Stroke Alert

On Episode 32 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the September 2023 issue of Stroke: “Prestroke and Poststroke Sulfonylurea Exposure and Functional Outcomes: A Post Hoc Analysis of the SHINE Trial” and “Sleep Duration Is Associated With Subclinical Carotid Plaque Burden.” She also interviews Dr. Alexandros Polymeris and Prof. Philippe Lyrer about their article “Tranexamic Acid for Intracerebral Hemorrhage in Patients on Non-Vitamin K Antagonist Oral Anticoagulants (TICH-NOAC): A Multicenter, Randomized, Placebo-Controlled, Phase 2 Trial.” For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230829.123365

On Episode 31 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the August 2023 issue of Stroke: “Cancer Prediction With Machine Learning of Thrombi From Thrombectomy in Stroke: Multicenter Development and Validation” and “Differences in Stroke Recurrence Risk Between Atrial Fibrillation Detected on ECG and 14-Day Cardiac Monitoring.” She also interviews Dr. Robert Starke about the article “Outcome Evaluation of Repeat Stereotactic Radiosurgery for Cerebral Arteriovenous Malformations.” For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230802.750121

On Episode 30 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the July 2023 issue of Stroke: “Temporal Trends and Determinants of Stroke Risk in Patients With Medically Treated Asymptomatic Carotid Stenosis” and “Diffusion-Weighted Imaging Lesion Reversal in Older Patients With Stroke Treated With Mechanical Thrombectomy.” She also interviews Drs. Thanh N. Nguyen and Simon Nagel about their article “Endovascular Versus Medical Management of Posterior Cerebral Artery Occlusion Stroke: The PLATO Study.” For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230629.275844

On Episode 29 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the June 2023 issue of Stroke: “Prevalence and Procedural Risk of Intracranial Atherosclerotic Stenosis Coexisting With Unruptured Intracranial Aneurysm” and “Adolescent Hypertension Is Associated With Stroke in Young Adulthood: A Nationwide Cohort of 1.9 Million Adolescents.” She also interviews Dr. Darren B. Orbach about his article "Transuterine Ultrasound-Guided Fetal Embolization of Vein of Galen Malformation, Eliminating Postnatal Pathophysiology." For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230530.62217

On Episode 28 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the May 2023 issue of Stroke: “Decreased Estimated Glomerular Filtration Rate and Proteinuria and Long-Term Outcomes After Ischemic Stroke: A Longitudinal Observational Cohort Study” and “Stroke Prevention and Treatment in People With Type 2 Diabetes: Is There a Role for GLP-1 (Glucagon-Like Peptide-1) Analogues?” She also interviews Drs. Kanishk Kaushik and Marieke J.H. Wermer about their article “Iatrogenic Cerebral Amyloid Angiopathy Post Neurosurgery: Frequency, Clinical Profile, Radiological Features, and Outcome.” For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230501.274417  

On Episode 27 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the April 2023 issue of Stroke: “Association Between Hospital-Documented Atrial Fibrillation and Central Retinal Artery Occlusion” and “Early Stroke and Mortality After Percutaneous Left Atrial Appendage Occlusion in Patients With Atrial Fibrillation.” She also interviews Drs. Wenting Zhang and Jun Chen about their article “Poststroke Intravenous Transplantation of Human Mesenchymal Stem Cells Improves Brain Repair Dynamics and Functional Outcomes in Aged Mice.” For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230407.897078

On Episode 26 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the March 2023 issue of Stroke: “Tenecteplase Treatment and Thrombus Characteristics Associated With Early Reperfusion” and “Dual Antiplatelet Therapy With Cilostazol for Secondary Prevention in Lacunar Stroke.” She also interviews Dr. Mitchell Elkind about the life and the legacy of Dr. Ralph L. Sacco, Stroke’s Editor-in-Chief, who died January 17, 2023. For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230308.776720

On Episode 25 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the February 2023 issue of Stroke: “Early Antiplatelet Resumption and the Risks of Major Bleeding After Intracerebral Hemorrhage” and “Using Noncontrast Computed Tomography to Improve Prediction of Intracerebral Hemorrhage Expansion.” She also interviews Dr. Lauren H. Sansing about her article “Role of Inflammatory Processes in Hemorrhagic Stroke.” For the episode transcript, visit: https://www.ahajournals.org/do/10.1161/podcast.20230203.583057.

On Episode 24 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the January 2023 issue of Stroke: “Covert Brain Infarction as a Risk Factor for Stroke Recurrence in Patients With Atrial Fibrillation” and “Subarachnoid Hemorrhage During Pregnancy and Puerperium.” She also interviews Dr. Georgios Tsivgoulis about his article “Clinical, Neuroimaging, and Genetic Markers in Cerebral Amyloid Angiopathy-Related Inflammation: A Systematic Review and Meta-Analysis.” Dr. Negar Asdaghi:         Let's start with some questions. 1) When during pregnancy is an intracranial aneurysm at the highest risk of rupture? 2) What does the presence of covert brain infarcts mean in the setting of atrial fibrillation? 3) And, finally, how is the inflammatory form of cerebral amyloid angiopathy different from the classic CAA form, and why is it important to differentiate between the two? We'll be answering these questions and much more in today's podcast. We're covering the latest in cerebrovascular disorders, and this is the best in Stroke. Stay with us. Welcome back to another issue of 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. Together with my co-editors, Drs. Nastajjia Krementz and Eric Goldstein, here's our article selection for the month of January. Symptomatic intracerebral hemorrhage is a feared complication of reperfusion therapies in acute stroke, so there's a lot of interest in looking for predictors of development of this complication, especially when you're making decisions for pursuing endovascular therapy. For many years now, we've known about some of these predictors, such as presence of a large infarct core and high blood glucose levels. But in the recent years, other radiographic markers of tissue viability, such as a poor collateral status and unfavorable venous outflow profile, have been shown to be predictors of post-reperfusion hemorrhagic transformation. In this issue of the journal, we learn about another imaging marker that can potentially predict parenchymal hemorrhage occurrence post-endovascular therapy, which is high hypoperfusion intensity ratio, or HIR, as measured by perfusion imaging. What is HIR? It's a long name for a simple ratio that can easily be measured by dividing the volume of tissue with Tmax delay of over 10 seconds to the volume of tissue with Tmax delays of over 6 seconds. Simply put, Tmax 10 divided by Tmax 6. These volumes, as you know, are typically provided to us by almost all post-processing perfusion softwares, and so this ratio can be easily calculated in the acute setting. So, in this paper led by Dr. Tobias Faizy from University Medical Center in Hamburg and colleagues, we learned that higher hypoperfusion intensity ratios are strongly associated with parenchymal hemorrhage occurrence after endovascular therapy. So, in summary, HIR, that is a quantitative ratio, can be used as a marker to risk stratify patients that are undergoing endovascular therapy in terms of helping us predicting the risk of development of intracerebral hemorrhage after reperfusion therapies. In a separate study in this issue of the journal, we read a very interesting paper titled "Anti-Epileptic Drug Target Perturbation and Intracranial Aneurysm Risk." How are intracranial aneurysms even related to anti-epileptic drugs? Well, first of all, it's been known for a long time based on genome-wide association studies that there are multiple common genes that are associated with increased risk of intracranial aneurysm development. Now, some of the largest genetic studies to date have shown pleiotropy between genetic causes of development of intracranial aneurysms and genes encoding targets for anti-epileptic drugs. Now that's a fascinating finding because finding commonalities between these genes may help find new treatment targets for intracranial aneurysms. So, in this paper in this issue of the journal, the investigators from the University Medical Center in Utrecht found an association in the expression of anti-epileptic drug target gene CNNM2 and intracranial aneurysm risk. They found that certain anti-epileptic drugs, such as phenytoin, valproic acid, and carbamazepine, that are expected to lower CNNM2 levels in the blood may subsequently lead to a lower risk of development of intracranial aneurysms. And, of course, a reasonable follow-up study to this would be to investigate whether persons exposed to these anti-epileptic drugs have indeed a lower risk of unruptured intracranial aneurysms and subarachnoid hemorrhage, and how variation in CNNM2 expression can lead to development of aneurysms. Bottom line, CNNM2 may be a relevant drug target for treatment of cerebral aneurysms. As always, I encourage you to review these papers in detail in addition to listening to our podcast today. My guest on the podcast today is the Chairman of Neurology at the University of Athens, Dr. Georgios Tsivgoulis. He joins me all the way from Greece to talk about cerebral amyloid angiopathy-related inflammation, or CAA-ri. He's a remarkable researcher, and I can say with absolute confidence that we cannot find a better summary of this very tough topic elsewhere. He ends the interview with an intriguing account of the early description of dementia in Greek mythology. But first, with these two articles. What are covert brain infarcts, or CBIs? Are these the John Wick or the James Bond of the stroke world? After all, they operate undercover. They're ominous and attack without warning. That's probably why they're also called silent infarcts. Now, whatever we call them, we need to know how prevalent they are and what does their presence actually mean. Let's dive into this topic. For at least two centuries, if not longer, we've known about covert brain infarcts. Early description of these lesions is credited to Amédée Dechambre, a medical intern at Salpêtrière Hospital in Paris who noted that there are strokes that can cause symptoms like hemiplegia, but also strokes that are asymptomatic, or so he thought at the time. In the modern times, while we agree with our pathology forefathers that CBIs are different from symptomatic strokes, we also know that they are not entirely asymptomatic. The symptoms can be subtle and tend to sneak up on the patient, but what is clear is that amassing of covert brain infarcts results in an