, and slight reduction in their PTT, had a 4.5-fold increase in the risk of in-hospital mortality and a fivefold increase in the risk of in-hospital stroke as compared to the COVID-19 patients with the lowest mean values for all the five biomarkers mentioned above. So, important information to keep in mind as we treat hospitalized COVID-19 patients, and we await more prospective data on this topic. Dr. Negar Asdaghi:                        Arteriovenous malformations, or AVMs, are congenital vascular lesions that are associated with long-term excess mortality and morbidity, essentially almost all related to their risk of intracerebral hemorrhage. Roughly half the patients with brain AVMs present with intracerebral hemorrhage, resulting in a first-ever hemorrhage rate of about 0.5 per 100,000 person years. Dr. Negar Asdaghi:                        Annual risk of hemorrhage is estimated at 1 to 4% for all comers with AVMs, but varies significantly, and can be as low as 0.9% in patients with unruptured, superficially located brain AVMs with superficial drainage, but may be as high as over 34% in patients with ruptured, deeply seated brain AVMs with deep venous drainage. So, treatment would entirely be dependent on the type of presentations and characteristics of each patient with an AVM. Dr. Negar Asdaghi:                        Whether unruptured AVMs should be managed clinically or treated either endovascularly or surgically is the subject of the ARUBA trial that is a randomized trial of unruptured brain AVMs. The enrollment of ARUBA was halted by the study's DSMB board, but medical management was found to be superior to treatment arm for the primary outcome of symptomatic stroke and death. Dr. Negar Asdaghi:                        Since then, there's been a lot of focus in the literature and comparison of outcomes between treated and untreated patients with unruptured AVMs, but less has been published on characteristics of patients who suffered from periprocedural stroke, an important part of the primary outcome of ARUBA. So, in the current issue of the journal, we have the study titled “Treatment-Associated Stroke in Patients Undergoing Endovascular Therapy in the ARUBA Trial.” Dr. Negar Asdaghi:                        Dr. Joshua Burks and colleagues from the Department of Neurosurgery at the University of Miami and colleagues evaluated 64 patients with unruptured AVMs enrolled in the ARUBA trial who underwent endovascular treatment as part of the trial and looked at the characteristics of those who suffered a perioperative stroke, defined as a stroke recorded at or within 48 hours of intervention, as this would represent a direct procedure-related complication rather than sequelae of, say, treated or partially treated AVM itself. Dr. Negar Asdaghi:                        All patients who initiated endovascular intervention, including attempted interventions in cases where therapy was aborted secondary to technical or anatomical limitations, were included regardless of randomization or subsequent withdrawal from the study beyond 48 hours following the intervention. So, what they found was that 16% of interventions resulted in stroke, 11% hemorrhagic, and 5% ischemic strokes. And they had no perioperative mortality, which is good news. Dr. Negar Asdaghi:                        In univariate analysis, they found many factors that were more commonly seen in patients that suffered from perioperative stroke as compared to those who did not have a stroke perioperatively. Those factors included, for instance, female sex. Over half of these patients were female. Close to half were enrolled in France. And over 40% of those who suffered a stroke in the perioperative timeframe had Spetzler-Martin grade two AVMs. Dr. Negar Asdaghi:                        When they accounted for all confounding variables, they found that endovascularly treated unruptured AVMs that are supplied by the posterior cerebral artery cortical feeders and those with Spetzler-Martin grade two and three had a higher perioperative stroke risk as compared to their counterparts without these characteristics. Interestingly, there are also significant geographical disparities in the risk of stroke in that patients treated in the United States or Germany had a significantly lower stroke risk than patients treated in other countries. Dr. Negar Asdaghi:                        So, what did we learn from this study? There are patients and lesion characteristics that increase the risk of stroke associated with endovascular treatment of unruptured AVMs. The current study suggests that AVMs with cortical arterial feeders from posterior cerebral artery and those with grade two and three Spetzler-Martin were associated with a higher risk of procedural and periprocedural stroke. Dr. Negar Asdaghi:                        And very importantly, as with every surgical intervention, the risk of a procedure is operator-dependent, as well as center-dependent. And these are important factors to keep in mind as technology evolves and more treatments become available to decide whether to keep or to refer patients with unruptured AVMs to a more experienced center. Dr. Negar Asdaghi:                        Patients with mild ischemic stroke and transient ischemic attack are at high risk of having recurrent ischemic events, especially in the immediate aftermath of their symptom onset. Early diagnosis and initiation of secondary preventive measures, such as antiplatelet or anticoagulation therapies, in the appropriate setting considerably reduce this recurrent risk. Dr. Negar Asdaghi:                        Multiple randomized trials have shown that as compared to treatment with a single antiplatelet agent, dual antiplatelet treatment is more effective in reducing the risk of stroke and other major vascular events in the TIA mild stroke population, a benefit that comes with an expected increase in the risk of hemorrhage. Dr. Negar Asdaghi:                        THALES trial is one of the latest trials to determine the efficacy of dual, which is combination of ticagrelor and aspirin, versus mono-antiplatelet therapy, that is aspirin alone, in eligible patients with non-cardioembolic acute ischemic stroke and TIA. Now, it's important to keep in mind that the primary outcome of THALES is a composite of stroke or death, which included both ischemic and hemorrhagic events. Dr. Negar Asdaghi:                        Now, it's important to understand that while in the setting of a clinical trial, combining the risks associated with dual antiplatelet therapy, which is hemorrhage, and the potential treatment benefit, that is reduction of recurrent ischemic events, is appropriate as part of the outcome selection. In routine practice, this type of primary outcome can obscure the actual trade-offs between the benefits of dual antiplatelet treatment and its inherent hemorrhagic risk. Dr. Negar Asdaghi:                        So, in this issue of the journal, in the study titled "Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack," the THALES investigators led by Dr. Claiborne Johnston sought to separate the ischemic benefits of combination of ticagrelor and aspirin therapy from its hemorrhagic risks in patients enrolled in the trial. Dr. Negar Asdaghi:                        I'm joined today by Professor Johnston to discuss the findings of this paper. Dr. Johnston absolutely needs no introduction to the stroke community and our readership. He's a Professor of Neurology at Dell Medical School at the University of Texas at Austin. He's a leader in the field of cerebrovascular disorders, has served as the primary investigator of multiple randomized trials and large prospective studies to evaluate the preventive treatment outcomes in TIA and mild stroke, and has pioneered the development and validation of predictive models for recurrent stroke in this population. He's authored over 700 peer-reviewed manuscripts, has won several awards for research and teaching, and is recognized for his leadership in the field of medicine and healthcare. Dr. Negar Asdaghi:                        Good morning, Clay. We're delighted that you could join us on the podcast. Dr. S. Claiborne Johnston:           Well, thank you. It's wonderful to be here. Thank you for having me. Dr. Negar Asdaghi:                        Thank you. So, THALES is an exciting new addition to the most recent trials of dual antiplatelet therapy that studied mostly the role of clopidogrel and aspirin combination therapy. Can you please start us off by telling us why did we need a new trial in a very similar patient population? Dr. S. Claiborne Johnston:           Well, the primary reason was, yes, clopidogrel works in combination with aspirin in the setting, but clopidogrel is actually a prodrug. It requires conversion in the liver to its active form. And polymorphisms in CYP2C19 and Cyt P450 pathways are really common and associated with an inability or limited ability to convert that prodrug into its active form. So, there are a number of people who may not benefit much, if at all, from clopidogrel. So, it's kind of surprising that it works as well as it does. Dr. S. Claiborne Johnston:           Ticagrelor doesn't have that problem. It's not a prodrug. It acts directly on the P2Y12 inhibitor. And so, the hope was that we would have a more consistent and pronounced effect on risk reduction in patients after TIA and mild to moderate strokes. Dr. Negar Asdaghi:                        Primary efficacy outcome in THALES was different from the primary efficacy outcome chosen for the POINT trial, that was major ischemic events and death from ischemic vascular events, and that of the CHANCE trial, that was a combination of ischemic and hemorrhagic strokes in 90 days. Can you please tell us about the thought process behind choosing this particular primary efficacy outcome in THALES? Dr. S. Claiborne Johnston:           Yeah, so this was encouraged by the regulatory authorities. And so the primary efficacy outcome in THALES is all stroke, hemorrhagic and ischemic, and all death, hemorrhagic and ischemic. And we teased apart just the ischemic etiologies in POINT. Dr. S. Claiborne Johnston:           The rationale was that we were including all the major outcomes that the drug could impact. The problem is that people forget that it includes hemorrhagic events, and then they weigh that efficacy outcome against the safety outcome. And so there's confusion. There's sort of double-counting of safety elements in doing that comparison. Dr. Negar Asdaghi:                        Okay, great. And now, before we hear about how you disentangled the two safety and efficacy outcomes, can you please remind our listeners about the primary results of THALES, which was published obviously a few months ago? Dr. S. Claiborne Johnston:           Yeah, sure. So, it showed that the combination of ticagrelor and aspirin works. It reduced the stroke and death by about 17% over the 30-day period of treatment. So robust effect. There were some increased hemorrhages, and looking at severe hemorrhage as defined by the GUSTO definition, there was almost a fourfold increase, but it was tiny in absolute terms of 0.4% increase. Dr. Negar Asdaghi:                        Okay. So, now it's very important, as you mentioned, this disentangling of recurrent ischemic, again, safety from efficacy outcomes. Your current study that is published in the November issue of Stroke clarified these results. And we're excited to hear about those results. Dr. S. Claiborne Johnston:           That's right. So, there were two problems with the way people have interpreted the results of the THALES trial. One is this entanglement of safety events and both efficacy outcome and the safety outcome. The other was the use of relative risks as opposed to absolute risks, because a high relative risk for a rare event is less important than a small relative risk for a more difference between more common events. And so we wanted to deal with both of those issues. Dr. S. Claiborne Johnston:           So, we defined new outcomes that were not entangled. So, we defined major ischemic events, similar to what we had done in POINT, and then we defined major hemorrhage as being basically irreversible hemorrhage, and compared outcomes in the two groups. And what we found was that when we did it that way, for every 1,000 patients treated, we avoided 12 major ischemic events and produced three major hemorrhages. So, about a four-to-one ratio of ischemic benefit to hemorrhage risk. And that was true at various cutpoints for disability. Dr. S. Claiborne Johnston:           So, if we said, "Okay, yes, you had an event, and are you disabled at last follow-up at 30 days?" Then if we said that, there was also a four-to-one difference in disabling events, ischemic versus hemorrhagic. And if we said a two or greater, so moderate disability or worse, it was the same ratio, four-to-one. Dr. Negar Asdaghi:                        Okay, so four-to-one ratio of benefit. That's an important number to keep in mind. Also reassuring to see that this net clinical benefit or net clinical impact of the combination of therapy was practically the same across all the pre-specified subgroups in the trial. Were you at all surprised by the subgroup analysis? Dr. S. Claiborne Johnston:           Well you know if you do enough subgroup analyses, you're going to find differences, right? And thankfully, we have the looking at interaction terms to keep us honest, but even so, you look at 20 and you're going to have some significant interaction terms, as well. But yeah, it was reassuring that the effects were so consistent across groups. Dr. S. Claiborne Johnston:           I think there's been a tendency to over-interpret results from subgroup analyses. We don't have any evidence to suggest that we should be doing that here. I'm sure we can pick out groups that do better, and we've done that actually. The group with atherosclerosis does particularly well, but is that a chance event or is that real? I think we just have to be super-cautious about subgroup analyses. Dr. Negar Asdaghi:                        So, absolutely. One of the subgroups that I'm personally very interested in is just the time subgroup. So, all of the patients in THALES were enrolled within the first 24 hours, and the subgroup analysis did not show that there were any differences in terms of the net benefit between those that were enrolled earlier, within the first 12 hours, and those that were enrolled later, between 12 and 24 hours. But in routine clinical practice, we often see patients with TIA and mild stroke actually presented to us later than that timeframe entirely. Should we be giving them dual antiplatelet treatment? Dr. S. Claiborne Johnston:           That's a great question. So, we did an analysis in POINT where we modeled out, would we still have an important significant net benefit if we had started the trial later? And we didn't start the trial later, right? So, this was just pretending like anybody who had an event early on was not in the study in starting at a later timepoint and modeling that out. And basically what we found was that for out to three days, there was still a benefit. And, in fact, if you look at that data and look at those tables, you could even say, even out to five days. Dr. S. Claiborne Johnston:           I would say it's not unreasonable to do that given that the risks are so small and they're going to be even later with later treatment. But I would say, too, that even though we're not seeing greater impact within that first 24 hours versus 12 to 24, it just makes sense with event rates being as great as they are early on that if you don't treat with a preventive medication before an event occurs, it doesn't work. So, it just makes sense that as much as possible we ought to treat people as early as possible after their events. Dr. Negar Asdaghi:                        Very important findings and things to keep in mind. I want to ask you about the top two takeaway messages from the study. Dr. S. Claiborne Johnston:           One is that there's a favorable benefit-to-risk ratio for ticagrelor/aspirin in mild to moderate actually ischemic stroke and high-risk TIA from THALES. So that would be number one. Dr. S. Claiborne Johnston:           And then number two is watch your endpoints carefully. Think carefully, too, about whether balancing safety to efficacy events really makes sense and also whether focusing on relative risks really makes sense. I would encourage us, even though our journals tend to push us towards relative risks and we're more familiar with those, I'd encourage us to get more comfortable with using absolute risks in the way we look at data, but also in the way we talk to patients about their impact. Dr. Negar Asdaghi:                        Fair enough. I remember a few years ago, you visited us here at the University of Miami to deliver the annual Cerebrovascular Scheinberg Lecture. And you had mentioned that the idea of dual antiplatelet therapy treatment of patients with TIA mild stroke had come to you many years back when you were still in training, but it took many years for that idea to turn into reality, into randomized trials, and now translated into clinical practice. Dr. Negar Asdaghi:                        At the time, if you recall, this was right before you went to Europe to present the primary results of POINT at the European conference. And the trial results were not publicly available, so you were sworn to secrecy. You couldn't tell us about the results. It's been a few years since then. You've already completed yet another trial on this topic. Can I ask what's next for you and your team as it pertains to acute treatment of patients with TIA and mild stroke? Dr. S. Claiborne Johnston:           Well, there are a few things. So, CHANCE-2 is a really interesting trial. My role in that was peripheral, just really advisory, but it's an exciting trial. So, basically it's looking at people with those CYP2C19 polymorphisms that I mentioned before, people who don't rapidly and readily convert clopidogrel to its active form, and randomizing them to clopidogrel versus ticagrelor. Dr. S. Claiborne Johnston:           So, it's going to give us some head-to-head data on the two drugs and the people who may benefit the most from ticagrelor. And that is complete, and that will be published in the next few months. So, I that's going to be an important trial in people's thinking about how best to approach these patients. Dr. S. Claiborne Johnston:           The second is, you know, we're not done. We still have a 5% risk of events, even in those three dual antiplatelet therapy. And so we need more agents. And we need to think about secondary prevention extending to other groups as well, just as you said, longer periods of time, more severe strokes, people after thrombolysis/thrombectomy. Those are big groups of patients at extreme risk for secondary events, and we have no agents and no data right now. Dr. S. Claiborne Johnston:           I would be concerned about dual antiplatelet therapy in those patients, just given what we've seen about the risks of hemorrhage in the existing groups, which are again manageable and shouldn't change people's decision about treatment. But for the groups I just mentioned, risks of hemorrhage start to get greater. And so one worries about whether dual antiplatelet therapy's the right thing or whether other agents make more sense. So, yeah, we're interested in looking at other agents, some novel, for those other indications as well. Dr. Negar Asdaghi:                        Professor Johnston, thank you for your time, and we look forward to covering more of your research in the future. Dr. S. Claiborne Johnston:           Well, thank you. It's been a pleasure. Dr. Negar Asdaghi:                        Thank you. Dr. Negar Asdaghi:                        And this concludes our podcast for the November 2021 issue of Stroke. Please be sure to check out the November table of contents for a full list of publications, including two important topical review articles, one on thrombus composition after thrombectomy, and one on pearls and pitfalls of perfusion imaging in acute ischemic stroke, as advanced neuroimaging continues to play a critical role in decision-making for acute stroke therapies. Dr. Negar Asdaghi:                        Now, speaking of advanced neuroimaging and the immense role that neuroimaging plays in our day-to-day practice, let's take a moment as we end our November podcast to remember how the concept of medical imaging first began over 120 years ago with the discovery of X-ray by German professor of physics Wilhelm Röntgen. Dr. Negar Asdaghi:                        On Friday, November 8, 1895, while experimenting with electricity, Röntgen accidentally discovered a new kind of rays that he referred to as X-rays. He soon realized that X-rays were capable of passing through most substances, including the soft tissues of the body, but left bones and metals visible. Dr. Negar Asdaghi:                        One of his earliest photographic plates of his experiments was a film of his wife Bertha's hand with her wedding ring clearly visible. This was the first time that the inside of human body was seen without performing surgery. Dr. Negar Asdaghi:                        From Röntgen’s first X-ray image to the advanced neuroimaging that we review today on our portable devices, I can't help but wonder, what will your accidental discovery on a Friday fall afternoon in November do to advance the field of science and stroke 100 years from now, as we continue to stay alert with Stroke Alert. Dr. Negar Asdaghi:                        This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 9 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the October 2021 issue of Stroke: “Endovascular Therapy of Anterior Circulation Tandem Occlusions” and “Automated Perfusion-Diffusion Magnetic Resonance Imaging in Childhood Arterial Ischemic Stroke.” She also interviews Dr. Sepideh Amin-Hanjani about her article “Outcome Following Hemorrhage From Cranial Dural Arteriovenous Fistulae.” Dr. Negar Asdaghi: 1) Should perfusion imaging be incorporated into routine neuroimaging for stroke-like presentation in the pediatric population? 2) Is performing emergent cervical carotid stenting beneficial in patients undergoing endovascular thrombectomy for a tandem occlusion? 