Stroke Alert May 2021

On Episode 4 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two featured articles from the May 2021 issue of Stroke: “Association of Serum IL-6 With Functional Outcome After Intracerebral Hemorrhage” and “SARS-CoV-2 and Stroke Characteristics: A Report from the Multinational COVID-19 Stroke Study Group.” This episode also features a conversation with Dr. Alvaro Garcia-Tornel Garcia-Camba to discuss his article “Ischemic Core Overestimation on Computed Tomography Perfusion.”

Dr. Negar Asdaghi:

1) Can a pro inflammatory marker predict the hematoma size and clinical outcomes in patients with intracerebral hemorrhage?

2) What are the characteristics of stroke patients infected with coronavirus?

3) Is ischemic core reliably represented by the current established cerebral blood flow thresholds on CT perfusion imaging? Or are we underestimating the importance of perfusion overestimating the ischemic core?

We will discuss these topics in today's podcast. You're listening to Stroke Alert Podcast. Stay with us.

Dr. Negar Asdaghi:                                     From the Editorial Board of Stroke, welcome to the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. For the May 2021 issue of Stroke, we have an exciting program today, as we cover topics from the predictive role of inflammatory markers in intracerebral hemorrhage to characteristics of stroke patients infected with SARS-CoV-2 virus. Later in the podcast, I have the privilege of interviewing Dr. Alvaro Garcia-Tornel Garcia-Camba from Autonomous University of Barcelona on the topic of ischemic core overestimation by CT perfusion imaging. I hope you enjoy our podcast.

Dr. Negar Asdaghi:                                     Intracerebral hemorrhage is an aggressive form of stroke with high morbidity and mortality rates. Increased systemic inflammation may be correlated with more severe neurological presentation, larger hematoma volume, and worse clinical outcome in these patients. Elevated levels of interleukin 6, or IL-6, have been found in the experimental models of ICH and may represent a therapeutic target to reduce the inflammatory response in ICH if similar findings were replicated in clinical studies of patients with ICH.

Dr. Negar Asdaghi:                                     In the May issue of the journal, in the study titled “Association of Serum IL-6 With Functional Outcome After Intracerebral Hemorrhage,” Dr. Kevin Sheth from Department of Neurosurgery at Yale University and colleagues performed a pre-specified exploratory analysis of the patients enrolled in the FAST trial, testing the association of admission levels of serum IL-6 with baseline neuroimaging and functional outcome at 90 days.

Dr. Negar Asdaghi:                                     But just a reminder for our listeners that FAST trial was a multicenter randomized trial of the recombinant factor VIIa administered in two doses versus placebo in patients with spontaneous nontraumatic intracerebral hemorrhage presenting within three hours of symptom onset.

Dr. Negar Asdaghi:                                     So, in the current analysis, amongst 841 patients enrolled in the trial, 66% were included who had both baseline IL-6 measurements and the follow-up modified Rankin Scale on day 90. Patients were stratified into four quartiles based on their admission IL-6 serum levels from low/normal in quartile one to very high levels in quartile four. And their baseline characteristics, neuroimaging and outcomes were then compared.

Dr. Negar Asdaghi:                                     So, what they found is that patients with a poor outcome, defined as modified Rankin Scale of four or higher at 90 days, had a higher median admission IL-6 level than those with a favorable outcome. In their multivariate analysis, for each one nanogram per liter increase in IL-6 level, there was a 30% increase in the odds of a poor functional outcome after adjustment for various factors, such as age, intracerebral hemorrhage volume, baseline Glasgow Coma Scale, presence of intraventricular hemorrhage, hematoma expansion, ICH location, and recombinant factor VIIa treatment allocation.

Dr. Negar Asdaghi:                                     So, a higher IL-6 level at baseline was also found to be independently associated with higher baseline hematoma volume and was a predictor of perihematomal edema, an association that was stronger in patients with lobar rather than subcortical  ICH.

Dr. Negar Asdaghi:                                     Now, whether there is a causal relationship between IL-6 and outcomes in ICH, and importantly, whether the growing number of anti-IL-6 therapies have a role in the reduction of inflammation and improvement of clinical outcome in this population, are important subjects to consider and study in the future. So please stay tuned.