overall decline in cerebrovascular reserve of the brain. With the advent of neuroimaging, we now know that CBIs are age-dependent and prevalent, seen in almost 10 to 30% of even healthy adults, but much more prevalent in those with vascular risk factors, and they can be caused by nearly the entire spectrum of neurovascular disease, including large vessel, small vessel disorders, cardioembolism, and others. Now, how do these covert infarcts catch up in those with atrial fibrillation? Neuroimaging studies have shown that patients with A-fib, especially those untreated, have a higher percentage of embolic-appearing CBIs, and conversely, those with embolic formed pattern of CBIs are more likely to have undiagnosed A-fib. So the question is, what's the significance of CBI in those with confirmed A-fib? In this issue of the journal, Dr. Do Yeon Kim from Seoul National University and colleagues help us answer this question using the EAST-AF, which stands for East Asian Ischemic Stroke Patients With Atrial Fibrillation Study. So, the paper included over 1300 patients with A-fib and first-ever stroke without a prior history of TIA or stroke. And then they categorized these patients into those who had evidence of CBI on neuroimaging and those who didn't. So, what did they find? Forty-two percent of patients with A-fib and first-ever stroke had evidence of covert brain infarcts on neuroimaging. Let's think about it for a moment. These patients presented with what was thought to be their first-ever stroke, not knowing they already had some in their brain. Now, what makes things really worse is that over a quarter of these subjects had more than just one covert infarct. Not surprisingly, those with CBI tended to be older, had higher blood pressure, and had worse white matter hyperintensity burden. This is kind of expected and also not expected was the fact that most of these covert infarcts were actually embolic in pattern. Over 60% of them were embolic. Another 14% of cases had combined embolic and non-embolic-appearing CBIs. Now, overall, the one-year incidence of ischemic stroke and all-cause mortality was higher in those that had CBIs at baseline. When they started looking at the specific patterns of CBIs, those embolic-appearing CBIs had a threefold higher risk of recurrent ischemic stroke, whereas those with non-embolic-appearing covert infarcts had oddly a higher all-cause mortality rate but not recurrent ischemic stroke. And finally, just briefly, the authors noted that the addition of CBIs to the classic CHA2DS2-VASc score didn't meaningfully otherwise statistically improve the scoring metrics, so they left it at that. So, the take-home message is that 42% of A-fib patients presenting with first-ever stroke actually had prior strokes without even knowing based on this study. And most of these strokes were embolic-appearing, and these covert brain infarcts can be used as predictors of future clinical strokes in this population. Strokes should be the last thing to worry about when we think of pregnancy. In the United States, around 30 in 100,000 women, unfortunately, experienced a stroke during pregnancy, and between 6 to 8 in 100,000 deliveries are complicated by subarachnoid hemorrhage. What's the most common cause of pregnancy-associated subarachnoid hemorrhage? In the general population, close to 80% of subarachnoid hemorrhage cases are aneurysmal. Is this true for the pregnant population as well? And importantly, what's the contemporary incidence trend, risk factors, and outcomes of pregnancy-related subarachnoid hemorrhage? In this issue of the journal, Dr. Korhonen and Petra [Ijäs] and their colleagues from the Departments of Neurology and Obstetrics and Gynecology at Helsinki University Hospital will give us the answers to some of these questions through a nationwide population-based study in Finland. So, they looked at over one and a half million pregnant women who gave birth during a 30-year time period between 1987 to 2016. Subarachnoid hemorrhage was identified through appropriate ICD codes and then further adjudicated based on confirmatory information, including neuroimaging and data from lumbar puncture. A total of 57 cases of pregnancy-related subarachnoid hemorrhage was identified in this paper. The mean age of women was 33, ranging from 23 to 45, and the clinical presentation was typical for subarachnoid hemorrhage, including thunderclap headache and mild neurological symptoms. So, what did they find? So, first off, in terms of general observations, the overall incidence rate of pregnancy-related subarachnoid hemorrhage in this study was 3 over 100,000 deliveries. This is almost half the incidence rate reported from the nationwide registries in the United States. Seventy-seven percent of pregnancy-related subarachnoid hemorrhage cases were aneurysmal, so very similar to the general population. The other 23% were non-aneurysmal cases, but it's important to note that 40% of those non-aneurysmal cases also had vascular etiologies, so etiologies such as moyamoya syndrome, postpartum angiopathy, AVM, to name a few. Like non-pregnant patients with subarachnoid hemorrhage, the aneurysmal cases were sicker patients in general. They had a lower GCS at presentation, higher Hunt and Hess scores, and required more ICU admissions. The next finding is very important because it actually shows that development of subarachnoid hemorrhage during pregnancy significantly impacted obstetrical care. A total of 66% of women with subarachnoid hemorrhage during pregnancy ended up having a C-section and a high percentage of these cesarean sections were actually elective. This is in contrast with subarachnoid hemorrhages in the postpartum period where 67% of women had spontaneous vaginal deliveries. The other important finding of the paper was really highlighting the differences between pregnancy-related aneurysmal versus non-aneurysmal subarachnoid hemorrhages. We already talked about how, in general, aneurysmal cases had more severe neurological presentations, so, not surprisingly, they also had worse outcomes with a mortality rate of 16% for the aneurysmal subarachnoid hemorrhage cases, and only 68% of women with pregnancy-related aneurysmal subarachnoid hemorrhage reached a favorable outcome, which was defined in this study as modified Rankin Scale of 0 to 2. Other important differences included the fact that the incidence of aneurysmal subarachnoid hemorrhage increased towards the end of pregnancy and was highest in the third trimester. This ties in with the findings from prior studies all indicating that rupture of an aneurysm is most common in the third trimester. By contrast, the incidence of non-aneurysmal subarachnoid hemorrhage peaked in the second trimester in this study. And finally, in terms of risk factors, first let's talk about age. The incidence rate of pregnancy-associated subarachnoid hemorrhage increased with age of the mother. So, in this study, there were no cases noted amongst women aged below 20 years of age to an incident rate of 12 per 100,000 deliveries among women aged 40 years or over. So that's a fourfold increase from the overall incidence rate of pregnancy-related subarachnoid hemorrhage, and very important point that we learned from this paper. Apart from age, smoking beyond 12 weeks of gestation and hypertension were also independent factors associated with pregnancy-related subarachnoid hemorrhage. So, overall, hypertension, smoking are bad and are significant risk factors for pregnancy-related subarachnoid hemorrhage. And if we have to remember just one thing from this paper, let it be this one: The rupture of an aneurysm is most common in the third trimester of pregnancy. Cerebral amyloid angiopathy, or CAA, is an important cause of intracranial hemorrhage and refers to deposition of β-amyloid fibrils in the wall of the small- and medium-sized cerebral blood vessels, mostly involving cortical and leptomeningeal arteries. It is believed that the deposition of β-amyloid results in architectural disruption of the blood vessels, which then leads to perivascular leakage. That's the pathophysiological mechanism behind the development of cerebral microbleeds. And this process, of course, can cause frank vascular rupture resulting in cortical intracerebral hemorrhage or development of high-convexity subarachnoid hemorrhages. It is important to note that varying amounts of perivascular inflammation, that is inflammation surrounding β-amyloid-laden blood vessels, may be present in some CAA cases, rendering them the designation of inflammation-related CAA. However, frank vasculitic destruction of the vessel wall, such as what is found in amyloid-β-related angiitis, or ABRA, and primary angiitis of the central nervous system, is usually absent in most CAA-related inflammation cases. How these entities are best defined, diagnosed, and treated is subject of intense research. In this issue of the journal, in the study titled "Clinical, Neuroimaging, and Genetic Markers in CAA-Related Inflammation," Dr. Georgios Tsivgoulis and colleagues take us through a systematic review and meta-analysis of published studies of patients with CAA-related inflammation. I am joined today by Dr. Tsivgoulis himself to discuss this paper. He's a Professor of Neurology and Chairman of the Second Department of Neurology at the University of Athens School of Medicine. Dr. Tsivgoulis is the residency program director and the director of cerebrovascular fellowship program with extensive research and expertise in the field of stroke. Good morning, Georgios, and welcome to our podcast. Dr. Georgios Tsivgoulis: Good morning, Negar. I'm delighted to be here and delighted to present our findings, on behalf of all our co-authors. Dr. Negar Asdaghi:         Thank you very much for being here and congrats again on the paper. So, Georgios, let's start with this interest that's going on with using clinical and radiographic features to make the diagnosis of CAA-related inflammation in contrast to moving ahead and performing brain biopsy. Can you please start us off with a brief review of the newly proposed clinico-radiographic criteria for this condition, please? Dr. Georgios Tsivgoulis: Yes. As you mentioned, Negar, CAA-ri is a distinct, however, rare subset of cerebral amyloid angiopathy. Firstly, Greenberg and the Boston group published in Neurology in 2007 a paper highlighting that a diagnosis of a probable CAA-ri patient could be made on the basis of characteristic clinical and neuroimaging findings without requiring a biopsy. Following this observation, Chung and colleagues in 2010, in a seminal paper in JNNP, proposed the first diagnostic criteria for probable and definite CAA-ri. For the definite diagnosis, besides the typical clinical presentation with headache, encephalopathy, focal neurological signs and seizures, and the characteristic neuroimaging findings with T2 or FLAIR hyperintense asymmetric white matter