American Heart Association

Migraine, PFO, and Ischemic Stroke – Is There a Relationship?

Sami Al Kasab, MD

West BH, Noureddin N, Mamzhi Y, Low CG, Coluzzi AC, Shih EJ, et al. Frequency of Patent Foramen Ovale and Migraine in Patients With Cryptogenic Stroke. Stroke. 2018

Recently, there has been increasing evidence of higher risk for stroke in patients with migraine, in particular with migraine with aura. Interestingly, patients with migraine with aura have higher rates of PFO with right to left shunt, bringing up the question: What’s the relationship between migraine with aura, PFO, and ischemic stroke?

In this study, West et al evaluate the prevalence of PFO with right to left shunt in patients with cryptogenic stroke and who had a history of migraine. This was a retrospective analysis of data on patients presenting to the UCLA comprehensive stroke center between January 2008 and November 2017. Stroke etiology was classified based on the ASCOD phenotyping. Patients’ charts were also reviewed to identify patients who carried a diagnosis of migraine. Patients with migraine auras for > 50% of the time were classified as migraine with frequent aura. A PFO with right to left shunt was identified by the presence of positive bubble contrast study with TTE, TEE, or TCD.

Article Commentary: “Dual Antiplatelet Therapy in Transient Ischemic Attack and Minor Stroke With Different Infarction Patterns”

Philip Chang, MD

Jing J, Meng X, Zhao X, Liu L, Wang A, Pan Y, et al. Dual Antiplatelet Therapy in Transient Ischemic Attack and Minor Stroke With Different Infarction Patterns: Subgroup Analysis of the CHANCE Randomized Clinical Trial. JAMA Neurol. 2018

In the setting of the new acute ischemic stroke guidelines this year, one of the new recommendations is a Class IIa, Level of Evidence B-R recommendation that treatment for 21 days with dual antiplatelet therapy (aspirin and clopidogrel) beginning within 24 hours for patients presenting with minor stroke can be beneficial for early secondary prevention for a period up to 90 days from symptom onset. This recommendation was based solely off the CHANCE trial. In the original CHANCE cohort, they found that DAPT reduced stroke recurrence by about 30%.

Interview: Authors of “Intra-Arterial Delivery of Cell Therapies for Stroke”

A conversation with Dr. Raphael Guzman, Professor of Neurosurgery and Neurosciences at University Hospital Basel; Dr. Miroslaw Janowski, Associate Professor of Radiology at the Johns Hopkins University School of Medicine; and Dr. Piotr Walczak, Associate Professor of Radiology at Johns Hopkins University.

Dr. Raphael Guzman, Dr. Miroslaw Janowski, Dr. Piotr Walczak

From left, Dr. Raphael Guzman, Dr. Miroslaw Janowski, and Dr. Piotr Walczak.

Interviewed by Dr. Kaustubh Limaye (@kaustubhslimaye), Assistant Professor of Neurology in the division of Cerebrovascular Diseases at the University of Iowa.

They will be discussing the paper “Intra-Arterial Delivery of Cell Therapies for Stroke,” published in the May issue of Stroke. The article is part of a Focused Update in Cerebrovascular Disease centered on stem cells and cell-based therapies.

Dr. Limaye: I read your review in Stroke that deals with intra-arterial cell therapy for stroke recovery with great interest and enthusiasm. Can you summarize the important points of your article for our readers?

Authors: The concept of using stem cells as a strategy for treatment of stroke is a few decades old. There were hundreds of animal studies, dozens of clinical trials, and we are still far from effective therapy. Perhaps it is time to take a step back and think whether something has to be changed with the approach to developing cell therapy for stroke. One problem is that we scientists and clinicians have been overly optimistic or even ignorant. The typical approach for research on stem cell-based therapies was: Let’s inject some cells into the brain lesion and hope for the best. The challenge was immense as the stem cells of choice after transplantation are required to find their way migrating to the target, survive, proliferate, appropriately differentiate and exert therapeutic effect. We see first-hand that such a simplistic approach was not constructive. While open label preclinical studies were optimistic, practically all rigorous clinical trials failed to demonstrate satisfactory therapeutic effects. This status quo has hurt the field of stem cell therapy for stroke as scientists, grant reviewers and funding agencies gradually lose enthusiasm and abandon the concept of brain regeneration after stroke with stem cells, stifling any further progress. It is urgent that we work towards reversing that trend, and our strategy is to shift from a “do all” approach to addressing very basic challenges in a systematic manner. After identifying promising and highly potent sources of stem cells, which is now largely accomplished, the next step is to develop methods for effective and safe delivery of stem cells to the site of brain injury.

In Search for a Potential Biomarker for Small Vessel Disease: Is Plasma Aβ Level the Answer?

