All right, welcome, welcome everybody. So my topic is large-core ischemic stroke trials, the evidence, and what you need to know. 45-year-old, code stroke, five hours from last known well. And this is not a diagnostic dilemma, right? You have a left M1, an ICA, which looks hyperdense on that non-contrast CT. You have a pretty large, quite declared itself, area of ischemia, aspects of three. Here is the CTA. So we have, again, a vessel occlusion that we already knew was gonna happen. We have got an area of ischemia with very poor collaterals in that area. How many people over here will take this patient, aspects of three, and treat with endovascular treatment? All right, so this is a great, great, this is exactly why we wanted to do this session, because I saw only a few hands raised, and which brings me to the reason why, as radiologists, even if you're not a neuro-interventionist, a diagnostic radiology, we need to know some of these things. So what happened to this patient? This was a case in 2021. This is the day to MRI. We did not take this patient for endovascular treatment. Hemorrhagic transformation and hemicraniectomy for this, you know, this was the, and you can see, there is a left MCA and ACA infarct. Aspects of three and LVO, will you treat today? And that is the topic that we are gonna discuss, and I would say yes. In 2021, we did not, but today, we will treat. And what has changed? How many people, again, show of hands, have heard anything about the large core trials? Okay, so I've got, like, 50%, and it's okay if you have not heard. If you're not in the stroke field, if you're not doing it every single day, I'll tell you somebody who's really, really involved in the stroke team, in the stroke treatment and diagnostic, you know, triage. Stroke treatment is changing so rapidly, it's really hard to keep up, which is really, really good, by the way. So the large core trials in 2023 and 2024, angel aspects select to rescue Japan, Tesla, tension, and last day. What did these randomized control trials show? This was a complete endovascular treatment paradigm shift. So for the trainees who don't know much about endovascular treatment, it all started in 2015. Again, for the trainees, if you have never heard this, this is an efficacious treatment, like giving antibiotics to a patient with sepsis. What these trials showed is that there is benefit of the endovascular treatment over best medical therapy in anterior circulation, and yes, there was difference in imaging selection, and I will come to that. There was a consistent endovascular treatment effect. I also want to take a few seconds to thank all these patients. Remember, in their most vulnerable time, these patients and these families said yes to research, and research, what we do today, becomes tomorrow's clinical practice, and I've seen this again and again with stroke, so we are very thankful to our patients who say yes to research. So what about the large core trial characteristics? And stay with me, okay? This is a busy table, but stay with me. Number one, I want to show you that this is a diverse population. Japan, China, North America, Australia, Europe, Canada, US, Europe, and US. Look at the vessels occluded that they looked at. Mostly ICM1, a little bit of M2s over here, not a lot. Time from onset of treatment, six hours, 24 hours, this was up to 12 hours, so there's obviously differences. Aspect score, I mean, there was a time literally two years ago when it was aspects of six, nah, it's not gonna work. These trials looked at three to five, and even last day looked at zero to five. This is like, for me, it's like mind-boggling, right? And then, what is the primary endpoint? So MRS-3 or better, MRS-SHIFT, again, this was utility-weighted MRS and MRS-SHIFT. Again, for diagnostic radiologists, if you're not in this zone, I'm just gonna give you literally 10 seconds. What do I mean by modified rank and score? For the experts over here, you don't even have to think about it. But if you think about MRS zero to six, no symptoms. Remember, these are realistic patients coming with a cold stroke to dead. So when we say excellent outcomes, you're usually zero to one, good functional outcomes, zero to two. But of course, by five and six, it's severe disability and dead, right? So that's the MRS functional outcome that these trials were looking at. What about my imaging inclusion criteria? Like, as a diagnostic radiologist, how do I help? Again, remember, different diverse populations, so you're gonna expect some changes. Aspects of three to five over here, aspects three to five, also think about this. Depending on where it was done, whether you had MR or not, you can see some MR versus only CT. So again, aspects two to five with non-contrast CT. And so, you will see this heterogeneous imaging inclusion criteria. What about key outcomes, okay? How do I know that these trials were successful? If you look at 90-day shift MRS, again, stick with me, please, over here. Lots of tables. 90-day MRS, shift of MRS, pretty much everybody was positive, except, of course, Tesla, I think, missed the mark by a little bit. Again, they looked at multiple 90-day functional independence, independent ambulation. So these trials, again, consistently are saying that, you know what, even in large core, the endovascular treatment works. Obviously, a lot of systematic reviews and meta-analysis have been published. I would highly encourage anybody who's interested to read some of these. I want to highlight a few things. So this is a systematic review. This was, they looked at all the six randomized control trials, 1886 participants. What's the punchline? We already know this. Endovascular treatment is more effective than medical management with patients with large vessel occlusion, with large core. Now, benefits remain consistent despite an increase in the rate of symptomatic intracranial hemorrhage. And I'll show you some of the forest plots. The benefit is independent, again, in this meta-analysis, whether it's age, clot location, time from last known well, aspects, ischemic core volume, cause of stroke. Bottom line is this still is working even in these subgroups, right? So they did a, so these are forest plots of the MRS shift analysis, and you can say this is higher with endovascular treatment over here. So this was one. What about symptomatic ICH? That was what we used to be always worried about, right? Are we causing additional harm, right? And so, because the hemorrhagic complication, we don't want to cause that additional harm. None of the six trials really showed by themselves significant differences, but you can see the meta-analysis, you know, that you're seeing some, but again, that risk is small, okay? The risk is small, does not seem to offset the benefits of the endovascular treatment. What about MRS, like how low is low? Okay, I got it, three to five, sure. What about aspects less than three? Now, remember, one of those trials was going up to like zero. I mean, aspects of zero, again, for me, it's like, whoa, what were we looking at? And again, they're showing that, you know what? There is still that shift MRS benefits. They