lesions complicated with microbleeds and leptomeningeal or parenchymal gadolinium enhancement, and histopathological confirmation with amyloid deposition within cortical leptomeningeal vessels associated with perivascular, transmural or intramural inflammation was also required. The latest criteria developed in 2015 by Auriel and colleagues that were published in JAMA Neurology using a validation study modified the current criteria for the diagnosis of CAA-ri. In this paper, the author supported the use of empirical immunosuppressive therapy, avoiding brain biopsy, for patients meeting the criteria proposed for probable CAA-ri. They suggested that a brain biopsy should be considered in empirically treated patients who failed to respond to corticosteroid therapy within three weeks. The criteria by Auriel and colleagues are widely applicable in everyday clinical practice, and we also use this criteria for the inclusion of studies in our current meta-analysis. I would like to highlight for our audience that the latest criteria for CAA-ri were published in 2015 by Auriel and colleagues. However, these are different for the criteria for cerebral amyloid angiopathy than the latest criteria were published in 2022 in Lancet Neurology, OK? Dr. Negar Asdaghi:         Georgios, that was a great start for this interview. You had mentioned a lot of information here. I just want to highlight what you just said. So, we are using for this meta-analysis, the latest criteria in CAA-related inflammation published in JAMA by Auriel and colleagues. That's slightly different than, we're not referring to the 2022 criteria of cerebral amyloid angiopathy. It's an important distinction. We're going to talk about this a little more as we go through the interview, but I want to come back to your current paper and start from there. Can you please tell us about the importance of this paper, why doing a meta-analysis was important in your view, and tell us a little bit about the studies that were included in your paper? Dr. Georgios Tsivgoulis: Yes, thank you for that question. CAA-ri is an increasingly recognized entity since the recent diagnostic criteria by Auriel and colleagues published in 2015. In collaboration with the greater availability of the high-resolution MR, we can have now a reliable non-invasive diagnosis of possible or probable CAA-ri, avoiding the risk of brain biopsy. However, I need to highlight that the early diagnosis remains a great challenge for the clinicians and neurologists. Searching the literature, we observe that there is scarce data regarding the prevalence of the distinct clinical, neuroimaging, and genetic markers among patients diagnosed with CAA-ri. We believe that pooling all this information in the current meta-analysis would be very helpful for every clinician, increasing a comprehensive understanding of this rare cerebrovascular disorder. Consequently, we conducted this meta-analysis including 21 studies that recruited a total of 378 patients with CAA-ri. Our study involved only 4 prospective and 17 retrospective hospital-based cohorts of patients diagnosed with CAA-ri based on autopsy or biopsy or on the recent Auriel diagnostic criteria that do not require autopsy or biopsy. Due to limited data in the literature regarding this entity, we had to include only small cohort studies with at least five patients in our meta-analysis. We excluded case reports and case series with less than five patients. This is, by far, the largest available sample of CAA-ri patients in the literature. Dr. Negar Asdaghi:         OK, great. So, let me just recap this, more so for myself. So, we have 21 studies, and you excluded studies that included less than 5 patients. So, practically speaking, case reports. Dr. Georgios Tsivgoulis: Yes, and single-case reports. Dr. Negar Asdaghi:         Yes. And practically speaking, of the total number of patients that are included in this meta-analysis, you have 378 cases, and basically the diagnosis of CAA-related inflammation was either based on the newly proposed criteria or based on biopsy-confirmed or autopsy cases. Dr. Georgios Tsivgoulis: Which is the standard criteria. Dr. Negar Asdaghi:         So, now, I'm dying to ask you about these clinical and radiographic characteristics of patients with CAA-related inflammation in this meta-analysis. Dr. Georgios Tsivgoulis: The mean age of patients in the included studies was approximately 72 years old, and there was no obvious gender predominance. Fifty-two percent of the patients were of female sex. In our study, 70% of the included patients presented with cognitive decline, which was the most common neurological manifestation, while 50% of the total sample had focal neurological signs and 54% encephalopathy presentation. Symptoms such as headache and seizures were less common, 37 and 31% respectively. With regard to the radiological findings, hyperintense T2 FLAIR white matter lesions were very, very common in 98% of our patients, and they were also complicated with lobar cerebral microbleeds, with a prevalence of 96%, and these two were, by far, the most prevalent neuroimaging findings, that white matter hyperintensities coupled with a cerebral microbleed. The pooled prevalence rates of gadolinium-enhanced lesions was 54%, and also the prevalence of cortical superficial siderosis was 51%, which is also very high in this cohort of patients with CAA-ri. Dr. Negar Asdaghi:         OK. So many of the features Georgios said, you mentioned, from presence of white matter hyperintense lesions on T2 FLAIR to presence of cortical microbleeds or superficial siderosis, these features are also seen in patients with cerebral amyloid angiopathy. What are some of the important differentiating features between the two conditions? Dr. Georgios Tsivgoulis: Yes, this is an excellent clinical question. First of all, the lower age threshold for CAA-ri is 40 years old, whereas in cerebral amyloid angiopathy, the lower age threshold is 50 years. So, patients who are younger than 50 years can be diagnosed with CAA-ri, but they cannot be diagnosed with CAA. Another issue is that comparing the result of this meta-analysis with another recent meta-analysis focusing on CAA, on cerebral amyloid angiopathy, that our international multi-collaborative group published in Stroke in 2002, we also evaluated the presence of clinical phenotypes and radiological markers among patients with cerebral amyloid angiopathy. We have documented that transient focal neurological episodes are much more common in patients with cerebral amyloid angiopathy in contrast to patients with CAA-ri. These episodes, which are called TFNEs, transient focal neurological episodes, are attributed to cortical subarachnoid hemorrhage or cortical superficial siderosis. So, I think this is another important clinical distinction. The most important, however, differentiating features between the two entities are neuroimaging markers, in specific, in particular, T2 FLAIR hyperintense unifocal or multifocal lesions with mass effect. These are the most prevalent neuroimaging features among patients with CAA-ri, but they're very seldomly described in patients with cerebral amyloid angiopathy, in patients with CAA. Another characteristic neuroimaging finding very indicative of the inflammation is the leptomeningeal or parenchymal gadolinium enhancement. This finding has been very rarely described in patients with non-inflammatory cerebral amyloid angiopathy. So, the clinical distinction is not so solid. However, the neuroimaging distinction would provide us with very strong information that can help us differentiate these two conditions. Dr. Negar Asdaghi:         Excellent points, I have to say, golden points, not just excellent points. I'm going to try to recap this and see if I understood it correctly. So, for our listeners, we have two conditions that potentially have many common points. One is the cerebral amyloid angiopathy, and the second one, which is obviously the subject of this interview, is cerebral amyloid angiopathy-related inflammation. The most important differentiating factors between the two are actually the neuroimaging features, as Georgios mentioned. So, the first feature that was mentioned is presence of T2 FLAIR hyperintense lesions. Some of them are large and have actually mass effects. This feature is rarely seen in patients with CAA, and it's an important radiographic factor that is seen in patients with CAA-related inflammation. The second distinguishing feature was leptomeningeal enhancement, again, rarely seen in non-inflammatory CAA, but was seen in a significant proportion of patients with CAA-related inflammation. These were the neuroimaging features. You also mentioned two other factors. The median age of CAA-related inflammation was lower than CAA. That can be helpful. And also the entity of transient focal neurological episodes, or TFNE, is rarely seen in inflammatory cases of CAA, whereas it is described in cases with cerebral amyloid angiopathy and mostly related to development of either cortical subarachnoid hemorrhage or cortical superficial siderosis. I think I got this all, correct? Dr. Georgios Tsivgoulis: Excellent. Dr. Negar Asdaghi:         All right, so let's come now to the genetics of CAA. The apolipoprotein E gene is associated with the presence of amyloid angiopathy and development of lobar intracerebral hemorrhage, and we've learned about this in cases with cerebral amyloid angiopathy. Is there an association with ApoE, and did you find anything in this meta-analysis? Dr. Georgios Tsivgoulis: Another very exciting question. In 2007, there was a first report that the apolipoprotein ε4 homozygosity may be considered a risk factor for CAA-ri, and there was a strong correlation reporting a high prevalence of 77% of this apolipoprotein ε4 alleles among patients with CAA-ri. To justify this correlation, the hypothesis was that an underlying pathogenic mechanism, which increases the amyloid-β deposition and has a pro-inflammatory effect, may be suspected as the cause of this disorder. The largest, however, prospective cohort of CAA-ri patients conducted by Antolini and colleagues and was published in 2021 in Neurology, reported a much lower prevalence of apolipoprotein ε4 carriers accounting for 37%, 23% heterozygotes and 14% homozygotes. So, we also documented a pool prevalence of apolipoprotein ε4 homozygosity of 34%. So, we did not confirm the initial finding of 77%. However, in our meta-analysis, the homozygosity was 34%, and we need to have a cautious interpretation of these results because data is limited, and we need larger future population-based studies and in larger cohorts to evaluate the prevalence rate of these specific genetic markers. So, we can confirm an association between apolipoprotein ε4 homozygosity, however not as strong as originally reported in 2007. Dr. Negar Asdaghi:         OK. So, Georgios, thank you. And again, very