3) What are the outcomes of patients with intracranial hemorrhage secondary to dural AV fistula? These are the questions that we will answer in our podcast today. Stay with us. Dr. Negar Asdaghi:                        Welcome back to Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the October 2021 issue of Stroke, we have a comprehensive list of publications, from studying the role of C-reactive protein in outcome prediction after subarachnoid hemorrhage to studying the association of over 81 classes of routinely prescribed drugs with the risk of ischemic stroke, which I encourage you to review in addition to our podcast today. Later in the podcast, I have the pleasure of interviewing Dr. Sepideh Amin-Hanjani on her work with outcome prediction in patients with dural AV fistula–related intracranial hemorrhage. But first, with these two articles. Dr. Negar Asdaghi:                        Between 10-20% of patients with an anterior circulation large vessel occlusion have tandem occlusions. That means that they have a concurrent cervical carotid occlusion or significant stenosis in addition to their target intracranial occlusion. Performing endovascular therapy for a tandem occlusion is often difficult, providing technical and access challenges for the operator. Dr. Negar Asdaghi:                        In practicality, we have two options for carotid treatment in the acute setting. One option is doing nothing, or do carotid angioplasty predominantly to gain access to that target intercranial occlusion. But the second option is to do an emergent carotid stenting. Currently, we have two ongoing clinical trials to assess the very question of whether emergent cervical carotid stenting is an option in tandem occlusions. One is the ongoing TITAN trial out of France, and the second one is a Canadian trial, Endovascular Acute Stroke Intervention - Tandem OCclusion Trial, or EASI-TOC. Dr. Negar Asdaghi:                        And while we await the completion of these trials, the treatment option for cervical carotid remains a contentious subject. Though performing emergent cervical ICA stenting is feasible, the opponents of the procedure highlight that emergent stenting is associated with higher rates of intracranial hemorrhage, a high risk of in-stent thrombosis, iatrogenic artery-to-artery embolization, and hemodynamic instability during stent deployment. Not to mention that it will increase time to reperfusion if stenting is done prior to the intracranial recanalization. In contrast, the proponents of emergent cervical ICA stenting argue that leaving the carotid alone can lead to an increased risk of infarct recurrence and infarct progression. Of course, it goes without saying that the current practice pattern is widely variable. So, in the current issue of the journal, Dr. Mohammad Anadani, from the Department of Neurology at Washington University School of Medicine, and a group of international collaborators from the TITAN and ETIS registries compared the outcomes of endovascularly treated patients with tandem occlusions in the anterior circulation who received concurrent carotid stenting to those who did not receive stenting of the carotid. Dr. Negar Asdaghi:                        It is important to note that the no-stent group included those with either no cervical carotid intervention or angioplasty alone. So, the authors identified 760 patients with a tandem occlusion that were included in the pooled analysis of TITAN and ETIS registries. TITAN stands for Thrombectomy in Tandem Lesions and endovascular treatment in ischemic stroke. That included EVT-treated patients; these are endovascularly treated patients with tandem occlusions from 18 comprehensive stroke centers across Europe and United States. And ETIS is an ongoing prospective multicenter registry that enrolls all patients treated with endovascular thrombectomy at six large comprehensive stroke centers in France. In both cohorts, treatment of cervical ICA was left at the discretion of the treating physician. Overall, cervical ICA stenting was performed in 56% of total patients with tandem occlusion. In the adjusted model, they found that the odds of favorable outcome and successful reperfusion were higher in the stent group. In contrast, the risk of any hemorrhage was higher in the stent group, but the rate of symptomatic hemorrhage was not different within the two groups. Dr. Negar Asdaghi:                        Some very important findings from their subgroup analysis include a stronger benefit from emergent carotid stenting, unfavorable outcome in patients with lower NIH Stroke Scale, and in patients in whom the etiology of carotid stenosis or occlusion was deemed to be related to atherosclerosis rather than dissection. Dr. Negar Asdaghi:                        So, what are the top three things we learned from this paper? Number one, we learned that emergent carotid stenting overall increased the odds of favorable outcome in patients with tandem occlusion. Number two, emergent cervical ICA stenting came with a cost of increased hemorrhage, perhaps related to the necessity of administering antiplatelet therapies in the angiosuite. Number three, benefit from emergent carotid ICA stenting in the setting of endovascular therapy was confined to patients with carotid occlusion or significant stenosis in whom the etiology was deemed to be related to athero and not dissection. And of course, people seem to benefit from emergent cervical ICA stenting in whom the presenting NIH Stroke Scale was mild. So, many things to keep in mind, and most important of all, that these results are from registry-based data, and we still have to wait for the results of the two ongoing trials to confirm these findings. Dr. Negar Asdaghi:                        Diagnosis of stroke in children is often delayed beyond the conventional thrombolytic and endovascular time windows. In 2018, randomized trials in adults showed that patients with an ischemic mismatch, that is the presence of a large ischemic penumbra in a setting of a small ischemic core, can significantly benefit from endovascular therapy. Whether these results can be directly applied to the pediatric population from simply the adult population is, of course, unknown. In this issue of Stroke, Dr. Mark Mackay and Melissa Visser, from the Department of Neurology, Royal Children's Hospital of Melbourne, and colleagues present the results of a retrospective, observational cohort study of 29 children who underwent MRI diffusion and dynamic susceptibility contrast perfusion imaging within 72 hours of stroke onset. Perfusion-diffusion mismatch was estimated using the RAPID software with the same criteria used in adults, which was defining ischemic penumbra as regions with a Tmax delay of more than six seconds and core as defined by diffusion positive lesions with corresponding low signal on the apparent diffusion coefficient, or ADC, map with values less than 620. Dr. Negar Asdaghi:                        Favorable mismatch profile was defined the same way that they are defined in the adult population, that is, core volumes less than 70 mL and mismatch volumes of over 15 mL with a mismatch ratio of over 1.8. Now, the primary goal of this paper was to demonstrate feasibility of assessing automated perfusion-diffusion mismatch in childhood stroke. So, among 187 children with confirmed stroke on MR imaging, 58 underwent perfusion imaging in the study and only 29 fulfilled the inclusion criteria. Most cases had cryptogenic stroke followed by local cerebral arteriopathy as part of their etiology of stroke. Vessel occlusion was confirmed in 12 cases, two of which involve the posterior circulation. So, RAPID detected an ischemic core in 66% of patients only, remembering that the remaining diffusion positive cases were excluded from this finding simply because either the ADC values were not below the 620 value or they had a smaller infarct core, at which point determining the ADC values becomes very difficult. Dr. Negar Asdaghi:                        Overall, three patients only had favorable mismatch profile as we defined earlier and we use to guide us for thrombectomy in the adult population. Of the three children who met the target mismatch criteria, only one received IV alteplase and none underwent thrombectomy, which makes this difficult to validate the penumbral thresholds that are used in the adults for the pediatric population. Dr. Negar Asdaghi:                        So, what are the top two points from the study? Number one, in this large cohort of children with confirmed ischemic stroke, only a third had perfusion imaging, and most cases received their neuroimaging more than 72 hours after their symptom onset. Number two, the ischemic mismatch as defined by the adult criteria was present in children even as late as 23 hours from symptom onset. So, in summary, this study and others confirm the feasibility of performing perfusion imaging in the pediatric population, but there remains a necessary reluctance in adoption of perfusion imaging as part of the stroke protocols in pediatric centers. Dr. Negar Asdaghi:                        There are a number of concerns that we should keep in mind, including contrast-induced nephrogenic systemic fibrosis and gadolinium deposition in the brain, which are major concerns in the pediatric population, especially in those kids with impaired renal function or those requiring multiple scans over time. You have to also consider unfamiliarity with stroke imaging protocols, given that the majority of stroke-like presentations in children are non-ischemic in origin, in which case, perfusion imaging performance is of little or no value. And there should also be technical considerations, including uncertainty regarding the optimal bolus injection dose, rate, and scan duration of kids. Lots to learn, but still, studies like this represent the first step forward to further our understanding of the role of perfusion imaging in pediatric stroke. Dr. Negar Asdaghi:                        Dural arteriovenous fistulas, or dural AVFs, are intracranial vascular malformations defined by abnormal communications within the dural leaf that's between meningeal arteries and dural venous sinuses and/or cortical veins. Dural AV fistulas represent approximately 10-15% of all intracranial vascular malformations and can remain asymptomatic or have a variety of neurological presentations, the most feared of which is intracranial hemorrhage. It is important to remember that much of the research on the topic is focused on high-risk features of dural AV fistulas associated with the risk of either initial or recurrent hemorrhage, things such as the pattern of venous drainage or location of the fistulas. But less is known about the clinical outcomes of these patients after they present with a bleed. Dr. Negar Asdaghi:                        The CONsortium for Dural arteriovenous fistula Outcomes Research, or CONDOR, Registry is an international multi-institutional database to study the outcomes of dural AV fistulas. In the current issue of the journal, in the study titled “Outcome Following Hemorrhage After Cranial Dural Arteriovenous Fistulae: Analysis of Multicenter CONDOR Registry,” Dr. Matthew Koch, from the Department of Neurosurgery at the University of Illinois in Chicago, and colleagues used this registry to determine the morbidity and mortality of dural AV fistula–related intracranial hemorrhage. I'm joined today by the senior author of the study, Dr. Sepideh Amin-Hanjani, to discuss this paper. Dr. Negar Asdaghi:                        Dr. Amin-Hanjani needs no introduction to the Stroke readership. She's a Professor of Neurosurgery and Co-Director of Neurovascular Surgery at the University of Illinois. She's the past Chair of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons Cerebrovascular Section. She serves on multiple national and international cerebrovascular committees, including serving as the Chair of the Neurovascular Intervention Committee for the American Heart Association Stroke Council. Good morning to you, Sepi, and thank you for joining us on the podcast. Dr. Sepideh Amin-Hanjani:          Good morning, Negar. I really appreciate the opportunity to have time to discuss this paper a little bit with you and the folks listening in today. Dr. Negar Asdaghi:                        Great, Sepi, let's start off with discussing the prevalence of dural AV fistulas. In the current era of increased availability and accessibility of vascular imaging, how often are these malformations found? And importantly, what are the known predictors of so-called bad neurological behavior or intracranial hemorrhage in these fistulas? Dr. Sepideh Amin-Hanjani:          So, I would say these are rare lesions, which is, I think, what makes it particularly useful sometimes to pay a little bit more attention to them because they're less frequently encountered, and so there's not as much thought about looking for these lesions when a patient presents with neurological symptoms or hemorrhage. And so I think highlighting it here is important. They are rare. They're probably, as you mentioned, only about 10-15% of all vascular malformations. The crude incidence is probably somewhere around 0.5 per 100,000. So, again, infrequently encountered. Dr. Sepideh Amin-Hanjani:          Because of the nature of the lesion, they're not as easily, I would say, identified incidentally. Unlike AVMs that will show up on routine MRI or aneurysms that'll show up on routine MRA, fistulas may or may not be apparent because of their nature. They're fed by dural arterial feeders; the fistula itself is within the dural leaflets. They can have venous drainage or ectasia associated with them. So, the secondary phenomenon of the venous congestion may show up on MR, but the actual fistula may be hard to identify. And I think, in some ways, that's why we tend to see them a little bit less incidentally, at least in my own practice, in my own experience, than we do when they present with symptoms, either non-hemorrhagic or hemorrhagic symptoms. Dr. Sepideh Amin-Hanjani:          There are some features of these fistulas that tend to predict if they're going to be bad actors, so to speak, if they're going to have those more aggressive symptoms of neurological dysfunction from venous congestion. Things like seizures, headaches, even dementia as a prolonged effect of venous congestion, or the most dreaded complications, in some ways, hemorrhage, which relates to if there is evidence of significant cortical venous reflux from the fistula itself. Dr. Negar Asdaghi:                        Perfect. So this is a great start to get us now to the topic of the registry. What was the overall purpose of the CONDOR Registry? Please tell us a little bit about the patient population, specifically the population of your interest that you included in your study. Dr. Sepideh Amin-Hanjani:          So, given the rarity of the condition, you find that in the literature, there's lots of kind of relatively smaller case series, and it's hard to make broader assessments of outcomes and treatments, etc., when you're looking at small retrospective series. So, the idea behind CONDOR, which was really launched by one of my colleagues, neurosurgeon Greg Zipfel at Wash. U. in St. Louis, was the idea of getting together a consortium of centers who have either previously published or have a particular interest in dural AV fistulas to collate our series and get a larger cohort of patients together that could be analyzed for just the kinds of interventions and outcomes that would be of interest in looking at a larger sample size. Dr. Sepideh Amin-Hanjani:          So, the consortium now is up to, I think, 16 or 17 centers. The data that was collected and analyzed for the purposes of this particular manuscript came from 12 centers and was over a thousand patients. So, really a large cohort that allowed us to do a deeper dive analysis on a number of topics, including looking at folks who had presented with hemorrhage. There's a number of other studies that have come out of this registry, and the collaboration to form the registry has also been published as well. And it's retrospective data, but the hope is that CONDOR will eventually transform into a prospective database that will allow us to get even higher level data for this condition. Dr. Negar Asdaghi:                        So, perfect. Sepi, I was going to ask this question of whether the registry's ongoing, so thank you for clarifying that, but coming back to your paper. So, you included those patients who have bled. This was data up until 2017. And it's important to look at this number, 25% of patients with dural AV fistulas in the CONDOR Registry up until the time that you looked at the data. That's 1 in 4 patients presented with an intracranial hemorrhage. Is this an overall good estimate of the risk of hemorrhage for this malformation, especially when we're counseling patients on this? Or do you think this number is higher than routine practice and that it's just basically biased because it's a hospital-based registry? Dr. Sepideh Amin-Hanjani:          I think both things are true in some ways, meaning that because this is a consortium of tertiary care centers, obviously there's a referral bias. Patients who are symptomatic or who have hemorrhage are more likely to be cared for in that setting. So, we are going to tend to see a higher proportion of the patients that are presenting with aggressive symptoms or with hemorrhage within this kind of cohort. Dr. Sepideh Amin-Hanjani:          But along with that, similarly, if you look at the features of these fistulae, they're the ones that have the cortical venous reflux, the high-risk features. So, in as much as to say, "do 25% of all fistulas hemorrhage?" No, because presumably there's a lot of more benign fistulas, ones that aren't discovered or aren't worked up that are low risk for hemorrhage that don't show up. But within the paradigm of, again, the construct of a consortium where you're looking at centers who are really taking care of patients presumably presenting more actively with neurological symptoms, I think this proportion is fairly representative. And it, again, speaks to the fact that depending on the type of fistula and the features of the fistula, it's going to be more or less likely to present in an aggressive manner, hemorrhage being one of those presentations. Dr. Negar Asdaghi:                        Perfect. So now let's talk about treatment modalities. A majority of patients in your study had undergone surgical intervention of the fistula. What was the most common intervention in this registry? And can you briefly tell us about the current treatment modalities, whether endovascular or surgical, that are available for dural fistulas? Dr. Sepideh Amin-Hanjani:          So, I think what we found with this registry, and these were centers both within the U.S. and internationally, that the most common treatment paradigm is endovascular, so embolization of AV fistulas. And I think that very much reflects current practice because of the relative, I think, being not an endovascular person, I probably shouldn't comment on the ease or lack thereof, but the ability to access these fistulae endovascularly and use a number of agents, including glue or other embolization materials to obliterate them. So, we certainly found that in the series, embolization, either alone or in combination with other modalities, was the most prevalent. Dr. Sepideh Amin-Hanjani:          Having said that, surgical intervention still has a significant role. Sometimes these fistulas can be difficult to access, depending on their supply or drainage endovascularly, and then the surgical option for obliterating them becomes important as well. And then, more rarely, lesions that are not amenable to either of those modalities can be treated with radiosurgery, although the concern there always with a hemorrhagic lesion is that the effect is not immediate, as opposed to embolization or surgery, where your goal is to obliterate the fistula and remove the source of hemorrhage, which is really the cortical venous reflux, immediately to make sure that there's not a risk for recurrence. Dr. Negar Asdaghi:                        Thank you. This is a great review of AV fistulas. So, coming back to the paper now to recap, you had a highly selected group of AV fistulas that presented with an intercranial hemorrhage, the majority of which underwent embolization in this cohort. So, what were the outcomes? And let's start with just a brief overview of what outcomes are actually collected in your study, and what did you find? Dr. Sepideh Amin-Hanjani:          Yeah, so we were interested to see, in kind of the current paradigm of management of these fistulae, when they present with hemorrhage. As you said, the great majority were treated. So, this is not a natural history study in the sense that it's not looking at untreated malformations after hemorrhage. It's looking at patients in the real world who pragmatically are going to present into tertiary centers with hemorrhage. What is their overall outcome with the current state of interventions that are available and with whatever primary injury is caused by the hemorrhage itself? Dr. Sepideh Amin-Hanjani:          That's really what the study is looking at, is what is morbidity and mortality after hemorrhage from a lesion like this, and current management paradigm for these fistulas. And in that context, we were looking to see if there were predictors of worse or better outcome in that situation following the hemorrhage itself, and defining morbidity as Modified Rankin score of 3 or greater, with the idea of looking at independent versus dependent outcome, and also looking at mortality. Dr. Sepideh Amin-Hanjani:          In other words, how severe are these patients in terms of their neurological outcomes if they do suffer hemorrhage event? We were able to define and look at a variety of potential predictors of outcome. The hemorrhage from dural AV fistulas can be either intraparenchymal intracranial hemorrhage or it can be subarachnoid, or it can be a combination thereof. There can be intraventricular hemorrhage, all depending on the venous congestion pattern related to the fistula. And the idea was, do any of those hemorrhage subtypes matter? Do the comorbidities of the patient matter? Do the specific angio-architecture or location of the fistula matter as relates to the outcome from the hemorrhage? Dr. Negar Asdaghi:                        Perfect. So, at 13% morbidity and 3.6% mortality associated with AV fistula hemorrhages in your study, tell us please about some of the independent factors associated with this primary outcome. Dr. Sepideh Amin-Hanjani:          Yeah. So, after we analyzed the features that were available within the database, really age emerged as a predictor of poor outcome. And I think that's not surprising. That's very true for the full range of cerebrovascular conditions. If we thresholded at age 65, folks older than 65 had a twofold risk of a worse outcome. Dr. Sepideh Amin-Hanjani:          The other things that we found, really a lot of the other features fell out on multivariate analysis, but the couple that remained strongly associated with poor outcome were folks who were on anticoagulants at the time of the hemorrhage. It was a small number within the cohort, but nonetheless, a very robust effect in that those folks did worse following their hemorrhage and certainly recurrent hemorrhage. Dr. Sepideh Amin-Hanjani:          Now, a lot of these fistulae were treated, but in the instance where recurrent hemorrhage did occur prior to treatment, or if the patient had not undergone treatment, recurrent hemorrhage certainly had a really significant effect on worsening outcome as well. That age effect, as I said, has been seen in other vascular conditions. Anticoagulant use as a predictor of poor outcome at the time of hemorrhage has also been seen as a predictor of worse outcomes and other conditions like aneurysmal hemorrhage, things of that nature, and, similarly recurrent hemorrhage. So we're finding similar features as have been described for other cerebrovascular conditions as relates to hemorrhagic lesions as being important predictors of poor outcome. Dr. Negar Asdaghi:                        Perfect. Very important features to keep in mind when we are dealing with patients with intracranial hemorrhage that are found to have these fistulas. So, things that you mentioned that I want to repeat just for our listeners were: age; recurrent hemorrhage that occurs if a patient is not treated and presented with a hemorrhage initially and added a recurrent one prior to receiving the appropriate therapy; and obviously, and not surprisingly as you mentioned, being on anticoagulants at the time of presentation with their hemorrhage. So, 1 in 6 patients, in summary, with dural AV fistula–associated hemorrhage in your study is dead or dependent follow-up. How does this morbidity and mortality, Sepi, compare to the outcomes from other vascular malformations, say, for instance, that of AVMs? Dr. Sepideh Amin-Hanjani:          Yeah, I think that's one of the things we're particularly interested to kind of compare and contrast. Now, one end of the spectrum, you have aneurysmal subarachnoid hemorrhage. I think out of all hemorrhagic vascular lesions, that has the worst outcome. We know morbidity and mortality of that far exceeds 50%. For AVMs, it's been pretty well described even from prospective series that you can have 10-15% mortality and about 30% morbidity related to an AVM hemorrhage. Dr. Sepideh Amin-Hanjani:          And we were interested to see if that was similar profile for fistulas. I think our results show that it's somewhat better than the AVM hemorrhage. The mortality is lower at about 3-4%, like you noted, and the morbidity is around 13% for survivors. But all in all, if you aggregate that, that is, as you say, a 1 in 6 chance of a very poor outcome. So, it's not trivial by any means and certainly much higher than the hemorrhagic consequences of something like cavernous malformations, where hemorrhages from cavernous malformations are rarely fatal. These dural AV fistula hemorrhages can be fatal and can result in long-term morbidity. I think that has implications in terms of how we think about risk-benefit profile of treatment for a malformation, an AV fistula that's discovered and has predictors that would indicate it's at high risk for hemorrhage. Dr. Negar Asdaghi:                        Thank you very much, Sepi. I think you've already eloquently summarized all of this, but I want us to leave our listeners with your top two or three takeaway messages on the topic. Dr. Sepideh Amin-Hanjani:          Thanks, Negar. So, I think the key takeaways that we took from looking at this analysis is that we now at least have some idea about what the morbidity and mortality related to dural AV fistula hemorrhage is. That 1 in 6 number, as you indicated, really benchmarks what morbidity and mortality for the condition is. Now, what's the relevance of that? I think, by inference, we can take this into practice in a couple of different ways. Dr. Sepideh Amin-Hanjani:          First would be that if a patient presents with a fistula with high-risk features for hemorrhage, that knowing this morbidity and mortality related to hemorrhage certainly informs that discussion about treatment and certainly favors the idea of treating fistulas at high risk for hemorrhage based on cortical venous drainage early to prevent this morbidity and mortality from occurring. Dr. Sepideh Amin-Hanjani:          Secondly, I think it argues towards making sure that there's a thorough workup done when a dural AV fistula is suspected, even if it's presenting with more benign symptoms like tinnitus, for example, or is discovered incidentally, and that workup really should be thorough enough to determine if there are high-risk features from this fistula. And that workup really entails catheter angiography because that's truly the way to determine if these cortical venous reflux and other features that are most associated with hemorrhage are present or not. So, I think those two key elements should be kept in mind. Dr. Sepideh Amin-Hanjani:          And finally, given the rarity of the condition and because these are complex and heterogeneous lesions, I think it makes sense upon discovery or suspicion of a dural fistula to really refer these to tertiary centers that manage these conditions frequently enough to be able to determine those risk features and to offer the appropriate type of treatment for it, whether it be, as we discussed, mostly embolization or surgery. Dr. Negar Asdaghi:                        Dr. Sepideh Amin-Hanjani, congratulations on this work, a huge collaboration and a great addition to the existing literature of vascular malformation–related intracranial hemorrhage. It was a pleasure having you on the podcast today. Dr. Sepideh Amin-Hanjani:          Thank you so much, Negar, much appreciated. Dr. Negar Asdaghi:                        And this concludes our podcast for the October 2021 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including two articles published online in September simultaneous with their presentation at the European Stroke Conference, which appear in the October issue of Stroke. The first article is on clinical outcome of thrombolysis with tenecteplase, and the second one discusses the effects of fluoxetine on outcomes after acute stroke, results from EFFECTS randomized controlled trial. Dr. Negar Asdaghi:                        Now, for a second year in a row, the European Stroke Conference was entirely online, bringing a wealth of knowledge and stroke expertise from all over the world to a completely virtual audience. Now, we hope to soon return to our good old times when we traveled for conferences, but let's take a moment and think about the magnitude of this virtual accomplishment, the incredible role that technology plays in our abilities to do research and provide healthcare. And we owe this to the men and women that pioneered the development and the ever-growing fast-paced progress of computer sciences. Dr. Negar Asdaghi:                        Ten years ago in October, the world lost one such pioneer. Steve Jobs, the father of mobile technology and digital revolution, is recognized not just for his technical creations but also for his way of life, his incredible mind that led to the seemingly utopian ideas for how things should be. In a powerful commencement speech he delivered at Stanford University a few years before his death, he talked about his life experiences, the power of mind, and the power that lies in doing every part of one's work with absolute perfection and love. So, in honor of his genius and the legacy he left behind, we end our October podcast with his parting words of wisdom to the graduating class of 2005: "Stay hungry, stay foolish." And, as always, stay alert with Stroke Alert. Dr. Negar Asdaghi:                        This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 8 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the September 2021 issue of Stroke: “Risk of Fractures in Stroke Patients Treated With a Selective Serotonin Reuptake Inhibitor” and “Carotid Plaques From Symptomatic Patients Are Characterized by Local Increase in Xanthine Oxidase Expression.” She also interviews Drs. Jukka Putaala and Markku Kaste about their article “Should Tenecteplase be Given in Clinical Practice for Acute Ischemic Stroke Thrombolysis?”