 So, this is Sravagunta, she's one of our wonderful interns. She's currently on her ophthalmology elective. She was one of the people that we're really happy to have matched here, and she's definitely demonstrated a lot of enthusiasm during her. Since we now have four interns, the interns get some ophthalmology elective time, and she's been really proactive in figuring out good ways to use her time learning from all different kinds of people, so she may approach you and ask to work with you as well. And today she's speaking about neuromyelitis-optica spectrum disorders. Thanks, Aileen. Good morning, everyone. So, today I'm gonna start off with a case presentation, then I'll talk about the diagnostic criteria for neuromyelitis-optica spectrum disorders, or NMO spectrum disorders. And the most important thing I'll discuss today is how to distinguish between NMO spectrum disorders and other demyelinating diseases, especially multiple sclerosis. Since the two diseases seem to present similarly, but they actually have very distinct pathophysiological mechanisms, and the treatment for them chronically is different. So, two weeks ago, I met a patient in neuro-ophthalmology clinic, a 72-year-old Caucasian female from Idaho. She had a previous history of multiple sclerosis, and she presented it three days after she had sudden onset, painless, right eye visual field deficit. And she didn't have any other neurological symptoms at the time. In her relevant past medical history, at age 40, she had an episode of difficulty walking for about six months, which gradually improved over time. At age 50, she had a loss of vision in her left eye, also painless, and her vision decreased to no light perception. Fortunately, she regained some vision in her periphery, but she remained at count fingers at one foot. At that time, she had an MRI of her brain that showed brain plaques, and she was diagnosed with multiple sclerosis at the time, and started on Capaxone, chronic immunosuppressive therapy. So here's her exam findings. The most important findings are listed in the yellow here. Her visual acuity was 2050, and in her right eye, the affected eye, and she was able to pinhold at 2040. In the left eye, she remained at count fingers, which is a chronic change for her. In her pupil, in her right eye, it was rounded and reactive. The left eye had a significant RAPD, and Ishihara color plate testing showed that she had diminished color perception in the right eye, and virtually absent in the left eye. The rest of her slit-lamp exam was relatively normal. On dilated fundus exam, you can see here that she had temporal pallor and telangiectasis of her right-sided optic nerve, and significant optic nerve swelling on OCTR and FL, superiorly, temporally, and inferiorly. On the left eye, she had significant nerve pallor, and OCTR and FL showed atrophy as well. She had a macular hole, and both macules showed RPE changes. On visual field testing, her golden visual field on her left eye, which was chronically affected, showed a secocentral scotoma and an inferior scotoma. And on right-eye Humphrey visual field, she had a secocentral scotoma. Two weeks later, when she came back for a follow-up, her visual field had progressed to include a superior autitudinal defect as well. So given our case presentation, a patient presented with right-eye, sudden onset, painless vision loss, our differential included ischemic changes, so arteritic or non-arteritic, a compressive optic neuropathy, inflammatory causes such as multiple sclerosis or NMO spectrum disorders, or other demyelinating diseases, or even an infectious etiology. So she was worked up for the differential, and the only real positive lab finding was an elevated aquaporn for IgG antibody, which is also known as NMO, or Myelitis Optica IgG. I should also mention that the patient had, it was treated with IV methylprednisolone, and her MRI findings didn't show any significant nerve inflammation of her optic nerve. So this brings us to our discussion of what is neuromyelitis optica and what are the spectrum disorders specifically. So there are multifocal CNS demyelinating diseases that mainly affect the optic nerve and spinal cord. And they have an interesting history. In 1894, DeVic published a case report of a patient who presented with simultaneous optic neuritis and myelitis. So this disease is often called DeVic's disease as well. In the same year, this student published a case series of patients who presented similarly. Then fast-forwarding about 100 years to the optic neuritis treatment trial. In this study, over 400 patients were enrolled, and only 10% of the patients in 1992 had a diagnosis of multiple sclerosis. If you look at the results 15 years later that were published in 2008, about 50% of patients had multiple sclerosis. But there's really no further investigation of patients who had neuromyelitis optica. One of the reasons might be because it's a rare disease, but also because neuromyelitis optica was often considered just a subset or another variant of multiple sclerosis itself. But this change in 2004, when Lenin and his colleagues published a groundbreaking paper which identified the NMO antibody, the IgG antibody, which showed that NMO was actually a distinct pathophysiological disease and also could be tested for objectively. And the fact the physiology of the disease is pretty interesting too. And it's also a distinct from multiple sclerosis which I'll go over. So the main target of the aquaporn for antibodies is the aquaporn for protein. It's a water channel that's most abundant in the CNS, especially in optic nerve and spinal cord. And these water channels help maintain homeostasis, especially in times of physiological stress. And they mostly line the plasma membranes of the astrocyte foot processes which line the blood-brain barrier here. So in this image, the aquaporn for antibodies, you can see them somehow they cross the blood-brain barrier attached onto the aquaporn for proteins themselves. Complement is activated. And this attracts neutrophils and eocytophils to the area and causes astrocyte death. The local inflammatory action then causes necrosis of the tissue in the same area and especially oligodendrocytes can also be affected. So the mechanism of demyelination is actually secondary to local necrosis itself. This is different from