An interview with Prof. Marc Ribo, MD, PhD, Assistant Professor at the Stroke Unit/Department of Neurology at the Hospital Vall d’Hebron, Barcelona, Spain.
Interviewed by Dr. Vera Sharashidze, MD, Vascular Neurology Fellow, University of Miami.
Dr. Sharashidze: First of all, thank you for taking time to discuss this very interesting article. What led you to become interested in this topic?
Prof. Ribo: My first interest in AI analysis of acute stroke imaging began when I met by coincidence with an expert engineer who wanted to use his skills to help stroke patients.
Dr. Das:Dr. Goyal, the Blogging Stroke team is happy to have you for an author interview today. Thanks for this provocative paper, which disrupts several currently accepted ideas that guide decision-making in stroke patients to make way for new innovation.
Let’s start by discussing the context in which this paper was conceptualized. The paper has a line-up of great authors, many considered visionaries in vascular neurology, across countries. Please tell us more about how this collaboration came into being.
Dr. Goyal: I have been thinking about the problem of defining ischemic core on baseline imaging for a long time. I noticed patients with a really bad-looking baseline CT, patients in which you would be inclined to call the whole MCA territory “core.” But when these patients went on to endovascular treatment and we managed to re-open the occluded vessel quickly, many of those did well, and their follow-up MRI scans showed that much of the parenchyma thought to be “core” was not actually damaged. More importantly, many of these patients did well clinically, resulting in a clinical-imaging mismatch. In addition, I was quite convinced that the so called “core” on CT perfusion was quite an exaggeration of the truth. In some ways, when many of the trials were being designed, they came in the aftermath of the Interventional Management of Stroke (IMS) 3 trial, and hence, people were over-conservative in their selection criteria. I then started talking to several of my collaborators and friends from all over the world, to see whether they felt the same way. This is when this collaboration was formed.
Sex differences might play a role in TIA/stroke diagnosis. Men and women could have variable TIA/stroke symptom characteristics. Women especially have been reported to have non-specific and atypical symptoms, which can result in a wrong diagnosis or no diagnosis. However, stroke in women tends to have a more severe and complicated course. The recent study by Gocan et al., published in Stroke, attempts to determine the relationship between clinical variables associated with a neurologist’s final diagnosis of TIA/stroke and the patient’s sex difference.
The authors conducted a retrospective analysis of the patient cohort from the Ottawa Hospital Stroke prevention clinic in 2015. The study identified 23 character variables for TIA/stroke diagnosis. Out of that, 15 variables were used, and the remaining eight were excluded due to the low frequency of occurrences.
The optimum imaging to evaluate patients presenting with acute ischemic stroke and determine suitability for endovascular thrombectomy (EVT) remains contentious. Non-contrast CT brain (NCCT) is universal, and CT angiogram (CTA) is necessary if EVT is planned. The added value of CT perfusion (CTP) is the subject of ongoing research and debate.
Lopez-Rivera et al. conducted a retrospective analysis of data collected in a study of implementation of EVT in the Houston area. They compared data from one center where CTP was carried out in all patients without contraindications (CTP-H – high usage) and three centers where CTP was carried out optionally at the discretion of the clinical team (CTP-L – low usage). Baseline populations differed significantly with CTP-H sites having higher proportions of patients with history of AF (24% vs 16%), diabetes (34% vs 21%), hypertension (77% vs 49%), hyperlipidaemia (45% vs 23%) and higher median NIHSS (14 vs 11), but better baseline modified Rankin scale (mRS) score (78% mRS 0-2 vs 66%). CTP-H sites also had proportionately fewer direct presentations but more early time window (0-6 hours) presentations and more patients treated with IV thrombolysis. The proportion of patients undergoing EVT in both CTP-H and CTP-L centers showed no significant difference, including amongst patients who had undergone CTP (47% vs 51%) and those who had not (41% vs 49%); those with large (>50ml) predicted ischemic core (53% vs 37%); and those with ASPECTS score <6 (32% vs 23%).
This article aimed to report observations of emergent large vessel occlusion (ELVO) ischemic strokes during the time of COVID-19 in one of the most affected cities in the United States, New York City. The association of strokes, prevalence and mechanisms are important to be investigated at this time as it is known that the virus invades cells and adheres to angiotensin converting enzyme 2 receptors that are distributed throughout the body, including the endothelium.
