NeuroVoices: Eoin P. Flanagan, MB, BCh, on the Potential Significance of Spinal Fluid Testing for MOGAD Diagnosis

In 2007, myelin oligodendrocyte glycoprotein antibody (MOG-IgG) became identified as a biomarker of central nervous system (CNS) demyelinating disease.¹ More than a decade later, in 2023, MOG-IgG-associated disease (MOGAD) was formally recognized as a separate disease, backed with international diagnostic criteria that differentiated it from multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), other demyelinating autoimmune disorders.² The condition is commonly associated with optic neuritis, acute disseminated encephalomyelitis, myelitis, cerebral monofocal or polyfocal deficits, brainstem or cerebellar deficits, cerebral cortical encephalitis, or combinations thereof.

Recent research shows that cell-based assays are optimal for the detection of MOG-IgG in serum, and that live cell-based assays may have an advantage over fixed assays.³ As of currently, MOG-IgG testing has primarily been observed in serum. Despite this, recent studies suggest that MOG-IgG in cerebrospinal fluid (CSF) may have diagnostic and prognostic utility for patients.⁴ In a newly published study in Annals of Neurology, findings revealed that CSF MOG-IgG testing had beneficial diagnostic utility in patients with a suspicious phenotype but negative serum MOG-IgG. This form of testing also revealed positive diagnostic utility in patients with low positive serum MOG-IgG results and diagnostic uncertainty.

Conducted by senior author Eoin P. Flanagan, MB, BCh, professor of neurology and chief of the Division of Multiple Sclerosis and Autoimmune Neurology at Mayo Clinic, and colleagues, these findings show the benefit of using CSF MOG-IgG testing in the clinical setting.⁵ In a new iteration of NeuroVoices, Flanagan, who also serves as the director of the Autoimmune Neurology Fellowship, recently sat down with NeurologyLive^® in an interview to further discuss the key criteria for diagnosing MOGAD. He also spoke about how the presence of MOG antibodies in spinal fluid may impact diagnosis and treatment. In addition, he talked about the challenges that exist in standardizing MOG antibody testing across different laboratories.

NeurologyLive: Can you provide an overview of the recently published research?

Eoin P. Flanagan, MB, BCh: MOGAD is a newly recognized demyelinating disease of the CNS. We know that there are other diseases like MS, but we also have NMOSD associated with aquaporin-4 antibodies. Now we have MOGAD as a third major category of diseases in the CNS inflammatory demyelinating diseases category. We know that this test was first developed for the MOG-antibody in blood to figure out if patients have the disease. Then you need to match it to their clinical and radiological syndrome. There were diagnostic criteria published in 2023 that identified MOGAD as a separate disease from other conditions.

In those criteria, if you have a serum positive MOG-antibody, and then if you meet certain clinical and radiological criteria, and you exclude other causes like MS, then you can meet the criteria for MOGAD. Also in the criteria, there was a section for spinal fluid, and if the antibody was positive in spinal fluid only, you would have to meet a slightly more stringent criteria for the diagnosis. If you either have a low positive in blood or spinal fluid, you need to meet some additional supporting features. With this recognition that MOG antibodies can be tested in the spinal fluid, we wanted to study amongst our cohort at the Mayo Clinic to see how the mock CSF performs and if it has any utility. The most important point, I suppose, would be if a patient was tested and was negative in the blood, could they be positive in the spinal fluid? And would you need to test that?

We looked at approximately 400 patients with a wide variety of different diseases, including MOGAD. What we found in this study was that most patients with MOGAD had positivity in both the blood and the spinal fluid; about, I think, 85% to 90% of patients who were positive in the blood were also positive in the spinal fluid. We found approximately, probably 5% to 10% or so of patients who were negative in the blood were positive in the spinal fluid only, and still had a syndrome compatible with MOGAD. That suggests that in patients where you're very, very suspicious, you should consider testing spinal fluid in addition to testing blood.