multiple sclerosis where the main inflammatory target is the myelin itself, myelin protein itself. So that's more of a direct mechanism of demyelination. So now that we know the pathophysiology, how do you diagnose the disease? In 2015, Winger-Chuck and colleagues published this international consensus criteria for diagnosing NMO spectrum disorders. And one of the main points they make early on in the paper is that we should get rid of the term NMO. And the term NMO should just be subsumed under the term neuromyelitis-optica spectrum disorders. So it's not really a list of disorders, but just kind of like a spectrum of the same pathophysiology. They established diagnostic criteria and they also set up some or made some suggestions for how to test for the disease, which specific antibody tests to use. So for patients who have been diagnosed or who have a positive or elevated aquaporn for IgG, they should have at least one of the following clinical, core clinical criteria that are listed here in order to be diagnosed with neuromyelitis-optica. So they can present with either optic neuritis or acute myelitis, or another characteristic brain stem syndrome. And this is the most significant change to the diagnostic criteria right here. So patients don't necessarily have to present with the first two. They could have a dorsal-ementulary syndrome, which is also like a areopostrima syndrome. They could present with intractable hiccups or unexplained nausea or vomiting. They could have an acute brainstem syndrome, an acute diencephalic syndrome, which could include the hypothalamus or the thalamus itself, or even a cerebral syndrome. And these last two should also have MRI findings that support the criteria. There are some patients who are diagnosed with neuromyelitis-optica spectrum disorders without having a positive aquaporn for IgG. In that case, the Winger-Chuck and his colleagues also made suggestions for how to diagnose those patients. They need to meet more of these clinical criteria, and they should also have additional MRI findings to support the diagnosis. So in their paper, they also discuss distinguishing characteristics on MRI or imaging findings to differentiate between NMO spectrum disorders and MS. So here's a classic picture of multiple sclerosis. This is the classic Dawson fingers that we see. This is a sagittal flare showing these colososceptal hyperintensities that are perpendicular to the lateral ventricles. In comparison, the NMO spectrum disorders that don't necessarily have perpendicular hyperintensities. This is an image that's an axial T1 with contrast. You can see in the deep white matter in the temporal lobe here, there's this lesion that's enhancing in a cloud-like pattern. And that cloud-like pattern is really specific for NMO spectrum disorders. So despite some of the distinguishing characteristics on MRI, over 15% of patients who have NMO spectrum disorders still meet MRI criteria for MS diagnosis. This is a really important slide for us to go over, which compares the differences between MS and NMO spectrum disorders. So firstly, the prevalence of the two diseases is very different. For NMO spectrum disorders, they're much rarer, more rare. The initial course of both diseases is similar, though. They often, patients often present with a relapsing remitting course. So they have an attack to their central nervous system, then they recover incompletely, but for some time, and then they have another attack of their central nervous system. Interestingly, NMO spectrum disorder patients, about 15% of them present with this monophasic presentation. And in that situation, they have just one hit to their CNS, and they tend to recover over time. But we're starting to find that these patients are oftentimes negative for the aquaporn for IgG, and we're finding that they're usually a younger subset of patients, and they tend to have a positive myelin oligodendrocyclico protein as well. So we might find that these patients end up having a complete separate disease in the future. The CSF findings for both diseases are different. So NMO spectrum disorder patients tend to have more white blood cells and pleocytosis. And in the CSF of MS patients, we often see more often the ligoclonal bands. And then in NMO spectrum disorders, it's common to see patients with other systemic autoimmune diseases, especially connective tissue diseases, like lupus or chogrens. And as we know, lupus itself can cause neuromyelitis, or sorry, optic neuritis. Bilateral optic neuritis is more common in neuromyelitis optical, and visual recovery is often worse for patients who have neuromyelitis optical. So in the study where patients were followed five years after an optic neuritis episode, over 50% of patients after five years had worse than 2,200 vision, which is unfortunate. This is not really comparing apples to apples, but in the optic neuritis treatment trial where over 50% of patients had multiple sclerosis, only 4% had less than 2,200 vision, so much worse visual outcomes with neuromyelitis optical. So now that we know some distinguishing characteristics, who should we actually test for the aquaporn for IgG antibody? So if you look at patients who've had just one episode of optic neuritis and no other neurologic history, only three to 5% of those patients end up being positive for the aquaporn for IgG, so it's pretty rare. But we should consider testing patients who have any of the two clinical characteristics that I mentioned earlier. So for example, a patient who has optic neuritis plus an acute brainstem syndrome. Patients who have bilateral visual symptoms, like we saw, more likely to have neuromyelitis optical, spectrum disorders, and recurrent optic neuritis for visual outcomes is also another reason to test. And finally, patients who have concurrent autoimmune diseases. So which test should you use to test for this antibody? Thankfully, there's over 40 assays out there, but thankfully the International Consensus Criteria recommended, made some recommendations and they suggested doing the live cell binding assay since it has the highest sensitivity and specificity of the other tests. At ARIP at the University of Utah, we have ELISA with reflex to immunofluorescence assay, but as you can see it's less sensitive, so there's a risk of false positives in patients who could have low titers of