important factor to keep in mind for our clinicians listening in. Unfortunately, based on what you mentioned, we don't have yet a genetic marker to, for sure, tell us if we're dealing with CAA-related inflammation, yes or no, as you mentioned. Just to recap, earlier on, there was studies to suggest a very strong association between apolipoprotein ε4 homozygosity and CAA-related inflammation. But later on, this was not confirmed by subsequent studies, and in your meta-analysis, you found 34% ApoE ε4 homozygosity amongst patients with CAA-related inflammation and could not confirm that original high association. OK, so with all of that, it's a lot of information. I have to go to the next question regarding controversies involving the levels of Aβ40, Aβ42, and P-tau proteins in CSF in the setting of CAA-related inflammation. Can you please tell us more about these biomarkers? Dr. Georgios Tsivgoulis: Yes. The overlap of Alzheimer's disease and CAA can be attributed to the coexistence of some degree of cerebrovascular amyloid deposition and amyloid plaque pathology, which is very common. And, of course, the evaluation of amyloid and tau proteins in CSF is of high significance for the prognosis and the evolution of CAA patients. In our previous review, we have summarized the literature and noticed that CSF concentrations of Aβ40 and, secondarily, Aβ42 were much lower in patients with cerebral amyloid angiopathy compared with Alzheimer's disease. Total tau and phospho-tau CSF levels were comparable to healthy controls in CAA and lower than patients with Alzheimer's disease. Moving now to CAA-ri, there were scarce data about these biomarkers amongst CAA-ri patients. The majority of the relevant studies have found relatively low levels of Aβ42 and Aβ40 in the CSF and high levels of P-tau. In the present meta-analysis, the pooled means of biomarker levels were based on the findings of only two studies with heterogeneity, and these limit substantially the validity of our observations. However, they confirm the previous reports indicating, as I said before, but I would like to repeat, low levels of Aβ42 and Aβ40 in the CSF and high levels of P-tau. Dr. Negar Asdaghi:         Perfect. So, thank you, Georgios. I'm going to recap what you said. So, we're talking about CSF biomarkers, and first what you mentioned is going back to the original studies concentrated on using these biomarkers as ways of differentiating between cerebral amyloid angiopathy and Alzheimer's disease. And very briefly, to recap what you said, in general, the levels of Aβ40 and, secondarily, Aβ42 was found to be much lower than the Alzheimer's levels in patients with CAA. Now coming to the inflammatory form of CAA, what you mentioned and what you found in this meta-analysis, practically speaking, confirmed that the levels of Aβ40 and Aβ42 in CSF are low and the levels of P-tau are high in this condition as well. So, one thing I want to ask as a secondary question to that is, that it sounds like these biomarkers are more or less similar in CAA and CAA -related inflammation, not that different. Is that correct? Dr. Georgios Tsivgoulis: It's absolutely correct. And I would also like to highlight a major limitation of the meta-analysis that we had available data from only two studies to pool the mean of these CSF biomarker levels. So, these results need to be acknowledged with caution, and we would love to repeat our meta-analysis after the publication of more studies and prospective cohorts measuring the CSF biomarkers in patients with CAA-ri. Dr. Negar Asdaghi:         OK. So, again, important to note, as you mentioned, that there's heterogeneity in data because of just paucity of information on this, but as we stand today, the biomarkers won't really help us in terms of differentiating between the two conditions that are CAA or CAA-related inflammation. And so, I think I've learned a lot from this interview myself, but I think we have to just talk briefly about the available therapies for CAA-related inflammation. Dr. Georgios Tsivgoulis: Yes. In our meta-analysis, we sought to summarize the available information regarding different therapeutic strategies and outcomes among CAA-ri patients. Our results supported our clinical experience indicating that corticosteroids represent the first-line treatment in these patients' outlook. Steroids have been associated with clinical and radiological improvement of the primary disease episode and decreased risk of subsequent relapses in patients with CAA-ri. Additional immunosuppressive therapies, including cyclophosphamide, mycophenolate mofetil, azathioprine, IVIG, or rituximab, have been also reported as adjunct therapies in selected cases with a more severe course of the disease. However, this is another limitation that needs to be acknowledged. That data regarding the treatment and the outcomes are limited and heterogeneous, which prevented us from drawing robust conclusions using a meta-analytical approach. And we believe that we need future cohort studies with prospective data validation in order to generate a proposal for a therapeutic algorithm management in these cases. Dr. Negar Asdaghi:         Thank you, Georgios. So, we have a condition that is now being more and more recognized. We now have criteria based on clinical and radiographic presentation features of patients that might help us with this diagnosis to differentiate it from cerebral amyloid angiopathy. And in terms of therapies, the idea is that the most studied drug is really just first-line therapy, that's corticosteroids. And then there's positive data regarding use of all other forms of immunosuppression, including, as you mentioned, cyclophosphamide, rituximab, and oral agents such as mycophenolate mofetil or azathioprine. We have limited information about those, but I want to highlight something you actually mentioned earlier on in the interview, which is the field is moving towards making these diagnoses based on clinical features and radiographic features that you had highlighted and actually giving patients immunosuppression early on and only move on to a biopsy if the patient had failed these therapies for a period of time, which you mentioned three weeks. So, I think it's important for us as clinicians to keep this evolving criterion and recommendations in mind. And before we end, I want to ask you a hypothetical question, Georgios. In your opinion, what's an ideal randomized trial for CAA-related inflammation in the future? Dr. Georgios Tsivgoulis: I think before going to the randomized, the ideal randomized trial for CAA-ri, and designing this trial, we need much more information regarding the underlying pathophysiological mechanisms. There are many unanswered questions. What is the diagnostic value of CSF biomarkers such as amyloid, we discussed earlier, and tau protein? And, of course, what is the value of CSF and the amyloid-β autoantibodies, if there is any? What is the value of genetic markers such as apolipoprotein E genotype and a correlation with the co-existing inflammation in CAA-ri? However, I don't want to defer this question. So, a typical answer would be that with regard to the ideal patients, we would want a young patient without comorbidities after the first manifestation of CAA-ri who has shown a good clinical and radiological response to corticosteroids in order to define the best second-line therapy. However, before answering all these questions in a clinical trial, if we can, I think that we need to understand the CSF and genetic biomarkers in order to uncover mechanisms regarding pathophysiology that can help us to design more targeted clinical trials studying novel disease-modifying treatments. Dr. Negar Asdaghi:         Thank you. Dr. Georgios, it's been a pleasure having you on the podcast, and I can say we've learned a lot. We look forward to having you back here and talk about that hypothetical randomized trial, and I'm sure one day hopefully will happen in our lifetime. Thank you for being here. Dr. Georgios Tsivgoulis: Thank you. Thank you for having me. It was a pleasure. Dr. Negar Asdaghi:         Thank you. Homer, the legendary Greek poet, described a case of dementia in his seminal work, The Odyssey, in the late eighth century before Christ. He described the cognitive decline of Odysseus's father, King Laertes. The detailed account of the king's mental decline, loss of short-term memory with retention of long-term memory combined with his depression and despair over the loss of his son, is dramatically accurate for a nearly 3,000-year-old description of dementia. Before I ended the interview, I had to use this opportunity to ask Georgios about lessons learned from ancient Greeks and this seemingly timeless disease. Dr. Georgios Tsivgoulis: Thank you for this question. King Laertes was indeed Odysseus's father, and it's a great paradigm describing dementia. However, the ancient history of dementia may be separated according to the Greek philosopher Posidonius in two periods. The first period is called dementia appearing due to old age, which is called in Greek, eros. And the second one is dementia appearing in other ages and mainly due to other reasons, called morosis. Posidonius of Rhodes was a Greek stoic philosopher of the second first century BC who strongly believed and suggested that morosis, which is that dementia appearing in younger ages due to other disorders, should be treated immediately after its onset. So, if I would like to end this podcast, I would just suggest that CAA-ri could be classified as morosis according to Posidonius. And what we could learn is that the early diagnosis is essential since the prompt initiation of corticosteroids should not be unreasonably delayed. Dr. Negar Asdaghi:         And this concludes our podcast for the January 2023 issue of Stroke. Please be sure to check this month's table of contents for the full list of publications, including a series of Focused Updates on post-stroke neurological recovery, from management of post-stroke attention deficit, neglect and apraxia to post-stroke memory decline. And with this, we end the start of our 2023 podcast series. Like all new things, a new beginning can come with new directions, and sometimes a new direction is all that we need. After all, as the legend has it, it was a direction of that falling apple back in the year 1666 that gave Isaac Newton the idea of the universal law of gravitation. Now, Isaac Newton has, without a doubt, given science some of its biggest discoveries in mathematics, physics, and astronomy. But most may not know that Newton had a pretty rough start in life. A January-born premature baby, he was thought not to survive the first few days of life. Newton had a difficult childhood, and at the age of 16, he was pulled out of school by his family and forced to become a farmer, a job he didn't like and he was miserably bad at. So, as we start a new year, let's remember that even the smartest people are not good at everything, and it does take time to find one's passion in life. Now, while things may not always be clear, what is clear is that a great way to find that center of gravity is, as always, staying alert with Stroke Alert. This podcast is produced by Wolters Kluwer and supported by the editorial team of Stroke. Our Stroke Alert podcast and production staff includes Danielle Cross, Eric Goldstein, Nastajjia Krementz, Ishara Ratnayaka, Erinn Cain, Rebecca Seastrong, and Negar Asdaghi. This program is copyright of the American Heart Association, 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