Dr. Negar Asdaghi:                                     We now move on to our next paper, examining the characteristics of stroke in COVID-positive patients. In the study titled “SARS-CoV-2 and Stroke Characteristics: A Report from the Multinational COVID-19 Stroke Study Group,” Dr. Ramin Zand from Geisinger Neuroscience Institute and colleagues from across the globe examine the characteristics of COVID-infected patients with neuroimaging-confirmed stroke from 71 centers across 17 countries. Patients were included in the study if presented to the hospital with stroke-related chief complaints and asymptomatic COVID infection, or had a stroke while being hospitalized for COVID, or patients with stroke-related admission who had confirmed prior diagnosis of COVID infection.

Dr. Negar Asdaghi:                                     A total at 432 stroke patients were included in the study. 75% of those had acute ischemic stroke, 21% with intracerebral hemorrhage, and the remainder had cerebral venous sinus thrombosis. The authors found that, in general, stroke characteristics and subtypes were different in COVID-infected patients as compared to non-COVID stroke patients based on the prior population-based studies for both ischemic and hemorrhagic stroke. Notably, amongst COVID-infected patients with acute ischemic stroke, a third had only asymptomatic COVID. They had an overall male predominance with a young median age, and that a quarter of ischemic stroke patients were younger than 55 years of age, and a similar percentage had no known identifiable vascular risk factors. Among those with available vascular imaging, close to 50% had evidence of a large vessel occlusion on vascular imaging. In considering the etiology of stroke as defined by the TOAST classification, only 10% of COVID-positive stroke population had small vessel disease in contrast to typically 30% of the general ischemic stroke population.

Dr. Negar Asdaghi:                                     Now, when considering the hemorrhagic stroke, despite smaller number of patients included in the study, similar differences in general classification of hemorrhagic stroke patients was noted. Specifically, 25% of hemorrhagic strokes had evidence of subarachnoid hemorrhage, over two thirds of which was non-aneurysmal, a much higher percentage than that reported amongst non-COVID infected patients. A third of hemorrhagic strokes in this population is related to cerebral venous sinus thrombosis, an observation that is in keeping with the general notion that COVID infection can create a hypercoagulable state.

Dr. Negar Asdaghi:                                      In summary, this study adds to the growing literature regarding the complex interplay between COVID infection and vascular disease, and the importance of understanding how this virus may play a role in clinical presentation of stroke.

Dr. Negar Asdaghi:                                      Various imaging modalities, including diffusion-weighted imaging, MR perfusion, and CT perfusion, are used to define the extent of ischemic core in patients presenting with acute ischemic stroke. In contrast to restrictions and delays associated with acquisition of an MRI study in the acute setting, CT perfusion is readily accessible with relatively fast acquisition times and is easily incorporated in the stroke-alert workflow. As a treating stroke neurologist, you make the decision not to proceed with endovascular therapy in an otherwise eligible patient due to presence of a large volume of ischemic core, as measured by CT perfusion, only to find out that perfusion overestimated the ischemic core. How often do we encounter this scenario? And what are the factors associated with ischemic core overestimation as determined by CT perfusion? Joining me now is Dr. Alvaro Garcia-Tornel Garcia-Camba from Autonomous University of Barcelona, who's the first author of the study titled “Ischemic Core Overestimation as Measured by CT Perfusion: Collateral Status, Time and Its Interaction.” Good afternoon, Alvaro. Thank you for joining us from Barcelona.

Dr. Alvaro Garcia-Tornel Garcia-Camba: Good afternoon, Negar. It is a pleasure to be interviewed in a Stroke Alert Podcast to talk about our work with you.

Dr. Negar Asdaghi:                                      Great, Alvaro. Endovascular treatment is routinely offered to patients with a target intracranial occlusion, or between 6 to 24 hours from symptom onset, or those without a known time of onset if they're determined to have a small ischemic core. Can you walk us through the evolution of stroke endovascular therapies from time-based to imaging-based decision-making, please?

Dr. Alvaro Garcia-Tornel Garcia-Camba: Yeah, well, I remember when I started my neurology training, that was nearly 10 years ago, that the most important biomarkers that we took into account in decision making was time and stroke severity. For decades, time had been the tool to select patients for thrombolysis. It was no different for patients that were considered for endovascular treatment at the beginning. And we did a variety of scales and scores for acute stroke infarct assessment on non-contrast CT and MRI, like ASPECTs score and the routine use of non-invasive angiographics tests for the selection of patients with large vessel occlusion and the new generation stent-retrievers, and in basic framework for patient selection started to grow, and this led to positive progress for endovascular treatment trials back in 2015. Perfusing imaging developed in parallel with SWIFT-PRIME and EXTEND-IA being the early window trials that used perfusion imaging to select patients for endovascular treatment, with the aim to estimate the ischemic core, the already infarcted tissue, and penumbra, the ischemic tissue that is still viable if reperfusion is achieved, on computed tomography perfusion as an effort to mimic the accuracy of diffusion imaging MRI core estimation. Multiple studies for the development of thresholds applied to computed tomography perfusion role data to estimate core and penumbra using diffusion imaging as the gold standard. And the mismatch concept was the finite and it was successfully applied in the extended window that was above six hours in DEFUSE 3 trial.