. Dr. Negar Asdaghi:         1) Are we ready to say goodbye to our old friend alteplase and replace it with a new one, tenecteplase, for acute stroke thrombolysis? 2) Does treatment of depression with SSRIs increase the risk of fractures in stroke patients? 3) When it comes to carotid intervention, should we continue offering treatment based on the degree of luminal stenosis, or are there better biomarkers in the horizon? These are some of the questions that we'll tackle in today's podcast. We're covering the best in Stroke. Stay with us. Dr. Negar Asdaghi:         Welcome back to Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the September 2021 podcast, we have an exciting program where we discuss some of the controversies in stroke therapies. The September issue also contains a Focused Update with a set of articles and comprehensive reviews on the topic of genetics and stroke, organized by Professor Martin Dichgans, which I encourage you to review in addition to our podcast today. Later in today's podcast, I have the pleasure of interviewing Drs. Putaala and Kaste, from Helsinki Institute, to help us with a burning question of whether there's enough evidence now to use tenecteplase instead of alteplase for ischemic stroke thrombolysis. But first with these two articles. Dr. Negar Asdaghi:         Over a third of stroke survivors either have depressive symptoms or a formal diagnosis of depression. Selective serotonin reuptake inhibitors, or SSRIs, are the mainstay of depression treatment and the most common antidepressants prescribed in the U.S. In addition, in 2011, we had the results of the FLAME trial suggesting that early poststroke treatment with fluoxetine, a commonly prescribed SSRI, improves motor recovery and functional independence in stroke patients with motor deficit. Though these results were not replicated in the subsequent larger FOCUS trial, the use of SSRIs poststroke dramatically increased over the past decade. So what are the side effects of using SSRIs poststroke? It's a known fact that adult stroke survivors are more likely to experience bone fracture, and that there's some evidence that SSRIs may increase this risk. Dr. Negar Asdaghi:         So, in the current issue of the journal, Dr. Graeme Hankey and Joshua Jones, from Faculty of Health and Medical Sciences, University of Western Australia, in Perth, and colleagues aimed to answer this question with a systematic review and meta-analysis of randomized controlled trials that included an SSRI treatment for an adult patient with a previous hemorrhagic or ischemic stroke and included incident fractures, either as a primary or secondary study outcome, amongst other criteria. So they found four randomized controlled trials that fulfilled their research criteria. Three of them looked at the effects of fluoxetine, used at a dose of 20 mg per day for six months duration, on functional recovery and outcomes after stroke. And one trial, which has studied neuroregeneration in vascular protection by citalopram, either at a 10 mg or 20 mg daily dose also for six months duration, in patients with acute ischemic stroke. So three studies included with fluoxetine and one study included citalopram. Dr. Negar Asdaghi:         So, what they found was that although the risk of falls, seizures and recurrent stroke were not statistically increased with SSRI treatment, it was actually a significant increased risk of fractures with a risk ratio of 2.36 in patients treated with SSRI as compared to the placebo. Now, how the SSRIs will increase the risk of fractures is still unknown. There are multiple postulated mechanisms that are discussed in the paper, such as SSRIs potentially increasing spastic motor activity, causing orthostatic hypotension, dizziness, delayed reaction time or temporary imbalance or sleep disorders. But the most important mechanism to keep in mind is the possibility of SSRIs lowering bone mineral density. It's also important to note that the duration of exposure to SSRIs is an important predictor of factors. It's worth noting that the usual SSRI exposure in patients with the primary diagnosis of depression is a lot longer than the exposure time in these trials. Dr. Negar Asdaghi:         So, what are the top two takeaway points for stroke physicians? Number one: Fluoxetine and citalopram SSRIs, used for six months poststroke, double the risk of fracture as compared to placebo in this meta-analysis. Number two: While the mechanism of this association is still debated, fracture prevention should be an important discussion point when considering prescribing an SSRI to stroke patients. Dr. Negar Asdaghi:         We all know that carotid disease is a major cause of ischemic stroke. Now we have to keep in mind that the bulk of the literature in carotid disease are practically concentrated on the association between the degree of luminal stenosis and the risk of recurrent stroke. So, in practice, we constantly counsel and discuss risk of future ischemia in symptomatic and asymptomatic carotid disease based on the degree of stenosis that's less than 50%, or between 50% to 70%, or over 70%. Dr. Negar Asdaghi:         But what if we learn that some plaques can be active despite causing small or little stenosis? And conversely, some may be active despite being very large. There seems to be a growing literature that much of the recurrent strokes are occurring in destabilized plaques. And it turns out that there are actually biomarkers that could cause this destabilization, and we can actually measure them. Xanthine oxidase, or XO, is one of these biomarkers. XO is a key enzyme involved in degradation of purine into uric acid. Now I'm trying to simplify a complex subject here. Xanthine oxidase oxidizes the conversion of hypoxanthine into xanthine and xanthine into uric acid. Along the way, it also does create a whole bunch of reactive oxygen species such as superoxide and hydrogen peroxide, which can create tissue damage. Dr. Negar Asdaghi:         Now, how is XO and serum uric acid levels related to carotid disease? Well, it turns out that XO is enhanced in carotid arteries with evidence of atherosclerosis. Better yet, in animal models, inhibition of XO is associated with reduction in progression of atherosclerosis. So, in the current issue of the journal, Drs. Morsaleh Ganji and Valentina Nardi, from Departments of Cardiovascular Medicine and Anatomic Pathology of Mayo Clinic in Rochester, Minnesota, and colleagues set out to investigate whether carotid plaques from symptomatic patients had increased expression of xanthine oxidase than their asymptomatic counterparts. So, what they did was they looked at 88 patients undergoing carotid endarterectomy for symptomatic or asymptomatic carotid disease, part of the routine clinical practice, and then measured the XO expression by immunohistochemical staining in CA obtained specimens. Dr. Negar Asdaghi:         In addition, they collected a number of serum samples and other demographics and vascular risk factors from the participating patients. They found four major findings in their paper. Number one: XO expression was indeed higher in symptomatic carotid arteries. Number two: Symptomatic patients had a higher serum uric acid levels. Number three: Higher XO expression was inversely associated with the serum levels of HDL. Number four: The symptomatic plaques had higher amount of macrophages expressing XO. Dr. Negar Asdaghi:         Very interesting, but these findings were irrespective of the actual degree of luminal stenosis. In fact, the asymptomatic carotid plaques patients, as routine practice dictates, had a higher degree of luminal stenosis, but they had lower expression of XO and other associated findings. So what did we learn from this study? Well, there seems to be a strong association between certain biomarkers, in this case xanthine oxidase, and symptomatic state of carotid plaques, suggesting that perhaps in future we'll have other ways of measurements that may help us decide on carotid intervention rather than just the symptomatic state of the artery and the degree of stenosis. Dr. Negar Asdaghi:         It's been over 25 years since alteplase was approved as the thrombolytic agent of choice for treatment of patients with acute ischemic stroke. But in the past decade, tenecteplase, a genetically modified variant of alteplase with regulatory approval for treatment of ST-segment–elevation, myocardial infarction, has gained interest as an alternative reperfusion therapy for treatment of patients with acute ischemic stroke. Whether tenecteplase is ready to completely replace alteplase in clinical practice is certainly a burning question faced by the stroke community today. This was the subject of a lively debate at the most recent and entirely virtual 2021 International Stroke Conference, where a panel of experts reviewed the current evidence regarding the use of tenecteplase in acute ischemic stroke, examining data from animal models, preclinical studies to dose escalation studies and randomized trials, directly comparing tenecteplase with alteplase, as well as the collective clinical experience to date with this thrombolytic agent. Dr. Negar Asdaghi:         The proponents of change point out the many advantages of tenecteplase over alteplase, including its ease of use, increased fibrin specificity, longer half-time and its non-inferiority to alteplase in the head-to-head trials. On the other hand, the opponents caution stroke physicians, drawing attention to the inherent issues with the already completed clinical trials of tenecteplase, and argue that more data is needed before tenecteplase is considered as a thrombolytic agent of choice in routine clinical practice. Continuing on this debate in the September issue of the journal as part of the Controversies in Stroke series, Drs. Jeffrey Saver and May Nour provide opposing views to Drs. Dawn Kleindorfer and Mollie McDermott on the present evidence and current guidelines around tenecteplase use in acute ischemic stroke. Dr. Negar Asdaghi:         Acting as moderators, the senior authors of paper, Dr. Jukka Putaala, Head of Stroke Unit at Neurocenter, Helsinki University Hospital, and Dr. Markku Kaste, Emeritus Professor of Neurology at the University of Helsinki and past chairman of Neurocenter, Helsinki University Hospital, in Finland, provide us with the balancing remarks on the issue. I'm joined today by Professors Putaala and Kaste to give us an overview on the debate of tenecteplase versus alteplase. Is it time to make the switch? Good morning from sunny Florida and good afternoon to you both in Finland. Thank you for joining us on the podcast. I hope the weather is as beautiful in Helsinki today as it is here in Miami. Dr. Jukka Putaala:           Here it is not as warm as you have, but we have had a really beautiful summer, and at the moment, although it is also autumn, temperature is around 20 Celsius, so it's just great. Dr. Negar Asdaghi:         It's great to have you both. The paper outlines a generally recognized criteria to support the use of any new pharmacotherapy. Can you please start us off by reviewing the components of this criteria and tell us, please, how many checkmarks does TNK get on this checklist when considered as a reperfusion therapy in acute ischemic stroke? Dr. Jukka Putaala:           These eight criteria include a well-characterized mechanism of action; strong preclinical data; evidence of benefits and safety in a closely related clinical condition, which here is myocardial infarction; important practical advantages over existing agents; the clinical efficacy in how the patient has demonstrated in randomized trials; and endorsement by national practice guidelines. Also, support from regulatory authorities. And finally, clinical effectiveness, which has demonstrated in routine care. We think that tenecteplase for acute ischemic stroke meets actually all of these eight criteria. But we could also think that a smaller number of criteria will be enough to satisfy or meet, would be sufficient. Dr. Negar Asdaghi:         Perfect. So definitely many important steps, starting with the basics all the way to post-marketing clinical experience. Markku, now over to you. Can you remind us about the mechanism of action of tenecteplase? And what are some of the similarities and differences in terms of pharmacodynamic and pharmacokinetics with alteplase? Dr. Markku Kaste:           So alteplase catalyze plasminogen cleavage to plasmin and, in turn, degrades fibrin in thrombi, yielding clot lysis. TNK, compared to alteplase, is 14-fold greater fibrin activity and 80 times higher resistance to plasminogen activator inhibitor-1, which means it has a longer half-life, which is a major advantage. Patients need only one injection. In case you're compared to alteplase, when you had to have third dose injection and then one-hour infusion, which delay the care of patient, if the patient need thrombectomy. So it takes an hour for the infusion before patient can be transferred to thrombectomy, and time matters in brain infarction. So the faster you are, the better it is for patients. Dr. Negar Asdaghi:         Perfect. So more fibrin specificity, as you mentioned, and longer half-time for TNK. And in addition, TNK is not a new drug. In fact, there is over two decades' worth of experience with this in cardiology. Can you also tell us about this? And also some of the preclinical and animal studies that make TNK a potential candidate as a thrombolytic therapy in stroke? Dr. Markku Kaste:           In animal studies, both in vitro model of mural platelet deposits under arterial flow and a rabbit model using extracorporeal arterial-venous shunts, TNK was more potent, showing benefits up to three hours versus one hour when alteplase was used. So, it's a major benefit already in animal experiments and in the code team, of course, it will be transferred in clinical practice. So, in myocardial infarctions, in three randomized trials, including our 17,000 patients, TNK showed significant reduction for bleeding rates and similar intracerebral hemorrhage rates and 30-day mortality. Dr. Markku Kaste:           So, these facts support the use of TNK, also in ischemic stroke, the results from myocardial infarction, some steady encouraging. Although we have to keep in mind that myocardial infarction is very homogeneous disease, it's arterial occlusion, while ischemic stroke can be caused by the local occlusion just like myocardial infarction, but also from artery-to-artery thrombi or from a cardiac emboli. And these three [inaudible 00:17:43] mechanisms generate different kind of thrombi, so we need a better drug than alteplase, which really is effective, whatever is the etiology of the occlusion of brain artery. Dr. Negar Asdaghi:         Right. Thank you. Jukka, now over to you. Before we review the data from randomized trials of tenecteplase, can you please tell us about some of the practical advantages of tenecteplase over alteplase? We're comfortable with alteplase. Why should we make the switch? Dr. Jukka Putaala:           The key practical advantages arise from the fact that tenecteplase can be given as one single dose; it takes only one minute. And if you compare that to alteplase, you'll have to give the bolus first, and then following the bolus is 60 minutes infusion. And that also has many advantages in clinical practice, for example, if you have a patient with large vessel occlusion in a remote hospital, which is not thrombectomy-capable, you can give tenecteplase and then put the patient in the ambulance and transfer swiftly the patient to the thrombectomy center. While, when using alteplase, you have to start infusion, which you have to have the nursing staff that is capable of monitoring the infusion and taking care of any complications arising during the infusion and so forth. Dr. Jukka Putaala:           With tenecteplase, you can immediately transport the patient to a thrombectomy site after the bolus without any infusion-capable paramedics staff. Another practical advantage is that by using tenecteplase, you avoid the potential gap between the bolus and the infusion, which means that there is at least several minutes or longer gap in four out of five patients treated with alteplase. You can also think the other scenarios during this coronavirus era, and you have 15 patients with suspected or very fast coronavirus infection. By using bolus, you don't need to put nurses in the same room with the patients many times with the infusion if you use alteplase. Instead, you can use tenecteplase, it's only one single bolus, and you can go away and you don't have to be exposed to potential coronavirus infection. Dr. Negar Asdaghi:         So, many important advantages, as you mentioned. It seems very reasonable, then, to use tenecteplase in routine practice if it is indeed non-inferior to alteplase. Jukka, what dose of tenecteplase should be used for treatment of acute ischemic stroke patients? And we're definitely excited to hear about the head-to-head trials with tenecteplase versus alteplase. Dr. Jukka Putaala:           Well, the trial, the dose is 0.25 mg/kg or 0.4 mg/kg. It depends if you have LVO, if you review the evidence what we have now available, you have to use the lower dose in LVO patients. But you can use the higher dose in non-LVO patients. All of this arises from the evidence we have available right now. So, basically, five randomized trials have been completed, to date, comparing tenecteplase with alteplase in acute ischemic stroke. And shortly, if they pull out these five trials and compare primary outcome, which is modified Rankin Scale 0 to 1 versus prior, which means excellent outcome. Dr. Jukka Putaala:           So, when pulling out these five trials, 58% percent of patients rates excellent outcome versus 55% of alteplase, and this satisfied the criteria for non-inferiority. Regarding safety and secondary outcomes, major intracranial bleeding, mortality, this meta-analysis according to five trials shows similar results for tenecteplase and alteplase. You have to consider some details of this trial. I think Markku was going to quickly review some of the details of the science and doses used in these trials later on. Dr. Negar Asdaghi:         So, yes, this sounds great for tenecteplase, but so now over to you, Markku. As Jukka mentioned, do we hear a "not so fast for tenecteplase"? Is the current data enough to say goodbye to alteplase entirely and completely turn over to tenecteplase? What are some of the issues with the already completed trials? Dr. Markku Kaste:           It's not today, we cannot say goodbye to alteplase. As Jukka referred to those trials, there's no reason to go into these really deep details because the trials are quite small compared to ordinary clinical randomized trials studying stroke care. Like I don't want to give neuroprotection agents, for example. One larger trial was, let's say, reasonably well designed. But as to say that most of these trials are not really double-blind randomized clinical trials. And so the results which can be generated is not as reliable as double-blind trials because, of course, there are reasons, I mean, colleagues randomizing cases may think that, OK, a randomizing case and I'm not totally convinced about TNK. And I think this gentleman or this lady really needs effective thrombolytic agents, so I give alteplase, while if another patient with a mild symptom, same physician may think, OK, this stroke patient will recover no matter what, so let us randomize the patient. Dr. Markku Kaste:           So, it means these kind of unbalanced randomization provides data which is not really reliable. We had to have lots double-blinded randomized trials before it's time to say goodbye, if this double-blinded randomized trial verified that TNK beats alteplase. And, of course, we need also meta-analysis of those advanced trials, and these things can take time, although many guidelines, like AHA guidelines, European Stroke Organization guidelines, Chinese guidelines, Indian guidelines, they, in a way, how do you say, might recommend use of TNK, but I think we need more reliable scientific evidence before it's time to say goodbye to alteplase. Dr. Negar Asdaghi:         So, Jukka, Markku already alluded to this. I wanted you to review this for our listeners, the national practice guidelines and drug regulatory authority guidelines around the globe with regards to the issue of tenecteplase versus alteplase. Dr. Jukka Putaala:           Yeah, actually, already American, European, Chinese, Australian and Indian guidelines are recommending tenecteplase into the guidelines, which were recently published in 2019, between 2019 and 2021. What we can read from the guidelines is that tenecteplase can be considered over alteplase. But we have to remember that the strength of the recommendation will remain weak at present and quality of evidence is by the facts that we discussed of these five completely randomized trials and meta-analysis pulling out the data. Qualitative evidence remains slow, and, therefore, the wording in the guidelines is that it may be reasonable to choose or consider alteplase. Tenecteplase might be considered as an alternative to alteplase in certain conditions. Dr. Jukka Putaala:           The recommendations are a little bit mixed in the guidelines, but generally, in large vessel occlusions, the guidelines say that you could consider TNK over alteplase or even that you should consider TNK over alteplase in large vessel occlusion before proceeding to thrombectomy. However, in cases without large vessel occlusion, the statements are more mixed and they say tenecteplase might be considered or even that alteplase is preferred over tenecteplase until we have more evidence. Dr. Negar Asdaghi:         Thank you, Jukka. Markku, what should be our final takeaway message for the practicing stroke physicians at this point considering the use of tenecteplase in routine practice?   