the antibody itself. So what we do here is we test with the ELISA and then if positive we can confirm by sending out to the Mayo Clinic for a cell-based or cell binding assay. So the treatment of NMO has been studied, but mostly in retrospective studies and in small populations. So the evidence isn't that well supported, but it's the best that we have so far. So the first line treatment is methylprednisolone, high dose IV for five days, and then with an oral steroid taper. And finally for chronic immunosuppressive therapy, this brings us back full circle for why it's important to distinguish between MS and NMO spectrum disorders because certain medications that are used for immunosuppressive therapy in MS patients can actually worsen or not adequately prevent relapses in patients with NMO. And these include Natalizumab, interferonbeta, and Fingolamon. We don't really know exactly why these don't adequately prevent those relapses in patients, but for interferonbeta, we know that it's possible that the T helper cells are sort of increased in number, and they in turn activate the B cells, and those B cells, of course, produce the immunoglobulins themselves. So the best therapy for patients is to do Ritexamab or Azethioprene. Ritexamab has become a favorite lately because it has a better therapeutic index, it reaches a therapeutic index faster than Azethioprene and Mycophenolate, and it has fewer side effects overall, and the dosing is easier, so patients only have to have dosing every six months. And then in the future, we can look forward to more specific therapies like Apoporamab. This is a small molecule binding inhibitor to prevent the binding of the IgG to the protein itself. Thanks for your attention. I'd like to especially thank Drs. Degree, Newfeld and Wang for helping me with this presentation and taking care of our patient. Showing the sensitivity and specificity. Yeah. I'm just trying to work my brain and the brain, the likelihood of edema, falls positively. So that's, so falls positively just specificity, right? The specificity is very high with all those tests. So I think the likelihood of edema falls positively when any of these tests is low, it's the problem's being a false and negative because the sensitivity of the test is lower. Yeah, that's true. Right? Yeah, that's true. So sensitivity is used for ruling out diseases. Yeah, so even with the best test, the sensitivity is still in the eight percent, which means that if five people come into your clinic and you really have an MMO, what when you're gonna misdiagnose and you, if you rely completely on the test. So even this test, which has really changed our ability to quickly diagnose this disease, you still have to think clinically. You can't rely on the test. And then could you also show the outcome saving that you put together? Yes. I think part of the reason that people with, neuro-myelous conscious spectrum have such poor visual acuties is because something so very recently, I think we were very bad at diagnosing and we don't treat it immediately and aggressively the visual outcome is poor. But I think now that we can, now that we have just a lot of tests to go into more and more aware of the disease, I don't think it's still gonna be not as good as copy and paste, but hopefully numbers gonna be improved. Yeah, who's that too? Well, final thank you, final comment. I wanted to make, you said suspect MMO when, yeah, the other thing is that I think certain ethnic groups are more likely to have MMO in a very good condition. That's true. I know like Southeast Asia, like Virginia, they have way more MMO than we see here. Yeah, African Americans, Afro-Brazilians, Caribbean populations as well, found to have higher prevalence of that. Okay, good. So that's another thing that's been done. This is great presentation. Thank you. Dr. Warner. So I just, you wanna go to your source. It's all very fine and large for the working group on MMO spectrum disorders to make recommendations. And interestingly, they're the ones who are the only ones currently who offer the cell-based assay. So they may have a little bit of bias towards doing the most difficult and offensive test first. I think that most of us would have the practice because of the specificity of the test. If you order it through ARUP and it's positive and the clinical syndrome fits then, you don't have to do the cell-based assay. I think that most of us probably end up doing the cell-based assay if we're really thinking that it is MMO and we're wanting to have confirmation. Although I think, again, most of us, if we really think that it's MMO, would end up treating it as such, even in the face of the negative test because of the slightly limited sensitivity. And I think that Brad's point about ethnic variation is extremely important. The other thing is there's a lot of practice variation in food tests for MMO. And so Dr. Grie, for instance, advocates testing for MMO in anybody with ocular radius. And I think that there are those of us who might say, well, perhaps if the MRI scan is absolutely classic for MS and they've had a nice relaxing remitting course that just all sounds like MS and they haven't had any of the other disinfecting disorder stuff, then it's maybe okay not to test it. Because it's not an inexpensive test. I don't know the exact cost, but I'm pretty convinced that it's not like a CBC. Right. So I think that some people would advocate bearing levels of testing and aggressiveness for MMO. I can see that, definitely. Is pain very helpful to these patients with ocular radius? Is that a significant factor? No. It can be painful for both. So what happened to your lady? Well, she's coming back to see Dr. Stacey Clarty soon, actually tomorrow, but to follow up to see how she does tomorrow. Because I think in her case, there was a very strong case we made for potentially being ischemic optic monopathy because of a lot of the cancer in the nerve, because of the swelling in the nerve, et cetera. We'll have to see what happens. Exactly, yeah. Was there another one that happened? It was possible. Yeah. Are you seeing any difference in the age that the developers have optimized? Well, there's, in literature, at least, there's a wide range of presentations. So they can be found in children and adults, but usually the median age of presentation is in the mid-thirties.