On Episode 23 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the December 2022 issue of Stroke: “Direct, Indirect, and Combined Extracranial-to-Intracranial Bypass for Adult Moyamoya Disease” and “Contemporary Incidence and Burden of Cerebral Venous Sinus Thrombosis in Children of the United States.” She also interviews Drs. Koji Tanaka and Andrew Demchuk about article “Significance of Baseline Ischemic Core Volume on Stroke Outcome After EVT in Patients Age ≥75 Years.” Dr. Negar Asdaghi:         Let's start with some questions. 1) Is direct bypass better than indirect bypass in preventing the future risk of vascular events in adult patients with moyamoya disease? 2) What is the contemporary incidence of cerebral venous sinus thrombosis in the pediatric population? 3) And finally, is endovascular therapy beneficial for patients presenting with a large ischemic core? We have the answers and much more in today's podcast. You're listening to the Stroke Alert Podcast, and this is the best in Stroke. Stay with us. Welcome back to another issue of 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. In our final podcast for the year, I'm thrilled to announce that Drs. Nastajjia Krementz and Eric Goldstein have joined our podcast as assistant editors to help us cover the latest and the best in the field of cerebrovascular disorder. And together, here's our article selection to close the year. As part of our Advances in Stroke, in the article titled "Focus on Anticoagulation for Valvular Heart Disease With and Without Atrial Fibrillation," we get an update on current evidence from randomized controlled trials on the use of direct oral anticoagulants or vitamin K antagonists in patients with valvular heart disease that are mechanical valves, moderate to severe mitral stenosis, or bioprosthetic valves from the perspective of stroke physicians. What that means is that data from randomized trials was analyzed based on whether the patient had a prior history of stroke or TIA. In this review, we learned that direct oral anticoagulants may be used in patients with bioprosthetic valves who have atrial fibrillation, although DOACs have never been shown to be superior over vitamin K antagonists. We also learned that vitamin K antagonists should be used in patients with rheumatic moderate to severe mitral valve stenosis or patients with mechanical valves with or without atrial fibrillation and, of course, sometimes during the first few months after either surgical or transcatheter aortic valve replacement in patients without atrial fibrillation. And finally, patients with bioprosthetic valves without AFib don't have any other indications to be treated with anticoagulants should be treated with antiplatelet monotherapy in the long run. In a separate article in this issue of the journal, from Dr. Yang and colleagues from China, we learn about the pathophysiology of radiation-induced brain injury with special attention to radiation-induced vasculopathy. These investigators show that hyperactivity of notch signaling pathway that in normal state is essential in vascular morphogenesis and maintenance of arterial identity actually results in abnormal accumulation and disturbance of vascular smooth muscle cells, resulting in arterial muscularization and arterial dysfunction seen in radiation-induced vasculopathy. What's interesting is that inhibition of the notch signaling pathway in their study resulted not only in a measurable reduction in radiation induced vasculopathy, but also an overall improvement in radiation-induced brain injury as measured by the cognitive function of the mice exposed to radiation in their study. This study takes us a step closer to possible therapeutic options for radiation-induced vasculopathy and radiation-induced brain injury using compounds that can potentially inhibit the notch signaling pathway. As always, I encourage you to review these articles in detail in addition to listening to our podcast. For our interview today, I have a special guest who's not only a prominent researcher and a pioneer in the field of acute stroke therapies, but also, he's an experienced educator who has trained many of the current leaders in the field of vascular neurology and has been influential in shaping the careers of many vascular neurology fellows over the years. Take a listen. Dr. Andrew Demchuk:   I've had the privilege of training fellows. I've been the director since 2004, and we've trained close to 100 fellows in Calgary over 20-some years now. Really, it's frankly an honor and privilege to be able to do that. These individuals come from all over the world. They're here to dedicate themselves to learning a subspecialty really, really well, and it's just a fantastic experience to interact with them all and all their cultures to help them learn those things, and doing it in a fun, enjoyable, comprehensive way. Dr. Negar Asdaghi:         And those are the words of Dr. Andrew Demchuk, who's incidentally my own vascular fellowship director as well. Andrew joins me all the way from Canada to talk about his latest paper on the very hot topic of outcomes of endovascular therapy in patients presenting with a large ischemic core. And true to form, he's accompanied by one of his current vascular fellows. The interview is definitely worth the wait after we review these two articles. Most of us have heard of the term "moyamoya." First described in Japan in 1950s, the term refers to occlusion or stenosis of the terminal portion of the internal carotid artery and is associated with dilated collateral vessels of the proximal middle cerebral artery. These collaterals have a hazy appearance on angiography resembling the puff of smoke, which is Japanese for "moyamoya." Moyamoya is categorized into two broad categories of moyamoya syndrome and moyamoya disease. Syndrome refers to the situations where the occlusion occurs due to another condition. Conditions such as Down syndrome, sickle cell disease, neurofibromatosis type one have all been recognized as associated with moyamoya syndrome. Of course, moyamoya syndrome can occur due to a secondary insult to the blood vessels, anything from radiation vasculopathy, as we reviewed earlier in the podcast, to autoimmune vasculitis, or even good old advanced intracranial atherosclerosis involving the distal ICA region can cause moyamoya syndrome. Now, in contrast to moyamoya syndrome, the term "moyamoya disease" is reserved for individuals with no vascular risk factors or known moyamoya predisposing conditions other than, of course, some potential genetic factors. The most recognized genetic association for moyamoya disease is polymorphism in the ring finger protein 213, or RNF213, gene on chromosome 17. But we also have to keep in mind that the majority of moyamoya disease patients have no identified genetic abnormalities. So, moyamoya is truly a complex condition, and the physicians have to navigate the many possible etiologies that may cause or be associated with this condition. But when it comes to treatment options, we're really limited here. Antiplatelets are generally used and have been shown to reduce mortality in both moyamoya disease and syndrome, and especially cilostazol, which is the favorite antiplatelet therapy of our own assistant editor, Eric, has been shown to be significantly associated with increased survival rate in patients with moyamoya disease. Eric really wanted me to talk about a recently published study out of Korea, which included over 9,000 patients, and that showed that patients treated with cilostazol had a better survival rate than any other antiplatelet therapies. Apart from antiplatelet therapies, medical treatment includes optimizing all other vascular risk factors, which, as we mentioned, are rarely present in this population. So, it all comes down to most cases, at some point, needing surgical treatment, with bypass surgery being the most commonly surgical intervention for this population. Three flavors of bypass are used: indirect, direct, or combination of the two. Indirect bypasses are kind of like long-term investments where the surgeon moves vascular tissue to the surface of the brain in hopes of promoting angiogenesis. Several procedures, such as performing multiple burr holes, pial synangiosis, dural inversion, or omental transposition, among other methods, are used. And broadly speaking, we can think of indirect procedures as angiogenesis-dependent methods, the effect of which takes months to recognize and, in general, are thought to be more efficacious in the pediatric population than the adult population. The direct bypass, in contrast, commonly referred to as extracranial-to-intracranial, or ECIC, bypass, is more of an immediate reward where the surgeon stitches a vessel directly from a donor extracranial branch, typically the superficial temporal artery, to a recipient artery, typically the middle cerebral artery, to provide a direct anastomosis between the two vessels. There are technical variations, of course, especially with regards to the number of donors and recipient arteries used, but essentially this method is an angiogenesis-independent method that results in a quicker revascularization, but it's unclear if this strategy is long lasting. A combination of direct and indirect bypass can also be used. So, the question is, which method is better, especially in the adult population? In this issue of the journal, in the study titled "Direct, Indirect, and Combined ECIC Bypass for Adult Moyamoya Disease," Dr. Nickalus Khan and colleagues report on a meta-analysis and systematic review of those with adult moyamoya disease who underwent either direct, indirect, or a combination bypass. The main study question was whether there's a difference in the rates of early ischemic or hemorrhagic strokes, defined as strokes occurring within 30 days of bypass, or late strokes, defined as strokes occurring after 30 days of bypass, in this population when comparing the different surgical techniques. They also compared the "favorable" outcome rate; however, this outcome was defined in each study between the various broad techniques of direct, indirect, and combined bypass. So, with that, let's take a very quick look at their methodology. They screened more than 4,000 articles and identified 143 articles for their