did this multiple subgroup analysis, which I already talked about, and you can see that, you know, this is higher, the shift MRS, which means it is better MRS, again, there is higher with that endovascular treatment. And again, I'm not going to go into every detail, because sometimes I know as a diagnostic neuroradiologist, you're like, okay, give me the punchline here, right? Here is one more thing that I wanted to highlight. So we know that randomized control trials, and they're always great, but don't underestimate the power of observational studies, because sometimes that is real data. And again, this has just happened in these last two years. So this is a new study that looked at not only those six randomized control trial, but looked at 10 observational studies. Again, increased the outcome of MRS, decreased mortality, it did not influence the risk of the symptomatic ICH. What about when they just looked at the observational studies? Higher likelihood of MRS zero to two, remember, that means the patient is functionally independent, lower mortality, but equal risk of symptomatic ICH. Again, I'm seeing like, you know, even in the observational studies, it seems to be doing well. But remember that, you know, this is an interesting, you know, kind of analysis over here where they said, okay, everybody who got endovascular treatment, what did they look like? So if you look at functionally independent versus MRS of five or six bedridden or dead, you can see that, you know, it is a higher proportion. Again, these patients with large cords are really sick. And so even if you got an endovascular treatment, there is 33 to 50% despite EVT. So, okay, I'm confused. What are the current guidelines? What do we know right now? The only guidelines that we have currently are from the Society Neurointerventional Surgery. And what they said is, here is a recommendation. You know, you always want to be evidence-based, right? In patients with anterior circulation who present within 24 hours, large infarct core, or aspects three to five and meet all other criteria, thrombectomy is indicated. And they have some sub-recommendations. What about our international audience? From those who in UK and Ireland, they changed their guideline in 2023 after the first couple of trials came out. And according to them, six to 12 hours, aspect score of three or more, irrespective of core infarct, 12 to 24 hours, aspects three or more, now you can use a CTP or MRP. I personally am waiting for the American Heart Association treatment guidelines, and they are yet to come. I know they are working on it, but it would be really helpful for us to look at these guidelines. But here's the problem. What happens in real-world translation? Here is one of the, we look at this case-by-case and we discuss this. We just discussed this last month. Here is a non-contrast CT. Again, this is a pretty big-looking MCA infarct, aspect of two. Here is my MCA occlusion. If I look at the CTP, it says only 52 ccs, but I would say this is almost underestimating. Do we take this patient? Yes, we did, because remember, this is a paradigm-shifting endovascular treatment. Tiki of three opened up that vessel. Reperfusion is good, but post-endovascular treatment, here is the diffusion. One thing I want to, again, for our diagnostic radiology friends, think about, be careful about before you start calling this infarct, because we are seeing a lot of this heterogeneity in the ADC and this kind of weird patterns of hemorrhage, and we don't understand, and maybe we have to be careful about calling this infarct and dead tissue. So we've been starting to look at these and we're not quite understanding. And to be very honest, what is dead? Is this deadish? And this is dead, dead, right? I mean, we don't, obviously we are not understanding something in the neuroimaging, because we know this is pannecrosis versus this is patchy necrosis. So this is something that we need to understand. And remember, the brain does not die in these big waves. It dries at this microstructural level. So there is these mini-cores and mini-penumbras, and so clearly the endovascular treatment has changed the paradigm, but we have still a lot of work. So this was a super quick whirlwind summary, large core trials, massive paradigm shift. We no more can deny endovascular treatment on core size alone, but we need, particularly as diagnostic radiologists, we need to help our stroke team and our interventional colleagues with core imaging understanding. And obviously there is a lot of future research being done. Thank you very much. So my talk will actually dovetail on Dr. Van Gaal's talk. Take all of these trials and sort of put them under a microscope and look at what were the inclusion criteria specifically with imaging, and start to take a look at what are the gaps? Because when we talk to people now, there's a lot of question about, well, who do we not take? It seems like we should take everyone. What core size do we stop? What imaging parameter do we stop and not take patients for thrombectomy? And there are still gaps in our knowledge. And so that's what I kind of want to explore with this talk. When we talk about core, what is large core? So there's several definitions of what large core is, and there's not consensus around what we call large core. Based on CT, there's the ASPECT score, which is the classic, has been used and is incredibly feasible. Everyone's got a non-contrast CT scanner available. So it's widespread and a feasible way to roughly measure a score and the amount of infarct territory. ASPECT score traditionally has been called a large core if the aspect is less than six. But this is a fairly arbitrary number, but this is kind of what we've historically been using to define large core. It's debatable. What about using CT perfusion to define core? Correlates well, CT perfusion correlates well with diffusion-weighted restricted diffusion, right? So that's another tool to be able to use to define core. But what are the thresholds? I mean, do we use a CBF less than 30% looking at 50 milliliters or 70 milliliters? What is our threshold volume? And that threshold volume and the way CTP can be interpreted changes depending on how far you are from the ictus and the moment at which the stroke occurred. Two minutes from the occurrence of a stroke, a CTP threshold with a 50 milliliters volume is very different from 24 hours out. So we don't take those things into account when we evaluate these. Our trials and our inclusion criteria use very rough metrics for inclusion and exclusion for feasibility sake, right? We wanna make these easy to get patients enrolled in and make a decision about who's eligible and who's not. So we tend to take liberties in terms of the nuance and the imaging that we can look at. So CTP in the early window, we know overestimates core. So that's something we kind of keep in mind. 50 milliliters in the early window may not represent core and only select two of the trials that were described included 50 to 70 ml core. So we'll go into a little bit about that. The correlation between CTP and aspects is not well established. So this is another