Shashank Shekhar, MD, MS
@Artofstroke

van Leijsen EMC, Kuiperij HB, Kersten I, Bergkamp MI, van Uden IWM, Vanderstichele H, et al. Plasma Aβ (Amyloid-β) Levels and Severity and Progression of Small Vessel Disease. Stroke. 2018

Leukoaraiosis, along with microbleeds and lacunes, are one of the most commonly encountered findings after a brain imaging in patients with multiple vascular risk factors. These changes are a result of small vessel disease (SVD). White matter disease is considered as a potential imaging marker for the development of dementia. Apart from traditional risk factors, e.g., hypertension, diabetes, etc., Aβ (amyloid β) has been proposed as an additional contributor to SVD. To investigate the association of plasma Aβ levels with severity and progression of SVD, the authors studied 487 participants in a prospective cohort RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort).

Using MRI-based Techniques for Easier Recognition of Hemodynamic Failure in Chronic Cerebrovascular Steno-Occlusive Disease

Gurmeen Kaur, MBBS
@kaurgurmeen

Fierstra J, van Niftrik C, Warnock G, Wegener S, Piccirelli M, Pangalu A, et al. Staging Hemodynamic Failure With Blood Oxygen-Level–Dependent Functional Magnetic Resonance Imaging Cerebrovascular Reactivity: A Comparison Versus Gold Standard (15O-)H2O-Positron Emission Tomography. Stroke. 2018

A major challenge faced by vascular neurologists and neuro-radiologists is accurately identifying the subset of patients with chronic cerebrovascular steno-occlusive disease, predicting those that have a propensity to develop hemodynamic failure and, as a result, have an increased risk of stroke.

Over the past few years, with development of imaging technology, multiple CT and MRI-based techniques have been developed to assess the degree of hemodynamic failure. Cerebral blood flow measurement using 15O PET scan has been recognized as the gold standard. There is a baseline measurement followed by a second scan with acetazolamide (Diamox) challenge.

Author Interview: Dr. Sean Savitz, MD, on “Intravenous Cellular Therapies for Acute Ischemic Stroke”

Dr. Sean Savitz

Dr. Sean Savitz

A conversation with Sean Savitz, MD, Frank M. Yatsu M.D. Chair in Neurology, Institute for Stroke and Cerebrovascular Disease, The University of Texas Health Science Center at Houston, on stem cell therapies for acute ischemic stroke.

Interviewed by Mark R. Etherton, MD, PhD, Assistant in Neurology, Massachusetts General Hospital, Instructor, Harvard Medical School.

They will be discussing the paper “Intravenous Cellular Therapies for Acute Ischemic Stroke,” published in the May issue of Stroke. The article is part of a Focused Update in Cerebrovascular Disease centered on stem cells and cell-based therapies.

Dr. Etherton: The data from MASTERS-1, as well as the animal studies, suggests a promising, immunomodulatory role for MAPCs in ischemic stroke, as well as for cells derived from other tissue sources. Can you speak to the advantages/disadvantages of MAPCs over other cell types?

Dr. Savitz: There are several advantages that make MAPCs appealing. One is that they have been studied extensively in pre-clinical animal models and now quite a bit in clinical trials, which has resulted in a significant amount of safety data obtained from these rigorously designed trials. So, in designing a therapy for stroke, I am of the opinion that it is important to choose a therapy based around animal studies and solid testing in early stage trials. We are encouraged by the fact that the clinical studies suggest MAPCs are safe in humans, and we already see signals suggesting that, if given in the right time window, the cells are effective to improve outcomes. In this respect, there are few if any other cell types that have gone this far on the continuum from animal studies to an impending phase 3 trial.

Author Interview: Dr. Bruce Campbell, on the EXTEND-IA TNK trial

Dr. Bruce Campbell

Dr. Bruce Campbell

A conversation with Dr. Bruce Campbell, MBBS (Hons), BMedSc, PhD, FRACP, co-principal investigator of the EXTEND-IA TNK trial and Head of Stroke at Royal Melbourne Hospital, University of Melbourne, about EXTEND-IA TNK and its implications for stroke care.

Interviewed by Kaustubh Limaye, MD, an Assistant Professor in the Division of Cerebrovascular Diseases at the University of Iowa (@kaustubhslimaye).

They will be discussing the article “Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke,” published in The New England Journal of Medicine.

