Stroke Alert December 2021

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.