Using MRIs to Detect Early Signs of Viral Infections in Multiple Sclerosis

Omar Al-Louzi, MD

This is a part 2 interview. Click here to view part 1.

Several studies from different fields of research support the pivotal role of the Epstein-Barr virus (EBV) in the development of multiple sclerosis (MS). Although with the large amount of evidence supporting the association of EBV and MS, there is still a gap in knowledge understanding of the mechanisms linking EBV to pathophysiology. Currently, there is ongoing research that aims to clarify whether EBV causes neuroinflammation via autoimmunity or antiviral immunity.¹ In addition, additional research is investigating if the interaction of EBV with genetic susceptibility to MS explains why the virus promotes immune dysfunction in susceptible patients.

In a recent interview with NeurologyLive®, Omar Al-Louzi, MD, an attendee from the annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, February 23-25, 2023, in San Diego, California, sat down at the forum to discuss the current use of imaging techniques incorporated in daily practice for monitoring infections in patients with MS. Al-Louzi, director of the Visual Outcomes Laboratory at Cedars Sinai, also talked about how clinicians can use imaging to learn more about how MS develops at the earliest stages. In addition, Al-Louzi shared his feelings about how clinicians manage progressive multifocal leukoencephalopathy (PML) and the areas that need improvement as well as how to combat those challenging areas.

NeurologyLive: What is the challenge that clinicians face in detecting PML lesions in the brain using imaging?

As far as imaging, it's one of the central ways that we can detect some of these reactivations of viral infections. Most commonly, we use it in PML, when a patient gets started on one of those treatments that has been linked to that reactivation occurring. Now, the challenge that most clinicians go through in daily practice is that sometimes the very early onset of PML lesions in the brain, this particular viral infection, can be hard to distinguish from MS lesions. Or it can occur in the vicinity of older lesions, causing this dilemma where we don't know if this new lesion is related to the virus itself. Is it related to MS activity? As the infection progressesmore, you will notice some features on the imaging that are very typical for this infection that was supposed to amass.

There are other tools that we use as clinicians, including certain blood tests, tests from the spinal fluid, that we can run to detect the presence of this virus or in the case of blood tests, previous exposure to this virus. But in many cases, those tests don't have the sensitivity to confirm the diagnosis. Even though they may return as negative, it may not necessarily exclude the presence of PML. Our hope is by introducing novel methods that MRIs can be analyzed on, we can get an early detection signal of the presence of this reactivation before symptoms develop. That’s the ideal target, if we could realize that someone is at risk for this virus or might be experiencing early signs of an infection, then oftentimes, altering their medications and their treatment plan is the first step to mitigating it. Because that will restore the effective immune response that can help fight the virus and get rid of it.

Can incorporating imaging surveillance following an EBV infection help patients in terms of their treatment and outcomes?

We've certainly seen a lot of research, including presentations here at ACTRIMS, that are doing a deep dive into this relationship between EBV and the onset of multiple sclerosis following that infection. We know based on these studies while a significant majority of the population gets exposed and infected with EBV, only a small proportion of those who get infected do go on to develop multiple sclerosis. There are certainly other factors at play here when it comes to the risk of developing MS following an EBV infection. I feel this is an ideal approach or an ideal way for us to incorporate imaging surveillance as part of telling who's at risk. Can we detect early signs of MS in those who might go on to develop MS following EBV infection?

It's also a tricky and challenging approach. Because when EBV symptoms are apparent, the most common clinical syndrome that happens is what we call infectious mononucleosis. That doesn't happen in the majority of people who get exposed to EBV . When it does, that's a very accurate marker of the infection occurring. We could foresee studies being designed where we could follow people who get the infection with routine MRIs to try and detect early signs of the development of MS or of those who tested positive for EBV serology, who might be at higher risk. Especially if there's genetic factors that could be linked to higher risk of autoimmunity or MS in specific, which we know exists. That will be an approach that I think is still being studied. We still need more information about how effective approaches could be. More importantly, if we use MRI in this particular context, does it result in an earlier diagnosis? Would it help the patient down the line in terms of how soon they're able to start treatment and modify their outcomes from an MS perspective?

Why is studying PML in patients with MS challenging, and what steps can be taken to address this challenge?

I think this is an area that is definitely evolving in our field, especially as we see a progressive increase in the number of medications that we use for MS and understanding which ones in particular have the highest risk of causing PML. The management depends on the underlying medication. More importantly, if the patient who develops PML has any other risk factors that put them at a position where their immune response might be suppressed outside of the medication that they're on or their particular MS treatment.

I would say that's the very first question that we as clinicians ask in this particular context. Oftentimes, if it's something that we feel is purely medication related, where there are no other known factors that could result in immune suppression, besides the medication itself, then, there are methods that we could not only stop the medication. But in the case of natalizumab, one of the infusion medications, we institute protocols to try to remove it from the body. We don't have any randomized clinical trials that actually assess the benefit of this particular procedure to try and do an accelerated removal; although, we oftentimes need to use it, particularly for people who received the infusions relatively recently, in terms of their onset of PML.

I do think there is this need for more studies, in particular clinical trials that delve into the aspect of what is the appropriate way to manage a PML infection once it's developed in a patient with MS related to medication. The good news is that in most cases, with early detection—which is really the key component here—we're oftentimes able to stop the infection or at least prevent any further neurological injury just with that alone, outside of any other risk factors for immune suppression. Based on the studies that we have about PML, comparing this infection in MS to other cohorts of patients, the outcomes tend to be relatively more favorable. The other aspect really is, which is a bit more challenging, is that PML is such a rare infection. This really limits our ability to study it within the context of big clinical trials of treatments. I think we need to pull the resources across multiple centers. That's going to be the next step, to hopefully establish registries and multicenter approaches that can leverage the power of collaboration between different centers across the country, if not the globe, to try and do the best for our patients as far as the treatment and management of PML.

In the second scenario, a patient with MS might have other immunosuppressive risk factors. Some of these include exposure to chemotherapy in the past, being on treatments that are not as readily reversible, and any other immunosuppressive conditions. If they have any history of underlying malignancies, or conditions for which their immune response might be suppressed, in addition to the MS, there are currently ongoing clinical trials that are being done to better understand whether instituting certain forms of immunotherapies could help patients who have conditions that do not allow them to reconstitute their immune response against the virus. But I would say the applicability in MS hasn't been studied yet. We're really looking forward to more data on that and how we can hopefully better manage PML and MS.

Transcript edited for clarity.

Click here for more coverage of ACTRIMS 2023.

REFERENCES
1. Aloisi F, Giovannoni G, Salvetti M. Epstein-Barr virus as a cause of multiple sclerosis: opportunities for prevention and therapy. Lancet Neurol. 2023;S1474-4422(22)00471-9. doi:10.1016/S1474-4422(22)00471-9