EXTEND-IA TNK randomized 202 ischemic patients with large vessel occlusion 1:1 between 0.25mg/kg tenecteplase and 0.9mg/kg alteplase prior to endovascular thrombectomy. The proportion of patients who had substantial (>50%) reperfusion or no retrievable thrombus on the initial angiographic assessment was approximately doubled in the tenecteplase group (22% vs. 10%), which met the non-inferiority threshold (p=0.002) and was indeed superior (p=0.03) to alteplase. Functional outcomes at day 90 were also significantly improved in the tenecteplase group in ordinal (shift) analysis of the modified Rankin Scale. Symptomatic intracerebral hemorrhage occurred in 1/101 patients in each group.

Dr. Limaye: First, accept my heartiest congratulations for the completion and success of the EXTEND-IA TNK trial. I think the results will benefit acute stroke patients with large vessel occlusion and open up more avenues in streamlining care of such patients. Would you like to share with our readers the timeline of this trial – from conceptualization to execution?

National Stroke Awareness Month: Interview with Dr. Jaroslaw Aronowski

Dr. Jaroslaw Aronowski

Dr. Jaroslaw Aronowski

A conversation with Dr. Jaroslaw Aronowski, Professor, University of Texas HSC at Houston, McGovern Medical School, Department of Neurology, Vice Chair for Research, Roy M. and Phyllis Gough Huffington Chair in Neurology, and 2017 recipient of the Thomas Willis Award for his work on acute cerebral ischemia, intracerebral hemorrhage, and neuroinflammation, in recognition of National Stroke Awareness Month.

Interviewed by Dr. Alexis N. Simpkins, Assistant Professor of Neurology, University of Florida School of Medicine.

They will be discussing Dr. Aronowski’s career path and research, including his advice to young researchers and clinicians working in the field of stroke.

Dr. Simpkins: What drew you to the field of stroke and research early in your career?

Dr. Aronowski: Since my childhood, I was fascinated by the brain and by the complexity involved in how it works. My first steps with neuroscience were to work on opioids and mechanisms associated with opioid dependence. On this topic, over 30 years ago, we demonstrated that there could be a cross talk between the immune system and CNS that drives opioid dependency. It was rather unorthodox to connect CNS with the immune system these days. Looking back, it was an amazing environment at the University of Texas in Houston that triggered my interest and curiosity about stroke. This is primarily because of Jim Grotta, who just started developing his Stroke Program at UT. Together, with Grotta, about 30 years ago, I started to build my journey and adventure with translational stroke. All this happened during exciting days when we (the stroke community) have just started to investigate ideas that rt-PA could be used to treat stroke. Another important stimulus for me was daily interactions with many bright stroke fellows who rotated in the basic research lab and who brought great amount of energy, curiosity and translational value to the animal research as a model to test novel treatments for stroke. Lewis Morgenstern (later faculty in the department) was particularly an important contributor to my future interest in the pathogenesis of ICH.

Author Interview: Dr. Lawrence Wechsler, MD

Dr. Lawrence Wechsler

Dr. Lawrence Wechsler

A conversation with Dr. Lawrence Wechsler, MD, Henry B. Higman Professor and Chair, Department of Neurology, University of Pittsburgh Medical School, about the role of cell therapy in chronic stroke.

Interviewed by Deepak Gulati, MD, Assistant Professor of Neurology, Ohio State University.

They will be discussing the paper “Cell Therapy for Chronic Stroke,” published in the May issue of Stroke. The article is part of a Focused Update in Cerebrovascular Disease centered on stem cells and cell-based therapies.

Dr. Gulati: Can you please summarize in simple words the mechanism of action of stem cell therapy in chronic stroke? Also, what are your thoughts on the modes of administration?

Dr. Wechsler: In chronic stroke, the most likely mechanism is paracrine release of growth factors and cytokines that act locally to promote functional recovery. These factors increase neurogenesis, synaptogenesis, angiogenesis and reduce inflammation. It is not known which of these processes is most important, and the pleomorphic effects of cell therapy make cell therapy an attractive approach in chronic stroke. Stereotactic implantation of cells in chronic stroke is most likely to be beneficial to assure delivery of cells to the area of injury in this late stage at a time when disruption of the BBB or homing signals are not operative to allow cells to reach the infarct area by other modes of delivery.

Author Interview: Dr. Zaal Kokaia, PhD

Dr. Zaal Kokaia

Dr. Zaal Kokaia

A conversation with Dr. Zaal Kokaia, PhD, Professor of Experimental Medical Research and the Head of the Laboratory of Stem Cells & Restorative Neurology at the Lund University Stem Cell Center in Sweden.

Interviewed by Gurmeen Kaur, MBBS, Vascular Neurology Fellow, Icahn School of Medicine at Mount Sinai.

They will be discussing the paper “Customized Brain Cells for Stroke Patients Using Pluripotent Stem Cells,” published in the May issue of Stroke. The article is part of a Focused Update in Cerebrovascular Disease centered on stem cells and cell-based therapies.