Stroke Alert

*/ ?>

Latest Episodes:

Stroke Alert July 2022 Jul 21, 2022

Show notes

On Episode 18 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the July 2022 issue of Stroke: "Impact of Shunting Practice Patterns During Carotid Endarterectomy for Symptomatic Carotid Stenosis" and "Socioeconomic Inequalities in Reperfusion Therapy for Acute Ischemic Stroke." She also interviews Dr. Magdy Selim about his article "Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage: A Post Hoc Analysis of the i-DEF Trial." Dr. Negar Asdaghi: Let's start with some questions. 1) Is deferoxamine mesylate yet another failed agent for treatment of patients with intracerebral hemorrhage, or is deferoxamine getting us closer than ever to an approved therapy for this deadly form of stroke? 2) Are different strokes happening to different folks due to their disadvantaged socioeconomic status? 3) And finally, how does a surgeon's personal practice preference to either routinely or selectively use carotid shunting during carotid endarterectomy impact the recurrent risk of stroke or death in patients with symptomatic carotid disease? We'll tackle these questions and a lot more in today's podcast as we continue to cover the cerebrovascular world's latest and greatest because, without a doubt, this is the best in Stroke. Dr. Negar Asdaghi: Welcome back to the July 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. The July 2022 issue of Stroke contains a range of really interesting papers that I'd like to highlight here. As part of our Cochrane Corner articles, giving us short summaries of the long systematic review of a given topic, we have two short articles, one on the issue of local versus general anesthesia for carotid endarterectomy, where we learn that based on the current evidence, there's no convincing difference between local versus general anesthesia in the risk of stroke and death within 30 days after the procedure. In the second Cochrane Corner article, titled "Information Provision for Stroke Survivors and Their Carers," we learn that stroke survivors and their caregivers routinely report dissatisfaction with information provided to them by their clinicians about their condition and how active approaches to information provision is superior to its passive forms in improving patients' involvement in their care, their satisfaction, and, ultimately and not surprisingly, their stroke outcome. Dr. Negar Asdaghi: As part of our original contributions in this issue of the journal, we have an important paper titled "The Risk of Early Versus Later Rebleeding From Dural AV Fistulas With Cortical Venous Drainage." We are reminded in this paper that cranial dural arteriovenous fistulas are classified based on their venous drainage into those with or those without cortical venous drainage, or CVD. Dural AV fistulas without CVD rarely cause intracranial bleeding, while those with CVD may cause hemorrhage. In this study, the authors show that the risk of rebleeding of dural AV fistulas with CVD presenting with hemorrhage is increased in the first two weeks after ICH, emphasizing the importance of early detection of these malformations by vascular imaging and early treatment of AV fistulas with cortical drainage. This paper is another analysis from the CONDOR registry. Our devoted Stroke Alert listeners recall that we covered this registry in more detail when we interviewed Dr. Amin-Hanjani last October on the outcomes of intracerebral hemorrhage patients found to have dural AV fistulas. I encourage you to review these articles in addition to listening to our podcast today. Dr. Negar Asdaghi: Later in the podcast, I have the distinct honor of interviewing Dr. Magdy Selim from Harvard Medical School on a critical analysis from i-DEF trial to examine the long-term outcome of patients with ICH who were randomized to receive deferoxamine versus placebo. As an expert in the field of intracerebral hemorrhage and a member of the recently published American Heart Association Guidelines Committee, Dr. Selim was not fazed at all about the neutral results of the trial. "The future of ICH is bright," he says, and in the interview, he tells us why. But first, with these two articles. Dr. Negar Asdaghi: Since its first reported successful surgery in 1953, carotid endarterectomy, or CEA, has become a common surgical procedure to prevent ischemic stroke in patients with carotid disease. CEA requires a temporary clamping of the carotid artery that is being worked on. During this time, the ipsilateral hemisphere is, of course, dependent on collateral flow from the posterior circulation or from the contralateral anterior circulation to maintain its perfusion pressure. Intraoperatively, various methods are used to monitor cerebral perfusion, and the risk of clamping-induced hypoperfusion is obviously variable for each patient depending on the patient's specific anatomy, their collateral status, and other risk factors. One way to protect the brain against possible clamp-induced ischemia is to do carotid shunting. The problem is that carotid shunting also comes with its own set of risks and problems. There's the risk of causing carotid dissection, embolization of pieces of the plaque during shunt insertion, or the risk of causing air embolism. Dr. Negar Asdaghi: There are also other shunt-related local complications that should be noted, such as possibility of causing injuries to the cranial nerves or development of neck hematoma related to the more extensive surgical exposure required for shunting. So, it's not surprising that the practice patterns with regards to shunting is quite variable amongst different surgeons. There are surgeons that are considered routine shunters, and those who are considered selective shunters, meaning that the shunt is inserted only in cases with a particular indication. The question is whether the surgeon's preference for shunting can impact the CEA outcomes. In the current issue of the journal, we have an interesting study led by Dr. Randall DeMartino from the Division of Vascular and Endovascular Surgery at Mayo Clinic, Rochester, where the authors look at the impact of shunting practice patterns during carotid endarterectomy on the following post-CEA outcomes: number one, in-hospital stroke and in-hospital death rates, and number two, combined stroke and death in patients with a recent symptomatic carotid disease, that is, carotid stenosis associated with a history of either ipsilateral stroke or TIA within the past 14 days of endarterectomy. Dr. Negar Asdaghi: So, the data for the study came from the ongoing Vascular Quality Initiative database, which comprises a network of more than 600 North American academic and community hospitals, and collects data on 12 different vascular procedures, one of which is CEA. The study included over 13,000 carotid endarterectomies performed from 2010 to 2019 for symptomatic carotid patients. This number came after they applied their exclusion criteria to all CEAs performed in the database during this timeframe, importantly excluding any asymptomatic carotid surgeries or those in whom surgery was performed after the two-week mark post qualifying TIA or stroke. Now, before we go over the results, let's go over some definitions used in the study. They had to classify surgeons to be able to do the study into two categories of routine versus selective shunters. So, what they did was to analyze all consecutive CEAs, whether they were done on symptomatic or asymptomatic carotids, in this database, aggregated at the surgeon level. Surgeons routinely shunting in over 95% of their procedures were gauged as routine shunters. Otherwise, they were classified as selective shunters. Dr. Negar Asdaghi: Now, coming to each case included in this study, each surgical case was, in turn, classified into four categories based on whether or not a shunt was actually used for that particular case: category one, no shunt used; category two, shunt used as a routine procedure; number three, shunt used for a preoperative, mostly anatomical indication; number four, shunt was used for an intraoperative indication, which, as we mentioned before, these are mostly intraoperative hemodynamic compromised situations. And here are the results: In total, 3,186 of surgeries, that is 24% of surgeries, were performed by routine shunters versus 76% by selective shunters. So, most surgeons were selective shunters in this study. The demographic of patients operated by the routine versus selective shunters were more or less similar with regards to the age of the patients, most of their vascular risk factors, and the degree of ipsilateral or contralateral carotid stenosis or occlusion, with a few notable exceptions, in that patients undergoing surgery by routine shunters were more likely White, more likely to have had a prior CABG, more likely to undergo the operation while taking a P2Y12 inhibitor antiplatelet agent, and these patients were more likely to have had a TIA rather than a stroke as their qualifying event, which probably explains why they were more likely to be operated on within 48 hours of symptom onset as well. So, the authors accounted for these differences when they did their multivariate analysis. Dr. Negar Asdaghi: The other thing to note was that overall, routine shunters used a shunt in 98.1% of their cases, whereas selective shunters used them in 46% of their cases. Now, in terms of their study outcomes, the shunting practice pattern did not impact the primary outcomes of in-hospital stroke or death, or a combination of these two outcomes, or even the odds of development of cranial nerve injuries or hemorrhage in the adjusted model, which is really good news here. But interestingly, in the final adjusted model, whether or not an actual shunt was placed during surgery did significantly increase the risk of postoperative stroke, with the odds ratio of 1.29, an effect that was entirely driven by the use of shunt by a surgeon classified as a selective shunter in this study. Dr. Negar Asdaghi: So, in simple terms, if a shunt was placed during CEA, it did increase the risk of stroke only if that surgeon was a selective shunter. Another interesting association was that amongst selective shunters, placing a shunt for a patient with a very recent ischemic event, that is, TIA or stroke within the past 48 hours prior to surgery, and placing a shunt for an intraoperative indication, meaning shunt placement was not pre-surgically planned, also significantly increased the risk of postoperative stroke. So, what we learned from the study is that, though a surgeon's shunting practice pattern did not have an impact on the overall postoperative risk of stroke or death, the placement of a shunt did indeed increase the risk of postoperative stroke only if it was placed by a surgeon who is a selective shunter, especially for an intraoperative indication in a patient with a recent ischemic event. Dr. Negar Asdaghi: So, shunts can be tricky, especially if they're done by a surgeon who doesn't place them routinely. So, my take-home message is that ultimately, like every other procedure in medicine, clinical outcomes are as much operator dependent as they are patient dependent, and for every procedure, it's fair to say that practice makes perfect. Dr. Negar Asdaghi: It is now more than 25 years since intravenous thrombolytic therapy has been approved for treatment of patients with acute ischemic stroke and more than seven years since randomized control trials demonstrated the efficacy of mechanical thrombectomy to improve clinical outcome in ischemic stroke patients with large vessel occlusions. To date, reperfusion therapies are the only available acute treatments for select patients with ischemic stroke. What do we mean by "select"? "Select" meaning that not all patients will benefit from these therapies, making it absolutely necessary for clinicians to be up to date with various indications and contraindications to use these therapies. Needless to say that the criteria for reperfusion therapies do not and should not consider the socioeconomic status of patients, but sadly, socioeconomic inequalities seem to impact the use of reperfusion therapies. Dr. Negar Asdaghi: In this issue of the journal, in the study titled "Socioeconomic Inequalities in Reperfusion Therapy for Acute Ischemic Stroke," Dr. Øgendahl Buus from Aarhus University Hospital in Denmark and colleagues studied the impact of the socioeconomic status of stroke patients on the odds of receiving reperfusion therapies in the large nationwide Danish Stroke Registry, or DSR. Now a bit about the registry: DSR contains prospectively collected nationwide data on all stroke patients admitted to Danish hospitals. It's interesting to note that in Denmark, stroke patients are exclusively admitted to public hospitals, and all departments treating stroke patients are obligated to report data to DSR. Now, for this study, they included over 63,000 stroke patients from 2013 to 2018. After excluding hemorrhagic stroke, TIAs, and other exclusion criteria of the study, they arrived at their sample size of 37,187 patients that were included in this study. Dr. Negar Asdaghi: Now, a few definitions. The socioeconomic status of each patient was determined based on three parameters. Parameter number one, their educational level. It was categorized into three levels of low, medium, or high levels of education. Category number two, income level. This was calculated based on the average family equivalent disposable income, or FED income, during five years prior to stroke onset, again classified into three categories of high, medium, or low income. And the third factor was the employment status of the patient during the calendar year prior to the stroke onset, also categorized into three categories of employed, unemployed, and retired. And, of course, the authors used various definitions to be able to fit special situations into these categories. For instance, a person who is temporarily unemployed due to illness or other special situation was still categorized under the employed category. So, that gave them, in total, nine groups to analyze across these three categories. Dr. Negar Asdaghi: And here are their findings. The median age of total stroke patients in the cohort was 73.2 years, 44.1% were women, 41% categorized under low educational level, 68% retired, and 33.3% had low income levels. Not surprisingly, patients and hospital characteristics varied tremendously across these nine groups of education, employment, and income, and a univariate analysis in general, low socioeconomic status was associated with more severe strokes, living alone, living at an assisted living residency, having had prior stroke, high comorbidity index score, hypertension, and late hospital arrival. So, they accounted for these differences in their multivariate analysis. Dr. Negar Asdaghi: Now, overall, the treatment rates of IV thrombolysis was 17.6%, which is actually considered a very high percentage as compared to other registry-based studies, but the percentage of IV thrombolytic use dramatically varied based on the different socioeconomic designation. So, let's look at this. In the univariate analysis, for education, intravenous thrombolysis rates were 19.3% among patients with high educational level compared to 16.2% among patients with low educational level. Let's look at income. For income, IV thrombolytic treatment rates reach 20.7% for high-income patients compared to 14.8% for low-income patients. For employment status, thrombolytic rates were 23.7% among employed patients compa…

