Central Vein Sign: A Biomarker to Alleviate MS Misdiagnosis

July 5, 2020

In part 1 of this interview, Daniel Ontaneda, MD, PhD, the co-principal of the CAVS-MS study, outlines the reasons for why the central vein sign can lower rates of misdiagnosing multiple sclerosis.

Daniel Ontaneda, MD, PhD

Utilizing magnetic resonance imaging (MRI) has been the standard method of locating multiple sclerosis (MS) lesions as a diagnostic tool for MS. While the imaging process has served its purpose over the years, recent additions to the literature suggest that nearly 20% of MS diagnoses are incorrect, leaving speculation and doubt over how precise the process is.

The staggering numbers led the National Institute of Health (NIH) to award Cleveland Clinic a $7.2M grant for the CAVS-MS study. Headed by Daniel Ontaneda, MD, PhD, the study will evaluate whether central vein sign can be an additional and safe biomarker that will ultimately help improve the rates of misdiagnosis.

Ontaneda, a neurologist at Cleveland Clinic’s Mellen Center for Multiple Sclerosis, and co-principal of the CAVS-MS study, sat down with NeurologyLive to discuss the clinical scenarios that contribute to misdiagnosis of MS, as well as the reasons for why central vein sign can be an easy add to diagnostic care.

NeurologyLive: What are some of the clinical scenarios that contribute to misdiagnosis of MS? Are there any apparent trends or similarities between cases that are misdiagnosed?

Daniel Ontaneda, MD: The problem of misdiagnosis that’s been identified recently has been our push to develop the diagnosis of MS and the tools that can make the diagnosis earlier and earlier. We’ve recognized the importance of early treatment in MS and the corollary of that is making sure we diagnose patients early. If you look at the evolution of the diagnostic criteria, they’re evolved from purely clinical criteria to criteria that incorporated cerebrospinal fluid (CSF) and MRI biomarkers. The overall trend has been that it’s easy to make diagnosis while also making the diagnosis early on. With each iteration of the diagnostic criteria, we’ve seen that with the diagnosis can be made with more use of the diagnostic biomarkers. One of the problems that we’ve identified has been that although MRI is a very useful tool, it’s a very sensitive tool for the diagnosis of MS. Perhaps there is some room to increase the specificity of the diagnostic area. As for the specific populations of those who are being misdiagnosed, there is definitely a bit of variety. A lot of this work was done by one of our co-investigators, Andrew Solomon, MD, who really put this on the map for the first time several years ago with a couple of seminal papers.

Essentially, what he found is that misdiagnosis was frequent, occurring in about 20% of patients. The majority of those cases of misdiagnosis were from misinterpretations of the MRI. This can happen in a few different scenarios. There are conditions that also produce spots in the brain that can be misdiagnosed as MS. Those include people with vascular risk factors. Additionally, those are individuals who are typically older, have a higher degree of hypertension, high cholesterol, diabetes, or who smoke. Those individuals tend to have more lesions and therefore can satisfy the MS diagnostic criteria when in reality they might not have MS lesions. There are other patients who have disorders that are associated with lesions or spots in the brain that aren’t MS lesions, with the most typical example being people with migraine headaches. That’s where you see this misinterpretation. The third category of patients who have a lot of neurological symptoms and perhaps may have non-specific brain changes. If a non-MS-trained neurologist is interpreting the patient with neurological symptoms that sometimes might fall along the spectrum of fibromyalgia and who also have some non-specific brain changes, there leaves that room that they might be inaccurately diagnosed with MS and have diagnostic criteria applied based on MRI changes that are nonspecific.

What about the central vein sign makes it a promising biomarker in MS, especially compared to other biomarkers currently being studied, like neurofilament light chain?

The advantage of the central vein is that it’s actually getting down to the pathology of MS. When you look at an MS lesion under the microscope, you can see that those MS lesions are typically centered around veins. We know that this is a pathological hallmark of the disease. We know that when we look at pathology, we can confirm that. What we’ve been searching for is a method to detect that using imaging and the central vein has emerged. It is promising for 2 reasons. First, it’s specific for MS and so we know if a lesion has a central vein, it’s likely that the lesion is an MS lesion increases significantly. The second is that we can implement this MRI algorithm quite easily into clinical practice. That is, we are already using MRI to make a diagnosis of MS, so adding a sequence that might be sensitive to central veins is a relatively easy addition that might make the diagnosis easier, as well as accelerate the diagnosis at the same time. I would also highlight the fact that the diagnostic criteria are somewhat complicated. You have to meet different criteria, whether that be clinical, MRI, or CSF. This requires a high level of expertise.

One thing about the central vein that’s interesting is that perhaps it can do away with some of that complication. It’s an easy kind of single readout test that has potential use. Just to clarify, we don’t intend the central vein to replace the diagnostic criteria, we intend the central vein to be used in conjunction with the diagnostic criteria. In that sense, it’s an easy biomarker to use and is something that you can reliably count 6 or 3 lesions while using MRI as well. Neurofilament light chain (NfL) on the other hand, contrasts central vein. There’s been a lot of work done with NfL as a treatment biomarker, but we know the specificity with MS is low. We know that NfL levels can perhaps increase with injury to the peripheral nervous system and increase injury in the nervous system outside of MS. That’s why central vein is quite attractive because it’s very specific to MS. We think its uncommon for other conditions to have lesions develop around veins. Its attractive because its pathologically sensitive, it’s easy to use, and its already a modality that neurologists and neuroradiologists are used to using every day. On top of all that, it comes with no additional risk to the patient.

Transcript edited for clarity.