Central Vein Sign as an Imaging Biomarker of Multiple Sclerosis

MedPage Today brought together three expert leaders for a virtual roundtable discussion on the joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the American Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS): Moderator Daniel Ontaneda, MD, PhD, from the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research, is joined by Enrique Alvarez, MD, PhD, from the University of Colorado Denver School of Medicine, and Gabrielle Macaron, MD, from the Université de Montréal in Quebec.

This second of four exclusive episodes explores the central vein sign (CVS) as an imaging biomarker of multiple sclerosis (MS) pathophysiology.

You can view other videos in this series here.

Following is a transcript of their remarks:

Ontaneda: I would like to move on to imaging biomarkers, which is my favorite topic. And there was some data that was presented at the ECTRIMS/ACTRIMS 2023 meeting that I think were particularly relevant — and they’re particularly relevant as we’re looking to the new MS diagnostic criteria. The new criteria will be discussed in Barcelona at the end of November, and I think a lot of the data that was presented at the meeting will be used at that meeting to help inform how we can incorporate certain imaging markers into the diagnostic criteria itself.

And so we can maybe start out with central vein sign. And the one study that I wanted to highlight was a poster presentation by Chris Allen from the University of Nottingham who works with Nikos Evangelou, and they have a study that they call DECISIve. It’s a fascinating study. Almost 200 patients were followed in this cohort — I think I’m not incorrect, a hundred and something — who had CIS required (they had a clinically isolated syndrome) and required CSF [cerebrospinal fluid] in order to meet dissemination in time, and so all these patients had to have spinal fluid. Patients were followed for over 18 months, and they all got central vein imaging at baseline.

And interesting, what that study found was that indeed the sensitivity of an abbreviated version of the central vein sign — that is calling out six lesions of the brain that have central vein — was actually a very sensitive marker. It was as sensitive as oligoclonal bands, and there was a large amount of agreement between CSF oligoclonal bands and the central vein sign.

And so this kind of speaks to the ability of the central vein sign to perhaps function even as a replacement as a CSF marker, such as oligoclonal bands. I mean, we know our dissemination in space criteria for the diagnosis of MS are already quite sensitive. And perhaps adding something more specific that can be done on the same scan that doesn’t require an invasive lumbar puncture are super interesting.

And then the second study that I would like to highlight was the CAVS-MS study work that we presented at the meeting. A total of 420 patients where we did central vein at baseline. We only followed these patients for 2 years, but we just looked cross-sectionally, and once again, we found really high sensitivity and specificity for diagnosis of MS, even in this early cohort.

And I think that’s what differentiates this study from many of the other studies that have been done in central vein, where a lot of the populations are slightly older and so you’re comparing the person who’s had MS for 20 years versus a person with migraine headache. And of course the differences there are going to be amplified. And in CAVS, which you participated in Enrique, we were taking patients who were presenting to RMS [relapsing multiple sclerosis] clinics. That is how we would use the test in clinical practice.

So relatively high sensitivity, close to 70%. And specificity is also high 70, 80% depending on the measure we used and the pre-post contrast. So all data that we’re going to use to hopefully incorporate into the diagnostic criteria.

So super-exciting, at least I’m excited about that. I’m not sure if you guys share my excitement or not.

Alvarez: No, I totally share that excitement. I think having been part of CAVS, and just saying that data, and I think just a little bit of experience with it, we’re starting to try and apply it in clinic. Some of these patients, and it’s like, hey, can we get a central vein before we do the spinal fluid analysis? Maybe in addition to it? But at least for now, just to kind of try and understand the marker better. But for some questionable cases, it kind of helps us sway in one direction or the other. So I share that excitement.

Macaron: Do you think…

Ontaneda: Yeah, go ahead, Gabrielle.

Macaron: …I was going to ask, do you think that this marker is going to make it to the next diagnostic criteria? That’s the burning question.

Ontaneda: Yeah, I guess that’s the burning question. I mean, I think that there’s sufficient data that demonstrates that the CVS is a both sensitive and specific diagnostic biomarker that can be applied easily with current MRI technology. So I think it has a place in the diagnostic criteria. That’s something that we’re going to have to defend that position. And I think the more complicated issue is where exactly would you put it in the diagnostic criteria?

But there was a couple presentations specifically by Xavier Montalban at this meeting, where it was kind of in a presentation, was thinking about should we rethink how we make a diagnosis of MS? So these old monikers of DIS [dissemination in space] and DIT [dissemination in time], although present and are helpful, the question is with such sensitive and specific tests, do we really need those anymore?

