 Good morning everybody, we're going to get started now. Our first speaker is going to be Chris French who is a PGY3 resident in neurology who's been doing his neuro ophthalmology rotation. And Chris loves ophthalmology, he said. And something that we may not have known about Chris is he was a golfer at the collegiate level, okay, in Montana he was on the golf team. And in a tournament he got a hole in one. It was a perfect swish, zero bouncer, perfect swish, about 180 yards or so, so with an eight iron. So I took six in that one, but our team did not win the tournament. And, but I got mentioned in golf digest in the magazine and Derek asked if I had that article and I don't, I wish my mom would have kept it, but I don't think that she did for some reason. So, but anyway I'm going to talk about this and then just a couple of quick cases associated with this. This is not a topic that I really know about or that I've done research with or anything, it's just something that I recently saw while in neuro ophthalmology clinic, but I'm sure that I'll see it quite a bit more even if I switch over to ophthalmology or just in neurology either way. So, especially with the high use of these, these medications and then all the other new ones that are actually coming out. So, so it'll be seen a lot more. So I'm going to start off with a case and then talk about some other stuff. So this is the patient that we saw. So it was a 44 year old female who had sudden loss of vision in her left eye. What really happened is so she woke up on a Sunday morning and then just had a really blurry vision and just couldn't really see anything down in her, just her left eye she noticed. And she's had dry eyes in the past, but so didn't really think a whole lot about it. But then it just kept on getting worse, more pain in the eye. She ended up going to her optometrist the next day. And the optometrist noticed that there was possibly a little bit of disc swelling and so he ordered an MRI. He's worried about optic neuritis. And so that was actually completed the next day. She went in and had that the next day, but then it didn't get read for two more days. So by the fourth day she was having a lot worse vision, still just in the left eye. No problems in the right eye of what she was aware. Another symptom that she had been noticing was that she just was going to the bathroom all the time, like 40 times a day or more. Her optometrist ended up calling her and then referred her to neuro-ophthalmology. And so we ended up seeing her last Monday, I think that was. So this is kind of a little more of her story. So by the time she saw us on October 3rd, she felt like she was getting better. She had a lot less pain in her eye. Nothing's still in the right eye of what she was aware. And then she felt like her vision was getting a little bit better, especially to light perception and then movement a little bit. She continued to have increasing urgency and she was, like during the visit she had to go to the bathroom probably every 10 or 15. So her past medical history is interesting. She had otherwise been extremely healthy, no other problems. Until 2009 she was diagnosed with seronegative rheumatoid arthritis. She started on methotrexate at that time with a little bit of help in her joint symptoms, but not a whole lot. She got to the point where she was requiring a lot of assisted devices to get around most of the time and spending a lot of time in the wheelchair because of that. So they ended up starting her on inbrel along with the methotrexate as an adjunct therapy. And that was in April of this year. So by the time she saw us she had been on inbrel for over five months. And then she also had this strange diagnosis of calcium pyrophosphate deposition disease at the same time they took a sample, they aspirated one of her joints and found that in there. So not gout, but pseudo gout. And that was her only surgery is a little bit of debreatment of those crystals in there. So her family history is not real impressive at all. No MS, no ocular problems in her history at all. And no neurologic problems in the family other than I think history of migraines. So she's married, she's a fifth grade teacher from Elko, Nevada, no alcohol, tobacco, or illicit drugs. And this is her medication list. So the methotrexate and folic acid since 2009, vitamin D, mulvic, and then the inbrel which she was on from April 20th to September 22nd. So about five months, exactly. And then kind of going back and really getting a better history neurologically to see if she had any of these other little deficits kind of MS history, she did or complain of some lower extremity peristegias. So some numbness and tingling in her bilateral feet about nine months ago, so four months before starting to the inbrel, that she just associated with either the CPPD or the rheumatoid arthritis that was getting worse. So when she came and saw us, her exam was pretty normal. She wasn't encephalopathic or anything. No obvious abnormalities looking at her. But then on a neuro exam, so her visual acuity in her left eye was 2,200 without correction. It wasn't able to do stereophics or anything. She had an APD that was pretty big in the left eye. Full central scatoma, right arcute in the right eye that she wasn't symptomatic for her. And then fundoscopy showed