 Russell, thank you so much for the introduction. As he mentioned, my name is Rujur Rai. I'm a research fellow for Dr. Katz and Dr. Ambati. And thank you so much for the opportunity to speak today. I've had a wonderful experience at the Moran so far, and I look forward to working with all of you over the next year. When I found out that I was going to be speaking with my good friend Wyatt Messenger here, I knew it was gonna be a tough act to follow. What, as you saw, was an excellent presentation on some of the fascinating research that we're doing with C-R-A-L. I knew I had to come up with something good, and I was struggling for a topic. So I did what every enterprising modern day professional does when they have a really important problem to solve. I Googled it. Looking at exhibit A, I thought, perfect. This is the best cop out. All I have to do is bring in a bunch of hamburgers and we can call it a day. And then I remembered the slogan. It's what's for dinner, not for breakfast. So that's not gonna work. I'm to exhibit B then. I guess I'll have to deliver an actual grand rounds. But don't worry, I'm not gonna just copy the cartoon figure here. My representation is gonna be original. Because this is an eye center, I'm gonna talk about an interesting case that I saw with Dr. Katz and Dr. Joss in your ophthalmology clinic. Because I'm a fan of Seinfeld, I'm gonna replace the blah, blah, blah with yada, yada, yada. And since I'm an overachiever, I figure why settle for just the med students when I can put the whole audience to sleep, right? So let's get started. And if you're all snoring by the end of this talk, I'll know that I've succeeded. Patient TS is an 18 year old girl who presented to the ED the symptoms of pain and vision loss in the right eye. She describes a pain as being mild in severity, located behind the eyeball and occurring with eye movement. She describes a vision loss as a dimming and clouding of the vision that progressively worsened over two days to a complete loss of vision. Her ocular history was significant only for refractive glasses, nor social history was notable for her Asian ethnicity. The remaining of her history was otherwise unremarkable. On ocular exam, she had no light perception vision and a large afferent pupillary defect in the right eye. We were also able to elicit that pain that she'd mentioned earlier with extraocular motion testing. Her soot lamp and fundus exams were unremarkable. The lack of optic disc edema suggested it's a retro bulbar process as opposed to anterior. So given these findings, you were quite concerned for optic nerve damage and we ordered an MRI of the brain and orbits to evaluate further. On your left on the T2 axial cross-section with fat saturation, you can see that there is increased signal intensity and enlargement of the right optic nerve. On the T1 coronal sequence, you can see that the same affected nerve has enhancement with gadolinium contrast. This indicates inflammation and edema of the optic nerve. There were no intracranial white matter lesions apart from a small one millimeter focus of flare hyperintensity in the periventricular region. And a spinal MRI was also later obtained which showed no longitudinally extending spinal lesions or other abnormalities. So what's going on? Well, let's put the pieces together. We have a female patient in her late teens with sudden, painful, monocular vision loss. There are many other possibilities and etiologies for optic neuropathy, but this is a pretty classic textbook picture of optic neuritis and therefore the most likely diagnosis. At the top of my differential, I have demyelinating optic neuritis because this is the most common cause of optic nerve disease in an 18 to 40 year old. However, I'm also keeping some non-demyelinating causes of optic neuritis on my radar because many of these conditions can often mimic the clinical features that we see with demyelinating optic neuritis, including enhancement of the nerve with contrast on MRI and also responsiveness to steroid therapy. So with all this in mind, we've ordered a comprehensive CSF and serum workup to look for inflammatory, infectious, and metabolic causes of optic neuropathy. In the meantime, because our preliminary leading diagnosis is a demyelinating optic neuritis and we have a very low suspicion that there is an infection going on, we chose to treat the patient empirically with high-dose intravenous corticosteroids followed by oral corticosteroids as per the optic neuritis treatment trial. This intervention, while not shown to have long-term improvement in visual outcomes, has been shown to accelerate visual acute recovery in the short term by about one to two weeks. When the patient returned for follow-up one month later in your ophthalmology clinic, she had only a modest recovery of revision to 2150 and also had associated residual defects in color