Dr. Markku Kaste:           Before your paper has been accepted and published in high-quality journal, it takes weeks, mostly it takes months, even a half a year. While in Stroke Conference, you get the most recent data, which is, let's say, generated last week or even the same day. So, when you want to really provide high-quality care of your patient, keep you updated. And then it's best for you and her, and it's better, of course, for your patient. International Stroke Conference and also European Stroke Conference, they are excellent places to get the most recent, yet unpublished, reliable information. Dr. Negar Asdaghi:         Professors Jukka Putaala and Markku Kaste, thank you for summarizing a large body of evidence for our listeners. We're definitely excited to learn how tenecteplase will ultimately stand against the old competitor and perhaps learn that both may be reasonable thrombolytic options, depending on the specifics of the clinical setting. Dr. Negar Asdaghi:         And this concludes our podcast for the September 2021 issue of Stroke. Please be sure to check the September table of contents for the full list of publications, including two special reports on consensus recommendations from the 11th STAIR Consortium, that is, Stroke Treatment Academic Industry Roundtable. Dr. Negar Asdaghi:         The first report is intended to enhance patient, clinician and policymaker comprehension at modified Rankin Scale findings in clinical trials and quality improvement initiatives. The second report from the STAIR Consortium is on top priorities for cerebroprotective studies, an important manuscript where the roundtable considered and presented a new paradigm for evaluation of putative therapies that may work together with recanalization treatments to improve outcome after ischemic stroke, with special attention to using the correct nomenclature, such as replacing the term "neuroprotection" with "cerebroprotection" when the intention of an investigation is to demonstrate that a new treatment benefits the entire brain, rather than neurons alone. Or replacing the term "time window" with "tissue window" or "target window" when selecting patients for recanalization therapies to enhance the notion that various elements of the neurovascular unit show vulnerability to ischemia evolving over different time scales in different brain regions. An important paradigm shift in ways we think of the brain under ischemic attack. With that, we invite you to continue to stay alert with Stroke Alert. Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 7 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the August 2021 issue of Stroke: “Stroke Risks in Adult Survivors of Preterm Birth: National Cohort and Cosibling Study” and “Roles of Phytoestrogen in the Pathophysiology of Intracranial Aneurysm.” She also interviews Drs. Nirav Bhatt and Diogo Haussen about their article “Reliability of Field Assessment Stroke Triage for Emergency Destination Scale Use by Paramedics: Mobile Stroke Unit First-Year Experience.” Dr. Negar Asdaghi: 1) Can preterm birth be associated with increased risk of stroke in adulthood? 2) Can a plant-based diet high in phytoestrogens reduce the risk of aneurysm formation and aneurysmal rupture in postmenopausal women? 3) What is the predictive ability of FAST-ED score in detection of large vessel occlusion? We will review these questions in today's podcast. You're listening to the Stroke Alert Podcast. Stay with us. Dr. Negar Asdaghi:         From the Editorial Board of Stroke, welcome to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The August 2021 issue of Stroke covers a wide range of topics from examining if the presence of spot sign modifies the treatment effect of tranexamic acid in patients with intracerebral hemorrhage to the results of the PRESERVE randomized clinical trial examining whether intensive blood pressure lowering in patients with severe cerebral small vessel disease can be associated with progression of white matter damage as detected by diffusion tensor imaging or MRI studies, which I encourage you to review in addition to our podcast today. Dr. Negar Asdaghi:         Later in today's podcast, I have the pleasure of interviewing Drs. Diogo Haussen and Nirav Bhatt from Emory University on their work on reliability of FAST-ED scale when used by the paramedics in mobile stroke units and learn about the implementation of mobile stroke units in Atlanta. But first with these two articles. Dr. Negar Asdaghi:         Preterm birth, defined as birth prior to 37 weeks of gestation, affects approximately 11% of births worldwide. Today, with the advent of modern neonatal and pediatric care, the majority of preterm babies survive into adulthood. Multiple studies have shown that adult survivors of preterm birth are at increased risk of developing vascular risk factors, such as diabetes and hypertension, and have a higher incidence of ischemic heart disease as compared to their age-matched individuals born at term, though the association between preterm birth and risk of stroke is not well studied. Dr. Negar Asdaghi:         In the current issue of the journal, Dr. Casey Crump from Departments of Family Medicine and Community Health and Population Health Science and Policy at Icahn School of Medicine, Mount Sinai, New York, examined whether preterm birth is associated with an increased risk of stroke and its major subtypes in adulthood. The authors use the prenatal and birth information obtained from the Swedish Birth Register, which contains information for nearly all births in Sweden since 1973. The study cohort included over 2,200,000 singleton live births in Sweden from 1973 to 1994. These years were chosen to allow for sufficient follow-up into adulthood. The study cohort was examined for the earliest diagnosis of stroke from the time the participants turned 18 through September 31, 2015, and the maximum age of included population is 43 years. Stroke was identified using ICD codes from all primary and secondary diagnosis in the Swedish Hospital and Outpatient Registries and all deaths attributed to stroke in the Swedish Death Register. Dr. Negar Asdaghi:         Cosibling analyses assess for potential shared, familial confounding factors, such as genetic and environmental factors, that could contribute to development of stroke. In 28 million person-years of follow-up, 4861, or 0.2% persons, were diagnosed with stroke between 18 to 43 years of age. The authors found that low gestational age at birth was associated with a significantly higher risk of first-time stroke in adulthood. In their adjusted model, as compared to those born at full-term, the hazard ratio for any stroke associated with early preterm, that is birth between 22 to 33 weeks of gestation, was 1.4, and the hazard ratio for late preterm, that is birth between 34 to 36 weeks of gestation, was 1.22, both of which were statistically significant. Interestingly, each additional week of gestation was, on average, associated with a 3% lower risk of first stroke in adulthood. Dr. Negar Asdaghi:         Similar associations were found in men and women and for both hemorrhagic and ischemic strokes. These findings were only partially explained by shared genetic or environmental risks of preterm birth and stroke within families, suggesting important direct effects of preterm birth on risk of stroke. Multiple putative mechanisms that could potentially link preterm birth with increased stroke risk were discussed in the paper as well, including interaction of fetal angiogenesis during the critical developmental period leading to reduced capillary density and increased arterial stiffness, to persistently elevated levels of anti-angiogenic factors, which are correlated with increased blood pressure development and development of hypertension in adulthood. In summary, the study findings suggest that preterm birth should be recognized as a risk factor for stroke later in life, and survivors need early preventive evaluation and long-term clinical follow-up into adulthood to reduce their lifetime risk of stroke. Dr. Negar Asdaghi:         The incidences of intracranial aneurysm and aneurysmal subarachnoid hemorrhage are high in postmenopausal women, suggesting estrogen may be protective against aneurysm formation or aneurysmal rupture. However, estrogen-containing hormone replacement therapy is also associated with an increased risk of other significant adverse outcomes, such as increased risk of breast cancer and ischemic stroke, and is not routinely recommended for primary prevention of chronic conditions in postmenopausal women. Isoflavones, a type of phytoestrogen, are plant-based, diet-derived compounds with properties similar to estrogen. Two types of isoflavones, genistein and daidzein, are found in soybeans, chickpeas, and lentils and are thought to be the most potent phytoestrogens that exert estrogenic activities with tissue and receptor specificity. Regular consumption of isoflavones has been shown to alleviate the vasomotor symptoms of estrogen deficiency and associated with reduced incidence of estrogen-dependent diseases in postmenopausal women. Daidzein, once ingested, is converted to its bioactive metabolite, equol, which preferentially binds to estrogen receptor beta, a receptor subtype responsible for the protective effect of estrogen against the formation and rupture of intracranial aneurysms. Dr. Negar Asdaghi:         In the paper titled "Roles of Phytoestrogen in the Pathophysiology of Intracranial Aneurysm," Dr. Tomoki Hashimoto from the Barrow Aneurysm and AVM Research Center, Departments of Neurosurgery and Neurobiology, the Barrow Neurological Institute, and colleagues investigated whether the phytoestrogens daidzein and its bioactive form, equol, are protective against the formation and rupture of intracranial aneurysms in ovariectomized female mice. Intracranial aneurysms were induced by combining systemic hypertension and a single injection of elastase into the CSF at the right basal system. Ovariectomized mice were fed with an isoflavone-free diet. The systemic treatment with equol delivered via an implanted mini-osmotic pump in the treatment group (0.5 mg/kg/day) or vehicle (in the control group) began one week before aneurysm induction and was continued for four weeks thereafter. So, what they found was that equol treatment significantly reduced the incidence of aneurysm formation compared to vehicle, and there was a trend for equol-treated mice to have a lower incidence of aneurysmal rupture than control mice, while there was no difference in the blood pressure noted between the two groups. Dr. Negar Asdaghi:         Furthermore, systemic treatment through equol decreased mRNA expression of proinflammatory cytokines, such as IL-6 and interleukin-1β. Importantly, equol seems to require estrogen receptor beta, as the observed protected effects of equol against aneurysm formation was not duplicated in ovariectomized estrogen receptor beta knockout mice. The authors further demonstrated that dietary daidzein reduced the incidence of aneurysm formation, an effect that was dependent on the conversion of daidzein to equol as the beneficial effect of this dietary supplement was abolished in mice that were fed vancomycin, which prevented the intestinal microbial conversion of daidzein to equol. In summary, this study showed that both dietary oral daidzein or the systemic use of its bioactive metabolite, equol, protect against aneurysm formation in ovariectomized female mice through the activation of estrogen receptor beta and subsequent suppression of inflammation. These results indicate a potential therapeutic value of phytoestrogen in prevention of intracranial aneurysm formation and related subarachnoid hemorrhage. Dr. Negar Asdaghi:         Early recognition of stroke-like symptoms, combined with increased utilization of revascularization therapies, have greatly improved the clinical outcomes of patients with acute ischemic stroke, but have similarly resulted in an ever-growing demand on the stroke systems of care. In the era of endovascular thrombectomy, a prehospital scoring tool with predictive abilities for detection of a target vessel occlusion can greatly assist in the appropriate triage, transfer, and activation of the endovascular team for eligible patients, all the while preventing the inevitable fatigue that accompanies the overuse of the system by properly triaging out those who have a lower likelihood of needing endovascular therapy. For any scoring system used in the prehospital setting, the need for precision needs to be balanced with notions such as ease of administration, time consumption, and reproducibility, as decisions made in the field are invariably fast and frequently made in unstable situations. The Field Assessment Stroke Triage for Emergency Destination, or the FAST-ED scale, is one such stroke scale that meets many of the above-stated criteria in patients with stroke-like presentations to predict a possible large vessel occlusion. Dr. Negar Asdaghi:         In the paper titled "Reliability of FAST-ED Scale Use by Paramedics: Mobile Stroke Unit First-Year Experience," Drs. Nirav Bhatt and Diogo Haussen and colleagues, from the Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, and the Department of Neurology at Emory University School of Medicine in Atlanta, report on the reliability of the FAST-ED score in the prehospital setting when used by the paramedics in a mobile stroke unit. I'm joined now by Drs. Bhatt and Haussen to discuss this paper. Good afternoon, Nirav and Diogo. Thank you very much for joining us. Dr. Nirav Bhatt:               Thank you so much for the invitation. I'm very happy to be here. Dr. Diogo Haussen:         Thank you very much. It is a great pleasure to join you. Dr. Negar Asdaghi:         Right. In this paper, the FAST-ED score was administered by the paramedics in a mobile stroke unit. So Nirav, to get us started, please tell us about the concept of a mobile stroke unit, how long it's been implemented in Atlanta, and what it means for patients with stroke-like symptoms who would possibly have a large vessel occlusion. Dr. Nirav Bhatt:               The mobile stroke unit, or the MSU, is an ambulance equipped with a CT scanner and state-of-the-art telemedicine capabilities and is operated by the Grady Emergency Medical Services that covers majority of Metro Atlanta and many of its suburbs, caring for a population of a little over 500,000. It was specifically incorporated to expedite care amongst patients with suspected strokes and went into operations on 30th May, 2018, Monday through Saturday, 12 hours a day, 8 a.m. through 8 p.m. It is operated by a group consisting of an EMT driver, a paramedic, an emergency medicine registered nurse, and a CT technician. So, when a patient has symptoms suspicious for a stroke, the MSU is activated either through 911 dispatch or by an ALS ambulance crew evaluating a possible stroke alert patient in the field. After the initial stroke triage performed by the MSU crew, if there is a persistent suspicion for stroke, the patient is transferred to the MSU and a noncontrast CT scan of the brain is immediately performed. Dr. Nirav Bhatt:               These CT images are transmitted via the telemedicine platform and are available for review by the vascular neurologist and neuroradiologist in real time. With the help of telemedicine technology, a remotely located vascular neurologist then examines the patient. So, with the help of telemedicine and CT scanner, it allows the remotely located vascular neurologist to identify patients who may qualify for IV alteplase, which is then administered in the MSU to qualifying patients, and these patients get subsequently transported to a stroke treatment center. Now, if the neurological exam is concerning for a large vessel occlusion and the non-contrast CT scan does not show corresponding early ischemic changes, these patients get transferred specifically to a comprehensive stroke center for consideration of thrombectomy. At our centers, some of these patients get directly transported to the neuro-angio suite for further imaging and possible thrombectomy. Thus, the MSU serve a very important goal of expediting critical neurological care for a stroke patient, not only by administering IV alteplase in the field to qualifying patients, but also early triage and transport of qualifying patients to the neuro-angio-suite and with earlier activation of neuroangiosuite. Dr. Negar Asdaghi:         Perfect, Nirav. An important and a growing concept, bringing treatment to patients and helping with triaging them appropriately, as you mentioned, which I'm sure we'll see more of in the United States and across the world. Now, Diogo, over to you. Can you tell us about the FAST-ED score, its components, then about the reliability of FAST-ED score in the prehospital setting prior to your current study? Dr. Diogo Haussen:         So, the landmark trials published in 2015 defined mechanical thrombectomy as this very effective and powerful treatment of large vessel occlusion stroke patients, and the clinical and the public health impact of this treatment are certainly highly dependent on the rapid triage of these folks into the appropriate destination. So, this involves the prompt identification of patients with severe symptoms by the emergency medical system personnel, and obviously the transportation of them for a thrombectomy capable center. So, some scales had been proposed earlier on, and the FAST-ED was then developed, and it aimed to help with the identification of patients with a higher probability of having a large vessel occlusion stroke. So, in 2017, we validated the scale on stroke patients that had undergone contrast-enhanced vascular images, which had not been done before, in this publication led by Fabricio Lima and Raul Nogueira in Stroke, in the Stroke journal. Dr. Diogo Haussen:         So, this paper demonstrated that FAST-ED had higher accuracy than RACE and CPSS. The main limitation at the time was the fact that the FAST-ED score derived from the NIH Stroke Scale and, therefore, had to be validated in the field. The FAST-ED scale stands for the important features that are involved with stroke care and recognition and triage, such as facial palsy, arm weakness, speech changes, and time. Then we complimented this with findings of critical dysfunction illustrated by eye deviation and also denial/neglect. So, the FAST-ED has the following scoring system: So, facial palsy scored from zero to one; arm weakness from zero to two; speech changes, which is aphasia, from zero to two; time is just for documentation, but not for really any decision-making in terms of the scale itself. So, eye deviation goes from zero to two, and denial/neglect from zero to two, and again, was designed based on the items of the NIH Stroke Scale with higher predictive value for large vessel occlusion strokes. I think Nirav is going to discuss a little bit more about why we chose those cutoffs, but they're all designed in a specific way. Dr. Negar Asdaghi:         Perfect. So a quick score that can be administered easily by different healthcare personnel. So, please tell us, before we go back to Nirav, about your paper's methodology. What were you hoping to expand on the existing knowledge with this paper? Dr. Diogo Haussen:         I'm just going to repeat a few things, but our mobile stroke unit is equipped obviously with a CT machine and is staffed by an EMT driver and emergency medicine registered nurse, a paramedic, and a CT technician. So, a remote evaluation of patients by a vascular neurologist is then performed through this video-based telemedicine platform. The MSU, as he mentioned, is routinely accompanied by an Advanced Life Support–staffed ambulance, which responds to the suspected stroke calls, and sometimes then calls in or calls off the potential of our stroke code. And as part of this MSU evaluation, the FAST-ED is then administered by the MSU paramedic via the FAST-ED smartphone application that was designed. And then an independent NIH is performed by the registered nurse within the MSU. So, subsequently, the patient is transferred into the MSU itself and a non-conscious CT is performed. Once the scan is completed, the patient is evaluated by the vascular neurologist in a two-way video conference where the FAST-ED is then estimated by the physician. Dr. Diogo Haussen:         So, all patients are then transferred to the comprehensive stroke center, where further evaluation, including vascular imaging, is performed. The vascular imaging data was formerly read by neuroradiology and then followed by an independent read by the vascular neurologist for the identification of large vessel occlusion strokes, which we define in this paper as an intracranial occlusion off the internal carotid, the M1 or the M2 branches of the middle cerebral artery or the basilar artery. The study encompassed our initial experience, which was from May of 2018 till August of 2019. And we have some other goals, but the initial experience was planned to allow us to investigate, once again, this most important feature, which is the potential reliability of the estimation of the FAST-ED score by paramedics in the field. Dr. Negar Asdaghi:         Perfect. Thank you for this background, Diogo. Now Nirav, we're ready to hear about the study results. Dr. Nirav Bhatt:               So, in the first 15 months of operation of the mobile stroke unit, we analyzed data on 173 eligible patients. We had an almost equal distribution of our patients in terms of gender. We had 52.6% females, and the majority of our patients were Black. We found that FAST-ED scores matched perfectly between paramedics and vascular neurologists 56% of the time, and there was only a zero to one point difference in 91% of the cases. Cases in which the discrepancy of the FAST-ED score between the paramedic and vascular neurologist was two points or higher were less than 9%. Overall, the intraclass correlation of FAST-ED score between the paramedic and the vascular neurologist was 0.94, indicating excellent interrater reliability. Dr. Negar Asdaghi:         Thank you. You found a higher interrater reliability between the paramedics and vascular neurologists for scores of three or above on the FAST-ED scale. Higher FAST-ED scales also were more specific in terms of detection of a target vessel occlusion. How should your results be interpreted in our day-to-day practice, Nirav? Dr. Nirav Bhatt:               That is correct. When vascular neurologists recorded a FAST-ED score greater than or equal to three, paramedics also recorded a FAST-ED score greater than or equal to three in 87.5% of the instances, and when a vascular neurologist recorded a FAST-ED score of greater than or equal to four, the paramedics also recorded a FAST-ED score of greater than or equal to four in 92% of the instances. This is suggestive that when the patients presented with a moderate to a severe stroke, that EMS paramedics were highly reliable in identifying the neurological severity of these patients. This provides a sound basis for more widespread utilization of FAST-ED as a simple and reliable tool that can be utilized by paramedics to identify stroke severity in the field. Dr. Negar Asdaghi:         Thank you, Nirav. Simple indeed. I know Diogo briefly alluded to this, but can you also tell us a little more about how FAST-ED compares to the other prehospital scoring systems in terms of their interrater reliability and LVO prediction? And what should be our takeaway message from your paper? Dr. Nirav Bhatt:               Yes, absolutely. So, just to give you an example, the Los Angeles Motor Scale, LAMS, tests for facial droop, arm drift, and grip strength, but does not really test for cortical signs. We know that a lot of patients with subcortical strokes will have those features, meaning facial droop, arm drift, and decreased grip strength. Similarly, while RACE is very similar to FAST-ED, it tests for leg weakness in addition to what FAST-ED does. It also puts a lot more emphasis on the facial droop as compared to FAST-ED. And with that, I want to draw your attention to a study that we cited in our paper where these scales were compared head to head, and while the accuracies of all the prehospital scales were found to be acceptable, the accuracy of RACE and LAMS were slightly higher than that of FAST-ED. However, it should be noted that in almost 35% of the cases, a complete FAST-ED score could not be reconstructed largely due to data and availability regarding patients' neglect. Dr. Nirav Bhatt:               This percentage for data and availability for RACE was even higher, meaning we have to consider the feasibility of these scales when we recommend the widespread adoption of these scales into our communities. Overall, the takeaway from this entire study is we strongly believe that there needs to be a system in place for prehospital stroke triage in order to identify and transport the patients to the right destination rapidly. However, the choice of individual scales should be made after consideration of the geographical characteristics of a particular community, and also that experience and that comfort with the level of training required for reliable performance of each of these scales by the EMS personnel. Dr. Negar Asdaghi:         Thank you so much, Nirav. More to come on this, I'm sure, in the future. Thank you for joining us on the podcast today. Dr. Nirav Bhatt:               Thank you so much. It was our pleasure. Dr. Negar Asdaghi:         Thank you, Drs. Nirav Bhatt and Diogo Haussen. Thank you for joining us on the podcast today, and we look forward to covering more of your work in the future. This concludes our podcast for the August 2021 issue of Stroke. Please be sure to check out the August table of contents for the full list of publications, including a special report on the safety of the mobile stroke units and a descriptive review of the amount of radiation exposure to the public, patients, and staff from these mobile units. With that, as our work to save every brain cell from ischemic and hemorrhagic damage continues, we invite you to stay alert with Stroke Alert. Dr. Negar Asdaghi: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 6 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the July 2021 issue of Stroke: “Prevalence and Clinical Correlates of Intracranial Dolichoectasia in Individuals With Ischemic Stroke” and “Dose Escalation and Safety of Capsaicin for Cerebral Perfusion Augmentation.” She also interviews Dr. Osama Zaidat about his article “Impact of Age and Alberta Stroke Program Early Computed Tomography Score 0 to 5 on Mechanical Thrombectomy Outcomes.” Dr. Negar Asdaghi: 1) Is intracranial dolichoectasia the new intracranial atherosclerotic disease? 