Full show notes at the publisher

Stroke Alert July 2022 Jul 21, 2022

Show notes

Full show notes at the publisher

Stroke Alert June 2022 Jun 16, 2022

Show notes

On Episode 17 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the June 2022 issue of Stroke: "Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage" and "Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm: Prevalence and Practice Patterns." She also interviews Dr. Bruce Campbell on his article "Role of Intravenous Thrombolytics Prior to Endovascular Thrombectomy." Dr. Negar Asdaghi: Let's start with some questions. 1) Is vitamin D that golden key to recovery from intracerebral hemorrhage? 2) Endovascular therapies seem to have prevailed where thrombolytics have failed. In the era of fast and furious thrombectomy, what is the role of pre-thrombectomy thrombolysis? 3) And finally, 20 years of clinical research has failed to demonstrate the superiority of anticoagulation over antiplatelet therapies for treatment of patients in sinus rhythm with low left ventricular ejection fraction, and yet, our practice patterns have not changed. Why do we remain resolute in prescribing anticoagulation despite the lack of evidence? We're back here to tackle the toughest questions with our Stroke Alert Podcast because this is the latest in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome back to another extremely motivating Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The June 2022 issue of Stroke contains a number of interesting articles. As part of our Advances in Stroke, we have two articles, one on the topic of cost-effectiveness of stroke care to inform health policy and the second on the current state and the future of emerging stroke therapies. As part of our Original Contributions category, we have an interesting study by Dr. [Ben] Assayag and colleagues from the Department of Neurology at Tel Aviv Sourasky Medical Center, where we learned that just over 10% of patients with TIA and stroke developed post-traumatic stress disorder, or PTSD. Higher presenting stroke severity, preexisting white matter disease, and having anxious coping styles are risk factors for development of post-stroke PTSD. Dr. Negar Asdaghi: In another Original Contribution, by Dr. Daehoon Kim and colleagues from Yonsei University College of Medicine in Seoul, South Korea, we read with interest on the topic of whether or not we should be anticoagulating frail patients with atrial fibrillation. In this large population-based cohort, which included patients with atrial fibrillation older than 65 years of age with frailty as defined by a score of equal or greater than five on Hospital Frailty Risk Score, we learned that despite their frailty, patients with atrial fibrillation still significantly benefit from oral anticoagulation therapy. In this study, those treated with anticoagulation had lower net adverse clinical events as compared to those untreated. We also learned that direct oral anticoagulants provided lower incidence of stroke, bleeding, and mortality over Coumadin. This paper really provided practical information on treatment of frail patients with atrial fibrillation. So, I encourage you to review these papers in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. Bruce Campbell from University of Melbourne in Australia on an especially timely topic, that is the role of intravenous thrombolytics prior to endovascular therapy. Dr. Campbell is a leading authority on the topic, and his interview does not disappoint. But first, with these two articles. Dr. Negar Asdaghi: In the setting of intracerebral hemorrhage, or ICH, aside from the primary brain insult that occurs at the time of hemorrhage, secondary brain injuries continue for days and sometimes to months mostly due to the pathological response of the brain to byproducts of hematoma lysis or RBC degradation products. Today, the majority of spontaneous ICH cases are not surgically evacuated, so we rely on the body's own ability to clear blood for hematoma clearance, and obviously the faster the clearance, the better the outcome. Erythrophagocytosis by monocyte-derived macrophages contributes to hematoma clearance and ultimately to the functional recovery from ICH. So, it's conceivable that therapeutic approaches to enhance the endogenous erythrophagocytosis can potentially improve ICH outcomes. Vitamin D has been known to have variety of functions within the central nervous system, and it turns out that it may also be one such therapeutic option to improve the much needed erythrophagocytosis in intracerebral hemorrhage. Dr. Negar Asdaghi: In the current issue of the journal, in the study titled "Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage," a group of researchers led by Dr. Jiaxin Liu from the Department of Surgery at Queen Mary Hospital at the University of Hong Kong studied the effects of oral vitamin D administered two hours after the induction of hematoma in a rodent model of ICH using direct collagenase injection into the striatum of the mouse. Eighty-nine young mice and 78 middle-aged mice were included in the study and randomly divided into three groups. Group one were sham-operated mice; group two, ICH mice treated with vehicle, which was corn oil; and group three, vitamin D-treated ICH mice. In the third group, 1000 international unit per kg of vitamin D diluted in corn oil was administered orally using a pipette two hours after the induction of ICH to mice, and then daily afterwards. And here are their top three findings of this study. Dr. Negar Asdaghi: Number one, vitamin D-treated mice did better than vehicle on two neurobehavioral tests that were completed in the study. On the cylinder test, treatment with vitamin D significantly alleviated the asymmetric usage of four limbs at day seven, and vitamin D elongated the duration that the mice could run on the accelerated rod at day 10 on the rotarod test. Dr. Negar Asdaghi: Number two, in terms of hematoma resolution and perihematoma edema, it's an issue that we deal with, with ICH, they used MRI imaging for edema measurement on T2-weighted images, and then sacrificed the mice and used digital quantification of hematoma volume with fresh brain specimens. And they found that treatment with vitamin D significantly alleviated both the ICH-associated brain swelling on MR and resulted in significant reduction in hematoma volume on the fresh brain specimens when compared with the vehicle-treated group at day three and day five. Dr. Negar Asdaghi: And finally, their third main finding is in terms of erythrophagocytosis. So, the pathway that is mediated by the monocyte-derived macrophages is an endogenous pathway, that is, PPAR-γ (which stands for peroxisome proliferator-activated receptor γ) and its downstream scavenger receptor CD36 mediated. This pathway is essential for directing the endogenous erythrophagocytosis. Using flow cytometry, they found that vitamin D-treated mice had more mature macrophages expressing the scavenger receptor CD36, which was not expressed by the undifferentiated monocytes. Dr. Negar Asdaghi: Western blot analysis confirmed that vitamin D treatment increased the tissue levels of CD36 and the upstream PPAR-γ levels in the brain at day five after collagenase model. Locally, vitamin D-enriched phagocytes that were positive for PPAR-γ and CD36 in the perihematoma regions. So, in summary, vitamin D increased the number of mature macrophages rather than undifferentiated monocytes in the perihematoma region and accelerated the differentiation of reparative macrophages from bone marrow-derived monocytes. So, bottom line is that in vitamin D, we have a simple, accessible, and well-tolerated agent to improve both the ICH outcomes and enhance hematoma resolution, but this we all observed in rodents. So, we stay tuned with interest to find out whether the same success will be seen in humans treated with vitamin D after intracerebral hemorrhage. Dr. Negar Asdaghi: Patients with depressed left ventricular ejection fraction, or low EF, are at risk of development of ischemic stroke even if they remain in sinus rhythm. The optimal antithrombotic treatment for these patients is still unknown. Over the past two decades, we have a number of randomized trials studying the efficacy of oral anticoagulation, predominantly Coumadin, over aspirin therapy in prevention of all forms of stroke, that is ischemic and hemorrhagic, and death in patients with a low EF in sinus rhythm. Dr. Negar Asdaghi: The meta-analysis of WASH, HELAS, WATCH, and WARCEF trials showed that treatment of low ejection fraction patients in sinus rhythm with Coumadin does reduce the subsequent risk of stroke, but it comes at the cost of a higher major bleeding risk in this population. The COMMANDER HF clinical trial published in New England Journal of Medicine in October 2018 studied whether low-dose rivaroxaban at 2.5 milligram BID was superior to placebo in patients with recent worsening of chronic heart failure, reduced ejection fraction, coronary artery disease, but no atrial fibrillation, and very similar to its prior counterparts, it did not show that rivaroxaban was associated with a lower rate of combined death, myocardial infarction, or stroke as compared to placebo. But very similar to prior studies, it also showed that rivaroxaban-treated patients had a lower risk of subsequent ischemic stroke. This poses a conundrum for stroke neurologists treating patients with this condition, especially after they present with an embolic-appearing stroke. So, the question is, how often do we encounter this situation, and what do we do in routine practice? We know that when there is equipoise, there's practice variation. Dr. Negar Asdaghi: In the current issue of the journal, in the study titled "Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm," Dr. Richa Sharma from the Department of Neurology at Yale School of Medicine and colleagues examined the prevalence of heart failure with sinus rhythm among hospitalized patients with acute ischemic stroke and the physician's practice patterns with regard to the choice of antithrombotics in this population. Dr. Negar Asdaghi: So, let's look at their study. The study was comprised of five separate study cohorts of hospitalized acute ischemic stroke patients in the Greater Cincinnati Northern Kentucky Stroke Study for the year 2005, 2010, and 2015, and then four additional academic hospital-based cohorts in the United States during different timeframes. These were the Massachusetts General Hospital from 2002 to 2016, Rhode Island Hospital from 2016 to 2018, Yale-New Haven Hospital 2015 to 2017, and Cornell Acute Stroke Academic Registry from 2011 to 2018. All of these cohorts combined contributed to the 19,155 total number of patients in this study, which included over 14,000 patients that had documented left ventricular ejection fraction. Amongst those, 1,426 had a depressed EF and were included in this study. The investigator obviously excluded those with documented atrial fibrillation and flutter. And so the sample size for this analysis was 805 patients. And here are their main results. Dr. Negar Asdaghi: The overall prevalence of this condition, that is low ejection fraction and sinus rhythm, among hospitalized acute ischemic stroke patients was 5%. It varied slightly between the different cohorts in this study from 4 to 6%. In terms of the antithrombotic treatment patterns, this information was available in close to 500 patients in the cohort. Overall, 59% of patients were discharged on an antiplatelet treatment alone, and 41% on anticoagulation. But these percentages significantly varied between the different institutions and was as low as 22% in one of the cohorts and as high as 45% in another cohort. Dr. Negar Asdaghi: So, what were the factors that were associated with the use of anticoagulation at discharge? They found that the absolute percentage of left ventricular ejection fraction and the presenting NIH Stroke Scales were associated with anticoagulation use. That is, the lower the percentage of EF and the higher the presenting NIH Stroke Scale, the more likely physicians were to discharge the patients on an anticoagulation in univariate analysis, but in multivariate analysis, only the study site and presenting NIH Stroke Scale over eight were independently associated with anticoagulation use. Dr. Negar Asdaghi: Now, interestingly, 2002 to 2018, which was their overall study period, was a time during which some of the largest and neutral randomized trials on the topic of anticoagulation versus antiplatelet were published, including the WATCH and the WARCEF trial. But the authors found no temporal variation in anticoagulation practice patterns before and after the publication of the results of these trials. So, it appears that we didn't change our minds. So, overall, we have some important takeaway messages from this study. We learned that 5% of hospitalized acute ischemic stroke patients have low left ventricular ejection fraction and remain in sinus rhythm without atrial fibrillation. Today, over 40% of patients with this condition are anticoagulated at discharge despite the results of the randomized trials, but the practice is widely variable among different institutions, and a higher presenting NIH Stroke Scale is a significant predictor of anticoagulation use at discharge in this population. Dr. Negar Asdaghi: Almost 20 years after the approval of intravenous thrombolysis for treatment of patients with acute ischemic stroke, endovascular therapy was approved for treatment of select ischemic stroke patients with a large vessel occlusion. The two treatments are, therefore, entangled, as one was the standard of care while the second one was being tested. Therefore, all endovascularly treated patients enrolled in randomized trials would've received intravenous thrombolysis if eligible. Now, with the overwhelming success of endovascular therapy in achieving reperfusion in areas where IV thrombolysis has drastically failed, there're still critical questions regarding the added value of IV thrombolysis to endovascularly treated patients. The critical question remains as to whether eligible ischemic stroke patients who have immediate access to endovascular thrombectomy should receive prior IV thrombolysis, or should we skip the thrombolysis step altogether and just move to the angio suite as fast as possible. And there are, of course, arguments for and against each approach. Dr. Negar Asdaghi: In this issue of the journal, in an invited topical review titled "The Role of Intravenous Thrombolytics Prior to Endovascular Thrombectomy," we learn about these arguments as the authors go through a comprehensive review of the current literature on this issue. I'm joined today by the first author of this review, Dr. Bruce Campbell, to discuss this paper. Dr. Campbell absolutely needs no introduction to our Stroke listeners. He's a professor of neurology and head of neurology and stroke at Royal Melbourne Hospital, University of Melbourne, in Australia. He's a pioneer in the field of acute stroke therapies and acute neuroimaging. He has served as the lead investigator of multiple landmark randomized trials, including EXTEND-IA and EXTEND-IA TNK, and holds multiple leadership roles. He's the clinical director of the Stroke Foundation and co-chairs the Australian Stroke Guidelines Working Party and the coordinator of the National Brain School Training Program for Neurologists in Training. And, of course, last but not least, he's my friend. So, I'm delighted to welcome him to ou…