The timeline of this retrospective observational study is important as they highlight the 3-week period (March 21 to April 12, 2020) when hospitalizations and deaths due to COVID-19 were at their peak. Interestingly, in their exploratory analysis, the authors compared the study population with ELVO patients from March 20, 2020 backward to even include the entire year of 2019 (pre-pandemic). This is one of the most important strengths of this observational study, as it explores the potential cause-effect associations between COVID-19 and ELVO.
We saw a 59-year-old patient with diabetes, hypertension, hyperlipidemia, coronary artery disease with multiple bypass surgeries but no known history of atrial fibrillation (AFib), and extensive smoking history in office. The patient was admitted to the ICU with recurrent episodes of hemorrhagic shock from gastro-intestinal bleeds requiring embolization of gastric artery and subsequently exploratory laparotomy within a 1-month period. He developed wedge-shaped strokes involving bilateral middle cerebral artery territories during one of these hospitalizations. Subsequently, stroke work-up revealed mild atherosclerosis in the head and neck vessels, and a transthoracic echocardiogram showed a significant large patent foramen ovale (PFO) with right to left shunt without any evidence of straddling thrombus, atrial septal aneurysm, or left atrial enlargement. He was found to have deep vein thrombosis in bilateral lower extremities and had an inferior vena cava filter placed. The question then arises how strongly we attribute the strokes to PFO and if this patient will benefit from PFO closure. In this context, I read the recent update on nomenclature and classification of PFO-associated strokes published in JAMA Neurology by the PFO-Associated Stroke International Working Group, and I will discuss the salient points in this blog post.
Angiogenesis and neurogenesis are crucial processes for brain recovery after stroke. While the brain has the capacity to form new cerebral blood vessels and to generate new neurons from neural stem cells after stroke, these self-repair mechanisms are limited. Therefore, strategies to promote brain restorative processes beyond the endogenous recovery are highly desirable. In this study, Chan and colleagues demonstrated that an exogenously applied heparan sulfate with increased affinity for vascular endothelial growth factor was able to enhance angiogenesis and neurogenesis within the peri-infarct regions, as well as to promote neurological recovery after experimental stroke.
The team first purified heparan sulfate variant 7, a glycosaminoglycan sugar which has increased affinity for vascular endothelial growth factor, and tagged the molecule with fluorescent dye. The team experimentally induced stroke in rats using transient middle cerebral artery occlusion, and then they delivered heparan sulfate (or placebo) into the right lateral ventricle of the brain at day 4 after experimental stroke. The rats were assessed for neurological deficits, and rats treated with heparan sulfate showed a modest improvement in the modified neurological score 7 days after treatment (heparan sulfate vs placebo; 7.3±0.4 vs 8.8±0.5). Furthermore, the team tracked the distribution of the fluorescent tagged heparan sulfate and found the signals co-localized with endothelial cells (Collagen IV) and in neural stem cells (Nestin) within the peri-infarct regions. Histology analysis showed that heparan sulfate treatment enhances angiogenesis and neurogenesis (by approximately 3 to 7 folds) within the peri-infarct regions, without compromising the blood brain barrier integrity. The team also performed a series of cell culture studies and demonstrated that the heparan sulfate most likely stimulates vascular endothelial growth factor signaling.
Time is one of the most important elements when it comes to determining the efficacy of mechanical thrombectomy (MT) in acute stroke. The usual pathway across specialized stroke centers for initial evaluation of patients with suspected stroke includes a stop for neuroimaging like a multimodal-CT after the first clinical examination and before treatment. On the other hand, stroke imaging could be acquired directly in the angio-suite via flat-panel CT. There are some articles which defend this method as a faster and better way in terms of outcome to proceed with MT. However, this was not the subject of a clinical trial until now.
This was a prospective, single-center, parallel-group, open-label investigator initiated randomized trial in which the authors compare workflow metrics according to a CT-transit (CTT) pathway versus a direct transfer to the angio-suite (DTAS) pathway before MT. Both pathways include a non-contrast CT and a CT-angiography, plus a perfusion-CT (CTT) or a parenchymal blood volume imaging (DTAS) when presenting after 4.5 hours of symptom onset. The primary outcome of the study was time from stroke imaging to groin puncture. Other workflow metrics like admission to imaging or imaging to reperfusion time were also assessed, as well as final reperfusion and clinical outcome. The study included patients with an acute stroke secondary to a large vessel occlusion of the carotid territory with a National Institutes of Health Stroke Scale >7 and modified Rankin Scale 0-3 which undergo MT after a complete evaluation. In addition, intravenous thrombolysis (IVT) was performed if treatment criteria were fulfilled. Patients which required intubation between neuroimaging and groin puncture were excluded in order to minimize the mode of sedation bias. Wake-up strokes were also excluded because MRI was the preferred imaging method.
