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Introduction

Well, hello everybody. My name is Eoin Flanagan. I'm a neurologist at the Mayo Clinic. I work in the Neuroimmunology Laboratory at the Mayo Clinic and the autoimmune neurology and multiple sclerosis clinics. Today I'm going to talk about MOG antibody-associated disease (MOGAD) and in particular about the recent diagnostic criteria.

Disclosures

These are my disclosures here, which are not too relevant to this talk, which will focus mostly on diagnosis. 

Distinct inflammatory diseases of the CNS associated with demyelination

When we think about inflammatory diseases of the central nervous system associated with demyelination, then there are three major ones that we can think about. We have multiple sclerosis (MS), which ranges from radiologically isolated syndrome all the way to secondary progressive MS. We have aquaporin-4 antibody positive neuromyelitis optica spectrum disorder, which was the first antibody discovered as a biomarker of CNS demyelination. And today we're going to focus on the third well-defined disease, which is this myelin oligodendrocyte glycoprotein antibody-associated disorder or disease (MOGAD).

This is focusing on a study that was recently published in the Lancet Neurology in early 2023. This was a study led by Brenda Banwell and many of us were involved, and this is the international MOGAD panel proposed diagnostic criteria. 

MOG-IgG assay methodology¹

When we think about the MOG antibody assay methodology, if we just look here, this is done by what we call a cell-based assay. We have a patient serum and we run it in our laboratory, and we look for binding to MOG on the surface of these cells versus not binding to cells that don't have MOG on the surface. Then, if you do have MOG binding, you have a secondary antibody that binds to the FC portion of the MOG antibody and helps you get a readout of how much positivity you have.

In our laboratory, we use a flow cytometry called a FACS assay, and we're able to get a readout of the strength of positivity with that. Other laboratories might use an immunofluorescence technique to look at the antibody, where they look under the microscope for binding to the cell surface. Then what we can do after that, is we can do an endpoint titer, where we will assess and dilute each sample at different dilutions to give us the strength of positivity, and in our laboratory, we start at 20 and then we go to 40, 100, 1,000, 10,000. So, you can have an antibody titer anywhere from 20 to 10,000. 

MOG-IgG assay methodology and reporting^1-3

The MOG antibody assay methodology was included in the diagnostic criteria, and this is mentioned here. There are two types of cell-based assays. The one we use here at Mayo Clinic is the live cell-based assay, which does confer some slight advantage over the fixed cell-based assay in terms of sensitivity and specificity, but we really recommend cell-based assays. So either of these are appropriate tests to test for MOG antibodies. As I said, we use the flow cytometry and there are different cutoffs here. In our laboratory, a cutoff of 100 or greater is considered a clear positive or high positive, and a cutoff of 20 or 40 is considered a low positive.

When to order MOG-IgG and how to interpret^4-7

When do we order the MOG antibody and how do we interpret it? Well, one of the issues with the MOG antibody that we don't really see with the aquaporin-4 antibody is that at low titer, sometimes we can see some slight binding in disease controls. Up to 1%-2% of MS patients, for example, can have MOG antibodies and indeed, they looked at a hospitalized group of patients and found that 1%-2% of those patients could have low positive MOG antibodies. When you test MOG antibodies across multiple laboratories, there's pretty poor agreement for low positivity, so it's not as robust in that in one lab, it might be low positive, in another lab, it might be negative. While with the high positives, they're very reliable across all the laboratories.

What we suggest is we avoid testing in low-probability situations, so if you have a patient where everything looks extremely classic for multiple sclerosis, we don't recommend testing the MOG antibody because you might run into low positive results that can confuse the picture. Previously we did a study from our laboratory, and what we found was that the rate of false positives or positives in other diseases was reasonably high with the low titer results, so up to half of those patients had an alternative diagnosis. Well, once you got up to the high positive, almost all of these patients had MOG antibody disease. This is important because we know that MS is about 50 times more common, at least in our region of the world, than MOGAD. Therefore, if you test all MS patients because MS is 50 times more positive, you may get some false positive results. This was a major theme in the article highlighting that you need to avoid testing in low-probability situations. So, you want to be testing in a patient suspicious for MOG, and we'll go over some of the features.