a little bit of power. And then her slit lamp exam demonstrated this little spot. We kind of described it as a specific appearing lobulated unknown significance. And she said that she had had that for several years. So her motor exam was good. So her reflexes were abnormal and heated. So really brisk, but she had a right-up going tonal clonus. Other pathologic clients had decreased sensation in her right leg. And then she had a positive rhomburg. And she was unable to walk tandem. And she's always attributed that to the rheumatoid arthritis because it's gotten worse over the last two years. So one thing first is that she did bring with her an MRI scan. And I could not upload it for whatever reason. But this is the one that the optometrist did on September 20th or that he ordered. And basically what it showed are a bunch of enhancing lesions, kind of subcortical and periclosal. So at that time, because of all of her symptoms and everything that was going on, we decided to admit her to the hospital. So she was admitted, got three days of IV solumedrial high dose, got a lumbar puncture, rheum consulped, and then got further narrow imaging to see what was going on. So her lumbar puncture was positive for oligoclonal bands, but nothing else really. Rheum said that they agreed with the seronegative, rheumatoid arthritis as well as the CPPD. And then her MRI. So this is just a flare, axioplare. And so you can see the subcortical on the hearing here, the sag flare kind of shows the same thing, colosal, periclosal, on Dawson's finger-type looking lesions. And then the GAD-enhancing one shows the left. So they also image her whole spine because of all the bladder issues and her ataxi issues. So this one is just a stirred image and it shows the D-myelin right there. So the only active lesion that she has is right there. So she has the other older-looking lesions. And then this is her thoracic spine. So no enhancing ones on thoracic, but she has, I don't know if you guys can see these as well on here, but she has a bunch of T1-ish. This is so. So the impression here was probably subclinical or just undiagnosed multiple sclerosis that was either worsened by the TNF-alpha antagonist versus demyelination caused directly by the TNF-alpha antagonist. So the plan here, and this was between rheumatology and neurology was to stop the itanercept, which is too bad for her because it was so helpful for her and continue her methotrexate and then steroids and follow-up with rheumatology and possibly use something like retuximab in the future. And then follow-up with neurology as well to discuss possible MS with further surveillance neuroimaging. And this is kind of what happens with a lot of these cases that have been reported with this. So it does lead to a few questions. So kind of the big one is, does the patient or our TNF-alpha blockers directly causing CNS demyelination themselves, or do they just unmask or worsen previously undiagnosed multiple sclerosis? And so one of the things that has been posed is, is it a trigger for people without MS but have genetics susceptibility to MS that probably maybe would not have even gotten it? And so is there an inexpensive or a cost-effective way to screen these people before putting them on one of these TNF-alpha blockers? And there is a long relationship between CNS demyelination. So TNF-alpha, as we know, I mean it's been studied since the 70s, it's also known as coquectin but it's a cytokine pro-inflammatory regulator kind of thing, but it's kind of right at the center of the whole. And so it is activated by macrophages that's seen in the synovial fluid of people with rheumatoid arthritis and things like that. So things that it's used, that we use them for now are rheumatoid arthritis, ankylosing spondylitis with the bamboo spine there, psoriatic arthritis and then things like inflammatory valve disease and Crohn's disease. So really the first NNF-alpha blocker that people know or have known about is turmeric which has been used in Southeast Asia for a long time and the big thing is the curcuminoids that are found in turmeric. And this is kind of one of the main sizes that it's used in a lot of high-end Indian food. So they've used it for diarrhea, bloody diarrhea, before beefy. It's being studied, I think, that NIH has like 13 funded studies just for turmeric to see if it actually helps with. The first actual FDA approved drug was, I think, inbrella and so tannersep was the first one for rheumatologic diseases and infliximab was the first one for Crohn's disease. So a little over 10 years of experience with those so far and the next one was humera for rheumatologic disease. And then over the last two or three years, there's been these two other new ones which aren't used even close to as much yet. So inbrella and infliximab, I think there's probably over 300, 400,000 people in the country. So most of the studies or most of the data is collected from people on either infliximab or tannersep for prevalence of diseases. So a tannersep, for example, looking back through all the studies, incidence of demyelinating disease is about 30 per 100,000 people that are exposed to a tannersep. And the general population, just to kind of compare or put into perspective a little bit, of people with MS is about five per 100,000 per year. So there's 8,800 