Full show notes at the publisher

Stroke Alert June 2022 Jun 16, 2022

Show notes

Full show notes at the publisher

Stroke Alert May 2022 May 19, 2022

Show notes

On Episode 16 of the Stroke Alert Podcast, Dr. Negar Asdaghi highlights two articles from the May issue of Stroke: "Number of Affected Relatives, Age, Smoking, and Hypertension Prediction Score for Intracranial Aneurysms in Persons With a Family History for Subarachnoid Hemorrhage" and "Endovascular Treatment for Acute Ischemic Stroke With or Without General Anesthesia." She also interviews Dr. Patrick Lyden on "The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results." Dr. Negar Asdaghi: Let's start with some questions. 1) How is it that stroke can be cured in rodents but not in humans? 2) Are we wasting time or gaining time with general anesthesia before endovascular thrombectomy? 3) My father had an aneurysmal subarachnoid hemorrhage, Doctor. What is my risk of having an aneurysm, and how often should we check for one? We're back here with the Stroke Alert Podcast to tackle the toughest questions in the field because this is the best in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome back to the May 2022 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. For the May 2022 issue of Stroke, we have a number of papers that I'd like to highlight. We have seven articles as part of our Focused Update on the topic of neuroimmunology and stroke, organized by our own Stroke editors, Drs. Johannes Boltze and Miguel Perez-Pinzon. We also have an interesting study by Dr. David Saadoun and colleagues from Sorbonne University in Paris, where we learn that in patients with Takayasu disease, how the delay in diagnosis, as defined by the time from symptom onset to the diagnosis being over one year, was significantly associated with development of ischemic cerebrovascular events. In the Comments and Opinions section, we have an interesting study by Dr. Goldenberg and colleagues from University of Toronto on the benefits of GLP-1 receptor agonists for stroke reduction in type 2 diabetes and why should stroke neurologists be familiar with this new class of diabetic medication. Dr. Negar Asdaghi: Later, in the interview section of the podcast, I have the great honor of interviewing Dr. Patrick Lyden, one of the founding fathers of thrombolytic therapy in stroke, as he walks us through the Stroke Preclinical Assessment Network and what his hopes are for the future of stroke therapy. I also ask him for some advice, and he did tell us about the view from the top, as he truly stands on the shoulder of giants. But first with these two articles. Dr. Negar Asdaghi: In a landmark population-based study out of Sweden that was published in Brain in 2008, we learned that the odds of development of aneurysmal subarachnoid hemorrhage for individuals with one first-degree relative with a prior history of aneurysmal subarachnoid hemorrhage was 2.15. For individuals with two affected first-degree relatives, the odds ratio was 51. So, it's not surprising that a great deal of anxiety is caused within a family when a relative has an aneurysmal subarachnoid hemorrhage, especially if that family member was young or another member of the family had the same condition before. This scenario is commonly followed by a number of inevitable questions: Should all family members of the affected individual be screened for presence of an intracranial aneurysm? If yes, how often should vascular imaging be performed, and should other aneurysmal risk factors, such as age, sex, smoking, and hypertension, be also considered in the screening decision-making? In this issue of the journal, as part of a derivation-validation study, a group of investigators, led by Dr. Charlotte Zuurbier from University Medical Center at Utrecht Brain Center in the Netherlands, studied the ability of a simple scoring system that was developed in their derivation cohort to predict the presence of an intracranial aneurysm on vascular imaging. Dr. Negar Asdaghi: They then tested the scoring model in their validation cohort. So, for their development cohort, they used data on 660 persons who were screened at the University Medical Center for presence of an intracranial aneurysm because they had two or more affected first-degree relatives with a prior history of aneurysmal subarachnoid hemorrhage. The median age of participants at the time of first screening was 40, and 59% were female. Dr. Negar Asdaghi: So, in this cohort, the investigators simply looked at factors that were independently associated with finding an aneurysm on vascular screening by their multivariate analysis. And they identified the following factors; the first factor was the number of affected relatives. Now, a reminder that all of these people in the cohort had at least two first-degree relatives with an aneurysmal subarachnoid hemorrhage. And they found that amongst these people, those that had three or more family members with aneurysmal subarachnoid hemorrhage were significantly more likely to have a positive screening test for intracranial aneurysm. The next factor was older age — the older that relative, the more likely their screening imaging was positive for an aneurysm — and the other independent factors were smoking and hypertension. So they created the NASH acronym; N for number of relatives, A for age, S for smoking, and H for hypertension. When assigning points for each of these factors, the NASH scoring system had a C statistics of 0.68 in predicting whether or not someone would have a positive test, which is an intracranial aneurysm. Dr. Negar Asdaghi: And now a reminder for our listeners that C statistics gives us the probability that a person with a certain condition, in this case, a certain NASH score, will have the outcome of interest, in this case, an aneurysm found by vascular imaging. In general, for C statistics, the closer we get to 1, the more robust is our predictive model. Values over 0.7 indicate that we have a good model, but values over 0.8 indicate a very strong model. So the NASH score, at 0.68, has a reasonably good capability in predicting who will or will not have an intracranial aneurysm if we complete the vascular imaging. But it's not a very strong model, and this should be kept in mind. Let's look at some of their numbers. In their development cohort, the probability of finding an intracranial aneurysm for a person who scored low on NASH, that is a young person who never smoked and is not hypertensive, was only 5%, whereas the probability of finding an intracranial aneurysm in a person who scored high on NASH, that is an older person in their 60s or 70s, with three or more affected relatives, who is hypertensive and a smoker, was 36%. Dr. Negar Asdaghi: So, then they tested this NASH score in their external validation cohort and found that the likelihood of identifying an aneurysm increased as expected along the range of predicted probabilities of NASH. That is, the higher the score, the more likely to find an aneurysm on screening with vascular imaging. And the C statistics in the validation cohort was slightly lower than the C statistics in the derivation cohort. So, the important lesson we learned from this study is that the risk of having an intracranial aneurysm in a person who has a first-degree family member with a prior history of aneurysmal subarachnoid hemorrhage is substantially different depending on their NASH score, and this should be taken into consideration when deciding on screening and counseling various family members of the affected patient or prioritizing who should be screened first in routine practice. Dr. Negar Asdaghi: The ideal anesthetic management during endovascular therapy is still unknown. A number of studies have compared the different anesthetic options available during thrombectomy, which include general anesthesia, or GA, conscious sedation, use of local anesthesia, and no sedation at all. The main argument for doing endovascular therapy under general anesthesia is that although this procedure will take some precious pre-thrombectomy time, it does result in strict immobility. And that is really ideal in the sense that it improves catheter navigation and interpretation of angiography, in addition to obviously providing a secure airway and, of course, avoiding the need to have to do an emergency intubation in case of procedural complications. The argument against general anesthesia is not only the issue of time but also the risk of hypotension and hemodynamic compromise, especially during induction, and the loss of very valuable neurological examination in a completely sedated patient during the procedure. Dr. Negar Asdaghi: The question is, does general anesthesia improve or worsen neurological and functional outcomes post-thrombectomy? Several smaller randomized trials have looked at this very question, mainly comparing GA to all other forms of sedation during thrombectomy, but they have yielded inconsistent findings regarding the three-month functional outcome. Dr. Negar Asdaghi: Some of them showed that patients under GA ended up doing better. Some showed no difference in the overall outcomes. But overall, their pooled analysis suggested that GA might be superior to the competing counterpart, which is the conscious sedation, and associated with better functional outcome. But these centers had highly specialized anesthesia teams, and it's possible that their findings may not be generalizable to routine practice. So, in this issue of the journal, using the Swiss Stroke Registry, Dr. Benjamin Wagner from the Department of Neurology at the University Hospital in Basel and colleagues report on the outcomes of endovascularly treated patients in the Swiss Stroke Registry receiving thrombectomy for an anterior circulation stroke with or without general anesthesia. The primary outcome was disability on the modified Rankin Scale after three months. For this study, they excluded one out of the nine centers in the registry that had lots of missing data on their three-month follow-up. Dr. Negar Asdaghi: And so, from 2014 to 2017, 1,284 patients across eight stroke centers in the registry were included in this study. Sixty-six percent received thrombectomy under general anesthesia. On baseline comparison, the patients in the GA group were older, had a higher NIH Stroke Scale on admission, had worse preclinical functional status, and more likely to have presented with multi-territorial ischemic stroke. So, many reasons as to why people who underwent general anesthesia would have a worse clinical outcome in this study. So, now let's look at their primary outcome. In the unadjusted model, the three-month modified Rankin Scale was significantly worse in the GA group as compared to the non-GA group, which is obviously expected given the differences in their baseline characteristics. Dr. Negar Asdaghi: But what was surprising was that the odds of having a higher mRS score was significantly greater still in the adjusted models. They also did propensity score matching analysis, and they found that the NIH Stroke Scale after 24 hours, and the odds of dependency and death and mortality were all higher in the adjusted model in the GA group. They also looked at a number of secondary outcomes and found that door-to-puncture time was longer in the GA group. Dr. Negar Asdaghi: And also these patients were more likely to be transferred to ICU after treatment as compared to the non-GA treated counterparts. The authors point out that these real-world data are in keeping with the findings from the HERMES meta-analysis, which included over 1,700 endovascularly treated patients, and two previously published large registry data, one from Italy, which included over 4,000 endovascularly treated patients, and one from Germany, including 5,808 patients, all of them showing a worse functional outcome in endovascular therapy if the treatment was performed under general anesthesia, as compared to all other forms of sedation or no sedation at all. Again, these findings are in contrast with the reassuring results of the randomized trials on this topic, specifically in contrast to the AnStroke, SIESTA, and GOLIATH randomized trials, which compare GA to conscious sedation, showing either neutral or positive results in favor of general anesthesia pre-thrombectomy. Dr. Negar Asdaghi: So, in summary, what we learned from this real-world, observational study is that general anesthesia was associated with worse functional outcome post-endovascular thrombectomy, independent of other confounders, which means that the jury is still out on the ideal form of anesthesia for an individual patient prior to endovascular therapy, and we definitely need larger, multicenter studies on this topic. Dr. Negar Asdaghi: There are over a thousand experimental treatments that have shown benefit in prevention of neurological disability in animal models of ischemic stroke but have failed to show the same efficacy in human randomized trials. In fact, to date, reperfusion therapies, either in the form of intravenous lytic therapies or endovascular treatments, are the only successful treatments available to improve clinical outcomes in patients who suffer from ischemic stroke, and stroke remains a leading cause of death and disability worldwide. How come stroke can be cured in rodents but not in humans? Are neuroprotective therapies, or as more correctly referred to, the cerebroprotective therapies, the epitome of bench-to-bedside translational research failure? And if this is true, what are the key contributors to the scientific conundrum, and how can this be averted in the future? This is the question that a remarkable group of neuroscientists, led by Dr. Patrick Lyden from University of Southern California, are hoping to answer. Dr. Negar Asdaghi: In this issue of the journal, these investigators describe the rationale, design, feasibility, and stage 1 results of their multicenter SPAN collaboration, which stands for the Stroke Preclinical Assessment Network. I'm joined today by Professor Lyden himself to discuss this collaboration. Now, Professor Lyden absolutely needs no introduction to our stroke community, but as always, introductions are nice. So, here we go. Dr. Lyden is a Professor of Physiology, Neuroscience, and Neurology at Zilkha Neurogenetic Institute, Keck School of Medicine, at USC. He has truly been a leader in the field of preclinical and clinical vascular research with over 30 years of experience in conducting studies and randomized trials, including conducting the pivotal NINDS clinical trial that led to the approval of the first treatment for acute ischemic stroke in 1996. Throughout his exemplary career, he has accumulated many accolades and is the recipient of multiple awards and honors, including the prestigious 2019 American Stroke Association William Feinberg Award for Excellence in Clinical Stroke. Good morning, Pat, it's truly an honor to welcome you to our podcast today. Dr. Patrick Lyden: Thanks, I'm glad to be here. Dr. Negar Asdaghi: Well, in the era of successful reperfusion therapies, it seems that the new generation of stroke neurologists and interventionalists have their eyes, so to speak, on the clock and are interested in opening the blood vessels and opening them fast. In the age of reperfusion treatments, why do we still need to talk about the role of cerebroprotective treatments? Dr. Patrick Lyden: Well, not to sound too glib about it, but not everybody gets better after a thrombectomy. So, thrombectomy is good, it's more effective than anything else that we've tried before, but there are a remaining number of patients with a residual disability. Not only that, and from a more scientific standpoint, thrombectomy offers us the opportunity now to combine cerebroprotective th…