International MOGAD panel diagnostic criteria 2023

These are the diagnostic criteria that you'll find in the manuscript, and there are three major parts. First, you have to have a core clinical demyelinating event, and we'll break these down over the next few slides. Second, you have to have a positive MOG antibody test, and depending on how positive it is, if it's a clear positive or low positive, you may need some additional supporting features. And then you have to exclude alternative diagnoses or a better diagnosis, such as multiple sclerosis. 

A. Core clinical demyelinating event

If we think about the core clinical demyelinating event, we can see the six of these here. Optic neuritis is one that's the most common manifestation of MOGAD. Myelitis is another. Acute disseminated encephalomyelitis is something that happens most commonly in children, and we know MOG antibodies are quite common in children and this is an important one to think about. If you have some other type of brain or multifocal demyelinating lesions within the brain along with the clinical syndrome, we term that cerebral monofocal or polyfocal deficit. MOGAD in these patients may be similar to ADEM, but if you don't have encephalopathy, for example, you can't meet the ADEM criteria, and you may need to fall into one of these categories. If you have brainstem or cerebellar demyelinating lesions along with that type of syndrome, then that can be one of the core demyelinating events. Finally, if you have cerebral cortical encephalitis, which is an unusual and newly recognized syndrome where patients will often present with seizures, headache, fevers, and cortical signs, and they may have cortical T2 hyperintensity, I'll show some examples of that. These are the core demyelinating events. So you have to have one or more of these to be able to fulfill the criteria. This is required, so this is part A.

B. Positive MOG-IgG

The second part that's required, because it's called MOG antibody-associated disease, is a positive MOG-IgG. What we know is that that may be a clear positive, and if you have a clear positive — a strongly positive — MOG-IgG, then you don't need any additional supporting features. All you need to do is go to step C, which I'll talk about, which is to exclude alternative diagnoses. On the other hand, if you have a low positive MOG antibody in the serum, or if you have a positive result but there's no titer reported, or if your result in the blood is negative but you have a CSF positive result, then you need to have additional criteria. One of those is you need to be negative for the aquaporin-4 antibody, and then you need to have at least one of the following supporting clinical or MRI features that I’ll go over in the next few slides.

Supporting features: Optic neuritis

What about the supporting features if the patient has optic neuritis — if that's their core clinical event? Well, if it's bilateral, we can see an example here of bilateral optic nerve enhancement and bilateral optic neuritis. If you've bilateral simultaneous clinical involvement, then that's very suggestive of MOGAD. Or if you have a long lesion, what we say is greater than 50% of the length of the optic nerve like we see here, that's quite suggestive of MOGAD. If you have involvement of the optic nerve sheath here, that can count as a supporting feature. Or if you have prominent optic disc edema like we see here, that's very common in about 85% of MOGAD patients, you'll see a lot of swelling of the optic disc. So, if you have any of these features, that can count as one of your supporting features if your antibody is low positive or if you don't have it titer or you only have it positive in the CSF.

Supporting features: Myelitis

Similarly, if you have a myelitis, then the myelitis should either be longitudinally extensive, like we can see here extending over three vertical segments. It should be central and sometimes it has an H-sign where it involves just the gray matter on axial images or if it involves the conus. They're all suggestive features and counter-supporting features towards a myelitis episode.

Supporting features: Brain

And then, the supporting features for the brain episode if you have multifocal ill-defined T2 hyperintensities like we see here as an example. If you have deep gray matter involvements here, we see the thalamus and the basal ganglia, that's also a typical finding of MOGAD, or, if you have large, ill-defined lesions within the ponds or the middle cerebellar peduncle like we could see here, that can count as a supporting feature. Or if you have this cortical T2 hyperintensity, is what I mentioned with the cerebral cortical encephalitis where you have this swelling that you don't see on the other side and the cortex is swollen and sometimes they also have leptomeningeal enhancement, and this can be a supporting feature in the setting of that syndrome. This can be difficult to diagnose because sometimes these patients won't have any white matter lesions and sometimes people don't realize that this is a demyelinating condition, but if you look at the pathology, it confirms demyelination.