pooled analysis, the majority of articles being from Eastern Asian-based regions, and they had close to 4,000 combined, 4,000 direct, and 4,000 indirect bypass procedures for this analysis. And they had an average follow-up of over three and a half years. So, this is a great sample size for this large, pooled analysis. But they also performed a smaller meta-analysis where they were much more stringent with article selection, excluding pediatric papers, excluding articles containing only one surgical modality, or articles with insufficient outcome data. So, for that meta-analysis, they only had 43 articles qualified and were included in that meta-analysis. So, what did they find? In the larger pooled analysis, a significant benefit in favor of both direct and combined bypass techniques were noted in reduction of early and late ischemic strokes and late intracerebral hemorrhage. Also, a higher rate of that sort of vague favorable outcome was noted with both the direct or combined methods as compared to when indirect bypass techniques were used alone. So, everything in the large, pooled analysis pointed towards the direct bypass or combined technique performing better than all indirect bypass techniques, with only one exception, which was a lower incidence of early intracerebral hemorrhage rate in indirect bypass cases. So, that's one point to keep in mind. The second point was when they compared combined techniques to direct bypass. Overall, these procedures had more or less the same outcomes with the exception that the rate of late ischemic stroke was lower in the combined group than the direct bypass group. So, this is sort of the overall summary of what they found in that large, pooled analysis. When they were much more stringent with their selection criteria, focusing on the smaller meta-analysis portion of the study, what they found was that in the short term, there were no differences in outcomes of any type of stroke between any of these methods. So, basically, people, regardless of the type of bypasses they received, did the same with regards to the risk of intracerebral hemorrhage and ischemic stroke recurrence within the first 30 days after the bypass. But for the late stroke outcomes, whether ischemic or hemorrhagic, those with indirect bypass were nearly twofold more likely to develop late stroke after 30 days compared to those who've undergone the direct bypass. A similar pattern was found comparing combined bypass versus indirect bypass, in general, beyond the 30 days, with combined bypass doing better. Comparing direct versus combined bypass showed no difference regardless of timeframe. So, in summary, overall, it appears that combined or direct bypasses may be the best surgical strategies for treatment of adult patients with moyamoya disease. This study, of course, has many limitations, as does any meta-analysis, but most importantly, the authors focused on moyamoya disease in their analysis. It is presumed, but really unclear if patients with moyamoya syndrome would respond similarly to these different techniques. So, the question is, what surgical procedure are you using at your institution for treatment of adult moyamoya disease patients? And, of course, Eric wanted me to ask if your antiplatelet of choice is cilostazol for this population, yes or no. Leave us your comments, and let us know. Venous sinus thrombosis, or CVST, is a less common form of stroke most commonly affecting women and young individuals. In our past podcast, we've covered many aspects of CVST, especially when it comes to therapy with anticoagulation, anticoagulant of choice, and duration of therapy. In the October podcast, we reviewed a systematic review and meta-analysis comparing direct oral anticoagulants to vitamin K antagonists in the adult patients with CVST. But there are many aspects of this disease that we have not yet covered. For instance, you may ask, how common is this relatively uncommon condition? In the adult population, the incidence of CVST varies depending on the age of individuals studied, and ranges between 1.3 to 2.7 per 100,000 in women between the ages of 31 to 50, which is the adult population at highest risk for this disease. But the incidence of CVST, for instance, in the pediatric population is largely unknown. Some studies suggested an incidence rate of 0.67 per 100,000 in the pediatric population. That's roughly less than half the incidence rate in young female adults, but these reports are from the 1990s and are likely very outdated. Nowadays, many of the pediatric conditions, especially infectious conditions, that can predispose children to CVST are more readily diagnosed and treated. On the other hand, we now perform a lot more imaging than 30 years ago. Our neuroimaging modalities are more accurate, so we are more likely to diagnose CVST than before. So, the question is, what is the contemporary incidence of pediatric cerebral venous sinus thrombosis? In this issue of the journal, in the study titled "Contemporary Incidence and Burden of Cerebral Venous Sinus Thrombosis in Children of the United States," Dr. Fadar Otite and colleagues conducted a retrospective analysis of the New York State Inpatient Database, or SID, from 2006 to 2018, and the National Kids Inpatient Database, referred to as KID, from 2006 to 2019, for all hospitalized CVST cases. KID is the largest publicly-available pediatric inpatient care database in the United States, containing about 3 million pediatric discharges. They included over 700 hospitalized CVST cases from the SID database and 6,100 hospitalizations from the national KID database for the current analysis. And here's what they found. Number one, in terms of significant risk factors associated with CVST, congenital circulatory system anomalies, infections, head trauma, dehydration, and anemia were amongst the top CVST risk factors in the pediatric population. So that's very good to know. Number two, in terms of presentation, seizures were the most common presentation among all pediatric age groups, with close to half of infants with CVST presenting with seizures. Number three, in terms of outcomes, the rate of mortality was twice higher in the infants group as compared to all other age groups. And finally, the overall incidence of CVST, which was the main question of the paper, in this population was 1.1 per 100,000 per year, with a peak incidence during infancy of 6.4 per 100,000 per year. Interestingly, incident admissions also increased annually by 3.8% throughout the study period, which was close to 15 years in this paper. And the national burden of hospitalization dramatically and exponentially grew during the study period. So, here are the top three points from this study. Point one: Girls included less than half of all admissions nationally and statewide, and the overall burden of CVST was higher in boys than girls. That's a dramatic difference between the pediatric and adult populations. Point two: Incidence of CVST in infants was higher than five times that of other age groups at 6.4 per 100,000 compared to overall incidence in children, which was 1.1 per 100,000 people per year. Mortality was also two times higher in infants than in any other age group. And finally, point 3, incident admissions and national burden of hospitalization have dramatically increased over time, but it remains unclear whether true incidence has been on the rise or if simply more cases are recognized nowadays due to heightened awareness of this condition and our advanced neuroimaging capabilities. This study, of course, has some limitations. Data was only obtained on patients admitted, so many patients that may have had CVST but not admitted are not captured in this database. So, in summary, CVST can have catastrophic consequences in children and lead to long-term neurological deficits. Having a high clinical suspicion and early recognition remain crucial for prompt treatment and improved outcomes in this population. Dr. Negar Asdaghi:         Endovascular treatment, or EVT, is an effective method to achieve recanalization and to improve clinical outcomes in ischemic stroke patients with a target vessel occlusion. Both advanced age and having a large infarct volume at the time of presentation are negative predictors of beneficial outcomes post-EVT. Despite this, the neurological benefits of EVT seem to persist across the spectrum of age, and the same has been observed for a range of ischemic core volumes. But it's important to note that, in general, patients presenting with large ischemic core volumes were excluded from the original thrombectomy studies, and currently there's several ongoing trials to determine whether EVT is beneficial for the large core population. Now, the question that everyone is interested in answering is whether there is an actual ischemic core volume beyond which endovascular therapy is either futile or potentially even harmful, and if this magic futile core volume is the same for all patients, or does it differ depending on the age and other factors. In a previous podcast, in an interview with Dr. Osama Zaidat, we learned about that important interaction between the presenting ischemic core volume as measured by ASPECTS score and advanced age in an analysis of patients enrolled in the STRATIS registry. In that study, no one over the age of 75 achieved functional independence post-EVT if the presenting ASPECTS score was under 5 regardless of the angiographic outcomes. In that interview, we also discussed the limitations of STRATIS registry as a non-randomized, single-arm study, and the issues surrounding using ASPECTS score to define ischemic core. In today's podcast, we're going to revisit the important interaction between the presenting ischemic core volume and age while reviewing a pooled analysis of seven endovascular clinical trials in the paper titled "Significance of Baseline Ischemic Core Volume on Stroke Outcome After Endovascular Therapy in Patients Age 75 Years or Older." I'm delighted to be joined today by the first and senior authors of this paper, Drs. Koji Tanaka and Andrew Demchuk. Dr. Tanaka is an Assistant Professor of Neurology at Kyushu University in Japan. With his experience working at the leading center for conducting stroke clinical trials in Osaka, he has now joined the Calgary Stroke Program as a research fellow. And he's accompanied today by his fellowship director, Dr. Demchuk. Dr. Demchuk, of course, needs no introduction to our Stroke readership and our podcast audience. He's a Professor of Neurology at the University of Calgary Cumming School of Medicine. He's a stroke neurologist and a leader in the field of cerebrovascular research who has been involved in multiple clinical studies and randomized trials, including the seminal studies that led to the approval of EVT as the standard of care for treatment of stroke. And, of course, he's a very special guest of this podcast this morning as he was my very