caveat. DWI, so diffusion restriction, what we consider to be the gold standard, maybe a tarnished gold standard for infarct size. And this was touched upon briefly a little bit earlier, but in a study for patients who met study criteria, 16% of patients showed reversal of diffusion restriction after mechanical thrombectomy. So this reversal of restriction is a real thing that we have to keep in mind. So we talked a little bit about the six large trials published between 2022 and 2024. Again, this is amazing. But in the last two years, we've had six trials worth of data, and this is what we're trying to parse through. These are the studies that we heard about, Rescue Japan, Limit, Lasty, Angel Aspect, Select Two, Tension, and Tesla. And my goal here is to talk about the underrepresented groups. If you take all of these trials, look at the inclusion criteria and look at the data that they've actually collected, who did they enroll? What are the underrepresented groups? So the groups that we don't have good data for yet that we need to design large core trials for in the future. So when we look at this, what I want to bring your attention to is the predominant baseline imaging. Rescue Japan, Limit, and Lasty used MRI to estimate core volumes, whereas Angel Aspect, Select Two, Tension, and Tesla used CT or CTP. Angel Aspect and Select Two used CT and CT perfusion. And then the time windows are different. So Rescue Japan, Limit, and Lasty used less than six hours from presentation. The rest of the trials used less than 24 hours and Tension used less than 11 hours. So we'll talk about the implications of that. Low aspect score of zero to three. That's one of the underrepresented groups. When we look at these trials, zero to three was excluded in most of these trials, except for a few. What is zero to three? We had a nice overview of aspect score of zero to three. In this case, we've got a patient where the lentiform nucleus pushed your limb of the internal capsule, insular cortex, you've lost gray-white matter interface, frontal loperculum, temporal loperculum, and then once you go superganglionic, the two middle areas. So this is somewhere around a two or three on aspect score. So these large-core perfusion studies, especially in the later time windows, were underrepresented. So we don't know what happens in the later time windows. What about those patients without perfusion mismatch in any time window? Those are also underrepresented. And we'll talk about why here and look at the actual numbers. So if there's no perfusion mismatch, meaning there's matched defects in any time window in large volumes, those are patients that haven't been well-represented in all of these trials, and we'll look at the numbers. What about patients with baseline disabilities? So these trials all exclude patients that had an MRS of greater than two. So essentially, we're looking at a baseline healthy population. So if you've got a patient that has preexisting disability, we have less evidence to supply them. And it's important for us to have a discussion with those patients and their families about what to expect and what evidence we're going by. Age greater than 80. When we looked at the trials from 2015 and 2018, early on, we saw this effect size increasing as patients got older. So we have this idea in mind that older patients actually get more benefit from these procedures that we do in thrombectomy, while in these large-core trials, they're actually underrepresented in the trial results. So patients, the mean age in TESLA Select-2, ANGEL, and ASPEX was around 60 years of age. And then Rescue Japan LIMIT, Lasty and Tension, the mean age was around 70. So we don't have the same level of confidence in our data for patients that are above the age of 80. So when we focus on the imaging limitations, I wanna focus on MR-based studies in the early time window, CT-based studies with longer time windows, and then the question of mismatch versus match, and how do we interpret that? So starting with MRI-based studies in the early time window, the two studies we're looking at are Rescue Japan LIMIT and Lasty. Those are the two that used MRI. The limitation in Lasty was that they used DEWI B1000 levels to define their core infarct volume. And we know as neuroradiologists, B1000, I mean, you've got T2 Shine-through that can overestimate the size, right? So this is potentially an overestimation of size of core in the patients that they selected to get thrombectomy because they're using B1000 values. Rescue Japan LIMIT did use ADC thresholds. So they used a specific ADC threshold to look for reduced or restricted diffusion to calculate their core size. So they did have more accurate definitions of core, but Lasty did not, based on this, Lasty did not demonstrate an upper core volume limit. We can't use that trial's data to estimate upper core trial. Rescue Japan LIMIT suggested a possible upper limit threshold of 100 to 125 milliliters of volume. So that's something we kind of keep in mind, that patients that have over that volume of what we call estimated core based on MR ADC values, we don't have data for it. They may benefit, they may not. We just don't have the data for it yet. What about further imaging, further information that we need? We need further imaging information on core volumes of greater than 100 milliliters, as well as DWI aspect scores of zero to three. What about the CT-based studies and the longer time windows? So when we look at the CT-based studies, we've got angel aspects, select two, tension, and tesla. The benefit of thrombectomy with aspects of three to five beyond six hours was demonstrated by angel aspects, select two, and tension. So we've got good data for that. Four studies suggested that in aspects of three to five, meaning things that were larger core, quote larger core, benefited in the early time window. So we don't need to fuss about that as much and worry about those patient populations. But two studies demonstrated benefit up to 24 hours, angel aspects and select two. When we look at these two studies and try and dig down into what their imaging criteria were, both showed that aspects of three to five can have a wide range of CTP core values. So they did both CT, non-contrast CT, as well as CT perfusion, right? And they used CT to calculate an aspect space on CT. But when they looked at the CT perfusion, there's a wide range of values. So there's not a good correlation between our non-contrast CT aspects score that we're calling aspects on that and what our CTP volumes are. And when you look at a subgroup analysis for angel aspects, for CT aspects score of three to five, if the core volume, the CTP was less than 70, there was a modified rank and shift, meaning a demonstrated functional benefit at 90 days was 1.4 with thresholds above one. So we've got evidence for that. But if the core volume was greater than 70 and they had a CT that was three to five with the aspect score, then they didn't have overlap. That doesn't mean it's not a real phenomenon or that it does benefit those patients. It's just that we haven't demonstrated it yet. So in patients that have an aspect