vision and central scotoma on confrontational visual fields. As would be expected about four to six weeks out from episode of optic neuritis, she also now had evidence of optic nerve atrophy on fundus exam. This is corroborated here by the OCT of the retinal neurofibular layer where you can see there's 360 degrees of mild thinning. On automated perimetry, there was a diminished foveal threshold of 30 decibels which is in contrast to the normal value of 39 that was seen in the contralateral eye. This indicates that she has a central scotoma confirming the findings we saw with confrontational visual fields. How should we interpret these outcomes? Well, again, looking back at the data from the optic neuritis treatment trial, 92% of patients with optic neuritis have a final visual recovery to 2040 or better and only 2% of patients with optic neuritis have a final visual recovery to less than 2200. In most of the improvement that occurs occurs in the first, the third and fourth weeks out from the event. But this can continue, the improvement can continue for up to a year. Regardless, the majority of these patients as with our patient have persistent deficits in color vision, contrast sensitivity and the visual field. In our patient, as you can see taking this into context, she has, she's now three months out, at that time she was one month out and she had a visual recovery to only 2150. So her prognosis is relatively guarded compared to the standard optic neuritis patient. At this point, the lab results had come back and we saw that her CSF was positive for anti-aquaforin for antibody, which is a validated diagnostic biomarker for neuromyelitis optic eye having 76% sensitivity and 94% specificity. Apart from being a diagnostic tool, it's also thought to have potential value as a surveillance tool because the tighter levels of this marker correlate with attack severity, clinical disease activity and therapeutic response. So when I saw these results, I thought, hmm, I know all about MS because it's more common and we learn about it in medical school, but what's NMO? What's aquaforin for antibody? So I looked it up. Neuromyelitis optical, also known as Devick's disease is an inflammatory demyelinating disease of the central nervous system. These are the consensus guidelines for the diagnosis of NMO. For a patient to have definite NMO, they have to have optic neuritis and transverse myelitis, along with two out of three of these supportive criteria. The items highlighted in gold are those that pertain to our patient. As you can see, it should not have spinal cord involvement and therefore she would be considered as someone with probable NMO or possibly NMO spectrum disorder. However, that doesn't mean that she can't develop spinal cord disease at the later time. Transverse myelitis and optic neuritis do not have to occur concurrently. Often optic neuritis is the first presentation and it's followed months to years later by transverse myelitis. The etiology of NMO is poorly understood, but it's not to be autoimmune. And both animal and human models have shown that anti-aquaforin-4 antibody has a direct role in the pathogenesis. So what's the model for pathogenesis as we understand it? Aquaforin-4 is a transmembrane water channel protein that is normally expressed by astrocytes in the brain spinal cord and the optic nerve. Particularly in areas of the blood-brain barrier because astrocytes are functioned to help limit access of immune effector cells. What's not to occur in NMO is that by some unknown mechanism, the B lymphocytes are stimulated, produce an antibody against anti-aquaforin-4, which binds to the protein, elicits an inflammatory response and causes the myelin loss and urological impairment that we see clinically as NMO. Historically, it was classified under the umbrella of multiple sclerosis, but it's now seen as a discrete entity. This is clinical importance because the epidemiological distribution of the disease, the underlying pathophysiology, and the natural history of the disease are very different from MS and have implications in terms of the diagnosis, the prognosis and the treatment of this disease that require a different approach than from MS. I'm gonna walk you through now some of the differences between the two. The items again that are highlighted in gold are those that pertain to our patient. So from an epidemiology standpoint, NMO is about 25 times less frequent, occurs in the slightly older age group, has even greater predilection for women, is more likely to be seen in the non-caucasian population. NMO patients are, sorry, more likely to have a coexisting autoimmune condition and the major histocompassive padability gene allele that's associated with the two disease is disparate. Looking at clinical features, although occasionally intracranial lesions have been seen with NMO or NMO spectrum, it is for the most