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.