of three to five, but a core volume calculated by CTP of greater than 70, we just don't have data yet. Select two similarly showed lower odds ratio of 90-day improved MRS scores in patients over 100 milliliters on the CTP core. So again, these are areas where we still need more data. There was also a problem with low enrollment of the very large cores of greater than 100 mL of volume. So ANGEL aspect, their median core volume was about 60 mL and the interquantile range was around 29 to 86. And then the total core enrolled greater than 150 was about 15 patients with two in the thrombectomy arm. You can't really make assumptions or interpretations based on sample sizes like that. Select two, the total core enrolled greater than 150 mL was about 21 patients. So again, difficult to make interpretations based on numbers that are that small. So there's uncertainty about EVT response in perfusion mismatch patients with very large core volumes. Again, that's an area where we don't have good data for yet. And then finally, the question of mismatch versus matched core defects. So this is a table showing, and I'll just kind of quickly orient you to what we're looking at here. This is looking at the prevalence of mismatch. So how much mismatch was there in the overall volume of infarcted tissue? This is looking at the DWI aspect score. So eight to 10, these are patients that had almost no, had very small areas of core or infarcted tissue. We're starting to get bigger core infarcted tissue. And then three to five, we're starting to get what we think is larger core infarcted tissue. And when we look at the long time window or the extended time window, greater than six hours from last known well, about 50% of the patients had a mismatched volume. So what that means for us is that almost all the late window enrolled patients had a mismatched perfusion profile in the way these trials were designed in ANGEL aspects and SELECT2. So if we've got a large number of patients that are mismatched, then we don't know if we're actually capturing large core or if we're capturing patients that had potentially what we consider to be large penumbra. There were only 23 matched perfusion patients randomized to thrombectomy arm of the two trials that required perfusion imaging. So again, that kind of gives us a little bit of insight into what the limitations are. So there's uncertainty about the benefit of thrombectomy if there's matched patients, regardless of time window. Again, something that we need to explore. And this are probably, there's probably not as much equipoise out there in clinical practice. So these are things that need to come from real world data. Evidence does not support thrombectomy benefit has been established for unlimited core volumes. Data is needed for these subgroups, mismatch with core volumes that are greater than 100. And for aspects higher than three, thrombectomy is strongly supported. And then for no mismatch with core volumes greater than 70 in the early or late time windows, we still need more data. So how is diagnostic neuroradiologists and people in academics in imaging, can we help? There are alternative neuroimaging approaches. Again, net water uptake is one potential area to suggest to give us more information about what's happening at the parenchymal level. CBV index, trying to assess collateral status, hyperperfusion index ratios, as well as venous outflow are as yet under explored areas that could give us information about potential for recovery of tissue. So we also need to improve our definition of ischemic core. And Dr. Vagal talked about this a little bit a few minutes ago, but basically we don't really understand what DWI, CTP and non-contrast CT are measuring. These are fundamentally different pathophysiologic processes and our core measures are all very different using all of those. So those are just some of the limitations in large core trial. Hopefully we've given an overview of that and giving you some idea of where more data is needed and where to look for the future trials that may give us more information about this. So thank you. All right. So we're gonna talk about medium and distal vessel occlusions. And basically we're gonna cover two major topics of both how do we define them and how do we detect them? And then I guess the third part is gonna be what is the current literature and what's coming down the line in terms of randomized control trials for these? So first, how do we define medium and distal vessel occlusions? And this is actually surprisingly complicated, but I think the simplest approach to take is just using anatomy. This is where we can define the vessels based on their sulcal course. This is the most consistent approach, but even back in the large vessel occlusion trials from 2015 this wasn't really strictly followed. And as we get into talking about MEBOs or DEBOs, several approaches have been proposed. One was a functional one to say the term MEBO or medium vessel occlusion was vessel size one to three millimeters with a stroke scale of five or more or disabling deficits. But this is a challenging definition, especially if you're trying to read a study and find these because we don't necessarily have that information when we're reading. And so then the next is part of a morphometric analysis, combining size, tortuosity, and distance. And this I think is the most simple and straightforward approach. And this was proposed calling everything essentially that isn't a large vessel occlusion, a distal medium vessel occlusion or DMVO. So this is gonna align best with the anatomic definitions. There's no functional component and really it's gonna include everything that isn't our LVOs. So everything that's not an ICA, M1 or a dominant M2. And in order to go through this, we're gonna do a quick review of what our anatomic definitions are. So if we look here on an AP projection for the MCA, here's an M1, that's the horizontal segment or sphenoidal segment. And remember, this is not based on the bifurcation. This shows a pre and a post bifurcation M1 here. Not until we take that upward inflection. Do we enter the M2 segment? These are the insular or vertical segments. And we can see that nice kind of round shape. that's where these vessels are coursing through the circular sulcus. And that's why they're named for this coursing over the insula. And then as we take a lateral inflection one more time, we get into the M3s. These are our percular segments. And then finally, as we come out of the sylveon fissure, and we take another turn, these are going to be our cortical segments. And if we move on to a lateral projection, we can see if we line up those turns, we can draw a line across them on this lateral projection, and we can see that's going to be the margin of the circular sulcus as we go from M2 to M3. And finally, if we move down on this view, we have another line of turns here, and that's going to be the margin of the operculum from M3 to M4. If we move to our ACA, we have the same thing. We have a horizontal segment, that's our A1 segment up to the acom. And if we look at the lateral here, we can have our A2 segment here. This is the