Full show notes at the publisher

Stroke Alert May 2022 May 19, 2022

Show notes

Full show notes at the publisher

Stroke Alert April 2022 Apr 21, 2022

Show notes

On Episode 15 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the April 2022 issue of Stroke: "Kawasaki Disease May Increase the Risk of Subsequent Cerebrovascular Disease" and "Effect of Moderate and Severe Persistent Hyperglycemia on Outcomes in Patients With Intracerebral Hemorrhage." She also interviews Dr. François Gros-Louis about his article "Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function." Dr. Negar Asdaghi: 1) How would you counsel the parent of a child who has just recovered from Kawasaki disease on their child's future risk of having a stroke? 2) Should we or should we not treat stress hyperglycemia in the setting of acute intracerebral hemorrhage? 3) What is the CRISPR-Cas9 gene editing technology? And why, if you haven't heard of it already, you most definitely should be listening to this podcast? We're back here with the April issue of the Stroke Alert Podcast, and this is the latest in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome back to another extremely informative Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine, and your host for the monthly Stroke Alert Podcast. The April 2022 issue of Stroke contains a range of really exciting papers and topics. In the paper titled "Vascular Response to Spreading Depolarization Predicts Stroke Outcome," we have a really interesting in vivo mouse model of ischemic stroke, looking at the spreading patterns of cortical depolarization and the subsequent vascular response to this by way of hyperemia. The researchers from Zurich University, led by Dr. Binder and colleagues, walk us through how the patterns of hyperemia can actually predict the severity of subsequent ischemic injury. Dr. Negar Asdaghi: In a separate paper in this issue of the journal, we're reminded of how the classic NIH Stroke Scale can underestimate the severity of neurological symptoms and outcomes in patients with posterior circulation infarcts. In the paper led by Dr. Alemseged and colleagues, the investigators from the Royal Melbourne Hospital in Australia evaluate the prognostic accuracy of the Posterior NIH Stroke Scale, which is the modified version of the classic NIH Stroke Scale, in predicting the outcomes of patients with posterior circulation infarcts. Dr. Negar Asdaghi: I encourage you to review these papers in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. François Gros-Louis from Laval University in Quebec to discuss the latest in gene editing technology and how this technology has helped his team unravel the biological function of RNF213 susceptibility gene in Moyamoya disease. But first with these two articles. Dr. Negar Asdaghi: Kawasaki disease, which was first described in 1976, is an acute febrile illness predominantly affecting children younger than five years of age. In addition to fever, other clinical signs of the disease include rash, bilateral conjunctival injection, cervical lymphadenopathy, swelling of the hands and feet, and irritation and inflammation of the mouth, lips, and throat. Now, for those of us like me who are adult neurologists, here is a quick review of the pathophysiology of Kawasaki disease. Dr. Negar Asdaghi: This is a medium vessel vasculopathy, most significantly affecting the coronary arteries, a vasculopathy that is characterized by three linked pathological processes, necrotizing arteritis, subacute to chronic vasculitis, and luminal myofibroblastic proliferation. So, simply put, these processes can lead to stenotic lesions in various vascular beds, which are affected by this disease. Dr. Negar Asdaghi: And as we mentioned earlier, the most recognized vascular blood vessels affected by Kawasaki disease are the coronary arteries, which can lead to myocardial ischemia, infarction, and sudden death in these cases. However, involvement of other vascular beds, including cerebral vessels, are also increasingly reported as part of Kawasaki disease. Dr. Negar Asdaghi: So, in the current issue of the journal, Dr. Chien-Heng Lin from the Division of Pediatric Pulmonology at China Medical University Children's Hospital in Taiwan and colleagues studied the subsequent risk of cerebrovascular events in patients with Kawasaki disease. Using the National Health Insurance Research Database of Taiwan, they collected data on 8467 children with Kawasaki disease from 2000 to 2012. And for each child with Kawasaki, data was also collected on four randomly selected non-Kawasaki disease children who were matched with the Kawasaki cohort for sex, urbanization level of residence, and parental occupation. Dr. Negar Asdaghi: So, that gave them a sample size of over 33,000 children for their non-Kawasaki cohort. And then they compared the risk of subsequent stroke in children between the two cohorts. The study period for any given patient would end when the said patient was either diagnosed with a cerebrovascular disease or withdrew from the research database. Dr. Negar Asdaghi: So, in terms of their demographics, 61% of patients in the Kawasaki group were boys; 88% of the Kawasaki cohort were younger than five years of age. So, here are the findings. Number one, the incident rate of subsequent cerebrovascular disease was 14.7 per hundred thousand person years in the Kawasaki cohort versus only 4.6 per hundred thousand person years in the non-Kawasaki cohort. That's greater than a threefold higher incidence rate of cerebrovascular disorders for children who had Kawasaki disease before. Dr. Negar Asdaghi: This finding was independent of other potential confounders, which they adjusted for in their multivariate analysis. Now, the length of follow up was a median of 9.8 years for the entire cohort. And on the issue of time, they found two important associations. The first finding was that when the follow-up time was stratified by five-year periods, Kawasaki disease cohort patients showed a significantly higher risk of developing a stroke within the first five years after being diagnosed. Dr. Negar Asdaghi: And the second important association was that when they looked at the age at the time of diagnosis of Kawasaki, children who were younger than five years at the time of diagnosis were at a significantly higher risk of having a future stroke as compared to those who were older than five at the time of diagnosis. Dr. Negar Asdaghi: So, simply put, the risk of subsequent stroke was higher in children who acquired the disease at a younger age, and that risk was higher in the first few years after the diagnosis of Kawasaki disease. The authors discuss a number of putative mechanisms to link Kawasaki with stroke. The most important being a cardiac source of embolism that we already alluded to, but other etiologies, including medium vessel cerebral vasculitis, or hypercoagulability in the setting of increased systemic inflammation, and even Kawasaki disease-associated aneurysmal rupture to cause hemorrhagic forms of stroke, are discussed in the paper and should be considered in the correct setting in children with a prior history of this disease. Dr. Negar Asdaghi: So, what we learned from this large population-based pediatric study is that Kawasaki disease does indeed increase the risk of subsequent cerebrovascular disorders, and its influence is stronger in children who are diagnosed with this condition under the age of five, and the time period during which the risk of stroke is the highest is within the first five years after the diagnosis. Dr. Negar Asdaghi: In the setting of spontaneous intracerebral hemorrhage, or ICH, much research has focused on the association between hypertension and blood pressure-lowering therapies and hematoma expansion and functional outcomes, but a lot less attention relatively has been given to the impact of