2) What is the latest on collateral flow improvement through sphenopalatine ganglion stimulation in patients with acute ischemic stroke? 3) Is endovascular therapy futile in patients presenting with a low ASPECTS score? These are the topics that we will cover in today's podcast. You're listening to the Stroke Alert Podcast. Stay with us. Dr. Negar Asdaghi:         From the Editorial Board of Stroke, welcome to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. Dr. Negar Asdaghi:         For the July 2021 issue of Stroke, we have a systematic review and meta-analysis of safety and efficacy of dual antiplatelet therapy with P2Y12 inhibitors and aspirin versus aspirin monotherapy in patients with mild ischemic stroke or high-risk transient ischemic attack, which I encourage you to review in addition to today's podcast. Dr. Negar Asdaghi:         Later in the podcast, I have the pleasure of interviewing Dr. Osama "Sam" Zaidat, Professor of Neurosurgery and Neurology at Bon Secours Mercy Health Neuroscience Institute. Dr. Zaidat will speak to us about his work on endovascular therapy in patients presenting with a large ischemic core as determined by a low ASPECTS score on presentation. But first with these two articles. Dr. Negar Asdaghi:         In the setting of acute ischemic stroke, intracranial large-vessel disease is often equated with processes which result in narrowing of the intracranial vessels, such as what is seen in the setting of intracranial atherosclerotic disease, or ICAD, where much research has focused on the degree of noumenal stenosis. Less is known about intracranial dolichoectasia, or IDE, which is characterized by ectasia, that is dilation, or dolichosis, which is increased length or tortuosity of the intracranial arteries. Dr. Negar Asdaghi:         IDE can occur due to inflammatory, infectious, or genetic abnormalities. But much like its stenotic counterpart, or ICAD, most cases of IDE are diagnosed in the setting of uncontrolled vascular risk factors. Keeping in mind that the pathophysiology of ICAD and IDE are entirely different. Dr. Negar Asdaghi:         Despite recent advances in recognition of IDE beyond an arteriopathy involving the basilar artery alone, the prevalence of IDE in patients with acute ischemic stroke is unknown, in part related to the lack of a unified diagnostic criteria for this condition. In this issue of the journal, Dr. Victor Del Brutto from the Division of Cerebrovascular Disease at the University of Miami and colleagues studied the prevalence and clinical correlates of IDE among 211 consecutive acute ischemic stroke patients admitted to a tertiary care hospital during a four-month period. IDE was defined as either ectasia or dolichosis of at least one proximal intracranial artery equal or greater than two standard deviations from the study population mean as measured by semi-automated segmentation method. Dr. Negar Asdaghi:         So, what they found was that IDE was identified in 24% of stroke cases: a small percentage, which was only 5%, with only isolated ectasia; 9.5% with isolated dolichosis; and the rest with both ectasia and dolichosis. Anterior and posterior circulation were equally involved, but not surprisingly, the basilar artery was the single most common affected artery by IDE. After a complete stroke work-up, stroke was classified as cardioembolic in 25.5% of their population, large-artery atherosclerosis in 30%, small-artery occlusion in 14.5%, and undetermined in 25.5% of cases. Using cardioembolic stroke as a reference, the prevalence of IDE was significantly higher across strokes of undetermined etiology with odds ratio of 2.8. And there was a trend towards higher IDE prevalence in those whose stroke was classified as small-vessel disease. Dr. Negar Asdaghi:         Furthermore, IDE was considered the most likely pathogenic mechanism in 6% of the entire cohort, which represented over 23% of strokes initially categorized as undetermined etiology and 21% of those with strokes categorized in small-vessel disease category, suggesting a likely causal correlation between parent vessel dolichoectasia and occlusion of the small vessel perforators in these patients. Dr. Negar Asdaghi:         The authors concluded that IDE is an arteriopathy frequently found in patients with acute ischemic stroke and likely responsible for a sizable fraction of strokes initially categorized as undetermined etiology and those with small-vessel ischemic disease. Dr. Negar Asdaghi:         The concept of freezing ischemic penumbra refers to either pharmacological or non-pharmacological interventions that aim to reduce tissue energy requirements for increased oxygen delivery and collateral perfusion to the tissue at risk for ischemia while awaiting revascularization therapies. Sphenopalatine ganglion, or SPG, electrical stimulation via an injectable implant had been previously shown to augment collateral flow and improve clinical outcomes in patients with acute ischemic stroke. Dr. Negar Asdaghi:         The benefit of SPG stimulation is likely conferred not only from its potent collateral augmentation properties, but also from other mechanisms, such as blood-brain stabilization, direct neuroprotection and enhancement of neuroplasticity, though the need to implant the device diminishes its applications in the hyperacute stroke setting. Dr. Negar Asdaghi:         Capsaicin, the pungent ingredient in hot chili peppers, is an SPG chemical stimulator, which affects the trigeminal vascular system, resolving in vasodilation and improved collateral flow. In the paper titled "Dose Escalation and Safety of Capsaicin for Cerebral Perfusion Augmentation: A Pilot Study," Dr. Juan Manuel Marquez-Romero from IMSS Institute in Mexico and colleagues completed a dose escalation study of capsaicin ranging from 33 to 165 micromole topically applied to the posterior surface of the subject's hemi-palate in 30 healthy volunteers. By applying capsaicin in the palate mucosa, the SPG can be stimulated directly through the greater and lesser palatine nerves while minimizing that pungent sensation. Dr. Negar Asdaghi:         During the 20-minute applications, the investigators used transcranial Doppler to study various flow parameters, including the mean velocity, positivity index, and the CBF index, or cerebral blood flow index, over the middle cerebral artery. The median age of participants in the study was 21. All reported having consumed capsaicin in their diets sometimes in the past. So, what they found was, at baseline, TCD measurements and the calculations were all within normal limits. All the tested doses of capsaicin reduced augmentation of the MCA mean velocity while reducing the positivity index. The effects peaked between the five and the 10 minutes measurements and then returned to basal levels for all doses of capsaicin, except for the 66 micromole dose group, in which the effect remained stable with the same pattern. There were no side effects reported, and the investigators found no correlation between the perceived pungency and the dose of capsaicin administered. Dr. Negar Asdaghi:         The authors noted that capsaicin appears to produce a hemodynamic response in the intracranial circulation, similar to the one achieved with SPG electrical stimulation. Understanding that this is data from a small pilot study, the results are hypothesis-generating at this point, and further research is required to measure the safety and efficacy of capsaicin in the elderly stroke population. Dr. Negar Asdaghi:         Endovascular thrombectomy is an effective evidence-based treatment to improve outcomes in patients with acute ischemic stroke. Studies to expand the applications of this therapy to late-presenting patients, those with large ischemic cores, or distal occlusions are leading to major changes in clinical practice worldwide. Whether the ischemic core is measured by volumetric methods or by ASPECTS score, the presenting infarct core beyond which endovascular therapy is futile, or even potentially harmful, has not been established. Dr. Negar Asdaghi:         So, the commonly encountered question in routine practice is whether thrombectomy should be offered to patients with presenting low ASPECTS. In other words, what are the characteristics of patients who continue to benefit from thrombectomy despite presenting with a large ischemic core? In the paper titled "Impact of Age and ASPECTS of 0 to 5 on Mechanical Thrombectomy Outcomes: Analysis From the STRATIS Registry," we learn about the outcomes of thrombectomy-treated patients stratified into low and high ASPECTS categories and the specific interaction between increasing age and low ASPECTS. Dr. Negar Asdaghi:         I'm joined now by the first author of the paper, Dr. Osama "Sam" Zaidat, who's one of the principal investigators of the STRATIS Registry. Dr. Zaidat, of course, needs no introduction to our listeners. He's the past president of the Society of Vascular and Interventional Neurology. He's a leader in the field of neurointerventional therapists and currently is the neurology residency director and the endovascular fellowship director at the Bon Secours Mercy Health Neuroscience Institute. Welcome Sam. Welcome to our podcast. Thank you for joining us. Dr. Osama Zaidat:           Thanks for having me. I really appreciate Dr. Negar and the Stroke journal team for featuring our research and our results and sharing it with your listeners today. Thank you for having me. Dr. Negar Asdaghi:         Thank you very much. So, let's start by learning about the STRATIS Registry. Can we please hear an overview of the registry? Dr. Osama Zaidat:           Yes, that's a good question because this is kind of the database where we really go and mine for questions that we still need answers for in the stroke field. For example, and specifically in the thrombectomy field, the STRATIS Registry was designed to evaluate post-marketing, real-life experience and results using Solitaire device stent retriever as the first mechanical thrombectomy choice. So, if you have enrolled a patient, that means the first attempt to take the clot out was using the Solitaire device for large vessel occlusion that presented with acute ischemic stroke. Dr. Osama Zaidat:           We planned about 1,000 patients, so we needed a bigger patient population than the randomized trial. So, we have 1,000 patients treated with Solitaire device within eight hours from symptoms onset with large vessel occlusion presenting with acute ischemic stroke. To do that, we needed 55 medical centers with various clinical experience, various volume, and various operator experience because that really reflects a little bit of not a selection bias, meaning that data can be reproducible and can be validated across different spectrum of centers and neurointerventionalists and stroke neurologists for that matter. Dr. Osama Zaidat:           This also, the aim of it — the spectrum — in addition to validate and reproduce randomized clinical trial data, to try to address questions that are hard to address with a clinical trial. For example, what's the outcome in nonogenarians? What's the outcome in tandem lesion? What's the outcome in different technique we use in the lab? What's the outcome of large infarct sites? Until we find the randomized trial, we can have some signals from those large registry to really inform future randomized trial. Dr. Osama Zaidat:           So that's kind of the scope of the STRATIS Registry. Dr. Negar Asdaghi:         Perfect. So truly a real-life, large cohort of endovascularly-treated patients, allowing us to look at the many aspects of this therapy in real life, rather than in a randomized setting. Dr. Negar Asdaghi:         So, now coming to the current paper, we often think of low ASPECTS as a phenomenon of late presenters. Yet the current paper included endovascularly treated patients in a relatively early time window, within eight hours of symptom onsets. Please walk us through what percentage of your study patients actually had low ASPECTS, and what were their baseline characteristics as compared to high ASPECTS of patients? Dr. Osama Zaidat:           That's an excellent question. STRATIS was basically a core lab adjudicated. So, independent, experienced core lab have read all the angiogram outcomes and have read all the CT scan, all the MRI, so he doesn't know about what's going on at 90 days functional outcome. And we wanted to restrict the analysis to the available baseline CT scan that was evaluated by the core lab, like you mentioned. So, from the 984 evaluable patients, only 763 patients, almost 75%, had the CT scan available for the core lab and the core lab blinded to the functional outcome and blinded to the angiographic outcome have read the ASPECTS. Dr. Osama Zaidat:           So, this is a centrally read ASPECTS score by experienced interpreter that read them. So, 75% has available CT, or 763 patients. From those 763 patients, as a clinical practice out there, 92.5% had an ASPECTS of six to 10, consistent with the guidelines that we all treat on everyday basis. If the CT scan looks good, we treat. STRATIS is consistent with that. 92.5% had an ASPECTS of six to 10, or 706 patients. 7.5%, close to 8%, of the site had enrolled patients with low ASPECTS, or 57 patients have low ASPECTS, zero to five. So, about one out of maybe eight, less than one out of 10 patients, had low ASPECTS at the time the STRATIS was conducted between 2014 and 2016. Dr. Osama Zaidat:           People were following the AHA/ASA guideline, with an ASPECTS of six to 10 the majority of the time, like in the STRATIS. It came up to 92% with ASPECTS and 8%, very low ASPECTS, for example. Dr. Osama Zaidat:           So, kind of really what we like about the STRATIS, the real-life practice tried to adhere to the guideline for most of the time. However, we managed to find good sample size, 57, that people kind of did not necessarily, for one reason or another follow the guidelines. Dr. Osama Zaidat:           And I feel like the first things, when you asked me the second question, the baseline characteristics, is there is a difference between the low ASPECTS group and the good ASPECTS. The first thing, really, that stand out-- the young age. So, the age was 62 years versus almost 69. So there's absolute difference of about seven years between low ASPECTS and good ASPECTS, six to 10 versus less than five. And the P value was significant. The listener can look at the paper, but it was a very statistically significant ASPECTS. Dr. Osama Zaidat:           My feeling and my interpretation to this difference is that the physician felt, even with the low ASPECTS, he wanted to give the younger population a chance and take the clot out and see if they do well. So, I think they were more aggressive to take a low ASPECTS in a young patient than not necessarily offering them a mechanical thrombectomy, which probably mirrors what you do and what I would do in real life. If you have 55 years old and ASPECTS of four, you want to say, "Let me take the clot out and see how the functional status pans out." So, that's one thing. Dr. Osama Zaidat:           The other difference, besides the difference in age, slightly more diabetic in the low ASPECTS, but it didn't reach statistical significance. Slightly less AFib than the ASPECTS of six to 10. What really also makes sense, besides the age, is the stroke scale, the stroke severity scale. The stroke severity scale was higher in the low ASPECTS, which makes sense. The infarct is completed, the patient had a worse stroke scale at baseline. So, their stroke scale was almost 20 versus 17, consistent with literature and the good ASPECTS. So, 17 in the good ASPECTS, the average score, and 20 in the low ASPECTS, slightly higher stroke severity scale. Dr. Osama Zaidat:           What also makes sense in the low ASPECTS is you have more ICAT occlusion. When you have an ICAT occlusion, will lead to loss of collateral, will lead to more tissue, and more core infarct volume with a completed stroke. Dr. Osama Zaidat:           So, I feel like also that's consistent. So, the difference between the baseline characteristic can be summarized with younger age, higher proximal occlusion, and more severe stroke than usual. And then the general anesthesia use was more often because now you have more severe stroke, now you have more core infarct volume, you are more likely to need anesthesia than not. So again, that's also consistent. Dr. Osama Zaidat:           The onset to puncture time, because you may need more anesthesia, the patient was sicker to stabilize, the onset to puncture time was also more prolonged in the lower ASPECTS group versus the good ASPECTS. Dr. Osama Zaidat:           So, those are the differences at baseline, Negar, as you can see. Not sure how you think about it, how you feel about them as well, but kind of the best way to explain them. But I'm curious also to hear your thought about them, if you have any comment or questions. Dr. Negar Asdaghi:         Yeah, I think I want to repeat just what you said and the point you raised because it's, as you mentioned, it is not surprising to see that low ASPECTS patients are presenting with more severe strokes with higher NIH Stroke Scale, have more tandem occlusions or more proximal occlusions. They're obviously sicker patients. So, those differences were not surprising at all to a reader of your paper. What was surprising is that age gap that you mentioned within your low ASPECTS and high ASPECTS category, and that from the registry-based study is actually, exactly what you mentioned, is a signal that clinicians are more comfortable to push the guidelines boundaries in the younger population. That's something that has to be taken with a grain of salt, because we're not talking about a population-based study where we're comparing age groups between low ASPECTS and high ASPECTS. We're talking about a highly selected group of individuals who've already received endovascular therapy, and now we're comparing the age groups depending on their lower ASPECTS. So that's an important distinction that you beautifully outlined for our listeners. Dr. Negar Asdaghi:         Now, coming to your primary outcomes, please tell us about the reperfusion rates in the study and comparing the low to high ASPECTS categories. Dr. Osama Zaidat:           That's an excellent question, to try to see — in spite of you're taking the chances — and treating patients with low ASPECTS. How did they do functionally and angiographically? The angiographic outcome and revascularization success can be a surrogate of functional outcomes. So, let's try to review with your listeners and readers the reperfusion outcome, like you mentioned. If you look at the reperfusion outcome in the paper, and I direct the readers and the listeners to Table 2. Specifically, what stands out is the rate of complete reperfusion because that's the one with the highest difference and significance between the two groups, which is TICI 3. The frequency of obtaining TICI 3 was 83 patients out of 662 that had an angiographic outcome with a good ASPECTS was zero out of the 55 patients; none of them had a TICI 3 complete occlusion. Dr. Osama Zaidat:           What's really astonishing in the result is the fact that there's a statistical difference between complete reperfusion, TICI 3, between the low ASPECTS group and cohort versus the good ASPECTS cohort of six to 10, and the theory and explanation, one of the explanations at least that may be plausible, is the fact that you probably had a good collateral in the good ASPECTS to have less core infarct, and the good collateral reduced the clot length, because the pial flow goes all the way backward into the clot in a retrograde fashion and makes it probably more likely to have a successful removal of the clot and hence achieving a TICI 3. Dr. Osama Zaidat:           So, but overall, if you just lump TICI 2b or higher, the standard definition of successful reperfusion as TICI 2b or higher, there was no statistical difference between the group. It was 85.5% in the low ASPECTS and 87.6% in the good ASPECTS group. So, that was not statistically different. Dr. Osama Zaidat:           When we looked at the first-pass effect, there was a trend toward more first-pass effect in the good ASPECTS group, but 61% and 57% in the low ASPECTS. That's defining first pass as TICI 2b from the first attempt, and not TICI 3, for example. Dr. Osama Zaidat:           So again, you can see that your success of reperfusion probably related to the ASPECTS in an indirect way, as a surrogate of collateral. Poor collateral tissue dies quickly, low ASPECTS and higher core infarct volume, and hence low success of reperfusion, but again, the only statistical significance here is in the complete reperfusion and TICI 3. Dr. Osama Zaidat:           So, if you kind of evaluate if the reperfusion outcome translated to a difference in the functional outcome, yes, indeed. In the low ASPECTS group, three out of 10 patients achieved independence at 90 days, or to be precise, 28.8% of that cohort and population had mRS of zero to two at 90 days in comparison to 59.7% in the good ASPECTS group. Dr. Osama Zaidat:           So, it's almost six out of 10 patients in the good ASPECTS versus three out of 10 patients in the low ASPECTS group. Still, they achieved a good outcome because we don't have a control group, but in comparison to the good ASPECTS, it's lower outcome, as you can see on Table 2, as well. Dr. Osama Zaidat:           The mortality is higher; it's almost 31% in the low ASPECTS versus 13.4% in the good ASPECTS group. The symptomatic hemorrhage rate was 7% versus almost 1% only in the good ASPECTS group. So, functional outcome across the board is lower than the good ASPECTS, but since this is not a randomized trial, we don't know if doing nothing to those low ASPECTS will necessarily yield similar results. Dr. Osama Zaidat:           So, it could be better than control, but clearly it's the likelihood of the patient doing better correlates with a better ASPECTS, which we all kind of already know, but we want to try to identify the group beyond which, like you started, Dr. Negar, beyond which the mechanical thrombectomy may be futile. Dr. Negar Asdaghi:         Right. So a very unfortunate vicious cycle almost, that those who needed the first-pass effect, TICI 3 perfusion the most actually ended up achieving it less than their high ASPECTS counterpart, as you mentioned. And again, it's important to understand that these observations are based on an observational large registry study. Dr. Negar Asdaghi:         Now, you found an important interplay between age and low ASPECTS in the clinical outcomes from thrombectomy in your study. Can you please elaborate on those findings? Dr. Osama Zaidat:           Absolutely. That's an excellent question because that's kind of the unique part of our research and our paper is we're trying to really combine the low ASPECTS with another variable that we all know as a clinician and people who treat stroke on a daily basis, that influence outcome. If you combine two poor predictors of good functional outcome. A good predictor that they could predict the outcome one way or another in either direction, good or bad outcome, you know ASPECTS was one of them, and age. So, we wanted to see if there's a threshold beyond which, if