While the optimal timing of initiating or resuming anticoagulation in patients with acute strokes is said to be generally within 3-14 days, a treating neurologist may pause to consider the impact of recent IV thrombolysis or mechanical revascularization. Pharmacological thrombolysis carries an increased risk of brain hemorrhage, and reperfusion injury is a concern in the latter group of patients. At the same time, these potential adverse events must be weighed against the risk of recurrent thromboembolic events while anticoagulation is being held.
To address this issue, Giustozzi et al. set out to examine the incidence of both ischemic and hemorrhagic events in patients receiving anticoagulation following reperfusion therapies, as compared to untreated patients. The authors tapped into the RAF and RAF-NOAC datasets, which are prospective observational studies of patients receiving anticoagulation following stroke due to non-valvular atrial fibrillation. Primary outcome was the composite of any ischemic strokes and symptomatic intracranial hemorrhages, as well as other systemic embolism and bleeding events at 90 days. Furthermore, the authors conducted a multivariate logistic regression models to identify independent predictors of increased risk for the primary outcomes.
In 2014, when the concept of embolic stroke of undetermined source (ESUS) was proposed,1 confidence existed that ESUS could represent a single entity which would have benefitted from a unified treatment. However, after two randomized clinical trials did not show benefit of direct oral anticoagulation for secondary prevention of ESUS patients,2,3 it is now common opinion that these patients rather represent a heterogeneous population and are likely to benefit from tailored, personalized therapies. Today, ESUS represents a useful definition to identify patients deserving extended diagnostic workup, while prevention therapy for these patients remains elusive, and clinical stroke recurrence is still an issue. Both subgroup analyses from the above-mentioned clinical trials and new research studies have been developed or are ongoing, to better understand the pathophysiology of ESUS and help in patient selection.
In such a phenotypically heterogeneous population, one big effort is to identify patient subsets with a single or group of underlying mechanisms likely to respond to an established treatment. With this right purpose of uncover the “hidden structure” in a complex scenario, the recent study from Kamel et al.4 employs a machine learning approach. Firstly, a supervised machine-learning algorithm was developed to distinguish cardioembolic versus non-cardioembolic strokes in a population of 1083 patients with known stroke etiology, by entering data about demographics, comorbidities, vitals, laboratory results, and echocardiograms. After the learning process, the system finally resulted to distinguish cardioembolic from non-cardioembolic strokes with excellent accuracy (area under the curve, AUC=0.85).
As of October 25, @StrokeAHA_ASA is asking that authors hold new Letters to the Editor until January 2021, when a new system for letters will be implemented. See https://t.co/Q75Mq9M1EV for more information.
Starting Monday, October 25, we ask that authors hold new Letters to the Editor until January 2021, when a new system for letters will be implemented. See https://t.co/Q75Mq9M1EV for more information.
Mohammad Anadani, MD*
Elizabeth M. Aradine, DO
Rohan Arora, MD
Bahar M. Beaver, MD*
Anusha Boyanpally, MD
Alan C. Cameron, MB ChB, BSc (Hons), MRCP*
Pamela Cheng, DO
Kat Dakay, DO*
Danielle de Sa Boasquevisque, MD*
Reyes de Torres Chacon, MD
Victor J. Del Brutto, MD*
Rachel Forman, MD
Alejandro Fuerte, MD*
Parneet Grewal, MD
Deepak Gulati, MD*
Jennifer Harris, MD
Mausaminben Hathidara, MD
Kathryn S. Hayward, PhD, PT
Yan Hou, MD, PhD
Muhammad Rizwan Husain, MD
Richard Jackson, MD*
Wayneho Kam, MD
Gurmeen Kaur, MBBS*
Muhammad Taimoor Khan, MD
Abbas Kharal, MD, MPH*
Grace Y. Kuo, MD, MS, BA
Stephanie Lyden, MD, BS
Piyush Ojha, MBBS, MD, DM
Adeola Olowu, MD
Lin Kooi Ong, PhD*
Raffaele Ornello, MD*
Matthew Maximillian Padrick, MD, BA
Lina Palaiodimou, MD*
Robert W. Regenhardt, MD, PhD*
Shashank Shekhar, MD, MS*
Kristina Shkirkova, BSc
Ravinder-Jeet Singh, MBBS, DM*
Burton J. Tabaac, MD*
Melissa Trotman-Lucas, PhD
Tamaya Van Criekinge, PT
Elena Zapata-Arriaza, MD, PhD*
Charlotte Zerna, MD, MSc
*Senior Blogger