And one can imagine a series of criteria that one has based on what a presentation of MS would look like. You add in a brain MRI that’s compatible with MS, and then you add on any of a number of tests that can add specificity — oligoclonal bands, central vein sign, paramagnetic rim lesions, maybe a neurofilament level, maybe … volume threshold, something like that. And I was looking at the criteria for SLE [systemic lupus erythematosus], and sometimes it’s good to take ideas from other conditions. And the criteria for SLE are basically the number of classification of clinical themes plus a number of biomarkers. And if you meet either or of those two, you have a diagnosis. Or if you have lupus nephritis, which is kind of weird. So there’s … with all the diagnosis. Enrique is probably a little bit familiar with this because I know that your wife is an expert rheumatologist, so she probably gripes with that all the time.

Alvarez: Yeah, I mean, I think the specificity sometimes that we require, the bar that we sometimes have, and I’m not sure that sometimes it’s even there, outside of neuroimmunology, in other areas of neurology. But I guess we like to be very data-driven, maybe to a fault, because part of the part that to me doesn’t make sense is how the optic nerve still hasn’t made the criteria. It’s surprising to me.

We do this all the time in clinical practice. If somebody comes in with an optic neuritis, they’ve got positive bands and they have 10 periventricular lesions with Dawson finger morphology and everything else like this, you can’t tell me that that person doesn’t meet criteria for MS. It’s like, come on. That’s MS. And you’re going to treat them as an MS patient. And even RIS [radiologically isolated syndrome] to some extent, when we think about RIS, we’re usually thinking…Xavier also had a beautiful slide in one of his presentations with, I don’t know, it seemed like 20 different categories of RIS and all the different steps that you can kind of meet on the way to do this.

And the criteria to even make it into the RIS trials is like, that’s MS. At that point, that’s not even RIS, right? It’s the idea of pushing it earlier, because the patients that we tend to see in practice — where we like to apply this more — is the patient who has maybe less, fewer lesions, that has maybe some bands and maybe a couple of the lesions have central vein sign. And then you try to apply it in that situation.

So I get the idea of trying to get all this data. I feel like we’re sometimes one generation behind in our diagnostic criteria, and I think for optic nerve probably like four generations behind as far as including it. That’s just a personal opinion.

Ontaneda: Yeah, I mean, this came up a little bit when we were thinking about central vein and one of the potential ways that you could include central vein and say, well, you could use it to substitute for a requirement for dissemination in time. And I think there’s going to be some pushback. These people are going to say, well, you don’t have the data, you don’t have the longitudinal data.

But the reality is that the time where we could do these CIS studies where we followed CIS patients for 20 years to demonstrate that our biomarker baseline predicted development of an MS attack over time, is kind of gone. I mean, we’re treating all our CIS patients. A lot of our CIS patients are already meeting criteria. So even generating the data that is asked sometimes is somewhat difficult.

So I think I agree with Enrique; we have to be a little bit more pragmatic in how we think about the criteria and making a diagnosis of MS early. But at the same time, with very specific markers.

Alvarez: Where it could be really helpful is the patient that comes in with two periventricular lesions or three, so that meets the rule of threes. So let’s pick three lesions periventricular, all with a central vein sign, right? That to me, there’s not a lot of other things that are going to do that besides MS that don’t meet current criteria. And so where the central vein would be able to give you a little bit more of the dissemination in space at least, and it could be helpful.

I think the other part where it’s a useful biomarker is at the backend. So as we start to treat older patients, and it’s not uncommon to see that 60-year-old, 55-year-old who has been on high-efficacy therapy or has been stable for 10 years and all of a sudden their report comes back with one new lesion, subcortical, this and that, and you’re kind of like, is that MS? Is it not MS lesion? And some of these other things. And for those types of scans, we’re hoping to try and be able to add the central vein sign as well, just so that we could evaluate whether that makes it a little bit more likely, maybe that that lesion is an MS lesion, and not just a little subcortical stroke or a non-specific lesion of some other sort. So I think it’s going to have a lot of different uses and how we use it will be very interesting to see how it develops.

Ontaneda: Definitely. Definitely. So always, whenever we talk about the diagnostic criteria, it always brings up a lot of opinions, a lot of passion. So we could talk about that for a whole hour.

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