you combine the two, you can identify the patients that are almost less likely to benefit and the resources and the, if you may say, the resources and the message to the patient and their families should be with this consideration to try to provide guidance to the clinician nowadays. Dr. Osama Zaidat:           So, based on the previous data, we kind of wanted to really trichotomize the age into young, less than 65, 65 to 75, and 75. Dr. Osama Zaidat:           There is enough signal in the literature out there that 75 with low ASPECTS is a good cutoff to see. And indeed, we looked at that and we compared those three cohorts. We compared less than 65, 65 to 75, and more than 75 in the low ASPECTS group to see which one stands out. Now, the sample size is fairly small. So, I want to caution the reader and the listener to us today that this is a good signal, this is a good hypothesis-generating result; however, it needs to be reproduced in, again, large sample size and see if other researchers and investigators can have similar results. Dr. Osama Zaidat:           What we've found in this group of more than 75 and less than 65, I feel like the equipoise should remain between 65 and 75, but less than 65 is probably beneficial more than 75. Unfortunately, we could not find a strong signal of good functional outcome in those people more than 75. Dr. Osama Zaidat:           We had 12 patients; none of them achieved (mRS of) zero to two at 90 days, 0% at zero to two. And their mortality was close to 60%, and their symptomatic hemorrhage was close to 15%. So, when you treat a low ASPECTS (zero to five), and they are older than 75, the current data or the current signals suggest that the likelihood of good outcome is 0%, if you consider good outcome as (mRS) 0-2, and the likelihood of mortality close to 60%. More than half of them will die, and the likelihood of symptomatic hemorrhage is going to be higher, close to 16%. Dr. Osama Zaidat:           So, that's the cohort that we have to be very cautious about. I think the younger cohort had even better outcome than the overall zero to five. If you recall, from the previous question of Dr. Negar, discussion that the overall was 28.8%. If you restrict the analysis to the young, they have probably a good plasticity, good recovery, good rehab potential. If you look at those less than 65, their mRS zero to two went up to 44.8%, which is decent, acceptable, functional outcome in those young patients, and their mortality went down from 30% or 31% to 20%, and the symptomatic hemorrhage from 7% to 6%. So, it seems that there is a good signal in those less than 65 for being aggressive and try to provide them with a therapy, less aggressive with 75, and in between, where we really have no clear answer, and their mRS score was close to 20% versus 44 and 0%. So 44%, 18%, and 0%; less than 65, 65 to 75, and older than 75. Dr. Osama Zaidat:           Hopefully, this will shed the light and make the decision-making in the middle of the night probably more informed to the best of our knowledge nowadays. Dr. Negar Asdaghi:         Right. And how do these rates, the symptomatic intracerebral hemorrhage rates and mortality rates, compare in the low ASPECTS group as compared to those reported from the randomized trials? Dr. Osama Zaidat:           This is an excellent question because the randomized clinical trial had the advantage of having a control group, and the HERMES meta-analysis in all patient-level meta-analysis have looked at the CT ASPECTS. However, they combined it with the MRI ASPECTS, so kind of a heterogeneous population. It's not exactly the same, like the STRATIS low ASPECTS study that we're discussing today, and they have a very small sample size. What they found in that group from three to five, that 31%, so almost identical- if you think about -it to our outcome in the ASPECTS group. HERMES group didn't go to the 24 hour; they did up to six hours. Maybe the ESCAPE was 12 hours, the only one with the expanded time window, but interesting that their three to five ASPECTS had a good outcome of mRS zero to two at 31% versus 16% in the tPA group with an absolute difference about 15%. Dr. Osama Zaidat:           So, again, our result is consistent with the HERMES patient-level meta-analysis. However, in the (ASPECTS) zero to two group, they found the futility in the zero to two. They found 0%  (90 day mRS) in the mechanical thrombectomy. We didn't have that much of a sample size of zero to two (ASPECTS), and we didn't obtain a 0% (90 day mRS) similar to them, but we did obtain a 0% (mRS) if you are zero to five (ASPECTS) and older than 75. They have not really looked at the intersection and the interaction with the age like we looked at it, for example. So again, in their trial, the three to five (ASPECTS) is consistent with the ASPECTS with our low ASPECTS trial at 28.8% (90 day mRS) versus 31% in the HERMES meta-analysis, for example. Dr. Osama Zaidat:           MR-CLEAN group, however, even they have a better outcome, zero to four (ASPECTS), than us and HERMES, at about (90 day mRS) 36.7%. Their sample size was very small, less than 30 patients in the whole cohort, almost half the size of our sample size. So MR-CLEAN showed also, so if you think about it, the registry is close to 30% (mRS of 0-2 at 90 days), the randomized trial 31% to 35%. So, we are within the confidence interval of what's the likelihood of good outcome, which is almost one-third of the patients with low ASPECTS would have a good outcome. Dr. Osama Zaidat:           The good news that the standard care therapy with tPA gives you half of that outcome almost. So, there's a good signal that future randomized trial may be positive if they follow the STRATIS registry, HERMES, or MR-CLEAN data. Dr. Negar Asdaghi:         So, Sam, very important information and percentages to keep in mind as we counsel patients and family members, especially those elderly patients we see with large ischemic cores and low ASPECTS in the early timeframe from stroke onset. Dr. Negar Asdaghi:         I know you alluded to the future randomized trials, but I want to end with our takeaway message from your study, and how do you see these randomized trials in low ASPECTS population unfolding in the future? Dr. Osama Zaidat:           I mean, this is an excellent question that has two aspects about it. One is, can we use some of this data to guide us nowadays until we have future randomized trial? And I think each patient is individual, each family's individual family. I want the listener and the readers to take their time to explain the data to the patient. They have to keep in mind that there is a small sample size and also how definitive they feel about their reads with ASPECTS score, how definitive they feel about the large core infract, and is this plus minus one, is five the cutoff, in the elderly? Is it four or zero? Dr. Osama Zaidat:           So, I think if you are confident that your score may be zero to three, and the patient is more than 75, is more justifiable, kind of, at that extreme and to say this is less likely to benefit (from endovascular therapy) based on collective data. Dr. Osama Zaidat:           Again, without randomized trial, it's hard to strongly send a message, don't treat them (endovascularly) and futile. But based on HERMES, based on our analysis, extreme ASPECTS in older than 75, probably you have to be cautious taking them to the (cath) lab, for example. Now that's been said, the future trial will answer that. We are running the randomized trial ourself, myself and my co-PI, Dr. Albert Yoo, are doing an international TESLA trial. We are close to 125 patients randomized from two to five ASPECTS score and up to 85 years of age. So, we have almost 60-plus randomized in each arm, and we are hoping if we continue at this rate in the next two years to complete the enrollment and have some answer. Dr. Osama Zaidat:           Our sample size-it's an adaptive design trial called TESLA Trial--and our sample size is 300 patients. In Germany, there is an ongoing Tension trial. In U.S., there is another trial that mixed a CT scan with the perfusion for large core infarct called SELECT 2. That's ongoing, as well. And then a fourth trial, which is the IN EXTREMIS trial in France, that also going to answer it, and hopefully we can do a meta-analysis among those four large core infarct trials. Dr. Osama Zaidat:           Some of them allowed diffusion MRI, as well as CT scan; some of them allowed perfusion. And this way, if we combine all our data together, we can have probably a more reliable and precise answer to this important clinical question that has been identified by the National Institutes of Health [inaudible 00:36:43] as priority number one for thrombectomy following what we know so far. It's ranked as the next question that needs answer. Dr. Negar Asdaghi:         Dr. Sam Zaidat, congratulations on this work, and we look forward to the completion of TESLA results and the results of other randomized trials. Thank you for being with us today. Dr. Osama Zaidat:           Thank you for having me, and I appreciate the listener tuning in, and I appreciate the ASA and the journal team for having me. This is on behalf of my co-authors, the sponsor of the registry. Thank you very much. Dr. Negar Asdaghi:         Thank you. Now, before we end the July podcast, I want to draw your attention to a special invited report prepared by the Stroke Council Leadership on behalf of the American Heart and Stroke Associations on diagnosis and management of cerebral venous sinus thrombosis, or CVST, with vaccine-induced immune thrombotic thrombocytopenia. Dr. Negar Asdaghi:         This report is to heighten clinicians' awareness regarding the six cases of CVST, with thrombocytopenia in patients who received the Johnson & Johnson vaccine in the United States. Similar thromboembolic events were reported in Europe following the administration of AstraZeneca vaccination. These are adenoviral vector–containing vaccines, which are mechanistically different from the mRNA SARS-CoV-2 vaccines produced by Pfizer and Moderna. Dr. Negar Asdaghi:         The putative mechanism of vaccine-induced thrombotic thrombocytopenia is believed to be related to the leakage of DNA from the adenovirus-infected cells that subsequently binds to the platelet factor 4 and triggers the production of auto-antibodies against platelets. Dr. Negar Asdaghi:         The authors emphasize that while we wait for further research on the causal nature of the relationship of vaccines to CVST with thrombocytopenia, it is important to keep in mind that the reported risk of CVST associated with COVID-19 infection itself is far greater than that associated with vaccination. Dr. Negar Asdaghi:         And with that, we conclude our podcast for the July 2021 issue of Stroke. On behalf of the Editorial Board, I want to thank you all for listening and a special thanks to our healthcare providers and clinicians who continue to work on the front lines of this pandemic. We hope that you find this information useful, and until our next podcast, stay alert with Stroke Alert. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

Stroke Alert June 2021 On Episode 5 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the June 2021 issue of Stroke: "Preexisting Mild Cognitive Impairment, Dementia, and Receipt of Treatments for Acute Ischemic Stroke” and “Body Mass Index in 1.9 Million Adolescents and Stroke in Young Adulthood.” She also interviews Dr. Shyam Prabhakaran, from the University of Chicago, about his article "Predictors of Early Infarct Recurrence in Patients With Symptomatic Intracranial Atherosclerotic Disease." Dr. Negar Asdaghi: 1) Do people with mild cognitive impairment receive the same quality of stroke care as their cognitively normal counterparts? 2) Is there a causative relationship between the alarming rise in adolescent obesity and the rise in the incidence of stroke under the age of 50? 3) What are the independent predictors of radiographic recurrence in patients with symptomatic intracranial atherosclerotic disease? These are the topics that we will cover in today's podcast. You're listening to the Stroke Alert Podcast. Stay with us. Dr. Negar Asdaghi:                        From the Editorial Board of Stroke, welcome to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the June 2021 issue of Stroke, we have a range of publications that cover a variety of topics from activation of neuroinflammatory pathways and intracerebral hemorrhage to predictors of outcome in patients with mild and rapidly improving ischemic stroke, which I encourage you to review, in addition to our podcast. Later in today's podcast, I have the privilege of interviewing Dr. Shyam Prabhakaran from University of Chicago on his work with various radiographic biomarkers as predictors of outcome in patients with symptomatic intercranial atherosclerotic disease. But first, with these two papers. Dr. Negar Asdaghi:                        In the United States, one in five adults over the age of 65 have mild cognitive impairment, and one in seven have a formal diagnosis of dementia. With our aging population, these numbers are estimated to triple by year 2050. Prior studies suggest that patients with dementia are less likely to receive evidence-based stroke care as compared to those with normal cognition. Less is known about the quality of stroke care amongst patients with mild cognitive impairment. In their paper titled "Preexisting Mild Cognitive Impairment, Dementia, and Receipt of Treatments for Acute Ischemic Stroke," Dr. Deborah Levine from Departments of Neurology and Internal Medicine at the University of Michigan and colleagues studied the quality of care in acute ischemic stroke patients with mild cognitive impairment, or MCI, and preexisting dementia as compared to patients with normal cognition. Dr. Negar Asdaghi:                        This was a cross-sectional analysis of prospectively obtained data on adults with acute ischemic stroke included in the Brain Attack Surveillance in the Corpus Christi project from 2008 to 2013. Primary outcome of the study is a composite quality measure of defect-free care calculated by dividing the number of treatments that a patient received by the number of treatments they were eligible to receive. Defect-free care was defined as receipt of seven stroke performance measures when eligible, and included administration of IV tPA, use of antithrombotic therapy by end of hospital day two, administration of DVT prophylaxis, assessment for rehabilitation, discharge on antithrombotic therapy, discharge on lipid-lowering therapy, and discharge on anticoagulation therapy for atrial fibrillation. Dr. Negar Asdaghi:                        Amongst 836 adults included in this study with a median age of 65, 58%, that's over half of the patients in this study, had some degree of cognitive impairment prior to their presenting stroke. 44% of patients with preexisting dementia received defect-free care as compared to 55% with either normal cognition or mild cognitive impairment. The difference, they did not reach statistical significance after adjusting for the sex, vascular comorbidities, and BMI in multivariate analysis. However, preexisting MCI remain an independent factor to be negatively associated with receipt of IV tPA echocardiogram and assessment for rehabilitation. Similarly, after adjusting for all confounders, preexisting dementia remained negatively associated with receipt of antithrombotic therapy by day two, lipid-lowering therapy at discharge, and receiving an echocardiogram. The authors highlighted their findings as a call to action to improve the overall delivery of stroke care and measures to all stroke patients, and caution that disparities noted in their study might contribute to differences in post-stroke outcomes, such as functional disability and recurrent stroke in the growing population of patients with mild cognitive impairment and dementia. Dr. Negar Asdaghi:                        Having a stroke at a young age has profound personal, societal, and economic implications. For the young stroke survivors, a long life expectancy after stroke, and the cost of long-term care pose huge challenges to healthcare systems, which are different than that encountered in the elderly stroke population. Over the past two decades, the incidence of ischemic stroke has substantially increased in the young, with adults under the age of 50 now comprising 10% of all ischemic stroke cases. This comes in parallel with the continuous rise in the prevalence of adolescent obesity in many Western countries, but the association between the two remains unclear. In the current issue of the journal, Dr. Aya Bardugo from the Department of Military Medicine, Hebrew University, in Jerusalem, and colleagues studied the association of adolescent body mass index, or BMI, with first stroke event in young adults as part of a nationwide population-based study of 1.9 million adolescents, followed for a cumulative 9.48 million person-years. BMI values were categorized in five groups of underweight, low-normal, high-normal, overweight, and obese. Dr. Negar Asdaghi:                        So, what they found was that the incident rate of any stroke and ischemic stroke increased gradually across the five BMI categories. Importantly, the hazard ratio for ischemic stroke became significant, even in the high-normal BMI group at 1.4, and increased to 2 for the overweight and 3.5 in the obese category. Though a similar increase in the rate of hemorrhagic stroke was noted, there was no significant association between BMI and hemorrhagic stroke in the study. Not surprisingly, many vascular risk factors, including high blood pressure and diabetes, were also elevated in the higher category BMI adolescents. However, alarmingly, these trends remain significant even after adjustment for age, sex, sociodemographic factors, and when the data was limited to otherwise healthy adolescents, those without diabetes and those without high blood pressure. Overall, the authors found that overweight and obese adolescents had approximately two- to threefold increased hazard for ischemic stroke that could present prior to the age of 30 irrespective of sex, race, ethnicity, and socioeconomic status. Dr. Negar Asdaghi:                        The authors detailed various mechanisms in which increased adolescent BMI may lead to stroke in the young, including progressive risk of large vessel intra and extracranial atherosclerotic disease, increased cardiovascular disease, and a shift to young onset heart failure and atrial fibrillation, as well as a strong association with being high BMI in children and adolescents, and that of obesity in adults. These findings are important observations as we face a growing epidemic of childhood and youth obesity worldwide with the potential to increase the future burden of stroke in young adults. Dr. Negar Asdaghi:                        Intracranial atherosclerotic disease, or ICAD, is an important cause of ischemic stroke worldwide. In addition to neurological deficits caused by index event, patients with ICAD remain at high risk for development of recurrent ischemic events. The risk of clinical recurrence is estimated to be between 12% to 20% at one year based on prior studies, despite best medical management. But recent studies have shown that up to 25% of patients with symptomatic ICAD have evidence of radiographic recurrence on follow-up MRI imaging. Dr. Negar Asdaghi:                        Who will remain stable and who will have more events with symptomatic ICAD is a common question that practicing clinicians struggle with in routine practice. The Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease, or the MYRIAD study, aimed to get us closer to that answer. Joining me now is Dr. Shyam Prabhakaran, Professor of Neurology and Chair of the Department of Neurology at the University of Chicago, who was one of the principal investigators of the MYRIAD study and the first author of the paper in the current issue of the journal titled "Predictors of Early Infarct Recurrence in Patients With Symptomatic Intracranial Atherosclerotic Disease." Good afternoon, Shyam. Thank you for joining us. Dr. Shyam Prabhakaran:              Thank you, and good afternoon to you. Dr. Negar Asdaghi:                        Thank you. Shyam, can you please start by telling us how MYRIAD's design was different from prior studies of symptomatic ICAD? And what were the main objectives of the study? Dr. Shyam Prabhakaran:              Sure, so MYRIAD was conceived as a study to really unravel and study the mechanisms of recurrent stroke after symptomatic ICAD presentation. Prior studies, I think, have really helped in many ways, obviously to understand the natural history of the disease, including through clinical trials, where we learned about the different interventions that could be applied, medical and endovascular, through WASID and then SAMMPRIS. However, both of those studies, which provided probably the bulk of information about the disease in multi-center study, did not really focus on mechanisms, per se, understanding it through biomarkers, understanding whether certain subsets of patients have higher or lower risk of recurrence. So, MYRIAD was conceived to try to tackle that particular aspect of research that we felt was understudied. Dr. Negar Asdaghi:                        Yes, thank you. Traditionally, as you mentioned, the location and the degree of stenosis have been considered as important radiographic factors to predict outcomes in symptomatic ICAD. MYRIAD looked at many more imaging biomarkers than just degree of stenosis and the location. Can you please elaborate on those radiographic biomarkers that were included in MYRIAD? Dr. Shyam Prabhakaran:              Yeah. So, again, MYRIAD wanted to explore these imaging biomarkers, and we split them into three categories. One was biomarker of antegrade flow. What would help us understand the amount or volume of flow through a particular diseased artery? And we used quantitative MRA for that, which is a technique that's been around a long time, a phase contrast MR approach, to get vessel-specific flow measurements. And aim two thought of the distal flow beyond the stenosis and aimed to look at two types of imaging biomarkers that might answer the question of flow in the distal territory, one through perfusion imaging. So looking at CT or MR perfusion, but MR was the one that we selected, where we would measure the tissue flow through Tmax measurements, and then the other using TCD, transcranial Doppler, and vasomotor reactivity testing of the distal arterials. So that was aim two. Can we look at those biomarkers potentially as predictors of recurrence? And then the third was emboli detection, so the plaque vulnerability or instability biomarker. So, could we look at distal emboli in the territory and assess its role in predicting recurrence? So, those were really the main biomarkers tied to the objectives of the grant. Dr. Negar Asdaghi:                        Perfect. So, obviously, great, and a comprehensive various biomarkers looking at different imaging predictors of early recurrence. We're excited to hear about your primary results. So, what did your study find? Dr. Shyam Prabhakaran:              So, in MYRIAD, we enrolled 105 subjects who had symptomatic intercranial stenosis at 10 centers across the US. And we were able to track them for both the primary outcome, which was stroke in the territory of the stenosis, clinical stroke at one year, and the secondary outcome, which was radiographic occurrence of new infarcts on six- to eight-week MRI. So that was a prespecified outcome. In the primary analysis of the clinical outcome, we did find a fairly high rate of recurrent events. Roughly 10% of patients in the cohort had a recurrent clinical event at one year, consistent with findings from, say, SAMMPRIS, which with maximum medical or aggressive medical management found a roughly 12% recurrence. So, we were able to confirm that there is a high rate of clinical recurrence. However, none of the biomarkers that we were looking at, quantitative MRA, profusion imaging, transcranial Doppler for BMR or emboli detection were predictors of the clinical outcome at one year. So, that was our main results. Dr. Shyam Prabhakaran:              Our secondary outcome was recurrent infarcts on study-specific research MRIs performed at the sites, and looked for recurrences compared to baseline MRIs that were performed at the time of their index stroke or TIA. So, in this paper, we were really interested in looking at whether there were any specific predictors of recurrent radiographic infarct, and that really was an interest of ours because we did find such a high rate of radiographic recurrence. Roughly 24% of our cohort had a recurrent infarct on brain imaging at six to eight weeks. So, we recognized right away that this is potentially an unrecognized phenomenon, that there's potentially an excess of radiographic events to clinical events. And there could be, obviously, a potential consequence of this radiographic accumulation of disease. Particularly, it might be important to prevent those