vertical portion going straight up from the acom and heading up to the genu, but not including it. Only once we go over the genu, we have the short segment, which is the A3. And then we get into the supracolossal and postcolossal segments, our A4 and A5 divisions. Finally, our PCA, our P1, is going to be our horizontal segment off the basilar tip. We get to our next segment, it's going to course posteriorly, and this is going to be through the ambient cistern, so therefore the ambient segment. We're going to take a turn again as we enter the quadrideminal cistern and going around the quadrideminal plate. This is our P3 segment. And then finally, taking another turn for our P4 before we branch out into our P5 branches, our calcarine, paroxipital, splenial branches, et cetera. And the reason this is important is that all of these seven upcoming randomized control trials are including different divisions. And I'll highlight here, rather than reading all of these out, what I've shown on the right is what's excluded in these trials. So most of these trials are excluding our fourth and fifth order branches, with a couple highlighted in red on the inclusions here that they're really including proximal P1s in distal, proximal ACA in frontier AP, and really the whole thing for distals. And so it's important to remember these inclusions are discordant. And so once these trials start to roll out over the coming years, we have to remember to review the specific definitions very carefully. All right. So how do we detect these? So patient comes in, a stroke code is called, they get a neurologic exam. Be great if we have this information, but I know most of us who are reading these studies don't have this information, but that can help guide your eye to where to look. Then we're going to get your structural imaging, so we'll have a non-conhead CT if you're using CT. If your shop uses MRI, you'll have a GRE, a FLIR, in addition to your DWI, hopefully. These are going to give you your indirect signs of where you can find an occlusion. So as you're looking for your infarct, look for a hyper-dense vessel on the non-con, look for susceptibility vessel sign on your GRE, look for a FLIR hyper-intense vessel on your FLIR. These are all going to help guide your eye when you're looking at your vessel imaging to give you an idea of where to look. Then we get to our vessel imaging. So most places are going to have a single-phase CTA, can also have a multi-phase CTA, can have CT or MR perfusion, or you can have a time of flight if you're using MR. So going through all of these, how we can use them in a meticulous fashion to look for these distal vessel occlusions. So one, if we look here on the left, we can see, I'm going to follow this M2 out to the top of the circular sulcus, it's going to peter out right there, and we can see a corresponding bright vessel. So this is a distal left M2 occlusion with a corresponding hyper-dense vessel. Here is a susceptibility vessel sign for a right P3 seen on the non-con and seen on a GRE. And then here's a FLIR hyper-intense vessel sign proximal to a left M2 occlusion. And all of these are going to be signs of where to look when we get to our vessel imaging. The first two hyper-dense vessels, susceptibility vessel, these are going to be showing us red cell rich clots. So in order, we're going to see that in about 60% of patients to about 88% of patients. And then the FLIR hyper-intense vessel is where we see slow flow, either proximal or distal to an occlusion, that can be seen in about three quarters of patients. Important to remember that the susceptibility vessel sign can actually be quite sensitive, even more sensitive than your time of flight, because you can have a loss of signal at the edge of the slab, so you might not even see it like you see here, that P3 occlusion is very challenging to see. And then finally, remember, use this to focus your review of the vessel imaging. All right, so moving on to a single-phase CTA, this is going to be our highest resolution non-invasive vessel imaging, and this is going to require a really meticulous approach to catch these things. And so it's important to use our source 0.625 millimeter images, and remembering that these distal medium vessel occlusions, or DMVOs, can be as small as 0.75 millimeters. And as you do that, you want to use your statural and coronal reformats in the same source thickness, otherwise you're going to miss a lot of these, remembering that most standard recons are sent as two-millimeter thickness slabs. And starting with our MIPS, this is a great screen. You can look at the arterial arbor density, help focus you on a region of interest. But avoid being lulled into a false sense of security, because sometimes vessel overlap or good collaterals can mask these. Here we see a patient with a distal left M2 occlusion, you can see that here, and same patient on a sagittal reconstruction, you can see beautifully here. And that's important to remember, look at the course of the vessel. As you saw on those angiograms, use the normal course of the vessel, and use the appropriate reconstruction to look at it. So your horizontal segments, your A1, M1, P1, these are going to be very well seen on your coronal reformats. Your longitudinal segments, M2s, M3s, your third and fourth order PCAs and ACAs, these are going to be very well seen on sagittals. But this still has pitfalls. So poor arterial phase bolus, venous contamination, branch origin or stump occlusions, vessel overlap, anatomic variations, we're still going to be able to miss these like this branch occlusion seen here. And what we know is that the false negative rate for single phase CTA is about 30%, at least that. And this is from a study where patients who actually underwent thrombectomy for distal vessel occlusions and went back and re-reviewed these CTAs. So what's coming down the line to help this? So iodine mapped to energy CTA can improve contrast resolution. Photon counting CT, which has gotten a lot of play at this conference, can give us very high resolution imaging. We can see an example here where this M3 branch is really conspicuous in the photon counting with 0.2 millimeter sections. But this hasn't really been evaluated yet for this purpose. So the miss rate definitely increases as we search for these. Can advanced imaging help us find some more? So one option is multi-phase CTA. And this is really a time resolved CTA. We get three phases, peak arterial phase, a peak venous phase, we can see with the left M2 occlusion here. And as we look here, bouncing between these two images, we can see contrast pooling up to the side of the occlusion with that green arrow. Additionally, we see those collaterals coming in with the blue arrow. When we get to our delayed venous phase, we see even more collaterals. That's kind of drawing our eye towards the site of the occlusion. And this can assist in detecting both the site and the length of the occlusion alongside a collateral assessment. And you can overlay these with color and make it easy to see on one picture. And then the upside of this is that it's acquired fast, less susceptible to motion, lower