hyperglycemia and ICH-related outcomes. Dr. Negar Asdaghi: The current guidelines state that serum glucose should be monitored and both hypo- and hyperglycemia should be avoided in the setting of ICH. The older studies have given us inconsistent results as to whether or not hyperglycemia can increase the risk of ICH-related mortality. More recent studies have suggested that perhaps persistent hyperglycemia is indeed a predictor of poor neurological outcomes in ICH, but these results come from smaller single-center studies, which require further confirmation. And this confirmation is exactly what Dr. Adnan Qureshi from Zeenat Qureshi Stroke Institute and the Department of Neurology at University of Missouri and colleagues aim to give us in their study titled "Effect of Moderate and Severe Persistent Hyperglycemia on Outcomes in Patients With Intracerebral Hemorrhage." Dr. Negar Asdaghi: So, they use data from the ATACH-2 study, and a quick reminder that ATACH-2 was a multicenter randomized control trial of a thousand patients with acute spontaneous intracerebral hemorrhage enrolled within four and a half hours from symptom onset, and patients were randomized to either the intensive blood pressure control treatment arm to maintain their systolic blood pressure goal of 110 to 139 millimeter of mercury versus standard treatment arm, which was keeping their systolic blood pressure above 140, between 140 to 179 millimeter of mercury, in the first 24 hours after randomization. Dr. Negar Asdaghi: You will recall that enrollment of ATACH-2 was stopped early because of futility after pre-specified interim analysis. The main results of the trial was published in 2016 in New England Journal of Medicine, and the primary results did not show a lower rate of death or disability in patients assigned to the intensive treatment group. Dr. Negar Asdaghi: So, in the current paper, in this current issue of the journal, the authors looked at the glycemic status of the patients enrolled in the trial. As part of the trial, patients had a complete chemistry panel at baseline, 24, 48, and 72 hours from onset. So, they used the glucose measurement from this panel and defined moderate hyperglycemia as serum glucose level of over 140 and under 180 and severe hyperglycemia as serum glucose levels of equal or greater than 180. Dr. Negar Asdaghi: Now, persistent hyperglycemia was if two consecutive serum glucose levels were in the moderate or severe categories. And, very simply, they looked at the effects of hyperglycemia on ICH outcomes. And importantly, they evaluated whether hyperglycemia modified the effects of intensive blood pressure reduction on outcomes of ICH. So, of the thousand participants in ATACH-2, 11% had persistent moderate hyperglycemia, and 17% had severe persistent hyperglycemia. Those in the hyperglycemic group were more likely to be diabetic, not surprisingly, more likely to have a history of hypertension and dyslipidemia as compared to the normal glycemic patients. Dr. Negar Asdaghi: And here are the results. Number one, serious adverse events were higher in the hyperglycemic groups, whether we're talking about the moderate or the severe hyperglycemic groups. This is despite the fact that the rate of hematoma expansion and perihematomal edema was not different based on the hyperglycemic status. However, the hyperglycemic patients were more likely to have serious adverse events, which were operationally defined as complications that were not expected to have occurred from the study intervention, in this case, the intensive hypertensive therapy, and resulted in either death or prolonged hospitalization or persistent or significant disabilities. Now, serious renal adverse events, which are, of course, expected as a complication for aggressive blood pressure therapy, were also significantly higher in the hyperglycemic category. Dr. Negar Asdaghi: Now, their next important finding was that overall, both moderate and severe hyperglycemia was associated with higher odds of 90 days disability or death post-ICH adjusting for typical variables that could predict these outcomes, such as GCS score, hematoma volume, presence or absence of intraventricular hemorrhage, amongst other factors that they accounted for. Dr. Negar Asdaghi: Now, number three, this is perhaps the most important finding of the study. Among patients without a preexisting history of diabetes, both moderate and severe hyperglycemia increased the risk of death and disability at 90 days after adjusting for all the potential confounders, but hyperglycemia was not associated with these poor outcomes in those with a prior history of diabetes. I'm going to pause here to let this information sink in. Let's go over them again, stress hyperglycemia in non-diabetics was associated with poor ICH outcomes, but high sugars in diabetics did not predict the same poor outcomes. And finally, they looked at the possible interactions between the glycemic status and the ATACH-2 intervention, which as we alluded to earlier, which was intensive versus standard blood pressure therapy, and it turns out that the intensive systolic blood pressure reduction was indeed associated with a lower rate of hematoma expansion only in patients with normal glycemia, but not in those with moderate or severe hyperglycemia. Dr. Negar Asdaghi: So, this is again food for thought. Simply put, if the sugars are not well controlled, it appears that intensive blood pressure control would not lower the rate of hematoma expansion. Blood pressure lowering works when the sugar levels are controlled. So, overall, here are the two simple messages of this study. Number one, hyperglycemia in the acute setting of intracerebral hemorrhage is associated with poor outcomes or death only in those with stress hyperglycemia, meaning in those who have high sugar levels, but are not diabetic. Dr. Negar Asdaghi: Number two, there seems to be an important interaction between the acute glycemic status of the patients and how intensive blood pressure control can prevent hematoma expansion, in that intensive BP control is only effective in prevention of hematoma expansion if the sugar levels are normal. So, a lot of thought-provoking and hypothesis-generating findings, and definitely more to come on this topic. Dr. Negar Asdaghi: Moyamoya disease, or MMD, is an idiopathic disorder characterized by progressive stenosis of the supraclinoid internal carotid artery and its main branches in subsequent formation of a network of abnormal lenticulostriate collaterals. First described in Japan, the term "Moyamoya" is a Japanese expression for the puff of smoke and describes the characteristic appearance of the tangled and abnormal collateral vessels that are seen in angiography in various stages of the Moyamoya disease. Dr. Negar Asdaghi: Epidemiological studies have revealed several risk factors associated with Moyamoya disease, including Asian ethnicity, female gender, and a family history of the disorder. Given that 15% of MMD patients have a family history of this disease, it's not surprising that genetic factors are suspected to underlie its pathogenesis. Now, a polymorphism in the ring finger protein 213, or RNF213, gene on chromosome 17 has been identified as the strongest genetic susceptibility factor for Moyamoya disease specifically in the East Asian population. Dr. Negar Asdaghi: But despite the many advances in understanding the pathophysiology of MMD, as well as advances in animal models and genetic studies, to date, none of the animal models of RNF213 have quite replicated the vascular abnormalities that are typically seen in human Moyamoya disease. Dr. Negar Asdaghi: The scientists feel that this is related to how little is known about the exact biological function of RNF213 gene and the protein it encodes. So, in the current issue of the journal, in the study titled "Moyamoya Disease Susceptibi…

