Dr. Mayank Goyal and Dr. Saurav Das
Dr. Mayank Goyal, left, and Dr. Saurav Das

A conversation with Mayank Goyal, MD, PhD, Professor of Radiology and Clinical Neurosciences, University of Calgary.

Interviewed by Saurav Das, MD, Fellow in Vascular Neurology, Washington University School of Medicine, St. Louis.

They will be discussing the topical review “Challenging the Ischemic Core Concept in Acute Ischemic Stroke Imaging,” published in October 2020 issue of Stroke

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.

Dr. Das: The authors make strong arguments regarding the ambiguity associated with the term ischemic “core.” They propose it be replaced with the term “severely ischemic tissue with uncertain viability” (SIT-uv). Where will “penumbra,” tissue with Tmax > 6s on CT Perfusion scan, fall in this proposed lexicon?

Dr. Goyal: The reason for us to advise against using the word “core” is that current imaging techniques that are used in the acute stroke setting are just not able to accurately distinguish between severely ischemic yet viable tissue and irreversibly damaged tissue. We all agree that what we currently call “penumbra” on baseline imaging, i.e., tissue with Tmax > 6 sec. but largely preserved CBF, is viable. And, frankly, It is all about core. Knowing the penumbra is not critical to decision making. If the patient has significant symptoms and a small core, of course they are going to have a penumbra … you don’t need to see it or measure it. I do think that just like “core” measurement, the one of “penumbra” is also flawed (for the same reasons as described in the paper) but is not as critical for decision making. It becomes trickier when we start looking at what current perfusion softwares call “core,” for example, tissue with relative CBF <30%. As we have outlined in our manuscript, a single time blood flow measurement is not sufficient to reliably identify irreversible tissue damage. Numerous studies in cell cultures, animals, and humans have shown that brain tissue with relative cerebral blood flow far below 30% can survive, if the duration of ischemia is short. And there are, of course, all the additional issues as described in the paper: selective tissue loss; gray vs. white matter; other factors such as microangiopathic disease, diabetes, etc.

Dr. Das: How do you believe any discordance between the SIT-uv probabilities across different imaging modalities should be addressed, especially, in the absence of a gold standard to determine cell death within the SIT-uv? Will there ever be a gold standard, and what research may lead us there?

Dr. Goyal: This is certainly a central question in acute stroke imaging: What should be our gold standard? The honest answer is that we currently do not have one. Diffusion weighted imaging is often used as a reference standard, but DWI-reversal is a well-described phenomenon. One might think that pathologists would be able to examine the tissue and provide us with a definitive answer, but even they struggle with identifying tissue infarction since the transition from complete, central infarction to peripherally spared areas is gradual and non-linear rather than sharply demarcated, with interspersed areas of incomplete infarction between both extremes. Selective neuronal loss, i.e., death of single neurons with preserved glial cells and extracellular matrix, are other, complicating factors. In short, I do not expect us to have a reliable “gold standard” in the near future, but that does not mean we cannot work towards a better understanding of the pathophysiology of tissue infarction.

However, for an emergent situation like acute stroke, one does need to take a pragmatic viewpoint. The key issue is decision making: Should I go forward with therapy xx or yy, or not? If I say no, am I missing an opportunity to help this patient from an otherwise devastating disease? If I say yes, am I taking unnecessary risk? Am I spending valuable resources of what is clear to have a bad outcome? From that perspective, we need not have a “gold standard.” We just need to do better than what we are doing right now … and the first step is to acknowledge our current limitations on imaging.

Dr. Das: It is proposed in the paper that the consideration of eloquence, grey vs white matter involvement, selective neuronal loss, etc., in the SIT-uv might contribute to clinical outcomes. Using automated tissue characterization, we will achieve more granularity in defining these parameters in threshold-free probabilistic approaches. However, on the other hand, we are still using a gross six point modified Rankin scale to categorize clinical outcomes, which might not be an equally sensitive comparator. What are your thoughts?

Dr. Goyal: I completely agree with you. Clearly, the mRS scale is limited in its ability to capture more subtle functional deficits. mRS is also heavily weighted towards motor function, but nowadays, at least in Western countries, this becomes less of an issue, with modern technology allowing us to talk to our friends, family, and business partners via Zoom or Facetime without actually having to leave the house. The problem with outcome scales is that they have to go through a process of calibration, internal and external validation, and lastly, they have to be widely accepted and used. All these things are true for the mRS. Developing a new, more meaningful stroke outcome scale would definitely be desirable, but it is nothing that can be done overnight. It will require several years, and then there is still the question whether it will be accepted and adopted by the stroke community or not. For these reasons, I personally believe that we will keep up using mRS at least for the next several years.

But coming to the question that you are asking, I don’t think that in the near future mRS will be the limiting factor for making progress on the SIT-uv concept. There are several low-ASPECTS trials that are running currently. Irrespective of their outcomes, those datasets will provide an excellent opportunity to further validate the concepts. As you know, we are soon starting ESCAPE-NEXT (in follow-up to ESCAPE-NA1). It will be interesting in how the relatively biggish “cores” do with neuro-protection and fast reperfusion.

Dr. Das: Dr. Goyal, apart from replacing the erstwhile ischemic “core” with the term “SIT-uv” and being sensitive to the fact that all cells within the SIT-uv may not be already dead, what other practice recommendations do you have for stroke clinicians in light of this paper?

Dr. Goyal: What I would really like to recommend to all the physicians out there treating acute stroke patients is: Never forget that we are treating patients, not images. Look at the bigger picture, consider all the factors, including patient and family wishes. Keep in mind that our imaging techniques can only provide us with a rough estimate of tissue viability; do not over-rely on them. We need to understand that: (a) ischemic stroke due to LVO is a dismal disease; (b) we have a super-powerful treatment; (c) we have to recognize the limitations of our current imaging and continue to strive to make it better; and lastly, (d) please participate in trials to continue to move towards evidence-based (as opposed to opinion-based) medicine.

Dr. Das: Thanks again for your time, Dr. Goyal! It was a pleasure chatting with you.