contrast and radiation dose. And this has been assessed for DMVOs, and we can see that this is about 86 to 89% accurate for detecting these versus around 61% for CTA. Next going on to perfusion, we can see that this is really nice and easy. We get one image that shows us exactly where this is, and we can call the site of the occlusion based on our perfusion pattern. If we look at that far right image, we can see a non-dominant inferior M2 occlusion pattern, and we can see a non-dominant superior M2 occlusion pattern. So this is going to show us very nicely. Similarly, we can see A2s, P2s, P4s, for example. All of these are going to have characteristic wedge-shaped patterns. And so this has been studied for DMVOs, and we can see this has 100% sensitivity, 88% specificity. About 90% of these are going to be detected using a TMAC6 threshold. But important to remember to review those source maps, because that last 10% will be seen only using a TMAC4 threshold. And it's also significantly faster. Using the CTP alone takes about 4 to 10 seconds to read this versus about 160 seconds to look at the whole CTA. And how do you choose between these two? Well, they're just about as good as each other, as far as we can tell. About 91% sensitive or 90% sensitive between the multiphase and CTA, and similar high specificity for both. So whatever you choose, do the same thing every time so that everyone gets used to using it, and so that you have a systematic approach to the same thing for every case. All right, moving on to MRA. This really hasn't been studied in isolation. It's less frequently used overall, but it's usually done with MR perfusion, which should perform very similarly to CT perfusion. So we expect the same kind of thing. This does have its own artifacts, though. Smaller field of view, lower spatial resolution than CTA. And you can have specific artifacts like loss of signal at the slab edges or the spinetian blind with overlapping slabs. So you have to be aware of those things. Coming down the line, 7-Tesla or even 5-Tesla as a high field MR can show us some really beautiful pictures. We can see on the left here the 7-Tesla with very high small vessel resolution. But keep in mind, these pictures are from an 11-minute scan protocol. This is not going to work for stroke patients. So this has to be iterated a bit. All right, so what do we do for mechanical thrombectomies in this patient? And I'll fly through this a little quickly because I'm running out of time. And so the best study, I think, that encapsulates the state of the data here is this one, the retrospective DUSC study. And this included M3s, M4s, A2s, A3s, P1s, P2s, compared endovascular therapy to medical management and really showed no difference in outcomes for treating these. For MRS 0-1, MRS 0-2, symptomatic intracranial hemorrhage, and not significant difference from antemortality. But it did highlight that patients with a higher stroke scale of 8 or more or patients who were ineligible for IV thrombolysis, these patients might benefit from this treatment. But it was underpowered for this. And so the ESCAPE Mevo protocol showed us that they calculated we need about 500 patients to detect a treatment effect. And this study only had 321. And we'll see the same thing with many of these other trials that are out there. They all showed no difference in MRS 0-1. And these are all retrospective data. Possible benefit for higher stroke scale, possible benefit for patients who couldn't get IV thrombolysis, possibly more hemorrhages unclear. But it's all retrospective. Much of this is biased because it's retrospective and there is some clinical equipoise. And we need larger numbers for these, as I just mentioned. And also MRS 0-1 might be the wrong scale. It's a very motivated scale, especially for PCA occlusions. We may not be appropriately capturing a treatment effect. So the upcoming trials will fly through this. So there are seven trials coming out. And we can see that they're all over the world. And there were flags here, but they disappeared. And we can see the planned enrollment is mostly going to be around the number we want, around 500. So highlighted in red are a few that are going to be a bit lower than that. They're a bit all over the place when it comes to time window. So much like you heard earlier, we're going to see some that are up to 24 hours, distal, distal, oriental, mevo, and some that are in the six-hour window, and some that are in the middle at 12 hours. Most of these trials agree that we should have patients with a stroke scale of 4 to 5 or disabling symptoms, with the exception of discount in France, which is 5 or less. And then the primary outcome also is going to agree mostly across the board with an MRS ordinal shift or MRS 0 to 1, with the one exception being distals, which is really a study looking at technical reperfusion success, not patient outcomes. And then the imaging, just highlighted in green without reading this, these are the ones that are looking at patients who are being selected with some sort of advanced imaging, perfusion imaging, multi-phase CTA, and showing that there's something to rescue here. And the important thing here is we can see that we're going to be getting data soon. So distal, distals, and discount should be either finishing enrollment or finishing shortly. And they should be coming out with data in the next year. And we should see that the rest of the trials are going to start giving us some soon. However, Dusk just recently announced that they paused their enrollment. And so it's unclear what that reason was. Sounds like there might have been very few patients getting randomized. And so we'll have to wait and see what's going on with these trials. And so power concerns could still be an issue for these, though, as well. And we might need separate meta-analyses for the MCA, for the PCA, for the ACA. And that might come only as late as 2029 or 2030, honestly. And so in conclusion, it's going to be important to know your neurovascular anatomy to detect these. Perfusion and multi-phase CTA can help you detect them. There's currently some equipoise in actually treating these patients based on the current retrospective data. Possible groups that could benefit are higher stroke scale, those who can't get IV thrombolysis. And we're really going to get that randomized data starting in 2025. And that should help make some decisions. And thanks for your attention. Thanks for the kind introduction. And this is kind of the outline. I'll go through entries regulation, things post-regulation, talk about some systems of cure optimization, and then give a summary and outlook, and hopefully stay within the time. But just to give you some historical background, I'll show you graphs that are mostly like this. On the x-axis, there's always the time. And on the y-axis, there is usually either a degree of how advanced the imaging is or a measure of core size to kind of make this easier to understand. But overall, like with the trials from 2015 and 2018, you can see that as the time got longer and longer, the imaging got more advanced, from just like LVO detection to using