Dr. Alvaro Garcia-Tornel Garcia-Camba: And DAWN trial, the other late window endovascular treatment trial, used a slightly different approach using the core clinical measurements, taking into account clinical severity and age rather than the penumbral tissue to select patients for endovascular treatments. Both the studies had positive results and a number needed to treat comparable to early imaging trials. And we have learned in the past years that time is one of the most important prognostic factors in patients with an acute stroke. But the clock runs at different speeds depending on the specific patient that we evaluate. Tissue analysis on imaging is the way to calibrate this state.

Dr. Negar Asdaghi:                                      Thank you, Alvaro, for this nice review of the literature. Can you please tell us about the concept of ischemic core overestimation, specifically by CT perfusion? What was known in the literature before, and what prompted you to look into this in more detail in the current study?

Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, we consider ischemic core overestimation is present when the estimated score by computed tomography perfusion imaging is actually larger than the real core, which is the not salvageable tissue at the time of imaging. Most of the studies that have focused on computed tomography perfusion accuracy considered both types of error, that the estimated score is larger or smaller than actual real core normal using diffusion imaging as the ground truth. We wanted to focus on overestimation because of two reasons. The first one is because it might deny endovascular treatment for patients in which reperfusion might lead to better outcomes. And because the ground truth is that the core should increase its size over time, not decrease. The study that prompted me to further investigate on this concept was an article that was published back in 2017, that is ghost infarct core concept that it was published by the unit that I work in nowadays.

Dr. Alvaro Garcia-Tornel Garcia-Camba: And this is the two main factors succeeded with overestimation. In this case was slightly different because they consider core overestimation to be when the estimated core was 10 milliliters larger than the follow-up infarct where reperfusion that was achieving more than 50% of reperfusion after endovascular treatment for more than mTICI 2B or earlier imaging in time. We consider the main limitation of this specific study was the small size because it only included 70 patients. And that the software used for computed tomography perfusion analysis was not as validated at this time as RAPID is, the one that is used in our actual study.

Dr. Negar Asdaghi:                                      Right. Now, very important concept to keep in mind, especially because RAPID is now used worldwide everywhere in many institutions. And as you mentioned, we make therapeutic decisions based on volumetric assumptions of ischemic core that's given to us by RAPID. Alvaro, we're excited to hear about your study. Can you please tell us about your patient population, and how you define ischemic core and CT perfusion, and what measures were used to determine the final ischemic volume in your study?

Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, we included 407 patients from a single center retrospective database that was from 2014 to 2019. They had to have an anterior circulation intracranial large vessel occlusion, including in portions of M1, M2 of middle cerebral artery or terminal intracranial carotid artery occlusion. And they had to have baseline computed tomography perfusion, and they must have achieved reperfusion after endovascular treatment that we have defined as mTICI 2B at the end of the procedure, with a follow-up non-contrast CT at 24-48 hours, in order to measure the final infarct volume.

Dr. Alvaro Garcia-Tornel Garcia-Camba: Patients with unwitnessed stroke onset were included, and the estimated core and hypoperfusion intensity ratio that it's a perfusion imaging output that it strongly correlates with collateral flow were determined using RAPID automated software with default thresholds. That is a relative reduction of cerebral flow below 15%* as compared to contralateral hemisphere for estimated core and the ratio of tissue with a Tmax delay above 10 seconds in areas with a Tmax delay above six seconds for hypoperfusion intensity ratio.

Dr. Alvaro Garcia-Tornel Garcia-Camba: The final infarct that was the ground truth for comparison was calculated as the mean from two observers’ measurements using a semiautomatic method for non-contrast CT and patients with a parenchymal hemorrhage type 2 hemorrhagic transformation on follow-up imaging were excluded from the analysis. Ischemic core overestimation was considered when estimated core was larger than final infarct volume.

Dr. Negar Asdaghi:                                      Perfect. Can you please tell us about the main findings of the study?