Full show notes at the publisher

Stroke Alert March 2022 Mar 17, 2022

Show notes

On Episode 14 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the March 2022 issue of Stroke: "Natural Course of Cerebral Cavernous Malformations in Children" and "Direct Oral Anticoagulants Versus Warfarin in Cerebral Venous Thrombosis (ACTION-CVT)." She also interviews Dr. Mohammad Anadani about his article "Magnitude of Blood Pressure Change After Endovascular Therapy and Outcomes." Dr. Negar Asdaghi: 1) Are direct oral anticoagulants a reasonable alternative to warfarin for treatments of patients with cerebral venous thrombosis? 2) What are the predictors of first and recurrent intracerebral hemorrhage in patients with cerebral cavernous malformation? 3) Is there an optimal blood pressure target after successful endovascular thrombectomy? We have the answers and much more in today's podcast. This is the latest in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome to another incredibly informing Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The March 2022 issue of Stroke includes a number of papers published in conjunction with their oral presentation at the International Stroke Conference in New Orleans, from contemporary trends in the nationwide incidence of primary intracerebral hemorrhage, to disparities in Internet use among U.S. stroke survivors' implication for telerehabilitation during COVID-19 and beyond. I encourage you to review these timely topics in addition to listening to our podcast today. Later, in our interview section, I discussed the optimal blood pressure goal after endovascular therapy and the results of a subgroup analysis of the BP-TARGET randomized trials with Dr. Mohammad Anadani from the Department of Neurology at Washington University in St. Louis. But first with these two articles. Dr. Negar Asdaghi: Cerebral cavernous malformations, also referred to as cavernous angiomas, cavernomas, cav mals, or CCMs, are angiographically occult, low flow, vascular lesions with no large arterial inflow or venous outflow vessels. These are clusters of dilated sinusoidal vascular channels that are aligned by a single layer of endothelium without the normal surrounding vascular smooth muscles, and they lack the normal tight junctions between their endothelial cells. Cavernomas can be found in both children and adults. So, the question is, how do these lesions present, especially in children, and what is their natural course? Now, before we answer these questions, let's review a few important points about cavernomas and what is known about these lesions in the literature. Number one, cavernomas are acquired lesions. Although initially thought to be congenital, they're now known to be acquired as comparing by many reports of patients with normal MRI findings, who later developed a CCM. Number two, they're not always benign. While most of them can have a benign course, cerebral cavernomas can be a cause for headaches, seizure disorders and intracerebral hemorrhage, which is, of course, their most feared complication. Dr. Negar Asdaghi: Number three, though CCMs are rare vascular disorders with a prevalence of 0.6% in children and young adults, about a quarter of patients with a confirmed diagnosis of cerebral cavernous malformation are under the age of 18. And number four and finally, data seem to suggest that the risk of hemorrhage is potentially higher in the pediatric population than their adult counterparts. So, determining the natural course of CCMs and predictors of intracerebral hemorrhage is important for all patients, but especially important in the pediatric population. Now, in the current issue of the journal, in the paper titled "Natural Course of Cerebral Cavernous Malformations in Children: A Five-Year Follow-Up Study," a German group of investigators led by Dr. Alejandro Santos from the Department of Neurosurgery and Spine Surgery at University Hospital in Essen and colleagues studied the clinical presentation and predictors of intracerebral hemorrhage in their pediatric population over a 17-year study period. Dr. Negar Asdaghi: So, they identified 129 patients with a diagnosis of cerebral cavernous malformation that had baseline MRI imaging completed and at least one or more follow-ups during the study period. Now, some of these patients were treated surgically and some conservatively in the study. The mean age of their study was 10, and over 50% of their study population was male. Developmental venous anomalies, or DVAs, were detected in 15% of their study population, and 20% had brain stem cavernoma localization. Now, importantly, half of these kids, so that's 55.8% of their study population, presented with an intracerebral hemorrhage, and that's how their cavernomas were diagnosed. So, what were their top three findings? Dr. Negar Asdaghi: Number one, on the comparison of conservatively treated patients to those treated surgically, which was 37% of their cohort, they found that overall these two groups had comparable clinical characteristics and demographics with regards to sex, age, multiplicity of cavernomas, brain stem location, and family history of their lesions. But not surprisingly, those who were surgically treated were more likely to have presented with an intracerebral hemorrhage and less likely to be asymptomatic, meaning that their cavernoma was not an incidental finding as compared to those who were conservatively treated. Dr. Negar Asdaghi: Number two, when they looked at predictors of presentation with intracerebral hemorrhage, they found that family history of cavernomas and brain stem cavernomas were significant predictors of presenting intracerebral hemorrhage. Number three, when they excluded those who underwent surgery, the annual risk of hemorrhage for the overall untreated participants was 4.1%. However, we should note that this rate significantly varied based on certain characteristics of the patients. The risk of hemorrhage, or rather the risk of re-hemorrhage, was double this baseline, that is 8.1%, for those cavernomas that presented with a bleed at presentation. The annual rate of hemorrhage was equally high at 7.1% for brain stem cavernomas, and then this rate gradually declined for familial form cavernomas at 6.2% annual risk of hemorrhage and multiple cavernomas at 4.8%. And it went all the way down to 0.4% annual risk of hemorrhage for asymptomatic incidentally found cerebral cavernomas. So, in the multivariate analysis, presentation with an ICH remained an independent predictor of re-hemorrhage and cavernomas with a high hazard ratio of 14. That is 14-fold higher risk of hemorrhage in cavernomas that present with a bleed as compared to those that did not. Dr. Negar Asdaghi: Now, finally, on the association between DVAs and risk of hemorrhage, this study showed a possible reduced risk of hemorrhage in cavernomas that had associated DVAs, but this was not a statistically significant association. It is important to note that this finding is in keeping with the published studies in the adult population, but in contrast to the previously published data in the pediatric population. So, this association between presence of a developmental venous anomaly and cavernomas and the risk of subsequent hemorrhage needs to be furthered studied. So, what did we learn from this study? Pediatric patients with brain stem cavernomas and familial cavernomas have a higher risk of intracerebral hemorrhage as mode of presentation. The risk of re-hemorrhage is 14 times higher in cavernomas that present with an ICH as compared to cavernomas that did not bleed. And the probability of bleed tends to increase over time. Dr. Negar Asdaghi: Cerebral venous sinus thrombosis, or CVST, refers to thrombosis in the dural venous sinuses, cortical veins, deep cerebral veins, or a combination of these venous structures. CVST is an uncommon cause of stroke accounting for overall 1% of all strokes and can cause venous ischemic infarcts or intracerebral hemorrhage and importantly has a high morbidity and mortality if unrecognized and left untreated. Anticoagulation is generally the mainstay of therapy for CVST, which needs to be initiated as soon as possible, even in the presence of hemorrhage in the brain. The data regarding the choice of anticoagulation in CVST is generally extrapolated from randomized studies completed in patients with systemic venous thromboembolism, so conditions such as pulmonary emboli or deep venous thrombosis, and indicate that direct oral anticoagulants, or DOACs, are viable alternatives to traditional warfarin therapy in this patient population. This question was specifically studied in the RESPECT-CVT trial, which was a small European randomized trial that included 120 patients with cerebral vein thrombosis, randomized to either receiving dose adjusted warfarin or dabigatran at 150 milligram BID. Dr. Negar Asdaghi: The results of the study was published in JAMA Neurology in 2019 and showed that CVST patients treated with either dabigatran or warfarin were at low risk of recurrent venous thromboembolism, and they also showed a comparable safety profile in terms of risk of hemorrhage or mortality in patients treated with DOAC as compared to warfarin. But how do DOACs perform as compared to warfarin in routine practice is unknown. So, in this issue of the journal, in the study titled, "Direct Oral Anticoagulants Versus Warfarin in Cerebral Venous Thrombosis (ACTION-CVT): A Multicenter International Study," the ACTION-CVT investigators, led by Dr. Shadi Yaghi from the Department of Neurology at Brown University, aimed to compare the safety profile of DOACs to that of warfarin, in a multicenter international study that included 1025 imaging-confirmed CVST patients from multiple centers in the United States, Italy, Switzerland, and New Zealand. Dr. Negar Asdaghi: They had a number of exclusion criteria for this study, excluding patients with active cancer, those with a confirmed history of antiphospholipid antibody syndrome and those who were not treated with an oral anticoagulant. And after excluding these patients, it gave them their study sample of 845 CVST patients. So, what were their main findings? Number one, in keeping with a prior literature on CVST, these patients were young, their mean age was 44, and majority of them were women, so that was 67% of their cohort. And they found that a third of these patients were actually treated with a DOAC, and, in addition, another 15% received a DOAC at some times during their treatment course. Finding number two, the most common DOAC used in this population was apixaban, that was 66% of cases treated with a direct oral anticoagulant, followed by rivaroxaban in 18% of cases, and then dabigatran used in 13.5% of DOAC-treated cases. Dr. Negar Asdaghi: Important finding number three. A total of 27 patients had recurrent CVST, which also included patients with progression of their cerebral vein thrombosis on follow-up vascular imaging, and 17 patients had recurrent venous thromboembolism, and two had both. So, during their mean follow-up of 345 days, they had the rate of 5.68 recurrent venous thrombosis per 100 patient years. These rates were not different for DOAC-treated versus warfarin-treated patients in both unadjusted and adjusted models. Now, very important finding number four. When they looked at the rate of recanalization on follow-up imaging, for those in whom this information was available, partial or complete recanalization occurred in 86% of DOAC-treated patients versus 84% of warfarin-treated patients. This was not a statistically significant difference in the unadjusted or the adjusted models. Recanalization is, of course, an important determinant of outcomes in CVST and should be noted that recanalization is, of course, an important determinant of outcomes in CVST since persistent thrombosis through chronic raised ICP can potentially lead to a variety of neurological morbidities, such as chronic headache, chronic papilledema and increased risk of development of dural AV fistulas. Dr. Negar Asdaghi: Now, finally, in terms of safety profile, they had 31 hemorrhages, 23 intracranial, majority were symptomatic and 9 extracranial hemorrhages. The hazard ratio for hemorrhage or death was similar for DOAC- and warfarin-treated patients, again in the unadjusted and adjusted models. So, bottom line, in this large international cohort of patients with CVST treated with an oral anticoagulant in routine practice, patients treated with DOACs had similar clinical and radiographic outcomes and had a similar favorable safety profile when compared to those treated with warfarin. So, we stay tuned for the results of the ongoing randomized trials on this subject. Dr. Negar Asdaghi: What is the optimal blood pressure target after endovascular therapy? This is a commonly encountered question in routine clinical practice with a not-so-straightforward and easy answer. After a successful endovascular treatment, high systolic blood pressure targets are thought to be associated with increased risk of reperfusion injury and development of intraparenchymal hemorrhage, leading to worsening of clinical outcomes. Conversely, low blood pressure targets may worsen the ischemic penumbra, especially in the setting of incomplete perfusion. The current stroke guidelines recommendations regarding blood pressure control after endovascular treatment are mostly extrapolated from the post-thrombolysis studies. The BP-TARGET trial was a recently completed randomized study in France that aimed to assess the safety and efficacy of intensive blood pressure lowering, that is systolic blood pressure of less than 130, as compared to standard of care, that is systolic blood pressure between 130 to 185, after successful endovascular therapy in acute ischemic stroke. Dr. Negar Asdaghi: This was a neutral study, and the main results of the trial was published in early 2021 in Lancet Neurology. And if you missed it, well, as always, we're here with the Stroke Alert Podcast to fill in the gaps. So, we'll review the trial results with our podcast guest today, Dr. Mohammad Anadani, from the Department of Neurology at Washington University in St. Louis, who's also the first author of a paper in the current issue of the journal titled "Magnitude of Blood Pressure Change After Endovascular Therapy and Outcomes: Insight From the Blood Pressure-TARGET Trial." This was a post hoc analysis of the BP-TARGET trial, looking at the extent of blood pressure reduction and its implications of clinical outcomes. Welcome, Mohammad, thank you for joining us on the podcast today. Dr. Mohammad Anadani: Thank you for having me. It's a pleasure to be here with you today. Dr. Negar Asdaghi: Thank you. So, blood pressure control is a really simple and yet extremely complicated topic when it comes to the collateral support before reperfusion therapies, and then, of course, the possibility of reperfusion injury post-thrombectomy in the setting of an ischemic stroke related to a large vessel occlusion. Can you please give our listeners an overview of the topic of blood pressure control in this setting? Dr. Mohammad Anadani: Yes, absolutely. I totally agree. The topic of blood pressure control after, in patients with large vessel occlusion, is very complicated. And when we talk about blood pressure control, I think we should differentiate between pre-recanalization and post-recanalization. In the pre-recanalization period, the main focus should be to maintain adequate perfusion to ischemic penumbra to prevent infarct expansion. So, there is consensus that hypotension should be avoided at all costs pre-recanalization. When it comes to the post-reperfusion, here it gets a little bit…