some measurement of core with the CT aspects, the collateral score, or then, as we've seen in Xtend IA switch primate, and then Diffuse 3 and DAWN. Like with advanced imaging, Diffuse 3 really tested the penumbra concept in the late time window, and then DAWN really used this clinical core mismatch to identify patients who would benefit. But there are obviously some gaps here, right? So if you go past six hours, you really should have some sort of measure of aspects of collaterals. And then if you go past 12 hours, then for most parts, you need an MRI or you need perfusion weighted imaging, at least, to get an idea of core and mismatch. So when we try to kind of address these gaps, like more recently, there are two studies that did this. There is Resilient Xtend that was published, I believe, last year, and that showed pretty bidirectional results in looking at patients which are selected based on aspects from like 8 to 24 hours from last C-Normal. So they saw increased odds of MRS 0 to 3, but they also saw increased risk of MRS 5 to 6. So both benefit and harm. And they had to redo their primary analysis a little bit to get to that point. So it doesn't work as well as what we saw in Diffuse and DAWN. And then the MR Clean Late study that essentially is a late window escape, a child that was positive but also had some cautionary features. It showed that the symptomatic intercranial hemorrhagic risk was 7% in the trumectomy arm compared to only 2% in the medical management arm. So again, if you're trying to extend the time window without advanced imaging, you run into some issues, at least, even though some of these primary outcomes were positive. And so how do we get to large cores? This is from Hermist. So this was all the 2015 trials. And so they found that there's a strong relationship, as we all understand, between the ischemic core and outcomes. So if you have a small core, you do much better than someone who has a larger core. But they also saw that the infected core size did not really modify the treatment effect. So blue line is the treated patients. Red line is the untreated patients. So you have this delta here maintains throughout this graph up to 150. Now, of course, there weren't a lot of patients in this infected core size category enrolled in any of the trials. So this is mostly statistics. But that really brought us to the large core trials that have been reviewed in more detail. But again, looking at them in a similar way that I've looked at the earlier trials, you generally have trials that just looked at CT aspect. You have trials that looked at MR aspect. And then trials that included some perfusion-weighted imaging. And again, there are some exceptions. And I generally took what 90% of patients were enrolled for and ignored minor enrollment criteria that didn't result in enrollment of a lot of patients. To make this a little bit easier to understand. And then Tesla failed its primary endpoint, shorter trend. So there is a gap there in the late window patients with a CT aspect. Another way to look at this is to plot this as, again, time from onset on the x-axis and then aspect on the y-axis. So last, he enrolled with MRI mostly. But he went all the way down to an aspect of zero. But the only enrolled at the first six and a half hours. All the other trials were aspects of three to five. And then the enrolled much later. So we really have this gap of late window and also very large core patients. So aspect zero to two. And the core, that is depending on how much tolerance you have in reading the studies of 100, 220 ccs. And then here you see the average core size and the 95% confidence interval of all of these trials. And that red dotted line shows you the 70 cc threshold that we know from diffuse three up to which a thrombectomy definitely seems to work. And so of all these trials, really only last, he was significantly above the threshold. A lot of the others were hovering around this 90 to down to 60 ccs. So a lot of them are really more moderate in the core size. And so this is kind of summary what we know. So we know that for moderate size core, a patient's thrombectomy works really well. And again, only last, he went significantly above 100 ccs. And then, as is pointed out by one of the other speakers too, almost all the patients in select to an angel aspect, who were the trials that enrolled patients based on advanced imaging, almost all of these patients had a co-operative number mismatch. And so one of the points I'm trying to make is use of aspects. While it's very practical and it's easy to adopt in clinical practice, it has a lot of limitations. And I think we need to do better. And then we need to look at these ultra large core patients, above 125 or so. And also patients who have moderate size scores and have no mismatch, because we really don't have a lot of data there. Then you all know this. There are some limitations to CT and MR aspects. It has poor inter-rater reliability. There is only a moderate correlation with the infect volumes. There really isn't a standardized definition on what percent of a territory has to be involved to call a certain territory. And different trials have used different things. For CT, that might not matter as much. But for MRI, you can make the point, well, one voxel that is affected in an embolic shower might not be enough to qualify for that territory to count. Then, as is pointed out, for MRI, using an EDC threshold versus just diffusion hyperintensity on the B1000 maps likely makes a difference. And then on CT, the degree of hypertenuation and whether you count salcal effacement or not makes a difference, too. So these are all patients who have ICT or M1 occlusions here. And just like you can see that this patient here on the left side, I don't think my point is showing up, but the one on the, oh, perfect. Thanks. Yes, this patient here on the left side may have a very different prognosis when you get them to open up that vessel compared to this patient where you can see that the area is a lot darker. And so this is the best study that I found on the correlation between core volume and CT aspect. And you can see that there is a pretty, on a scatterplot, it's a pretty wide agreement. There's an overall correlation that is moderate with a correlation coefficient of 0.49. But you can see that individual patients really doesn't correlate much. So overall, we're getting into this paradigm, like Mahesh is sitting here in the second row, of we used to use imaging for patient selection. Diffuse 3, I think, was the peak moment for that, where really imaging decided whether a patient goes to the cath lab or not. And we've shifted to outcome prognostication with like tension and like LASTI. And also to some degree, I think, MIWU identification, CTA volumes in like every ED are going up like crazy. And it's really easy to miss these, as was pointed out. So I think those are the two most important things for clinical care at this point. But there are some other things. And this is a little bit of that, it's like repeating some of the slides that someone else already showed. But as far as like predicting outcomes, in