Dr. Alvaro Garcia-Tornel Garcia-Camba: We found out that ischemic core overestimation is a phenomenon that is more prevalent in patients with earlier window time and that the influence of poor collateral status are measuring using hypoperfusion intensity ratio with a cutoff point of 0.4. Previously as stated to discriminate between good and [inaudible 00:16:02] collaterals was stronger in patients with earlier window time. Patients with poor collateral status in the first four hours window had twice the odds of ischemic core restoration, as compared to patients that presented above four hours from symptom onset.

Dr. Negar Asdaghi:                                      Very interesting, Alvaro. CT perfusion overestimated the volume of ischemic core in 20% of your study population. What was the median volume of core overestimation, and what were the factors associated with this overestimation in your multivariate analysis?

Dr. Alvaro Garcia-Tornel Garcia-Camba: 83 patients presented with ischemic core overestimation. The median volumetric overestimation was 12 milliliters with an interquartile range of 56 milliliters. Apart from hypoperfusion intensity ratio and time from onset to imaging, terminal internal carotid occlusion location and complete reperfusion that was more than 90% of the people with modified TICI 2C–3 were independently associated with ischemic core overestimation on multivariate analysis. Within the [inaudible 00:17:12] and independent association with time from imaging to reperfusion, a variable that had been previously reported to influence the accuracy of core overestimation on computed tomography perfusion, and we believe that differences in baseline characteristics between the studies and the low variability in imaging reperfusion time in the core will explain why it was not statistically significant.

Dr. Negar Asdaghi:                                      Very important findings, Alvaro. Just reminding clinicians to pay attention to factors such as location of the occlusion and, as you mentioned, the hypoperfusion intensity ratio, in addition to the volume of the tissue with relative cerebral blood flow of less than 30% to define the ischemic core. So, definitely many important learning factors for all of us here. Alvaro, I want to finish by just a question that in routine clinical practice, CT perfusion is not commonly performed in those under six hours. And yet ischemic core overestimation seems to be a phenomenon most notably found in earlier presenters. So, what is the clinical implication of the ischemic core overestimation by CTP in late presenters?

Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, the rate of ischemic core overestimation was low in patients presenting above four hours from symptom onset. And I do not personally believe that clinically relevant overestimation is present in late presenters with witnesses at the stroke onset. Nonetheless, a high proportion of this population with late presentation do not actually have a clear symptom onset times. And it was witnessed in this group of patients, they [inaudible 00:18:46] not to perform in the vascular treatment for a large score on CTP only should be carefully taken given the results of our study. As taken solely in accountable volumetric estimation of core on computed tomography perfusion might lead to deny treatment to patient that could benefit from it.

Dr. Negar Asdaghi:                                      Very important, Alvaro. Again for our listeners, keep that ischemic core overestimation in mind when relying on CT perfusion in waker-upers and those with ischemic stroke of unknown time of onset. So, Alvaro, please tell us what's the most important takeaway message from your study, and what does the future hold for you in terms of your research?

Dr. Alvaro Garcia-Tornel Garcia-Camba: Well, it's a global message. I believe that contemporary perfusion imaging construct is based on fixed thresholds to estimate ischemic core. Those thresholds rely on [inaudible 00:19:37] patients with relatively small cores and early imaging. These models might have overfitted to those specific population characteristics. Different studies, including ours, have pointed that the accuracy of computed tomography perfusion core estimation is dependent on many variables. Some of them are known at the time of imaging, like degree of the perfusion after endovascular treatment or time from imaging to reperfusion. In order to improve our prediction accuracy for both core and prognosis estimation, further research should be focused on a multi-parametric approach that takes into account both clinical and imaging parameters, not only imaging parameters.

Dr. Negar Asdaghi:                                      Dr. Alvaro Garcia-Tornel Garcia-Camba, thank you for joining our podcast, and we look forward to covering more of your work in the future. And this concludes our podcast for the May 2021 issue of Stroke. Please be sure to check out the May table of contents for the full list of publications, including original contributions on clinical and basic and translational sciences, brief reports, editorials, comments and opinions, and much more. And remember that every breakthrough in science started somewhere from an idea that was then cultivated with care, determination, perseverance, and collaboration. A simple idea that someone might've heard somewhere in passing or on a podcast. So, keep working on your ideas, and until our next podcast, stay alert with Stroke Alert.

*Dr. Alvaro Garcia-Tornel Garcia-Camba confirmed following the interview that “15%” should be “30%.”