Central Vein Sign: Redefining MS Diagnostic Criteria

Daniel Ontaneda, MD, PhD

For part 1 of this interview, click here.

The high rates of misdiagnosis in multiple sclerosis (MS) are behind the National Institute of Health's (NIH) $7.2 million grant to Cleveland Clinic to investigate a relatively new biomarker, the central vein sign, and see whether it can improve the diagnostic criteria currently in place. High rates of misdiagnosis in MS come from a multitude of areas, including misreading MRIs and similarities between MS and non-MS lesions and presentations of other neurological disorders.

If successfully validated, the central vein sign could not only improve diagnostic accuracy in MS but do so in a more timely and efficient manner. Led by Daniel Ontaneda, MD, PhD, the goal of the CAVS-MS study is to validate the utility and validity of the biomarker over time, especially in those patients who do not have a typical presentation of MS or clinically isolated syndrome that fits the current diagnostic criteria.

NeurologyLive sat down with the neurologist at Cleveland Clinic’s Mellen Center for Multiple Sclerosis and co-principal of the CAVS-MS study to discuss the specific study end points and the long-term impact that the central vein sign could potentially have on the future of MS diagnosis.

NeurologyLive: What end points are you exploring to help measure the efficacy of this biomarker?

Daniel Ontaneda, MD: The study that we’ve proposed and got funded for is the validation of the central vein sign as a diagnostic biomarker in MS. There has been a lot of preparatory work that has gone into this, including research within our group and research from other groups which have shown the central vein to be sensitive and specific in cross-sectional studies.

We have noticed that in groups of patients with MS, there will be a central vein, but in those without MS, there is no central vein. I think what we were lacking was how well the central vein can work as a diagnostic biomarker when you follow patients over an extended time. The idea of the study is to take patients who were referred to MS clinics for a diagnosis of MS, apply the central vein and follow those patients over 24 months and determine who has developed MS. Some of those patients who come in will meet criteria and be diagnosed with MS immediately.

One of our study aims is to say, “How does the central vein compare with the traditional diagnostic criteria at that single presentation of those individuals who meet diagnostic criteria for MS?” The diagnostic criteria are informative for the group of patients who present with something we call a typical clinical event. These are people who have an episode of optic neuritis, or an episode of spinal cord myelination (otherwise known as partial myelitis). More specifically, these typical clinical events are called a CIS [clinically isolated syndrome] event.

That’s the track they used to get into the diagnostic criteria. As it is well known, the diagnosis of MS is based on dissemination of time and dissemination of space after 1 of these first clinical events. But, there’s a problem with the people who never present with a clinical event. These people that present with atypical symptoms that don’t meet the criteria for a typical event never get included into the diagnostic criteria. Many times, the patients who are misdiagnosed will be those with atypical presentations. They include people who don’t have a CIS, an optic neuritis, or who don’t have a partial transverse myelitis. Of the people who come to an MS clinic for a diagnosis, we calculate about 50% of them present with atypical events. A lot of those people won’t end up having MS, but what we want to demonstrate is, “is the central vein good at discriminating which of those people don’t actually have MS?” When we look at these people with atypical symptoms, we can do an MRI and see they have a couple of spots, but none of them have central vein, so they are not a patient to be worried about.

Finally, we’re going to look at patients with radiologically isolated syndrome. Those are patients who don’t present any symptoms, they just have an MRI that shows some spots on it and looks like MS. We know there are some things that help us determine which of those patients will develop MS. We think that the central vein sign as an additional marker may help refine the risk of what individuals have in getting a second attack. In general, what the study is trying to do is take a large body of evidence that was created in cross-sectional studies into a large multi-center prospective study that follows a total of 400 patients and validates the central vein as a diagnostic biomarker in MS. One of the ultimate goals is to actually get the central vein sign into the diagnostic criteria. Once again, we’re not trying to replace the diagnostic picture, we’re proposing that the central vein sign be used in addition to the currently available diagnostic criteria, and as an adjunct, to perhaps make neurologist’s lives a little easier.

If the central vein sign is indeed a useful biomarker for MS, what do you think is the potential impact on the diagnosis and management of the disease?

The central vein sign will accelerate the diagnosis in people who present with MS initially while also ensuring that the test will have a high specificity. In the individuals who could be interpreted as meeting the McDonald criteria based on MRI findings, there might be some patients in those groups who don’t end up having MS. Clinically, the implication is that we are not only going to make the diagnosis earlier but make fewer diagnostic errors with our patients.

Our ultimate goal is to take that 20% rate of misdiagnoses and reduce it drastically. By how much? We’re not sure of that yet. This test can be easy to use, can be done on essentially any scanner across the country, and can be interpreted by any neurologist looking at a screen.

Is there anything else for the clinical community to know about the study?

I would like to mention that the study is a collaborative effort being conducted under the auspices of the North American Imagine in MS Cooperative. They are a group of MRI centers and clinical centers across the US and Canada that have come together to make a research group. This is a group that is focused on advancing imaging biomarkers for MS. We got pilot funding for it and then we applied for this NIH grant. The NIH grant is a specific biomarker RFA. That is a mechanism that is specifically designed to take biomarkers and validate them in clinical practice. This fits perfectly with what we thought the central vein could be. It’s different in a sense because it’s a diagnostic biomarker, not a treatment biomarker.

It took several years of preparatory work to get where we are now. Some of the co-investigators have done seminal work and should be highlighted. The other co-principal of the study, Nancy Sicotte, MD, who’s at Cedar Sinai, is directing the project. Takeshi Shinhara, PhD, from the University of Pennsylvania, is our study statistician and will be the guy who will tell us if things worked or not. He’s brilliant, and has also been working on an automated detection, which is actually part of our grant. That will basically automate the results and a computer will spit out the answers for you. Finally, Andrew Solomon, MD, was the person who put the idea of misdiagnosis on the table for the whole MS community and has been an instrumental part of designing this study. Those are a few people, but obviously not everyone.

We are super excited, and the study will be across 12 different sites in the US and Canada. We’re going to be recruiting patients soon and hopefully we’ll get some answers to help the MS community and neurologists. This will hopefully help our clinical trials, make them cleaner, and have more reassurance that the patients will have MS. We think this is a benefit for the MS community as a whole.

Transcript edited for clarity.