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Eoin P. Flanagan, MB, BCh, on the potential significance of spinal fluid testing for MOGAD diagnosis

Eoin P. Flanagan, MB, BCh

Credit: Mayo Clinic

In 2007, myelin-oligendrocyte glycoprotein antibody (MOG-IgG) was identified as a biomarker for demyelinating disease of the central nervous system (CNS).1 More than a decade later, in 2023, MOG-IgG-associated disease (MOGAD) was formally recognized as a separate disease, supported by international diagnostic criteria that distinguish the disease from multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), other diseases. demyelinating autoimmune diseases.2 The condition is commonly associated with optic neuritis, acute disseminated encephalomyelitis, myelitis, cerebral monofocal or polyfocal disorders, brainstem or cerebellar disorders, 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 Currently, MOG-IgG tests are mainly observed in serum. Nevertheless, recent studies suggest that MOG-IgG in cerebrospinal fluid (CSF) may have diagnostic and prognostic utility for patients.4 In a recently published study in Annals of NeurologyFindings showed that CSF MOG-IgG testing had favorable 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 MOG-IgG serum 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 demonstrate the benefit of using CSF MOG-IgG testing in the clinical setting .5 In a new version of NeuroVoices, Flanagan, who is also director of the Autoimmune Neurology Fellowship, recently sat down with NeurologyLive® in an interview to further discuss the main criteria for diagnosing MOGAD. He also talked about how the presence of MOG antibodies in the spinal fluid can affect diagnosis and treatment. In addition, he spoke about the challenges that exist in standardizing MOG antibody testing across laboratories.

Top clinical takeaways

  • Testing both blood and spinal fluid for MOG antibodies shows potential to improve diagnostic accuracy, especially when clinical suspicion for a diagnosis is high.
  • The presence of MOG antibodies exclusively in the spinal fluid raises questions about immune mechanisms and implications for treatment, which warrants further investigation.
  • Despite the progress made in identifying MOGAD, the lack of proven treatments highlights the importance of enrolling patients in clinical trials for future advances in care.

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

Eoin P. Flanagan, MB, BCh: MOGAD is a recently recognized demyelinating disease of the central nervous system. We know there are other diseases like MS, but we also have NMOSD associated with aquaporin-4 antibodies. Now we have MOGAD as the third major category of diseases in the inflammatory demyelinating diseases of the CNS category. We know that this test was first developed for the MOG antibody in blood to find out whether patients have the disease. Then you have to tailor it to their clinical and radiological syndrome. Diagnostic criteria had been published in 2023 that identified MOGAD as a disease separate from other conditions.

If you have a serum-positive MOG antibody according to these criteria, and then if you meet certain clinical and radiological criteria, and you rule out other causes such as MS, then you may meet the criteria for MOGAD. Also in the criteria there was a section for spinal fluid, and if the antibody was positive only in spinal fluid, you would have to meet slightly stricter criteria for the diagnosis. If you have a low positive result in blood or spinal fluid, you must meet some additional supporting characteristics. With this recognition that MOG antibodies can be tested in spinal fluid, we wanted to investigate among our cohort at the Mayo Clinic how the mock CSF performs and whether it is of any use. The key point, I think, would be if a patient was tested and was negative in the blood, could he also be positive in the spinal fluid? And should you test that?

We looked at about 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 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 that probably about 5% to 10% of patients who were negative in the blood were positive only in the spinal fluid, and still had a syndrome compatible with MOGAD. This suggests that in patients in whom you are very suspicious, you should consider testing the spinal fluid in addition to testing blood.

Now I will say that the MOG antibody we know is a bit tricky. It’s a bit sticky. So sometimes patients with other conditions can have some low positive values. We know that in serum, and we know that when you get a high positive result, it’s very reliable. But the low positive results are a bit of a challenge, and you must use your clinical and radiological features to guide you to the diagnosis. We see the same thing in the spinal fluid: there are some cases that are positive, maybe 1 to 2% of the cases that are positive, that have other conditions. You also have to be careful with the low positive values, but with a high positive level in blood or spinal fluid it appears to be a very reliable test.

The other thing I can mention is that if you have a positive result in both the blood and spinal fluid then it is more likely to be MOGAD, whereas if you only have a positive result in serum, in itself a low positive result in serum, and it’s negative in CSF, which makes it more likely to be a false positive, because we know we have some problems with false positive results.

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

I think a few things, I guess. I think there are several tests for MOG antibodies around the world. We use something called a live cell-based test, where we take live cells and add the spinal fluid or blood to them to detect the antibody. There are other labs that use what’s called a solid cell-based assay, where the cells are killed and you assess cell binding to these inactivated cells. I guess we’ll have to see how these two techniques perform and how the solution performs compared to the live cell-based test. This requires a multicenter assessment. I think we should compare everyone’s different techniques because every lab is a little different. We should try to standardize across laboratories and see if we can find consistent results across many centers. So I think that’s one part.

The other thing is to determine: why do people only have antibodies in the spinal fluid? And what does that mean? Does this mean that they have immune cells in the CSF compartment that make antibodies that are not present in the blood, and so on? Or in the rest of the body? We need to better understand what is happening there, what the mechanisms are and what the implications are for the treatment of those patients. Should we get treatments that cross the blood-brain barrier and enter the cerebrospinal fluid to help treat these patients? I think there is still a lot to learn. We are in the early stages of spinal fluid research. But I consider the spinal fluid test to be quite useful, but also requiring the caution that we have with the serum MOG, that we know that there can be few positive false positives. We would be a little cautious about the cases that are just above the threshold at a low positive level.

Do you have any other comments you would like to share based on MOGAD and the importance of raising awareness and research into this condition?

I think with MOGAD we’ve really made a lot of progress over the last five to 10 years in identifying the disease and giving it its own identity, but we haven’t found a proven treatment yet. Clinical trials are currently open for MOGAD. We’re really trying our best to recruit patients into those trials because we know from our experience with NMOSD that there are 5 available, 4 of which are FDA approved, 5 proven drugs in that condition, but we still don’t have any proven drugs in MOGAD. I think it’s very important for neurologists among us, if you have a patient with relapsed MOGAD, to look for clinical trial sites and try to get the patients involved in those clinical trials so that we can have a proven treatment for patients with MOGAD so that we can have them available in treatments like we have with MS and NMOSD, but we don’t have that yet with MOGAD.

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

1. O’Connor KC, McLaughlin KA, De Jager PL, et al. Self-antigen tetramers distinguish between myelin autoantibodies against 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: the 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