large group patients, there's this group in Hamburg that showed like looking at the CT collateral score really predicts the response to VT. Again, it doesn't really show you patients who won't benefit, but it just predicts like how well they do afterwards. So this is certainly helpful. And then same for net water uptake was mentioned too. Again, the same group showed that a difference in like how dark that core is, like these patients have like different outcomes. So that might be something to incorporate into future trials as well. And then, as still unpointed out, right, like MIWU identification is just a lot easier if you do your perfusion-weighted imaging. And this is mostly triggered, at least in this study, by like capturing distal occlusions and posterior circulation occlusions. So don't scrap your CTP protocols quite yet. I think if the MIWU trials are positive, then this will be like a much easier way to find those. So in our upcoming RCTs on the end-to-end circulation, so there are a couple of trials on ultra-large core and matched infarcts. One of them is coming out from like my own group at Stanford. It's called the Outer Limits Trial, enrolling patients who have a core greater than 125 mLs or a core greater than 70 and no mismatch. There's the XL Stroke 2 study as well that enrolls cores greater than 100 and CT aspects of like 0 to 2. And in the extended time window, they look at a diffusion positive, but a negative flare. For low-NIHSS patients, where we also don't know what's going on right now, like we have three trials that all look at NIHSS of like 0 to 5 in different time windows with like different imaging, but all fairly conventional trials. So we'll have more answers like what to do with those patients. The MIWU trials, as still I mentioned, again, plotting them here, advanced imaging, advanced imaging going longer and longer in the time window. So we'll see how many of these, like how these turn out, and we'll find out soon, hopefully. Adjunctive IA thrombolysis is another topic. So for intravenous thrombolysis, the most trial did not really support use of adjunctive and the platelets, but the CHOICE trial for EVT showed that IATPA is helpful, even in patients who had complete or near-complete reperfusion. So there are several trials, including CHOICE-II for TPA, several TNK trials, terrafiband trials, DNAs to dissolve like neutrophil extracellular traps off. These are ongoing or are starting to recruit to like see if what CHOICE showed is reproducible. For the trabectomy techniques, there's a lot coming up, too. There's cyclical aspiration with like several companies working on that and enrolling patients right now, seeing if that results in higher first-pass effects, mostly. There is the, you know, like we're in the era of ED-8 aspiration catheters. So the SUMMIT MAX trial by Rod92 compares like their system compared to other aspiration catheters, and then other companies have single-arm trials as well. Other gaps that we need to look into at some point are like are balloon guide catheters helpful? The only randomized study is the PROTECT-NT trial that showed inferiority of balloon guides, so we don't know what's going on there. Dual stent retrieval technique, TWIN2WIN, was like an initial study that suggests that this is a good approach for certain clots. Rescue intracranial angioplasty and stenting, initial reboot was negative, so like we'll see what happens there. Transcarotid approach for trabectomy, Silk Road is looking into that. Ischemic pre- and post-conditioning, and then like vagal nerve stimulation are some of the other things that will be coming up. For posterior circulation, this is a lot easier. There are only two trials. There's ATTENTION and there's BAOGE. ATTENTION just enrolled everyone within 12 hours, like no measure of core. BAOGE had some degree of core with like a PC aspect and a PONS midbrain index, but really no advanced imaging. And the enrolled patients who had an NIH of at least 10 or higher. And so this is the post-circulation aspect, which I'm just going to skip over for now. And then this is something that is emergent to it. It's the CAHPS score, looking at T-max greater than 10 in instructors in the posterior fossa. And that in the retrospective study showed that patients who have limited CAHPS scores with reperfusion do well versus those who don't. Even with reperfusion, they all do poorly. And this is being tested in the clinical trial. So these are the next steps for posterior circulation. You have low-NIHS patients, 0 to 9, where we don't know what to do with them. Then perfusion-weighted imaging, the precise studies can look at the CAHPS score. And then there are several studies looking at, again, adjunctive IA thrombolysis with either TP or TNK. Systems of care, like we have to get IVT into patients quicker. We know that if it's given within the first two and a half hours, then it really improves efficacy of endovascular treatment. Transfer, you know, direct to comprehensive versus primary stroke center. RACE-CAT didn't show a difference, but there are other studies that we want to show on the next slide. Optimization of door-in-door-out times for PSCs. And then if and when to do repeat imaging. Those are questions that we haven't answered. So this is like RACE-CAT, as I said, in Spain didn't show a benefit. But then in Rhode Island, Brown showed that there was a difference with their optimized approach. This is like just a simulation that we did at Stanford, like using machine learning, essentially, and re-routing patients, taking you from this left graph where orange is bad, yellow is good, to outcomes that are a lot more equal across the Bay Area map. So this might be something that is interesting to look into. And then, yeah, so as a summary, over the last decade or more, we really have seen a lot of progress in acute stroke prevention and treatment. And most of the gaps are being filled in by current ongoing trials. And so like potential additional benefits are probably smaller and require larger sample sizes. And so we need to go multi-center globalization efforts, adaptive randomization protocols and StrokeNet are some of those approaches to address that. And then areas of particular focus that I think we as radiologists play key roles in are like minimized time to treatment, so like LVO identification in the field with like mobile stroke units, ultra-low field MRIs, wearable devices, whatever it might be. Systems of care optimization, as I said, like optimized routing strategies, LVO alert on like non-contrast studies and so on. The other arm is going to be like buying more physiologic time before reperfusion. So get, you know, like use the time with like neuroprotection strategies, ischemic preconditioning, et cetera. I think imaging will play a key role in like in testing neuroprotective agents. And then as a last point, recovery and rehab with like neurostimulation devices, including endovascular devices that will be interesting to watch.

ischemic stroke

endovascular treatment

large core patients

imaging techniques

Resilient Extend

MR Clean Late

Aspects scoring

neuroimaging

treatment pathways