part limited to the optic nerve and spinal cord. As we just talked about, the response is a B cell-mediated one as opposed to T cell. The local pathology of NMO is also far more aggressive than MS, causing more extensive demyelination, necrosis, and even cavitation of the nerve. We talked a little bit about the biomarker. I just wanna point out here that for MS, we usually look for oligoclonal bands, IgG, antibody synthesis, and myelin-basic protein. And sometimes, although we didn't see it in our case, you can see an increased white blood cell count in the CSF with NMO. As for laterality, in both diseases, you're more likely to see a unilateral presentation, but if you do see a bilateral presentation, it's disproportionately more likely to be NMO. The same thing goes with the presenting visual acuity. Both diseases can present with a range of visual acudes, but if you see a severe visual acuity of less than 2,200, it's disproportionately more likely to be NMO. About one-third of these patients have NMO. In terms of prognosis and treatment, there isn't a lot of good research out there right now that has directly looked at the outcomes between the two diseases, but there was a recent prospective observational study that looked at about 47 patients with MS and 30 patients with NMO and was able to find that the relapse rate, the visual outcomes, and visual disability for NMO are much worse than MS. Permanent disability for MNO also tends to occur earlier in the disease compared to MS, just because there's less recovery from the deficits that occur with each episode, so the morbidity occurs earlier. And one of the most important points is regarding interferon therapy, which for MS is key to, as a disease modifying agent, to slow the progression of disease, but an NMO has been shown to be ineffective and may possibly even be harmful. So we're just talking a little bit more about the prognosis. Within the first year after optic neuritis, most patients have had a relapse rate, 60% of patients have had a relapse, and within three years, 90% of the patients have had a relapse. You, as I described earlier, because there's less of a recovery from the deficits of each episode of NMO, you tend to see the stepwise deterioration with each recurrent episode of an NMO attack, and that's what causes the disability and morbidity associated with disease. And there isn't, there's very limited amount of data regarding this, but factors that are thought to be linked to poor prognosis is greater severity of the first attack, increased number of relapses in the first two years, an older age at onset of the disease, and antibody seropositivity for coexisting autoimmune conditions. And lastly, just a little bit about treatment. We talked a little bit about the acute treatment, so I wanna point out here that high dose IV corticosteroids, that's the same treatment that you would do for multiple sclerosis in the acute stage. And I also wanna point out that if there's a poor response, plasma freezes and IVIG are second line alternative options. The most important aspect of managing a patient with NMO is the long-term prophylaxis. So as we just saw, the disability is pretty great, and it's associated with relapses. So if we can reduce the number of relapses, we can reduce the morbidity in these patients. So some observational studies have shown that azathioprine, rituximab, and mycophenolate have reduced the annual relapse rate of NMO by about 70 to 80%. And so they are now seen as the first line monotherapy for maintaining its immunosuppression, something that is recommended for about five years after their initial event of optic neuritis, because this is the highest risk period for them to develop a relapse. So just some take-home points. MRI imaging and anti-acroporn for antibody testing aids in the diagnosis of NMO. NMO is a distinct clinical entity from MS with a poorer prognosis and a different treatment paradigm. In a patient presenting with optic neuritis, you should have a high index of suspicion for NMO versus MS if you see this in a non-cultation patient, if the vision loss is severe, less than 2,200 especially, and if there's bilateral involvement. And preventing relapses is the key to reducing morbidity. I'd like to give special thanks to the following individuals for the contributions that they've made to this presentation. These are my references. And thank you very much for your time. I'd love to take any questions that you have. Not your money. You know, I didn't look too carefully into papers on IVIG. I know it's still, I know that it hasn't been shown to be that effective for acute episodes. They've looked, they have looked at it actually more probably for long-term prophylaxis. But yeah, this isn't something that I've researched very, very carefully. Dr. Katz, do you, and Dr. Warner, do you have anything to add to that? Thank you so much.