own fellowship director. Top of the morning to you both, Andrew and Koji. Welcome to the podcast. Dr. Andrew Demchuk:   Thanks, Negar. It's great to be here. Dr. Koji Tanaka:               Thank you very much for your invitation. That is a great honor to be here. Dr. Negar Asdaghi:         Thank you both. Andrew, let's start with you. Can you please provide us some background on the pooled analysis and the HERMES collaboration, please? Dr. Andrew Demchuk:   Yeah, HERMES is a really, it's been a really fun journey. Years back, when these trials all came out roughly at the same time, right? There was a real quick succession of trials, the MR CLEAN trial was obviously first, and ESCAPE and others quickly followed it. It became very clear to us that it just made total sense to collaborate. And so we got together as a group and decided we will pool the data. We'll do it in a very careful scientific way with basically an independent statistical analysis, and develop a core imaging lab, and really actually share the workload amongst us. I remember one of the really interesting tidbits about HERMES is when we got together, in order, I think, to really build trust in the group, one of the important things we decided early was we were going to have a snake draft. If you don't know what a snake draft is, Negar, it's essentially where you take turns selecting a topic through each of the trials. So, every trialist got an opportunity to pick a topic, and we just went down the list until everyone had their turn, and then we'd start over again and do it again. And I think that really worked very well to be as democratic as possible with this, and as fair. And it really allowed for a lot to get done because whoever was motivated in the collaboration was able to do an analysis. Dr. Negar Asdaghi:         So, what a great summary of this collaboration. So, it's true collaboration between the trialists that basically gave us those seven original randomized trials. Andrew, can I just stay with you, and can you tell us a little bit about the patient population that were enrolled in those trials? Dr. Andrew Demchuk:   Yeah, I think one of the important things to know, and I think a limitation for any kind of analysis like this, is the trials generally were small core trials, right? I mean there are some, MR CLEAN was certainly a more generalized population, but many other trials, including ESCAPE, I mean the "S" and the "C" in ESCAPE is "small core," right? And so a lot of these trials were small core. So, we don't have a lot of data in larger core patients. But, as you can imagine when you do core lab analysis, you realize that some of the stroke patients weren't as small core as we thought they were when we enrolled them. So, there is some sufficient data to hypothesize. I would consider this paper very much hypothesis-generating. So, yeah, it is a limitation to be considered here. I mean, our sample size isn't very large in the big core patients. Dr. Negar Asdaghi:         Perfect. Thank you, Andrew. So, again, a recap for our listeners, that we are looking at pooled analysis of seven original trials of thrombectomy, but keeping in mind that those patients that were enrolled in the trials had, generally speaking, small presenting ischemic core. So, now, Koji, on to you. Can you walk us please through the current study, and what was the premise of it, and who was actually included in this study? Dr. Koji Tanaka:               Yes. In this study, we aimed to evaluate association between baseline ischemic core volume and the benefit of endovascular therapy over the best medical treatment on functional outcomes. Patients were categorized age over 75 years, and less than 75 years old. The primary outcome of interest was a modified Rankin Scale of three or less, and we included 899 patients who underwent this baseline ischemic core volume measurement, which corresponds to 51% of our patients in the HERMES collaboration dataset. Dr. Negar Asdaghi:         All right. So, just a quick recap of what you said. Thank you for this. So, we have 899 patients. Those patients were all included in the HERMES collaboration, but, of course, these are patients in whom we had presenting ischemic core measurements. And that will get me, actually, Koji, to my second question. Can you please walk us through how you did analysis of ischemic core volume measurements in this study? Dr. Koji Tanaka:               In this study, ischemic core volume was measured by CT perfusion in 591 patients and by diffusion-weighted imaging in 309 patients. We defined the ischemic core volume as a relative cerebral blood flow of less than 30% in CT perfusion and diffusion coefficient of less than 620 square micrometers per second in diffusion-weighted imaging. Previous studies showed ASPECTS moderately correlate with ischemic core volume in both CT perfusion and diffusion-weighted imaging. For example, ASPECTS of eight can be considered as ischemic core volume of 20 milliliters. But underlying [inaudible 00:28:21] were different between CT perfusion and diffusion-weighted imaging, and previous studies suggested CT perfusion occasionally overestimates the ischemic core volume was on diffusion-weighted imaging. In this study, the results did not change when analyzing CT perfusion and diffusion-weighted imaging separately. Dr. Andrew Demchuk:   Yeah, that's a really important point Koji makes, is that because we had sort of a, not quite a 50/50 split, we had a 60/40 split of CTP and DWI, we did analyze them separately, and the odds ratios of treatment effect were pretty similar at different core thresholds. So, they're fairly similar when you separate them out, but obviously the methodology is a little different between a CTP and a diffusion. And to Koji's point, he's absolutely right, the CTP has a tendency to slightly overestimate core when you compare to diffusion. Dr. Negar Asdaghi:         Yeah, and thank you. I think you already sort of alluded to what I was going to ask you and Koji, because, in reality, we have different ways of measuring core. We have the ASPECTS score, which is just a quick and dirty way of estimating or guesstimating core, and then we have CT perfusion, and we also have diffusion that sometimes is available to us, but not always. And the question is, in the heat of it, how we're going to measure the volume. With post-processing softwares, with CT perfusion, we get a quick potential ischemic core volume, but we don't have that capability with diffusion even if we did get diffusion. So, I think it's important to know that what Koji mentioned, an ASPECTS of eight can, more or less, in a quick fashion, be thought of as about 20 cc of core. And the other point that Koji raised was that CTP, again, this is sort of ballpark, can tend to overestimate ischemic core if you were to compare that with diffusion-weighted data. So, with that, now we have a study in which we have core volumes, and we're going to look at outcomes from endovascular thrombectomies compared to best medical management and see whether there is a correlation or interaction between ischemic core presentation, especially age. So, my next question would be to Andrew, can you walk us please through the main findings of the paper? Dr. Andrew Demchuk:   The whole goal of this paper was really to understand, are there thresholds in the older patients? When we looked at overall, and Bruce Campbell and the team wrote an important paper with HERMES and the CTP cohort overall, and the sort of message there was if you looked at shift analysis, there wasn't actually a core threshold found at all in HERMES for lack of benefit. There was a benefit across all the core volumes, but, of course, that's all ages. So, we were really interested in looking at the older patients because we felt there's more likelihood the core volume will matter in the elderly than in the younger patient. We know the younger population, it benefits overwhelmingly with EVT, it's hard to even find a core volume threshold. So, that was a premise. Essentially, we had 247 patients over 75 in the overall cohort, of which 98 had EVT. So, it was a decent population, and not a huge sample, but a decent sample. And so we looked at various things. The first thing that was interesting we found was that infarct volumes, the average infarct volume to achieve an mRS three or less, was lower in the older patients, significantly lower, was 23.9 for younger patients under 75 and 10.7 for the older patients. You tend to have much smaller infarcts to achieve good outcome. And so that was kind of interesting, and I think that's been shown by others. Then we got into the weeds to try to figure out, OK, what are these thresholds? And if there's one figure that matters, Negar, you know me to always point out that there's always one figure or table in a paper that's kind of where the money is, where the real learning is, and that's Figure 2 on this paper in my opinion, beautiful figure with four figure A, B, C, and D. And it really sort of nicely highlights these issues and these cutoffs. But what we saw is that in the older patients who received EVT, around 50 mils seemed to be a threshold to achieve zero three, you had to, to see treatment effect, you had to have a baseline infarct volume less than 50 mils for a zero three outcome advantage. For zero four, it was 85 mils. And then we looked at this issue of what we called futility, true futility. And that's a very controversial thing. What is futility, or how do you measure futility? And really, I think, we even had a debate about this as a HERMES group when we were designing the analysis, and we sort of landed on mRS five six. A 90% chance of mRS five six, right? That's quite the bar, right, to say true futility because some people argue mRS four is still not a horrible outcome. Culturally, that is an OK outcome in some situations. But when we did use that five six 90% threshold, it was 132 mils. So, you're getting up to these really large volumes. But here's the catcher in the whole thing, and Koji will probably speak to this a bit more. I don't want to steal his thunder too much, but this issue of reperfusion seemed to matter in this. And we'll come back to that maybe with another question. Reperfusion matters a lot when you think about these thresholds. Dr. Negar Asdaghi:         OK, so, Andrew, a lot of information, I don't know if I need a recap myself to recap, but basically what you mentioned is that for the older patients who received EVT, if we keep our eyes on the outcome of mRS of zero to three, it seems to be the magic core volume for that outcome post-endovascular therapy that it lands on the magic volume of 50 cc core. Did I get that right? Dr. Andrew Demchuk:   That's correct. Dr. Negar Asdaghi:         Then if you're still a bit more lenient with the definitions of what is favorable outcome, what outcomes we're looking at and so on, so forth, for an mRS of five to