C. Exclusion of better diagnoses, including MS

The third part for the diagnosis of MOGAD is you need exclusion of a better diagnosis, and that includes multiple sclerosis, which is going to be the most common differential diagnosis. And indeed, in the article, there are a number of red flags that are mentioned that might dissuade you from this being MOGAD. And these are really important to look out for in your patients because as I said, MOG antibodies can be positive at low titer in 1%-2% of patients. So, if you have progressive neurological impairment where you have more of a progressive course, we see that with multiple sclerosis, but we shouldn't see that with MOG. So that’s a big red flag. If you have rapid worsening of deficits over the course of minutes to a couple of hours, that's suggestive of a stroke and that's quite atypical for MOG. If you have no improvement following treatment with steroids, that's also atypical for MOG because in MOGAD cases the attacks tend to respond very, very well to steroids. So that would be a red flag. Or if you have MRI findings that are very suggestive of multiple sclerosis, say you have multiple ovoid periventricular lesions when you have CSF oligoclonal bands, or over time with MS we know that they get silent lesions and with MS, it means multiple scars, so the lesions don't tend to resolve, they tend to leave a scar. On the other hand, the MOG lesions do tend to resolve, and that is a big difference in the vast majority, probably three-quarters or more of the MOG antibody-associated lesions will resolve. Finally, if you have ongoing contrast enhancement that persists for six months, that might be suggestive of a tumor or some sort of vascular malformation, we don't see that with the demyelinating disease. It usually resolves within a couple of months with MS, with MOGAD, and with aquaporin-4 positive NMOSD. 

Conclusions

So, if we summarize today what the diagnostic criteria look like, one, you have to have one of these core clinical demyelinating events that we mentioned earlier. Two, because it's called MOG antibody-associated disease, you have to have a positive MOG antibody. And if you have a high positive, then all you need to do is move on and exclude a better diagnosis. If you have a low positive result, we know that those are a bit more problematic, and in those cases, you need to have an aquaporin-4 antibody negative result, and you need to have some supporting features that we mentioned on the prior slides. 

International MOGAD panel criteria

This is the group that was involved in the MOGAD panel criteria. We met up for almost a year-and-a-half via Zoom, and it was a really fruitful collaboration and lots of input from everybody to come up with these criteria, which I think are a major step forward for the field of demyelinating disease. Now we can clearly say that MOGAD is a separate disease from MS and aquaporin-4 positive NMOSD. Both MS and aquaporin-4 positive NMOSD have had diagnostic criteria for many years, and this is the first real international consensus criteria for MOGAD.

References

So, I will leave you with my references here, and thank you very much for listening.

1. Banwell B, Bennett J, Maringier R, et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD panel proposed criteria. Lancet Neurol. 2023;p268-282.
2. Waters P, Komorowski L, Woodhall M, et al. A multicenter comparison of MOG-IgG cell-based assays. Neurology. 2019;Mar 12;92(11):e1250-e1255.
3. Yeh A, Nakashima I. Live-cell based assays are the gold standard for anti-MOG-Ab testing. Neurology 2019, Mar 12;92(11):501-502.
4. Held F, Kalluri SR, Berthele A, et al. Frequency of myelin oligodendrocyte glycoprotein antibodies in a large cohort of neurological patients. Mult Scler J Exp Trans Clin. 2019. 2021 Jun 25;7(2).
5. Reindl M, Schanda K, Woodhall M, et al. International multicenter examination of MOG antibody assays. Neurol Neuroimmunol Neuroinflamm. 2020 Feb 5;7(2):e674.
6. Sechi E, Buciuc M, Pittock SJ, et al. Positive predictive value of myelin oligodendrocyte glycoprotein autoantibody testing. JAMA Neurol. 2021 June 1;78(6):741-746.
7. Redenbaugh V, Montalvo M, Sechi E, et al. Mult Scler J Exp Trans Clin. 2021 Nov 26;7(4).

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Image credit: Mayo Clinic