Now, I will say that the MOG-antibody we know is a little bit tricky. It's a little bit sticky. So sometimes patients with other conditions can have some low positive levels. We know that in serum, and we know that when you get a high positive result, it tends to be very reliable. But the low positives are a bit of a challenge, and you need to use your clinical and radiological features to help guide you towards the diagnosis. We find the same in spinal fluid that there are some cases that are positive, maybe 1 to 2% of cases that are positive, that have other conditions. You also have to be careful with the low positive levels but at a high positive level in blood or spinal fluid, it seems to be a very reliable test.

The other thing I can mention is that if you have a positive result in both blood and spinal fluid, it makes it more likely it's MOGAD while if you only have a positive result in serum, a low positive result on its own in serum, and it's negative in CSF, that makes it more likely it might be a false positive because we know we have some challenges with false positive results.

Based on the findings and their implications, what are the next steps in research?

I think a few things, I suppose. I think there are different assays around the world for MOG antibodies. We use something called a live cell-based assay where we use live cells and we add the spinal fluid or the blood to those to detect the antibody. There are other labs that will use something called a fixed cell-based assay where the cells are killed, and you assess for the cell binding with these inactivated cells. I think we need to see how those 2 techniques perform and how does the fix perform versus the live cell-based assay. That will require a multicenter assessment. I think we need to compare everybody's different technique because each lab is a little bit different, trying to standardize across labs and see if we can find consistent results across many centers. So, I think that's one part.

The other thing is to determine, well, why do people just have antibodies in the spinal fluid? And what does that mean? Does that mean that they have immune cells within the CSF compartment that are making antibodies that are not present in the blood and so forth? Or in the rest of the body? We need to better understand what's happening there and what the mechanisms are and what are the implications for treatment in those patients. Do we need to get treatments that will cross the blood-brain barrier and enter into the CSF to help treat those patients? I think there's still a lot to learn. We're in the early stages of the spinal fluid test. But I see the spinal fluid test as being fairly useful, but also requiring the caution that we have with the serum MOG, that we know there can be low positive false positives. We would be a little bit careful with those cases that are just above the cutoff at a low positive level.

Any other remarks you wanted to share based on MOGAD and the importance of raising awareness and research on this condition?

I think with MOGAD, we've really made a lot of strides in the last 5 to 10 years on identifying the disease, giving it its own identity, but we haven't yet found a proven treatment. Currently, there are clinical trials open for MOGAD. We're really trying hard to recruit patients into those trials because we know from our experience with NMOSD, where there are 5 available, 4 of which are FDA approved, 5 proven medications in that condition, yet we still have no proven medications in MOGAD. I think for neurologists out there, if you have a patient with relapsing MOGAD, it's really important to look out for clinical trial sites and try to enroll the patients in those clinical trials so that we can get a proven treatment for patients with MOGAD so that they can have availability in treatments like we have in MS and NMOSD but we don't yet have in MOGAD.

Transcript edited for clarity.Click here to view more NeuroVoices.

REFERENCES
1. O'Connor KC, McLaughlin KA, De Jager PL, et al. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med. 2007;13(2):211-217. doi:10.1038/nm1488
2. Banwell B, Bennett JL, Marignier R, et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neurol. 2023;22(3):268-282. doi:10.1016/S1474-4422(22)00431-8
3. 1. Waters PJ, Komorowski L, Woodhall M, et al. A multicenter comparison of MOG-IgG cell-based assays. Neurology. 2019;92(11):e1250-e1255. doi:10.1212/WNL.0000000000007096
4. Hacohen Y, Kerr W, Waters P. Intrathecal Production of MOG-IgG: Highlighting the Need for CSF Testing in Clinical Practice. Neurology. 2021;97(1):12-13. doi:10.1212/WNL.0000000000012177
5. Redenbaugh V, Fryer JP, Cacciaguerra L, et al. Diagnostic Utility of MOG Antibody Testing in Cerebrospinal Fluid. Ann Neurol. Published online April 9, 2024. doi:10.1002/ana.26931