six, then when we talk about futility of endovascular thrombectomy, the volume that you mentioned, and again I want to ask you this, this volume is for elderly over the age of 75, is 130 mil. Dr. Andrew Demchuk:   132, but yeah, absolutely. But there's a real catcher here, and we need to really emphasize the catcher in this. Dr. Negar Asdaghi:         Okay. I will ask you one more question before I go to Koji, which I'm sure is going to tell us more about that catcher. Andrew, can you please tell us about the factor of time? I feel like that is something that we need to discuss, as well. Your study included patients early on in their stroke onset, but we're talking about an important interaction. The question is, do you think the results of this interaction would be different or impacted by the value of time? Dr. Andrew Demchuk:   Hypothetically? It must, right? I think that that must be the case. We don't have any data specific to this. That would be an interesting Aurora analysis to do. Now, of course, the challenge with late window analysis is, we are really small core in our late window trials, we probably have even a much smaller proportion of large cores. So, to be able to even tackle that question in the late window is, I don't know if we have the data yet, to be honest. But it makes sense that you would expect the thresholds to be a bit lower the later you are in the window. But that is a hypothetical opinion. Dr. Negar Asdaghi:         Right, so, I want to take that and come to Koji. I want to digress a little bit to Koji and see how we can understand the finding of this current analysis of this paper. So, small core patients early on into their onset, we're looking at the interaction between age and their core volume and coming up with numbers 50 cc for the elderly population. If you're looking at the outcome of zero to three or 132, as Andrew pointed out, for an MRS of much higher, four or five. Dr. Andrew Demchuk:   Actually five, six, 90% chance of five, six. So, it's there. It's like almost everybody got five, six, took 132 mils to get there. So, it's like this extreme outcome. Dr. Negar Asdaghi:         Right, so, exactly, and I have to correct it, again, mRS of five or six or dead or almost dead mRS basically. Dr. Andrew Demchuk:   In 90% of patients. Dr. Negar Asdaghi:         90% of patients. So, we have these important numbers here, and I want us to basically understand these numbers in these volumes in the context of the recently published RESCUE-Japan LIMIT study. Can you tell us a little bit about that study and how we can make sense of these volumes in the setting of that paper? Dr. Koji Tanaka:               In the recent RESCUE-Japan LIMIT trial, the median ASPECTS was lower, and baseline ischemic core volume was greater than those in our study. And surprisingly, the median ischemic core volume in that trial was close to our threshold to predict less than 10% of patients achieve a modified Rankin Scale of four or less after endovascular therapy. We thought this is due to much higher complete reperfusion rate in HERMES patient. We have much interest in their additional analysis for outcomes in elderly patients by reperfusion status. This potential benefit of endovascular therapy in the area is promising for the future clinical trials. Dr. Andrew Demchuk:   I think just to add to that, it was actually really interesting, Negar, because when we were analyzing all of this and then the trial came up and it was actually really nice because we're like, OK, how does our data relate to their data? And that's where Table 2 comes in, and it would almost be worth putting on the pod, whatever, I don't know if you have on your podcast website, you have one figure that you can sit there with as you listen to the podcast, because that would be the figure. Dr. Negar Asdaghi:         We'll work on that Andrew, but tell us a little bit more because, really, when I read the trial results, the way I understand it is that people enrolled in RESCUE-Japan that were older than 75, and these are all large core patients, benefited more from endovascular therapy than their younger counterpart. How do I understand that? I don't know how to wrap my head around that finding. Dr. Andrew Demchuk:   You want to try to answer that, and then I'll add? Dr. Koji Tanaka:               As I mentioned previously, we want to know about the exact patient population just only for elderly patients, whether they have a exactly larger ischemic core volume or as well as their functional outcome. How many patients achieved modified Rankin Scale four or less or three or less, or more than five or six? Dr. Andrew Demchuk:   Koji's point's very important. We actually don't have the breakdown of the mRS, so we don't know if they created a lot of fours, or threes, or what. So, that's one issue. But I think that the key to this whole thing is to understand that this is a 2022 trial. HERMES data is essentially a 2015 equivalent where we're looking at a number of clinical trials who roughly ended between 2014, 2016. So, the technology, the technique, the operators, are just at a different level back then than now. And quite frankly, EVT is an improving treatment. We probably don't even fully understand how much, I mean, we're just getting better at it. And I think what's happened here is the reperfusion rates have improved. And our HERMES reperfusion rates, remind me, Koji, I think they're about half, we think, in HERMES, than like the TICI 2bs, threes, are half in HERMES what they got in RESCUE-Japan LIMIT. So, when you achieve successful reperfusion, what were the numbers here? TICI 3 was 43% in the Japan RESCUE LIMIT, and 8.6% in HERMES. Okay, TICI 3s were not ... Now that may be slight differences in core lab interpretation, but we were just starting to get good at 3s. We were getting a lot of 2bs and some 2cs, but we weren't getting a massive number of 3s back in 2015. Well, voilà, now we are, right? We're hitting home runs when we didn't before. And I think that has really shifted the goalposts on the large core. If you open the vessel, they can still do well if they're elderly, but you've got to really open that vessel. And in HERMES, we only did that in a small portion of patients. So, these thresholds are sort of representative of 2015 skill. Dr. Negar Asdaghi:         Golden points, Andrew and Koji, both of you. I want to recap what you mentioned here. A note to all of our audience and listeners that we are looking at an analysis with RESCUE-Japan, an analysis of a 2022 study. And the patient population that were enrolled were also treated much later in terms of time than the patient population that was enrolled in the HERMES collaboration and in all of the trials that contributed to HERMES. So, we've got to remember that EVT is this fluid, ongoing, everyday-improving therapy, from our techniques to everything else, you know, how fast we get patients to the angiosuite. And the point that you raise, I want to repeat that, the percentage or the odds of achieving a perfect reperfusion was, in RESCUE-Japan, was 43% odds of TICI 3 reperfusion, whereas only 8.6%. So, when we're talking about all of these predictive modeling or predictive factors that will tell us who's going to do well, who's not going to do well, it also is predicated on the angiographic success. And perhaps in the earlier trials or even the early study that we covered as part of the STRATIS registry, we put everybody, TICI 3s with TICI 2b or better, whereas nowadays we accept the best, TICI 3s, and maybe that improved percentage in the most recent trial, the RESCUE-Japan, really did what it had to be done for the elderly population to keep that in mind. And Andrew, before we end our interview, I want us to get your top two takeaway messages from this paper. Dr. Andrew Demchuk:   Clearly, elderly patients do better when their strokes are smaller, that we know, compared to younger patients. But it's all about hitting the home run. It's all about hitting the home run. Figure 2C and 2D, you can see that if you achieve that high TICI score, a significant proportion of elderly patients potentially could still benefit, 30–40% reasonable outcomes with bigger cores if you get those high TICI scores. So, it is about hitting the home run in reperfusion in the elderly. You need to go for it, and hopefully you're successful, because if reperfusion isn't successful, then generally the outcomes are not ideal and they certainly worsen as the core volumes become larger, bigger. Dr. Negar Asdaghi:         Before I ended the interview, given Andrew's tremendous experience as a longtime fellowship director and seeing that he was flanked by two of his fellows, one past, myself, and one present, Koji, I had to ask him one final question of what his philosophy is as an educator. Dr. Andrew Demchuk:   I have a sort of philosophy on life with fellows. I always look for the special power in a fellow. I realized a long time ago we’re all, we’re not perfect, nobody’s perfect, I’m not perfect, but there’s usually a special power in people, and if you spend the time to get to know them, you identify that special power, and you really help harness it because you know that if they can harness it when they go back to their faculty job, they’re going to really contribute something special to their team, right? You can imagine six special powers from six different people in a team. Now you’ve got a real team, right? If you know what your power is, you know your limitations, but you know where your strengths you can add to the group, and that’s what we try to do here when we can. It’s not always, you know, special powers, you have to kind of seek them out. But they’re there in most people, and that’s really important for career down the line. Dr. Negar Asdaghi:         And this concludes our podcast for the December 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including our very interesting Stroke Images series. In this month, we have a case of progressive cervical myelopathy secondary to a dural AV fistula supplied by the anterior inferior cerebellar artery. We also have a separate case of carotid rete mirabile imaged with a four-dimensional flow MRI study. And with these cases, we bring our 2022 Stroke Alert Podcast series to an end. Over the past 12 months, we've ended our podcasts with various inspirational tales. From the moving account of the American runner Steve Prefontaine and the remarkable journey of the Syrian refugee and Olympian swimmer Yusra Mardini, to the discovery of positron and Commander Armstrong's landing on the moon, our podcast stories have but one thing in common, which is the story of human perseverance and consistency in the face of hardship. So, as we end 2022 to start 2023 anew, Andrew's comments on finding that special power in each of us resonate with our resolution to stay alert with Stroke Alert. This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.