radiographic occurrences in the future if they are affecting an individual's performance on cognition or even physical function as a result of accumulating lesions. So, we were really interested in seeing whether there were some early predictors of this six- to eight-week recurrence that we saw at a high rate. So, the paper looked at clinical factors, as well as imaging factors, that were available in the MYRIAD cohort, really trying to delve into a model that we could use to identify a subset that is at the highest risk of these early recurrent infarcts. Dr. Negar Asdaghi:                        Right, so very, very important findings. So, just to reiterate for our listeners, one in four patients in your study had evidence of radiographic recurrence despite clinically seemingly having no clinical events. So, this clinical radiographic dissociation would have absolutely gone unnoticed had it not been for these early MR images that were performed in the study. So, I want to clarify this from a pathophysiological standpoint. Is it hypoperfusion, plaque rupture, or both? Based on your results, what is the driving factor in development of new ischemia in symptomatic ICAD? Dr. Shyam Prabhakaran:              So, one of our main findings here, which is reported in this paper, is that those with multiple infarcts at their index stroke, so a pattern on diffusion-weighted imaging that was more than a singular infarct lesion, was a strong, independent predictor of having a recurrent event, recurrent infarct at six to eight weeks. And the part that isn't really highlighted in the paper, but is true, is the other factor that was co-mingled with multi-lesion, multi-infarct and index was borderzone pattern. They were co-linear, and they were essentially the same patients who were borderzone also had multiple lesions. So, one way we've interpreted this, and I can speak to a little bit about the different biomarkers that were studied in addition to the infarct pattern, but one way we've interpreted this is that multi-lesions can probably fall under two subsets. Dr. Shyam Prabhakaran:                           It could either be in this borderzone pattern, where you have multiple lesions due to hypoperfusion mechanisms, typically within either cortical or internal borderzones. And that may be then telling us about a mechanism of low flow. On the other hand, some of these patients could also have scattered lesions that are embolic in etiology and suggest a plaque that was unstable and potentially showered at their index event, resulting in that pattern that we saw. So, both of them probably are mixed in. We're favoring the borderzone because they were so co-linear that that probably was the more likely mechanism. And we're probably concerned that that could also be a factor that leads to early recurrence because flow failure typically is associated with critical hypoperfusion and imminent recurrence. Dr. Shyam Prabhakaran:              But, interestingly, in the paper, we talk about this, none of the specific prespecified biomarkers that were looking at flow, perfusion imaging, vasomotor reactivity were significant by themselves as predictors of recurrent infarct. So, it's a little hard for us to know why. It could be that the technology that we use, perfusion imaging, is still not quite picking up the kind of flow failure that we need to. Maybe it's more subtle than even we found because we looked at different cut points of Tmax and other parameters on perfusion imaging, and yet, we're not able to find a cutoff that was predictive, likewise with vasomotor reactivity. So, it could be that those are not quite good enough surrogates of hypoperfusion. And yet, borderzone or multi-infarct patterns may have been a surrogate of hypoperfusion. So, I think the short answer here is that it could be both mechanisms, plaque instability and hypoperfusion, although we're maybe favoring hypoperfusion because there was a strong co-linearity with borderzone pattern. Dr. Negar Asdaghi:                        Understood. Now Shyam, recurrent events on maximum medical therapy, this is not what we like to hear. Where do you see the future of symptomatic ICAD therapy? Now in your view, is there a role for interventional treatment or other therapies in a select group of ICAD patients? Dr. Shyam Prabhakaran:              I think that's really where we still face real challenges. I think the work done by many of the investigators before us on maximum medical therapy and interventional therapies have found, obviously, that there are some benefits to the medical approaches that we now consider standard of care. The dual antiplatelet therapy, the lipid-lowering therapy, the lifestyle management that SAMMPRIS also implemented and successfully showed some benefits of physical activity. So, those things clearly matter. And yet, the clinical event rate is still very high, and the radiographic event rate is even higher. So, you have this real challenge facing clinicians and patients of a disease that has a very high rate of recurrence, much higher than the other subtypes of ischemic stroke, and certainly higher than, say, AFib patients even, where we sometimes obviously are concerned and adopt strategies to lower risk. So, we are in a position, I think, today where we have to go back to the well and think about novel strategies. Dr. Shyam Prabhakaran:              Now, flow is a component of this, and I do think that SAMMPRIS, albeit now almost a decade ago, tested an interventional approach. It may be worth revisiting interventional strategies. Of course, we know from endovascular therapy for ischemic stroke, try once and fail, and try again, and you might find a different result because technologies get better, practitioners, proceduralists get better. So, that's one angle that I think people are very interested in, is whether or not an interventional approach for flow failure patients is a path forward. And that, I think, will get a lot of attention in the years to come with new studies that are being designed. Dr. Shyam Prabhakaran:              I think the other important point here is that aggressive medical management in the current day and age may still have room for improvement. Maybe the drugs that we're using, especially with DAPT and lipid-lowering therapies, they're not as quick or necessarily universally responsive for every patient. So, we know that about clopidogrel, that there's a certain rate of non-responders. We could probably do better than that with other choices, antiplatelet choices or even anticoagulant choices, which are being considered. And we know that lipid-lowering therapy with statins works well, but perhaps PCSK9 drugs could be considered in this population to lower cholesterol levels even more rapidly and more aggressively. So, all of these, I think, should be on the table as we move forward. Dr. Negar Asdaghi:                        Dr. Shyam Prabhakaran, thank you for joining us on the podcast today. We look forward to having you back here and covering more of your work in the future. Dr. Shyam Prabhakaran:              Thank you for having me. Dr. Negar Asdaghi:                        Thank you. And this concludes our podcast for the June 2021 issue of Stroke. Please be sure to check out the June table of contents for the full list of publications, including an important update from the American Stroke Association and the Stroke Council on how cerebrovascular disease is expected to temporarily fall from the fifth to the sixth leading cause of death in the United States in 2020. Sadly, this is not because of advances in stroke prevention and therapies, but rather because mortality from COVID-19 will displace stroke as a leading cause of death, a grim reminder of the year we put behind us and the many lives lost to this global pandemic. And yet we look ahead with hope, and with the promise that science has the power to resolve and the ability to push the human race forward. Every small step, every question will get us closer to learning more, answering more and knowing more. So, as we end this podcast today, we look forward to asking more at our next, and our promise to stay alert with Stroke Alert. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 4 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two featured articles from the May 2021 issue of Stroke: “Association of Serum IL-6 With Functional Outcome After Intracerebral Hemorrhage” and “SARS-CoV-2 and Stroke Characteristics: A Report from the Multinational COVID-19 Stroke Study Group.” This episode also features a conversation with Dr. Alvaro Garcia-Tornel Garcia-Camba to discuss his article “Ischemic Core Overestimation on Computed Tomography Perfusion.” Dr. Negar Asdaghi: 1) Can a pro inflammatory marker predict the hematoma size and clinical outcomes in patients with intracerebral hemorrhage? 2) What are the characteristics of stroke patients infected with coronavirus? 3) Is ischemic core reliably represented by the current established cerebral blood flow thresholds on CT perfusion imaging? Or are we underestimating the importance of perfusion overestimating the ischemic core? We will discuss these topics in today's podcast. You're listening to Stroke Alert Podcast. Stay with us. Dr. Negar Asdaghi:                                     From the Editorial Board of Stroke, welcome to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the May 2021 issue of Stroke, we have an exciting program today, as we cover topics from the predictive role of inflammatory markers in intracerebral hemorrhage to characteristics of stroke patients infected with SARS-CoV-2 virus. Later in the podcast, I have the privilege of interviewing Dr. Alvaro Garcia-Tornel Garcia-Camba from Autonomous University of Barcelona on the topic of ischemic core overestimation by CT perfusion imaging. I hope you enjoy our podcast. Dr. Negar Asdaghi:                                     Intracerebral hemorrhage is an aggressive form of stroke with high morbidity and mortality rates. Increased systemic inflammation may be correlated with more severe neurological presentation, larger hematoma volume, and worse clinical outcome in these patients. Elevated levels of interleukin 6, or IL-6, have been found in the experimental models of ICH and may represent a therapeutic target to reduce the inflammatory response in ICH if similar findings were replicated in clinical studies of patients with ICH. Dr. Negar Asdaghi:                                     In the May issue of the journal, in the study titled “Association of Serum IL-6 With Functional Outcome After Intracerebral Hemorrhage,” Dr. Kevin Sheth from Department of Neurosurgery at Yale University and colleagues performed a pre-specified exploratory analysis of the patients enrolled in the FAST trial, testing the association of admission levels of serum IL-6 with baseline neuroimaging and functional outcome at 90 days. Dr. Negar Asdaghi:                                     But just a reminder for our listeners that FAST trial was a multicenter randomized trial of the recombinant factor VIIa administered in two doses versus placebo in patients with spontaneous nontraumatic intracerebral hemorrhage presenting within three hours of symptom onset. Dr. Negar Asdaghi:                                     So, in the current analysis, amongst 841 patients enrolled in the trial, 66% were included who had both baseline IL-6 measurements and the follow-up modified Rankin Scale on day 90. Patients were stratified into four quartiles based on their admission IL-6 serum levels from low/normal in quartile one to very high levels in quartile four. And their baseline characteristics, neuroimaging and outcomes were then compared. Dr. Negar Asdaghi:                                     So, what they found is that patients with a poor outcome, defined as modified Rankin Scale of four or higher at 90 days, had a higher median admission IL-6 level than those with a favorable outcome. In their multivariate analysis, for each one nanogram per liter increase in IL-6 level, there was a 30% increase in the odds of a poor functional outcome after adjustment for various factors, such as age, intracerebral hemorrhage volume, baseline Glasgow Coma Scale, presence of intraventricular hemorrhage, hematoma expansion, ICH location, and recombinant factor VIIa treatment allocation. Dr. Negar Asdaghi:                                     So, a higher IL-6 level at baseline was also found to be independently associated with higher baseline hematoma volume and was a predictor of perihematomal edema, an association that was stronger in patients with lobar rather than subcortical  ICH. Dr. Negar Asdaghi:                                     Now, whether there is a causal relationship between IL-6 and outcomes in ICH, and importantly, whether the growing number of anti-IL-6 therapies have a role in the reduction of inflammation and improvement of clinical outcome in this population, are important subjects to consider and study in the future. So please stay tuned. Dr. Negar Asdaghi:                                     We now move on to our next paper, examining the characteristics of stroke in COVID-positive patients. In the study titled “SARS-CoV-2 and Stroke Characteristics: A Report from the Multinational COVID-19 Stroke Study Group,” Dr. Ramin Zand from Geisinger Neuroscience Institute and colleagues from across the globe examine the characteristics of COVID-infected patients with neuroimaging-confirmed stroke from 71 centers across 17 countries. Patients were included in the study if presented to the hospital with stroke-related chief complaints and asymptomatic COVID infection, or had a stroke while being hospitalized for COVID, or patients with stroke-related admission who had confirmed prior diagnosis of COVID infection. Dr. Negar Asdaghi:                                     A total at 432 stroke patients were included in the study. 75% of those had acute ischemic stroke, 21% with intracerebral hemorrhage, and the remainder had cerebral venous sinus thrombosis. The authors found that, in general, stroke characteristics and subtypes were different in COVID-infected patients as compared to non-COVID stroke patients based on the prior population-based studies for both ischemic and hemorrhagic stroke. Notably, amongst COVID-infected patients with acute ischemic stroke, a third had only asymptomatic COVID. They had an overall male predominance with a young median age, and that a quarter of ischemic stroke patients were younger than 55 years of age, and a similar percentage had no known identifiable vascular risk factors. Among those with available vascular imaging, close to 50% had evidence of a large vessel occlusion on vascular imaging. In considering the etiology of stroke as defined by the TOAST classification, only 10% of COVID-positive stroke population had small vessel disease in contrast to typically 30% of the general ischemic stroke population. Dr. Negar Asdaghi:                                     Now, when considering the hemorrhagic stroke, despite smaller number of patients included in the study, similar differences in general classification of hemorrhagic stroke patients was noted. Specifically, 25% of hemorrhagic strokes had evidence of subarachnoid hemorrhage, over two thirds of which was non-aneurysmal, a much higher percentage than that reported amongst non-COVID infected patients. A third of hemorrhagic strokes in this population is related to cerebral venous sinus thrombosis, an observation that is in keeping with the general notion that COVID infection can create a hypercoagulable state. Dr. Negar Asdaghi:                                      In summary, this study adds to the growing literature regarding the complex interplay between COVID infection and vascular disease, and the importance of understanding how this virus may play a role in clinical presentation of stroke. Dr. Negar Asdaghi:                                      Various imaging modalities, including diffusion-weighted imaging, MR perfusion, and CT perfusion, are used to define the extent of ischemic core in patients presenting with acute ischemic stroke. In contrast to restrictions and delays associated with acquisition of an MRI study in the acute setting, CT perfusion is readily accessible with relatively fast acquisition times and is easily incorporated in the stroke-alert workflow. As a treating stroke neurologist, you make the decision not to proceed with endovascular therapy in an otherwise eligible patient due to presence of a large volume of ischemic core, as measured by CT perfusion, only to find out that perfusion overestimated the ischemic core. How often do we encounter this scenario? And what are the factors associated with ischemic core overestimation as determined by CT perfusion? Joining me now is Dr. Alvaro Garcia-Tornel Garcia-Camba from Autonomous University of Barcelona, who's the first author of the study titled “Ischemic Core Overestimation as Measured by CT Perfusion: Collateral Status, Time and Its Interaction.” Good afternoon, Alvaro. Thank you for joining us from Barcelona. Dr. Alvaro Garcia-Tornel Garcia-Camba: Good afternoon, Negar. It is a pleasure to be interviewed in a Stroke Alert Podcast to talk about our work with you. Dr. Negar Asdaghi:                                      Great, Alvaro. Endovascular treatment is routinely offered to patients with a target intracranial occlusion, or between 6 to 24 hours from symptom onset, or those without a known time of onset if they're determined to have a small ischemic core. Can you walk us through the evolution of stroke endovascular therapies from time-based to imaging-based decision-making, please? Dr. Alvaro Garcia-Tornel Garcia-Camba: Yeah, well, I remember when I started my neurology training, that was nearly 10 years ago, that the most important biomarkers that we took into account in decision making was time and stroke severity. For decades, time had been the tool to select patients for thrombolysis. It was no different for patients that were considered for endovascular treatment at the beginning. And we did a variety of scales and scores for acute stroke infarct assessment on non-contrast CT and MRI, like ASPECTs score and the routine use of non-invasive angiographics tests for the selection of patients with large vessel occlusion and the new generation stent-retrievers, and in basic framework for patient selection started to grow, and this led to positive progress for endovascular treatment trials back in 2015. Perfusing imaging developed in parallel with SWIFT-PRIME and EXTEND-IA being the early window trials that used perfusion imaging to select patients for endovascular treatment, with the aim to estimate the ischemic core, the already infarcted tissue, and penumbra, the ischemic tissue that is still viable if reperfusion is achieved, on computed tomography perfusion as an effort to mimic the accuracy of diffusion imaging MRI core estimation. Multiple studies for the development of thresholds applied to computed tomography perfusion role data to estimate core and penumbra using diffusion imaging as the gold standard. And the mismatch concept was the finite and it was successfully applied in the extended window that was above six hours in DEFUSE 3 trial. Dr. Alvaro Garcia-Tornel Garcia-Camba: And DAWN trial, the other late window endovascular treatment trial, used a slightly different approach using the core clinical measurements, taking into account clinical severity and age rather than the penumbral tissue to select patients for endovascular treatments. Both the studies had positive results and a number needed to treat comparable to early imaging trials. And we have learned in the past years that time is one of the most important prognostic factors in patients with an acute stroke. But the clock runs at different speeds depending on the specific patient that we evaluate. Tissue analysis on imaging is the way to calibrate this state. Dr. Negar Asdaghi:                                      Thank you, Alvaro, for this nice review of the literature. Can you please tell us about the concept of ischemic core overestimation, specifically by CT perfusion? What was known in the literature before, and what prompted you to look into this in more detail in the current study? Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, we consider ischemic core overestimation is present when the estimated score by computed tomography perfusion imaging is actually larger than the real core, which is the not salvageable tissue at the time of imaging. Most of the studies that have focused on computed tomography perfusion accuracy considered both types of error, that the estimated score is larger or smaller than actual real core normal using diffusion imaging as the ground truth. We wanted to focus on overestimation because of two reasons. The first one is because it might deny endovascular treatment for patients in which reperfusion might lead to better outcomes. And because the ground truth is that the core should increase its size over time, not decrease. The study that prompted me to further investigate on this concept was an article that was published back in 2017, that is ghost infarct core concept that it was published by the unit that I work in nowadays. Dr. Alvaro Garcia-Tornel Garcia-Camba: And this is the two main factors succeeded with overestimation. In this case was slightly different because they consider core overestimation to be when the estimated core was 10 milliliters larger than the follow-up infarct where reperfusion that was achieving more than 50% of reperfusion after endovascular treatment for more than mTICI 2B or earlier imaging in time. We consider the main limitation of this specific study was the small size because it only included 70 patients. And that the software used for computed tomography perfusion analysis was not as validated at this time as RAPID is, the one that is used in our actual study. Dr. Negar Asdaghi:                                      Right. Now, very important concept to keep in mind, especially because RAPID is now used worldwide everywhere in many institutions. And as you mentioned, we make therapeutic decisions based on volumetric assumptions of ischemic core that's given to us by RAPID. Alvaro, we're excited to hear about your study. Can you please tell us about your patient population, and how you define ischemic core and CT perfusion, and what measures were used to determine the final ischemic volume in your study? Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, we included 407 patients from a single center retrospective database that was from 2014 to 2019. They had to have an anterior circulation intracranial large vessel occlusion, including in portions of M1, M2 of middle cerebral artery or terminal intracranial carotid artery occlusion. And they had to have baseline computed tomography perfusion, and they must have achieved reperfusion after endovascular treatment that we have defined as mTICI 2B at the end of the procedure, with a follow-up non-contrast CT at 24-48 hours, in order to measure the final infarct volume. Dr. Alvaro Garcia-Tornel Garcia-Camba: Patients with unwitnessed stroke onset were included, and the estimated core and hypoperfusion intensity ratio that it's a perfusion imaging output that it strongly correlates with collateral flow were determined using RAPID automated software with default thresholds. That is a relative reduction of cerebral flow below 15%* as compared to contralateral hemisphere for estimated core and the ratio of tissue with a Tmax delay above 10 seconds in areas with a Tmax delay above six seconds for hypoperfusion intensity ratio. Dr. Alvaro Garcia-Tornel Garcia-Camba: The final infarct that was the ground truth for comparison was calculated as the mean from two observers’ measurements using a semiautomatic method for non-contrast CT and patients with a parenchymal hemorrhage type 2 hemorrhagic transformation on follow-up imaging were excluded from the analysis. Ischemic core overestimation was considered when estimated core was larger than final infarct volume. Dr. Negar Asdaghi:                                      Perfect. Can you please tell us about the main findings of the study? Dr. Alvaro Garcia-Tornel Garcia-Camba: We found out that ischemic core overestimation is a phenomenon that is more prevalent in patients with earlier window time and that the influence of poor collateral status are measuring using hypoperfusion intensity ratio with a cutoff point of 0.4. Previously as stated to discriminate between good and [inaudible 00:16:02] collaterals was stronger in patients with earlier window time. Patients with poor collateral status in the first four hours window had twice the odds of ischemic core restoration, as compared to patients that presented above four hours from symptom onset. Dr. Negar Asdaghi:                                      Very interesting, Alvaro. CT perfusion overestimated the volume of ischemic core in 20% of your study population. What was the median volume of core overestimation, and what were the factors associated with this overestimation in your multivariate analysis? Dr. Alvaro Garcia-Tornel Garcia-Camba: 83 patients presented with ischemic core overestimation. The median volumetric overestimation was 12 milliliters with an interquartile range of 56 milliliters. Apart from hypoperfusion intensity ratio and time from onset to imaging, terminal internal carotid occlusion location and complete reperfusion that was more than 90% of the people with modified TICI 2C–3 were independently associated with ischemic core overestimation on multivariate analysis. Within the [inaudible 00:17:12] and independent association with time from imaging to reperfusion, a variable that had been previously reported to influence the accuracy of core overestimation on computed tomography perfusion, and we believe that differences in baseline characteristics between the studies and the low variability in imaging reperfusion time in the core will explain why it was not statistically significant. Dr. Negar Asdaghi:                                      Very important findings, Alvaro. Just reminding clinicians to pay attention to factors such as location of the occlusion and, as you mentioned, the hypoperfusion intensity ratio, in addition to the volume of the tissue with relative cerebral blood flow of less than 30% to define the ischemic core. So, definitely many important learning factors for all of us here. Alvaro, I want to finish by just a question that in routine clinical practice, CT perfusion is not commonly performed in those under six hours. And yet ischemic core overestimation seems to be a phenomenon most notably found in earlier presenters. So, what is the clinical implication of the ischemic core overestimation by CTP in late presenters? Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, the rate of ischemic core overestimation was low in patients presenting above four hours from symptom onset. And I do not personally believe that clinically relevant overestimation is present in late presenters with witnesses at the stroke onset. Nonetheless, a high proportion of this population with late presentation do not actually have a clear symptom onset times. And it was witnessed in this group of patients, they [inaudible 00:18:46] not to perform in the vascular treatment for a large score on CTP only should be carefully taken given the results of our study. As taken solely in accountable volumetric estimation of core on computed tomography perfusion might lead to deny treatment to patient that could benefit from it. Dr. Negar Asdaghi:                                      Very important, Alvaro. Again for our listeners, keep that ischemic core overestimation in mind when relying on CT perfusion in waker-upers and those with ischemic stroke of unknown time of onset. So, Alvaro, please tell us what's the most important takeaway message from your study, and what does the future hold for you in terms of your research? Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, it's a global message. I believe that contemporary perfusion imaging construct is based on fixed thresholds to estimate ischemic core. Those thresholds rely on [inaudible 00:19:37] patients with relatively small cores and early imaging. These models might have overfitted to those specific population characteristics. Different studies, including ours, have pointed that the accuracy of computed tomography perfusion core estimation is dependent on many variables. Some of them are known at the time of imaging, like degree of the perfusion after endovascular treatment or time from imaging to reperfusion. In order to improve our prediction accuracy for both core and prognosis estimation, further research should be focused on a multi-parametric approach that takes into account both clinical and imaging parameters, not only imaging parameters. Dr. Negar Asdaghi:                                      Dr. Alvaro Garcia-Tornel Garcia-Camba, thank you for joining our podcast, and we look forward to covering more of your work in the future. And this concludes our podcast for the May 2021 issue of Stroke. Please be sure to check out the May table of contents for the full list of publications, including original contributions on clinical and basic and translational sciences, brief reports, editorials, comments and opinions, and much more. And remember that every breakthrough in science started somewhere from an idea that was then cultivated with care, determination, perseverance, and collaboration. A simple idea that someone might've heard somewhere in passing or on a podcast. So, keep working on your ideas, and until our next podcast, stay alert with Stroke Alert. *Dr. Alvaro Garcia-Tornel Garcia-Camba confirmed following the interview that “15%” should be “30%.”

On Episode 3 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two featured articles from the April 2021 issue of Stroke. This episode also features a conversation with Dr. Simon Nagel, from Heidelberg University in Germany, to discuss his article “Predictors for Failure of Early Neurological Improvement After Successful Thrombectomy in the Anterior Circulation.” Dr. Negar Asdaghi:                       1) Is Andexanet a cost-effective treatment for the reversal of coagulopathy in factor Xa-associated intracranial hemorrhage? 2)  Are statins safe and efficacious in secondary prevention of stroke in the elderly population? 3)  What are the predictors of futile recanalization amongst successfully treated patients with endovascular therapy? We have the answers to the above and much more in today's podcast. You're listening to Stroke Alert Podcast. Stay with us. Dr. Negar Asdaghi:                       From the Editorial Board of Stroke, welcome to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the April 2021 issue of Stroke, we have an exciting program today where I have the privilege of interviewing Dr. Simon Nagel from Heidelberg University in Germany on predictors of failure of early neurological improvement or futile recanalization after successful thrombectomy. But first I want to review these two interesting articles. Dr. Negar Asdaghi:                       Factor Xa inhibitors, such as apixaban, edoxaban and rivaroxaban, are commonly used for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation. Bleeding is a serious adverse consequence of treatment with anticoagulants, including factor Xa inhibitors, with intracranial hemorrhage representing the most devastating form of such adverse events. Dr. Negar Asdaghi:                       Anticoagulant-associated intracranial hemorrhage typically results in larger hematoma volumes, higher risk of expansion, and worst clinical outcomes as compared to their spontaneous counterparts and requires immediate reversal of coagulopathy. Andexanet alfa is a recombinant modified factor Xa protein which is an effective antidote to reverse this coagulopathy, though it comes with an increased risk of thromboembolic events, either from Andexanet itself or delayed or lack of resumption of anticoagulation in the setting of intracranial hemorrhage. Dr. Negar Asdaghi:                       It is important to note that the estimated cost of Andexanet is between $25-50,000 US dollars, depending on the standard versus high dose used, and this medication is currently not available in many countries, including in Canada, and even in the United States, it's still not accessible in many centers mainly due to its high cost. Now, when Andexanet is not available, the non-specific antidote of prothrombin complex concentrate, or PCC, is used, carrying an approximate cost of $4-8,000 US dollars, depending on the dosage used. Dr. Negar Asdaghi:                       PCC, which is a combination of various clotting factors, together with protein C and protein S, have a limited efficacy and reversal of Xa inhibitors coagulopathy. In the absence of randomized control trials to directly compare Andexanet to PCC, there remains a significant gap in knowledge with regards to comparative efficacy, adverse events, and cost-effectiveness of these therapies for life-threatening bleeding, specifically intracranial hemorrhage, in the setting of Xa inhibitor use. Dr. Negar Asdaghi:                       In the current issue of the journal, Dr. Andrew Micieli and colleagues from the Division of Neurology, Department of Medicine, Universities of Toronto and Calgary, in Canada, did a comparative analysis between Andexanet and PCC in a study titled “Economic Evaluation of Andexanet Versus Prothrombin Complex Concentrate for Factor Xa-Associated Intracranial Hemorrhage.” Using a patient population on chronic factor Xa inhibitor treatment, when presenting with an intracranial hemorrhage, the authors applied a probabilistic Markov model over a lifetime horizon for each patient to evaluate the cost and benefits if either Andexanet or PCC was administered to reverse the coagulopathy. Dr. Negar Asdaghi:                       Estimates of outcomes, dosing, and administration protocols for Andexanet were derived from the ANNEXA-4 study and from the UPRATE study for the PCC. These are two previously published large cohorts of treatment for these agents, respectively. Dr. Negar Asdaghi:                       So, what they found was an overall reduction in the occurrence of fatal intracranial hemorrhage with Andexanet therapy, estimated around 18%, as compared to PCC, estimated at 34%, specifically if the antidote was administered in the first cycle, which is the first 30 days following intracranial hemorrhage. This, of course, came at a cost of a higher thromboembolic event rate measured as composite outcome of myocardial infarction, TIA stroke, deep vein thrombosis or pulmonary embolism of approximately 10% in the Andexanet-treated group as compared to 5% in the PCC-treated group. Dr. Negar Asdaghi:                       Now, the cost analysis of the study is very interesting. The authors found that Andexanet, for its incremental effectiveness in gaining quality-adjusted life year, had an incremental cost over PCC. This cost-effectiveness ratio was close to $220,000 US dollar per quality-adjusted life year gain for Andexanet. Dr. Negar Asdaghi:                       And as such, as things stand today, this therapy is not cost-effective and represents low value for reversal of factor Xa–associated intracranial hemorrhage over the standard of care, which is PCC. So, this study provides an important insight, not only for the physicians, but also for health policymakers, as they critically evaluate the merits of Andexanet therapy compared to the current standard of care. Dr. Negar Asdaghi:                       So, moving on now from oral anticoagulants to statin therapies and other medication commonly used in the secondary prevention of ischemic stroke, the second article we will discuss today in our podcast looks at the use of statins poststroke in the elderly population. About a third of stroke patients are over the age of 80, and with the aging population and increased life expectancy, this proportion is estimated to double by year 2050. Dr. Negar Asdaghi:                       Stroke survivors who are over the age of 80 have increased 30-day and one-year mortality rates and remain at higher risk for recurrent cardiovascular events as compared to their younger counterparts. Statin therapy has been shown to reduce the risk of composite cardiovascular events in stroke survivors, but randomized data regarding their safety and efficacy in the elderly population is limited. Dr. Negar Asdaghi:                       Treatment with statin is not without its own challenges in the elderly population. These patients are more likely to be on multiple medications that can interact with statins, and there's also some evidence that the frail population may be more prone to statin side effects such as muscle pain, risk of rhabdomyolysis, increased blood glucose levels, increased risk of diabetes, and liver problems that have all been reported in the setting of statin use. Dr. Negar Asdaghi:                       In this issue of the journal, Drs. Lefeber and colleagues from the Department of Geriatrics in Utrecht University in Utrecht, Netherlands, study this subject in their paper titled “Statins After Ischemic Stroke in the Oldest: A Cohort Study Using the Clinical Practice Research Datalink Database.” This was a retrospective analysis of over 5,900 patients aged 65 years and older who were hospitalized and then discharged for a first ischemic stroke during a 17-year study period from 1999 to 2016 who were not on statin prescription in the year prior to their index hospitalization. Dr. Negar Asdaghi:                       The authors compared the primary outcome, which was a composite of recurrent stroke, myocardial infarction, and cardiovascular-related mortality, within the elderly patients, those over the age of 80, to the younger population, those over 65 but under 80 years of age, based on the number of years that they had a statin prescription poststroke. That is comparing at least two years of statin prescription time with no statin treatment or less than two years of prescription time compared to no treatment at all. Dr. Negar Asdaghi:                       So, what they found was that 53% of their population were actually over the age of 80, and in over half of these elderly patients, a statin was prescribed within 90 days of the index date. And not surprisingly, 38% of this elderly population had moderate to severe frailty, an index that has been linked to statin intolerance and its common myalgia side effect. Now, in terms of their main finding, more than two years of statin prescription compared to no statin prescription was significantly associated with a lower risk of the primary endpoint for both the over and the under 80 age groups. Dr. Negar Asdaghi:                       This association remained true in their adjusted model, not only for the primary outcome, but also for all-cause mortality rates, which was significantly lower in the statin-treated patients. After a correction for the mortality rate of close to 24% during the first two years, the number needed to treat for reduction of composite recurrent stroke, myocardial infarction, and cardiovascular-related mortality was 64 and the number needed to treat for reduction of all-cause mortality was 19 in the group over 80 on a statin prescription during a median follow-up of 3.9 years. Dr. Negar Asdaghi:                       So, in the absence of data from randomized controlled trials, this study provides reassuring results regarding the efficacy of statins in reduction of cardiovascular events in the patients aged 80 and older, keeping in mind that a third of the elderly population in the study was significantly frail, at risk for development of possible statin-related adverse effects. Dr. Negar Asdaghi:                       Much has changed in the field of reperfusion therapies since the publication of the positive results of the thrombectomy trials in 2015. Advances in patient selection processes, rapid access to advanced neuroimaging, the use of newer generations of thrombectomy devices, and improvement in systems of care have all played important roles in the growing success of endovascular therapy. Dr. Negar Asdaghi:                       But even with today's rigorous selection criteria and fast thrombectomy timelines, there remains a significant proportion of endovascularly treated patients in whom the successful radiographic recanalization do not translate into early neurological improvement. In our previous podcast, we report how the odds of favorable outcomes with thrombectomy decreases with an increase in the number of retrieval attempts during the procedure amongst successfully recanalized patients. Today, we dive deeper and look into other independent variables that may predict odds of futile recanalization. Dr. Negar Asdaghi:                       Joining me now is Dr. Simon Nagel from Department of Neurology at Heidelberg University Hospital in Germany, who is the senior author of the study titled “Predictors for Failure of Early Neurological Improvement After Successful Thrombectomy in the Anterior Circulation.” Good morning, Simon, and thank you for joining us. Dr. Simon Nagel:                           Good morning, or even good evening, from Germany. Thank you, Negar. It's a pleasure to be here, of course, especially in these times when you don't get to personally speak to a lot of international colleagues. Dr. Negar Asdaghi:                        That's great, Simon. Can you start us off, please, with some background on futile recanalization? What do we know about this medical work, and what prompted you to look into this topic in more detail? Dr. Simon Nagel:                           I guess, in most studies, futile recanalization is defined as a technically successful recanalization by a TICI score of 2b upwards, but an outcome on day 90 of only three to six points on the modified Rankin scale. And many papers have examined a selected number of parameters for the association with futile recanalization being either clinical, radiological, laboratory or procedural, which is why we wanted to be very comprehensive in our approach by including 38 different variables from the above-mentioned spectrum in our own analysis from our monocentric registry in Heidelberg. Dr. Negar Asdaghi:                        Perfect, so a very important concept to keep in mind in light of the increased demand to perform endovascular therapy. So, can you tell us, you alluded to it, but can tell us a bit more about the study design, the population you studied, and specifically why you choose failure of early neurological improvement at the time of discharge as opposed to that more conventional outcome measure of modified Rankin scale at day 90 poststroke? Dr. Simon Nagel:                           That's a good point, Negar, and you're right, we did maybe choose an unconventional end point since the definition of early neurological improvement is usually based on the NIHSS at 24 hours, but this study was driven from a very clinical perspective, that is the one from the stroke physician on the ward who is receiving the patient after the procedure, after all the acute decisions have been made. And then we have to do our best during the following days managing the complications, the deficit, and finding out why the stroke happened in the first place, until the patient is then either discharged home or back to the referring facility or to a normal board or to rehabilitation. Dr. Simon Nagel:                           But a considerable amount of patients, we found, did not improve until this discharge, although the procedure was a technical success. So some reasons for that are obvious, but some of them are not, and we wanted to find more about this, especially since early neurological improvement has been proposed as a surrogate for good outcome later on. Dr. Negar Asdaghi:                        Right. So we're very excited, Simon, to hear about the main study results. What were some of the predictors of failure of early neurological improvement in your study, and were you at all surprised by any of those developments? Dr. Simon Nagel:                           A lot of known factors that have been previously described to show an association with early neurological improvement or failure of that were found in our univariate analysis, namely 21 of 38, but only a few remained independent predictors after selecting with the elastic net approach and logistic regression modeling. Some of them are obvious by definition, which is symptomatic intracranial hemorrhage. Then, of course, the ASPECTS on follow-up was a predictor, and this obviously beat the baseline ASPECTS and also potentially the collateral score, which was significant in univariate analysis, but we included also over 20% of patients with a premorbid disability of more than two on the Rankin scale so premorbid condition was an independent predictor. Dr. Simon Nagel:                           We had eight patients with end stage renal failure in our analysis, so we did include that as well, and dialysis is a very strong predictor of failure of early neurological improvement. But also, admission glucose was, so higher levels of that, and then procedural parameters like reaching thrombolysis. So, if you do imply this, this was a factor that was positively associated with early neurological improvement. And then, also, the time from groin puncture to final recanalization was associated, so the longer it took, and this obviously beat also the stent retriever attempts in the analysis, the longer it took, the more likely that it was that failure of early neurological improvement was observed. And last but not least, general anesthesia was associated with that, but there is a sense of bias in this analysis because we have a SOP that we generally perform awake sedation. That means only patients that are not eligible for that, that are not doing well, will be treated under general anesthesia, so this variable has to be interpreted with caution. Dr. Negar Asdaghi:                        So, very interesting, Simon. I want to emphasize to our listeners that in your study, 20%, that is one in five successfully recanalized patient, did not clinically improve post-thrombectomy up until discharge. This is a considerable percentage to keep in mind. Now, in our day-to-day practice, many of us also accept a TICI 2b as a measure of a successful recanalization. In your study, you included a more rigorous definition of successful recanalization. How do you think your results would have changed had you included those who have achieved a TICI 2b, and why did you exclude that population? Dr. Simon Nagel:                           According to the mTICI definition, 2b means that more than half of the previously occluded vessel is reperfused, which also means that almost 50% is not. That might have been a success in the advent of thrombectomy and when this was defined in 2013, but I don't think it's adequate to call this a successful recanalization these days. When this was re-defined by David Liebeskind in 2018 with a eTICI score, 2b is still not considered anything more than two-third of the territory, and only 2c is a nearly complete reperfusion, leaving just 10% of the vessel territory occluded or not reperfused. Dr. Simon Nagel:                           This is why we thought it is a more appropriate definition of successful thrombectomy, and this is what we think should be attempted in day-to-day practice. In our cohort, almost 50% achieve TICI 2c or 3, and if we would have included 2b, 83% of patients would have achieved that. I can't tell you what our analysis would have looked like if we included 2b, it might have been different, but I can tell you that that would require a new analysis of the data. Dr. Negar Asdaghi:                        Yes, and we keep that in mind for sure that the new way of definition is to keep 2c or better. So Simon, I agree that definitely your study has given us a clear roadmap regarding early outcome expectations in patients undergoing thrombectomy. What should be our final take-away from your study? Dr. Simon Nagel:                           I guess, before I can tell you, you have to bear in mind that this is a monocentric retrospective analysis, hence, there is bias to be expected, and choosing a different definition of early neurological improvement then may be useful, might have given us a different result. It is also important to be clear from what perspective you are looking at the data. For example, this analysis does not necessarily help with predictors for outcome that help you make a decision if you should treat the patient or not since we included many parameters that are not yet available at that point in time when you need to make the decision to treat the patient. Dr. Simon Nagel:                           But, I think it's fair to say that you should, according to our results, apply thrombolysis whenever indicated, that you should be as quick as possible with your procedure, and that you should manage blood sugar well, as well as other medical complications, and that you should not expect too much early improvement in case the patient has a premorbid condition or if the motor cortex is involved, which was also a significant outcome, which I didn't mention earlier, and, of course, by definition, if symptomatic hemorrhage occurs. Dr. Simon Nagel:                           Hemorrhagic transformations, on the other side, do not seem to independently influence failure of early neurological improvement. Dr. Negar Asdaghi:                        Dr. Simon Nagel, it's always a pleasure speaking with you, and thank you for being with us. And this concludes our podcast for the April 2021 issue of Stroke. And as I leave you today, I want to remind us all that for every minute left untreated a brain under an ischemic attack loses an average of 1.9 million neurons. So whether you're just starting off or you're a well-established clinician or researcher in the field of vascular neurology, your work and that of your colleagues are part of a quest to save the most valuable commodity of human life, which is the brain, and, for that, we're proud to review your work in stroke and highlight the best in vascular neurology in our future podcasts. So until our next podcast, stay alert with Stroke Alert.