Full show notes at the publisher

Stroke Alert February 2022 Feb 17, 2022

Show notes

On Episode 13 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the February 2022 issue of Stroke: "Cannabis Use and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage" and "Infertility, Miscarriage, Stillbirth, and the Risk of Stroke Among Women: A Systematic Review and Meta-Analysis." She also interviews Dr. Pierre Amarenco about his article "Intracranial Hemorrhage in the TST Trial." Dr. Negar Asdaghi: 1) Can marijuana use increase the risk of ischemic stroke in patients with aneurysmal subarachnoid hemorrhage? 2) Is there an association between infertility or miscarriage and development of stroke later in life? 3) Does lowering the bad cholesterol increase the risk of intracerebral hemorrhage? We will cover these and much more in today's podcast. This is the latest in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome to another exciting Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. Dr. Negar Asdaghi: The February 2022 issue is the second installment of Stroke's annual Go Red for Women issue. This is to highlight the journal's continuous effort to bring to attention the research which focuses on reduction of sex disparities and enhancing inclusivity in stroke care. This issue of the journal features a number of articles from sex disparities in enrollment in randomized trials of stroke, to sex-related differences in ischemic stroke presentation, outcome of endovascular therapy, plaque composition of carotid stenosis, and the sex-dependent rupture rate of cerebral aneurysms and the risk of subarachnoid hemorrhage, which I encourage you to review in addition to listening to today's podcast. Dr. Negar Asdaghi: Later in the podcast, I have the distinct honor of interviewing one the leaders in the field of secondary stroke prevention, Dr. Pierre Amarenco from Bichat University in Paris, to discuss the latest analysis of the association between LDL cholesterol levels and intracerebral hemorrhage risk in a sub-analysis of the Treat Stroke to Target trial, and what is next to come on cholesterol-lowering therapies post-ischemic stroke. But first with these two articles. Dr. Negar Asdaghi: It should come at no surprise to our listeners that the use of marijuana in its variety of forms is increasing not only in the United States, but also across the globe, both for recreational purposes and also for treatment of a range of medical conditions. There's also a growing body of evidence to link marijuana use to cerebrovascular disorders, including ischemic and hemorrhagic strokes. In fact, national surveys in the United States show that over two million Americans with established cardiovascular disorders currently use or report having used marijuana in the past. Dr. Negar Asdaghi: Aneurysmal subarachnoid hemorrhage is a hemorrhagic stroke subtype that is frequently complicated by cerebral vasospasm and delayed cerebral ischemia, or DCI. Now, we know that development of DCI can significantly increase the neurological morbidity and mortality related to the disease. So, the question is, can marijuana use increase the risk of DCI in subarachnoid hemorrhage? And what is the difference between cannabis and marijuana? And how are they even related to the brain and vascular disorders? Now, to answer these questions, we first have to do a quick review of three key points. Dr. Negar Asdaghi: Key point number one: The word "cannabis" refers to all products derived from the plant cannabis sativa. This plant contains about 540 chemical substances. The word "marijuana" refers to parts of or products from the plant with substantial amounts of tetrahydrocannabinol, or THC. THC is the active ingredient of marijuana responsible for mediating its psychoactive effects through activation of G protein-coupled cannabinoid receptors, which are easier to remember as CB1 and CB2 receptors. Dr. Negar Asdaghi: Key point number two: CB1 and CB2 receptors are diffusely expressed throughout the brain, but interestingly, CB1 receptors are also richly expressed across various vascular beds, including the cardiac and cerebral vessels. So, there we have it, a connection between marijuana and the blood vessels. Dr. Negar Asdaghi: Key point number three: The differential activation of CB1 receptors in cerebral vessels may lead to vasoconstriction or vasodilation, potentially linking marijuana to vasospasm seen in aneurysmal subarachnoid hemorrhage, which then leads to DCI. But it should be noted that THC can also lead to ischemia through other mechanisms, such as altering the brain's oxidative capacity, impairing mitochondrial respiratory chain complexes, and increasing reactive oxygen species in free radicals. So, causing brain ischemia through mechanisms other than vasospasm. Dr. Negar Asdaghi: So, with these three points in mind, in the current issue of the journal, in the study titled "Cannabis Use and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage," Dr. Joshua Catapano from the Department of Neurosurgery at the Barrow Neurological Institute and colleagues report on the outcomes of 1,014 aneurysmal subarachnoid hemorrhage patients treated over a 12-year period at their institution from August 2007 to July 2019. Dr. Negar Asdaghi: The primary exposure was cannabis use, which was detected by routine urine toxicology at the time of hospital presentation with subarachnoid hemorrhage. Patients were also screened for the use of other vasoactive substances, including cocaine, amphetamines, and also tobacco use. The primary outcome was DCI defined as cerebral infarction detected either by CT or MRI or proven on autopsy after exclusion of procedure-related infarctions. Dr. Negar Asdaghi: And here's what they found. Number one: Overall, 36.2% of their patient population with aneurysmal subarachnoid hemorrhage developed DCI. 50.2% of their total population had poor functional outcome defined as modified Rankin Scale of over two by the time of discharge, and 13.5% died. These are important reminders that aneurysmal subarachnoid hemorrhage remains a deadly form of stroke, despite modern neurosurgical and neurocritical care advances in treatments. Dr. Negar Asdaghi: Number two: 4.5% of their patient population tested positive for cannabis. And here's the alarming finding of their study. The rate of DCI was significantly higher in those who were positive for cannabis, that was 52%, versus only 35% in those negative for cannabis. This association was not seen with other vasoactive agents such as cocaine and methamphetamine. Now, radiographic vasospasm was also significantly more common in cannabis users, the rate of which was 88% in cannabis users than in non-users, which was 70%. Dr. Negar Asdaghi: Now, number three: When they adjusted for baseline patient characteristics, presenting Hunt and Hess classification, and other vasoactive substances and active smoking, cannabis use was independently associated with an increased likelihood of development of DCI. So, what did we learn from this study? Active cannabis users were 2.7 times more likely to develop ischemic stroke post-aneurysmal subarachnoid hemorrhage as compared to their non-user counterparts. This is one of the largest studies to potentially link marijuana to development of cerebral ischemia in this population. Dr. Negar Asdaghi: There is now ample scientific evidence to connect some pregnancy-related complications, such as gestational hypertension, gestational diabetes, preeclampsia, and some pregnancy outcomes, such as preterm birth or having small-for-gestational-age infants, to an increased long-term risk of cerebrovascular events in the mother. Infertility, miscarriage and stillbirth are also common abnormalities in the process of conceiving and being pregnant, but whether there is an association between these abnormalities and development of future vascular disorders in women is not clear. Dr. Negar Asdaghi: In the current issue of the journal, in the study titled "Infertility, Miscarriage, Stillbirth, and the Risk of Stroke Among Women," Dr. Chen Liang from the School of Public Health at the University of Queensland in Brisbane and colleagues report on the results of a systematic review and meta-analysis on this topic. So, let's dive into it. Dr. Negar Asdaghi: First, a brief look at their methodology. After a comprehensive literature search, a total of 18 studies were included in this meta-analysis, including over 7,800,000 women between the ages of 23 to 63 with a mean follow-up of 3.8 to 19 years. So, a big study. Five studies evaluated the association between infertility and stroke. Infertility was defined in broad terms as either a formal diagnosis or receiving fertility treatment or testing through databanks or medical records. And the other 13 studies explored the association between a history of either miscarriage and/or stillbirth and the main outcome of the study, which was stroke. Dr. Negar Asdaghi: In 11 studies, the outcomes of ischemic and hemorrhagic strokes were specified, four studies only reported on the ischemic stroke, and the rest did not identify the stroke subtype. So, what did they find? Well, their first finding was on the association between infertility and stroke. Overall, the five studies included over 4,600,000 women, and this association was inconsistent due to heterogeneity of the results between the different studies. But, when excluding the one study from Asia, which created most of the heterogeneity in results, infertility was indeed found to be associated with a 17% increase in the risk of stroke in the mother. In terms of possible causes, well, they looked at common infertility etiologies and vascular risk factors, and not surprisingly, they found many connecting points. Dr. Negar Asdaghi: For example, polycystic ovarian syndrome is a common cause of infertility and is frequently associated with insulin resistance and type 2 diabetes. Endometriosis, another cause of infertility, is commonly associated with hyperlipidemia and hypertension as a result of chronic systemic inflammation. Another example is premature ovarian insufficiency that could increase the risk of stroke through elevated follicle-stimulating hormone, a lower level of estrogen, and a relatively elevated level of androgen. Dr. Negar Asdaghi: So, their next finding was on the association between miscarriage and stillbirth in stroke. As you know, both of these conditions, so miscarriage and stillbirth, describe pregnancy loss at various stages. A stillbirth is the loss of fetus after the 20th week of development while a miscarriage refers to a loss of pregnancy before the 20th week of gestation. Women with a history of miscarriage had a 7% increased risk, and those with a history of stillbirth had a 38% increase in the risk of stroke later in life. Now, since having a miscarriage is a very common occurrence, it's important to pay attention to their dose response sub-analysis. When data was available on the number of miscarriages or number of stillbirths, increased risk of stroke was apparent among women with three or more miscarriages, but not two or less. For stillbirths, similarly, a history of repeated stillbirths was associated with increased risk of stroke, but evidence on association for a single stillbirth with stroke was insufficient. Dr. Negar Asdaghi: These are important findings to keep in mind when reviewing these results, and importantly, when counseling patients in routine practice. Now, in terms of causes, the authors discuss a variety of associated mechanisms, such as persistent endothelial dysfunction, a common cause for both pregnancy loss and vascular disease, elevated level of homocystine, autoimmune disorders, including presence of antiphospholipid antibodies and a cause for both pregnancy loss and development of arterial stenosis, noting that especially for the autoimmune conditions, specifically in the case of the APS syndrome, pregnancy loss is likely to be repeated, which is consistent with the findings of their subgroup analysis and dose response analysis in the paper, showing that repeated miscarriages and stillbirths are more likely associated with a higher risk of stroke rather than a single event. Dr. Negar Asdaghi: So, bottom line, what my takeaway from this study is, that many factors that can cause infertility, miscarriage and stillbirth can also cause vascular disorders, and these associations should be kept in mind when treating women at a younger age for fertility and pregnancy-related complications. Dr. Negar Asdaghi: Intensive therapy to lower serum lipid levels with the use of statins is recommended after transient ischemic attack or ischemic stroke of atherosclerotic origin. Treatment with statins has been shown to reduce the risk of major vascular events in the stroke population, but there remains a concern regarding an increased risk of development of intracranial hemorrhage with this therapy. Whether this increased risk of ICH is a class effect related to treatment with statins, or is associated with a certain low target levels of LDL cholesterol, is uncertain. Dr. Negar Asdaghi: The Treat Stroke to Target randomized trial tested the hypothesis that a target level of LDL cholesterol of less than 70 milligram per deciliter would be superior to a target range of 90 milligrams to a hundred milligram per deciliter in reducing the overall cardiovascular events after an ischemic stroke or TIA in patients with evidence of atherosclerosis. The primary results of the trial was published in New England Journal of Medicine in early 2020. Dr. Negar Asdaghi: In the current issue of the journal, in the study titled "Intracranial Hemorrhage in the Treat Stroke to Target Trial," the trial investigators report the results of a pre-specified analysis of the TST trial to evaluate the baseline and on-treatment predictors of incident ICH. I'm joined now by Dr. Pierre Amarenco, who's the first author of the study and one of the primary investigators of the TST trial, to discuss this paper. Dr. Amarenco is an internationally renowned neurologist who absolutely needs no introduction to the Stroke readership, but as always, an introduction is nice. Dr. Negar Asdaghi: He's a Professor of Neurology and the founder of the Department of Neurology and Stroke Center, as well as the SOS-TIA Clinic, at Bichat University Hospital in Paris. He's a leader in the field of secondary prevention of stroke with special interests in treatment of patients with TIA and mild stroke. He has served as the primary investigator of multiple randomized trials of antithrombotic therapies, lipid modifying agents, and acute revascularization treatments. Dr. Amarenco leads the international TIA registry involving centers from 21 countries around the globe. Welcome to our podcast, Pierre. Thank you so much for joining us all the way from Paris. Dr. Pierre Amarenco: Good afternoon, Negar. Thank you for asking me. Dr. Negar Asdaghi: Well, thank you for being here. Let's start with the Treat Stroke to Target trial. It addresses an important gap in the secondary prevention of ischemic stroke literature. Can you please start us off with an overview of the trial? Dr. Pierre Amarenco: Yes. The objective of Treat Stroke to Target trial was to evaluate in 2,860 patients with ischemic stroke of atherosclerotic origin randomized into a target LDL cholesterol less than 70 milligram or a target LDL cholesterol 90 to 110 milligram per deciliter to see the benefit in the lower target group as compared to the higher target group. That was the purpose of the TST trial. Dr. Negar Asdaghi: And the trial, Pierre, was terminated early. Do you mind comment…

