Continuing Evolution of MOGAD Diagnosis, Remaining Questions in Antibody Titer Testing

WATCH TIME: 5 minutes

Over the last 2 decades, the understanding of inflammatory demyelinating disorders of the central nervous system has radically changed with the identification of specific autoantibody-associated conditions distinct from multiple sclerosis, namely aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein (MOG)-IgG-associated disease. In the most recently published diagnostic criteria of MOGAD, the identification of MOG-IgG was considered a core criterion, marking a major step in improving care and diagnosis rates.

That criterion, which was authored by Jeffrey Bennett, MD, PhD, and others, noted that MOGAD is typically associated with acute disseminated encephalomyelitis, optic neuritis, or transverse myelitis, and is less commonly associated with cerebral cortical encephalitis, brainstem presentations, or cerebellar presentations. In collaboration with the Siegel Rare Neuroimmune Association (SRNA), NeurologyLive^® gathered Bennett and autoimmune expert Benjamin Greenberg, MD, for a Roundtable Discussion highlighting the latest updates in the diagnosis, treatment, and research of MOGAD.

In episode 2, Greenberg, who serves as a pediatric neurologist at the University of Texas Southwestern Medical Center provided commentary on the changes in how MOGAD is diagnosed, the positives with established criteria, and the questions surrounding titers and timing of the testing. Bennett, currently a professor of neurology at the University of Colorado School of Medicine, mentioned the fluidity of the diagnostic criteria, the importance of timely testing and eliminating delays, as well as the potential impact of the upcoming McDonald criteria.

SRNA is also hosting the 2024 Rare Neuroimmune Disorders Symposium (RNDS) on October 18-20th. The RNDS was created to bring together individuals diagnosed with acute disseminated encephalomyelitis (ADEM), acute flaccid myelitis (AFM), MOG antibody disease (MOGAD), neuromyelitis optica spectrum disorder (NMOSD), optic neuritis (ON), and transverse myelitis (TM) and clinicians and researchers that focus on these disorders. Invite your patients who may benefit from attending either virtually or in person in Dallas, TX. Healthcare professionals are also welcome to join! Learn more here.

Transcript edited below for clarity.

Marco Meglio: My next question for you both—obviously, MOGAD is a relatively newer disorder. We're still learning a lot about MOGAD in relation to other similarly presenting disorders like MS and NMOSD, as you alluded to earlier. So, how will the diagnosis evolve, or not evolve, over the coming years? Can you discuss how we're going to diagnose MOGAD as we incorporate more technology, assays, imaging, and things like that?

Benjamin Greenberg, MD: I think it's important to note that there is now a published diagnostic criteria for anti-MOG-associated disorder. It really starts, as Jeff mentioned, with the clinical history and imaging, meaning you have a patient that fits a known phenotype associated with this antibody. Then, you do reliable testing, getting an appropriately high titer of the antibody to correlate with what you're seeing clinically and on the MRI. The gray area, I think, comes around the titers and timing of the testing.

What we’ll likely see in the next few years are more studies fleshing this out. The gray area includes, for instance, if you get back a titer of 1:40, how is that different from 1:100? In the right clinical scenario, we struggle with what to do with individuals who look like they have anti-MOG-associated disorder but either have a low titer or the testing wasn’t done acutely. By the time a person is tested, the event is in the past, and their results come back negative. You look back and think, "Geez, the event they had a year ago really looks and sounds like an anti-MOG event, but now their titers are negative." Could they have been positive and then reverted to negative? A lot of work is going to be done around these scenarios to give more guidance to clinicians.

In general, if you take the revised McDonald criteria for multiple sclerosis, the international diagnostic group for neuromyelitis optica, and the anti-MOG-associated diagnostic criteria, each of them references the others. They point out red flags and when testing should be done, or when to be wary of a diagnosis. I find that if you take all three together, they are consistent with each other and give clinicians good guidance on when to test and how to interpret a clinical scenario.

Jeffrey Bennett, MD, PhD: Ben brings up a great point. Our diagnostic criteria are very fluid, and they're becoming more specific and sensitive as we learn more about these disorders. We’re understanding how we, as clinicians, can sometimes fall through the cracks in mistaking one for the other. MOGAD holds an interesting status—it’s the only disorder among these that requires a serologic test for its diagnosis.

As Ben mentioned, the delay between testing and disease onset can affect the results of that assay. Treatment may also affect results, and our knowledge is still evolving. There may be groups of patients who essentially have MOGAD but don’t test positive for the antibody. We've known this from the beginning—some patients who were seropositive for MOG antibodies had an attack, then lost the antibody, yet still had another attack and remained antibody-negative. That tells us right there that some MOGAD patients may be negative for our antibody tests.

Going forward, we’re going to get more sophisticated in testing for MOGAD, as Ben said. We’ll need to understand how the assays are done and how they impact diagnostic sensitivity. We’re also going to appreciate clinical clues that might be more specific for one disease or another. You mentioned the revised McDonald criteria for MS, which will be previewed at an upcoming meeting at ECTRIMS this month. That’s going to incorporate new domains into MS diagnosis, new tests that aren’t necessarily specific for MS.

We’ll have to be careful as we move forward because NMOSD and MOGAD might overlap with these diagnostic criteria, and that could make it harder to make a clean diagnosis. So, assays will be critical, and we might even need different assays that look for non-antibody-dependent diagnostic abilities. Also, whether we get the antibodies from the spinal fluid or the serum may affect our ability to refine diagnoses moving forward.