Full show notes at the publisher

Stroke Alert January 2022 Jan 20, 2022

Show notes

On Episode 12 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the January 2022 issue of Stroke: "Efficacy of Intravenous Mesenchymal Stem Cells for Motor Recovery After Ischemic Stroke: A Neuroimaging Study" and "Cumulative Concussion and Odds of Stroke in Former National Football League Players." She also interviews Dr. Mike Sharma about his article "Frequency and Patterns of Brain Infarction in Patients With Embolic Stroke of Undetermined Source: NAVIGATE ESUS Trial." Dr. Negar Asdaghi: 1) Can repeated concussions increase the risk of stroke in professional athletes? 2) Does stem cell therapy enhance the recovery from ischemic stroke? 3) ESUS stands for "embolic stroke of unknown source." Is ESUS just a fancy new term, or is there more to it than meets the eye? These are some of the topics that we will discuss in today's podcast. We're covering the best in Stroke. Stay with us. Dr. Negar Asdaghi: Welcome to a new year of Stroke podcasts. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The January 2022 issue of Stroke covers a host of topics, from molecular biomarkers and drug targets in brain arteriovenous malformation to examining the role of calcium in atherosclerotic carotid disease, which I encourage you to review in addition to listening to today's podcast. Later in the podcast, I have the honor of interviewing Dr. Mike Sharma from McMaster University in Hamilton, Ontario, on his work with embolic stroke of unknown source and some of the therapies to soon be studied in this population, including the new Factor XI inhibitors. But first with these two articles. Dr. Negar Asdaghi: Stem cells are truly the new kids on the block of therapies to potentially enhance stroke recovery. There's now four decades worth of experience with preclinical research and studies with animal models to evaluate the safety and efficacy of stem cell therapies and stroke. Now, this is a complex topic, and I will try to simplify it as much as possible. So, what are the things that we need to know about stem cell therapy and ischemic stroke? Well, first, in humans, the bone marrow has emerged as the widely used source of stem cells, primarily because of its long track record of safety profile. In fact, bone marrow derived cell populations, some examples being mesenchymal stem cells, mononuclear cells, endothelial progenitor cells, are the leading candidates for stem cell therapies in ischemic stroke. Number two, stem cells can be practically delivered to the brain through a variety of pathways. Intravenous and intra-arterial treatments have been and are currently being studied, but stem cells can also be delivered intranasally and, of course, surgically transplanted in the brain. Dr. Negar Asdaghi: So, with these in mind, there are two recently concluded clinical trials of mesenchymal stem cells in adult stroke patients. The STARTING-2 trial, which stands for the Stem Cell Application Researches and Trials in Neurology-2, was one of those two trials. This trial evaluated the safety and efficacy of intravenous autologous, meaning from the same individual, mesenchymal stem cells in patients with moderate to severe neurological deficit originating from the middle cerebral artery territory infarct within 90 days of symptom onset. The primary results of the trial was published in Neurology very recently in February of 2021, and if you missed it, well, luckily, you are listening to the podcast today. So, here's a quick recap of the trial. Fifty-four patients were enrolled in the trial with mean stroke onset to randomization of 20 days. Patients were randomized 2:1 to either receive intravenous mesenchymal stem cell treatment or placebo. Dr. Negar Asdaghi: Well, in terms of the primary outcome, stem cell therapy did not improve the primary outcome, which was improvement of modified Rankin Scale at 90 days after treatment. So, disappointing, but secondary analysis showed a significant improvement in lower extremity motor function in the stem cell group as compared to the control group. So, in the current issue of the journal, in the study titled "Efficacy of Intravenous Mesenchymal Stem Cells For Motor Recovery After Ischemic Stroke: A Neuroimaging Study," the STARTING-2 collaborators, led by Dr. Jungsoo Lee from the Department of Physical and Rehabilitation Medicine from Sungkyunkwan University School of Medicine in Seoul, South Korea, aimed to look at this improved motor recovery in more detail using advanced neuroimaging. So, of the original 54 patients in the trial, 44 were eligible for the current neuroimaging study. Participants underwent a variety of testings, including diffusion tensor imaging and resting-state functional MRI studies, at the time of enrollment and then 90 days afterwards. Dr. Negar Asdaghi: So, not surprisingly, at baseline, patients in both the stem cell and control group had comparable demographics, clinical characteristics and infarct volumes, as well as similar motor function, which was measured by the Fugl-Meyer, or the FMA, score. So here's a look at their main findings. So, number one, the FMA scores that were comparable at baseline were significantly higher at follow-up in the stem cell-treated group. Number two is the interesting results; they looked at the motor pathways using diffusion tensor imaging. So, they looked at fractional anisotropy values of the corticospinal pathways and the posterior limb of the internal capsule. Now, just a quick review of a somewhat complex concept of the fractional anisotropy for our listeners. In general, FA is one of the calculated parameters in DTI with a value between zero to one, and what it does is that it defines the degree of diffusion directionality. Dr. Negar Asdaghi: A value of zero means that the diffusion is isotropic, meaning it is unrestricted or equally restricted in all directions. A value of one means that diffusion occurs only along one axis and is fully restricted along all the other directions. So, it's easy to understand in terms of axons creating white matter tracts. When the tracts are intact, then the FA values would be high because the diffusion is occurring only in one direction as the tract is intending it to do so, whereas if the white matter tracts are damaged, then the uni-directionality of the tract would be disrupted and the molecules would diffuse freely in various directions and the FA values for that white matter tract is then, as expected, reduced. So, in the stroke model, for example, if a neuron in the motor cortex is damaged, the white matter tract related to that region will, over time, degenerate, a process which we know as Wallerian degeneration and, as such, the FA values of that tract is expected to decrease as we go from the acute to the chronic stages of stroke. Dr. Negar Asdaghi: So, back to the current study. At time zero, FA values for the corticospinal tract and the posterior limb of internal capsule were fairly similar between the two groups, but interestingly, at 90-day follow-up, those in the control group had a significant and expected drop in their FA values, whereas those who had received stem cell therapy did not show a significant drop, meaning that intravenous administration of mesenchymal stem cells did modulate and perhaps prevented degeneration of the motor tracts after stroke. The third and final interesting finding of the study was the findings of the resting-state functional MRI. They used RS, or resting-state, fMRI as a measure of functional motor connectivity and found that stem cell treatment increased the strength of ipsilesional connectivity in the motor network and prevented a drop in the strength of intrahemispheric connectivity, whereas these findings were not seen in the control group. Dr. Negar Asdaghi: So, what does this all mean? We now have some detailed neuroimaging evidence that indeed stem cell treatment can facilitate motor recovery possibly by reducing degeneration, which is what their DTI data showed, and potentially by leading to positive motor network organization or reorganization, which is what the resting-state fMRI findings showed. So, obviously, lots still to come in this topic and a reminder to our listeners that there are ongoing clinical trials on this topic. So, we will stay tuned as the neuroprotection and regeneration paradigm is truly changing for ischemic stroke with stem cell therapy. Dr. Negar Asdaghi: Sports-related concussive symptoms typically resolve within a few weeks of the injury, but there is now ample scientific evidence to suggest that repeated concussion can cause long-term neurological disorders extending way beyond the short-term post-concussive period. How can traumatic brain injury, or TBI, be a cause for stroke? Well, in the more severe forms of TBI, it can actually cause damage to the large vessels and cause dissection, but there is more and more research showing that even milder trauma can lead to microvascular disruptions and even alterations in coagulation pathway, which will then increase the risk of stroke. So, how about repeated mild trauma or repeated concussion in professional athletes? Is concussion a risk factor for stroke in this population? Dr. Negar Asdaghi: Well, in the current issue of the journal, in the study titled "Cumulative Concussion and Odds of Stroke in Former NFL Players," Dr. Benjamin Brett and Zachary Kerr from Department of Neurosurgery, Medical College of Wisconsin, and Department of Exercise and Sports Science, University of North Carolina at Chapel Hill, and colleagues report on a cross-sectional study that included professional football players who had at least played for one year in the National Football League and were over the age of 50 at the time of the study. Dr. Negar Asdaghi: Now, before we go over the results, there are a few important definitions from this study to note. Number one, concussion was defined as a blow to the head followed by a variety of neurological symptoms, such as headache, dizziness, loss of balance, etc. Getting knocked out or being unconscious was not necessary to define concussion. For our listeners, this is an important shift from the original definition of concussion that required some alteration of level of consciousness. Number two, the participants were asked as part of the study survey about a history of stroke, which was defined as any health provider giving the participant the diagnosis of stroke at some point in their life. So, there were no mandates of any neuroimaging or particular testings to confirm this diagnosis as part of the study. So, with these in mind, 979 participants met the study inclusion criteria and were included in the study. The mean age was 65 years ranging from 50 to 99, self-reported lifetime concussion history was recorded, and the participants were then divided into five categories of zero, meaning never had experienced concussion, to those with over 10 concussions. Dr. Negar Asdaghi: So, the first important finding was that over a quarter of their study population actually were in the over 10 concussions category. The second finding was the overall prevalence of stroke was 3.4% amongst the pro-NFL players, which was significantly lower than that expected from age-matched normative population, meaning the prevalence of stroke amongst U.S. men over age of 50. So, in simple words, being athletic is a good thing and not surprisingly is associated with a lower risk of vascular disease. But what they found was that NFL players with a history of 10 or more prior concussions had five times the odds of stroke as compared to those with no prior concussions in the adjusted models. So, what we learned from this study is that traumatic brain injury, specifically repeated TBI, however mild, seems to be an independent risk factor for stroke. Microvascular disruptions and potentially alterations in coagulation pathways have been proposed as potential mechanisms for this association. Dr. Negar Asdaghi: About a quarter of patients with ischemic stroke do not have a clear cause for the stroke and fall under the cryptogenic or unknown category. In 2014, an international panel of experts developed a criteria to define a group of patients with cryptogenic stroke that are likely to have an embolic, but yet undefined source for their ischemic event and called them ESUS, which stands for "embolic stroke of unknown source." These were operationally defined as non-lacunar brain infarcts without significant proximal arterial stenosis or known cardioembolic sources of infarct. Now, the idea behind the development of this new term, ESUS, was to identify a more homogenous subgroup of cryptogenic stroke patients that would perhaps benefit from preemptive anticoagulation therapy over the standard antiplatelet treatment for secondary prevention of stroke. Dr. Negar Asdaghi: Indeed, since 2014, ESUS has become a rather commonly used terminology in the stroke literature with multiple ongoing and a few already completed randomized trials examining the efficacy and safety of the newer oral anticoagulants in patients with ESUS over antiplatelet therapy. Similarly, much has been done to further study the clinical and radiographic characteristics of patients with ESUS. In this issue of the journal, in the study titled "Frequency and Patterns of Brain Infarction in Patients With Embolic Stroke of Undetermined Source," the NAVIGATE ESUS randomized control trial investigators set out to examine the radiographic characteristics and infarct patterns of ESUS patients enrolled in the NAVIGATE ESUS randomized trial. Dr. Negar Asdaghi: Joining me now is the first author of the paper, Dr. Mike Sharma, to discuss the findings of this paper. I always say that my guest needs no introduction, and today's guest is, of course, no exception to that. Dr. Sharma is well known to our Stroke readership. He is a stroke neurologist and a scientist at the Population Health Research Institute at McMaster University in Ontario, Canada. He is truly a leader in the field of clinical epidemiology in secondary stroke prevention with an interest in randomized trials, covert stroke, and economics of stroke care. He holds the Michael G. DeGroote Chair in Stroke Prevention and is the immediate past chair of the Canadian Stroke Consortium and also leads the Hamilton McMaster Stroke Program. Good morning, Mike. It's so good to connect with you after so many years. Thanks for being with us. Dr. Mike Sharma: Good morning, Negar. It's a pleasure to talk to you again, and thank you for that kind introduction. Dr. Negar Asdaghi: Well, thank you so much. Can you please start us off with a brief summary of what the NAVIGATE ESUS trial set out to do, and what were the main findings of the trial? Dr. Mike Sharma: So, in NAVIGATE, we really wanted to advance the care of patients with cryptogenic stroke. Cryptogenic has been a somewhat nebulous term for decades, and care really hasn't advanced beyond using aspirin. The problem with that term is, there is no agreed upon criteria to define cryptogenic stroke. Sometimes it means that the workup is incomplete, where there are multiple competing causes or indeed there is a disagreement as to what the cause is. So, in NAVIGATE, we took a different approach, which was to look for markers which would identify patients who had strokes which were embolic. Our feeling was that they might respond better to anticoagulation than antiplatelet therapy. So that was the main goal in NAVIGATE, was to use this construct of ESUS to test the hypothesis that anticoagulation will be more effective in preventing stroke recurrence than antiplatelet therapy. Dr. Negar Asdaghi: And what did the trial find? Dr. Mike…

Full show notes at the publisher

Our TOPPODCAST Picks

Follow Us

Stay Connected

Related Podcasts

Links

Stay Connected