new cases per year of, so it is a lot of alpha blockers. So that kind of raises the question or it kind of points more towards directly causing demyelination rather than just unmasking it in previous cases. Right. Definitely, yeah. Yeah, and so not a large group. I think the biggest one that I saw was like 15 people at a time with rheumatoid arthritis who had MS at the same time or who were diagnosed with both of them. But I think there's a connection. I didn't really look into exactly what the connection was or anything, but I think for a long time people with psoriatic arthritis, MS, other autoimmune and rheumatologic diseases, there's always kind of this connection with these inflammatory diseases, but I don't know. I think people are kind of looking at that still. And so there's not a whole lot of data, the biggest one I saw was 15 people. The most common symptom associated with a demyelinating disease that they find out that who are exposed to a tannersep is peristegias and then optic neuritis is the second most common one. And the approximate time with the a tannersep anyway, that the FDA has seen is about five months, so it is temporarily related that way. So long-term safety, so they did do a meta-analysis of 22 clinical studies with just a tannersep. And so interestingly, I'm not sure the importance here, but there are about 4,000 total patients, so 3,300 younger people under 65 and then 600 over 65. Interestingly, about eight of them had demyelinating disease that were under 65 exposed to a tannersep and none over 65 don't know the importance there. But there's been no clinical trials about any a tannersep in patients with MS and there's good reason for that. But other TNF-alpha antagonists, one really similar to a tannersep that's not FDA-approved is lintercept and that's been associated with worsening MS. And so I'll show one slide on that. And so just really quickly, in a TNF-alpha is very associated with these inflammatory diseases. Like I said, it's in the synovial fluid of people with rheumatoid arthritis and things like that. But it's also found in high levels in people with active or progressive MS. So it's identified in active lesions and autopsy specimens. It's toxic to oligodendrocytes and vitro. It worsens the experimental one with the mouse when you give mice with this, it actually worsens that. And they have elevated, patients have elevated levels in the serum and CSF in progressive MS, macrophages from MS, red blood cells or other blood cells of people with progressive MS. And so this was really the first big study that really looked at a TNF, or an association between a TNF sclerosis. And so it was a two-year study and basically the graph says that also really all they did was look at the TNF-alpha and the CSF and serum and compare that to how people's physical exam was or their functional exam was. And so they just said that there was probably a direct relation between the level of TNF-alpha and how badly they were affected. And this is the little mouse model that's been around forever since the 1930s. The pathologically looks like MS in humans. And so this kind of sparked a little bit of the interest in using TNF-alpha antagonists for patients with MS in the 1990s. And so the reason was because when they give TNF-alpha to these mice, it actually worsened them, worsened the disease and killed the mice. But when they gave them a blocker, a TNF-alpha blocker, it actually prevented the patients if they got an early, or the mice prevented them from getting the disease. So that just suggested that depleting TNF-alpha that led to this study in neurology was basically the lintercept, which is the same as a very similar to a tannercept, multiple sclerosis study group in 1999. And they actually had to stop this early because the patients were getting harmed, basically. So the results were that exacerbations were significantly increased. They occurred earlier and neurologic deficits were more severe than people who were not exposed to lintercept. And so this brought about a little bit of caution from the FDA. They looked at 19 people who were exposed to a tannercept or infliximab, who had demyelinating disease, and they said that all of these neurologic events were temporarily related to the medication. And then when they stopped it, all of them had partial or complete resolution on discontinuation. So they said avoid these in patients of known or suspected MS. And so I'm just gonna show a couple of quick cases. I thought this was funny because this is from the Journal of Rheumatology. So they're advertising for infliximab, but then the title of the article is a tannercept and this MS in transverse myelitis was kind of funny. But this was a very similar one to our patient that we saw. So it was a 57-year-old female who had rheumatoid arthritis on methotrexate, then put on a tannercept as an adjunct, and then ended up having demyelinating and a little bit of transverse myelitis or partial myelitis. So they stopped the tannercept, her MRI is right there, she had positive olgoclonal bands, and it was presumed that she had pre, and she had no changes with her fall. That's different than this one. This patient with rheumatoid arthritis or a sudden onset of blurred vision on steadiness who continued to get worse after the tannercept. And her initial MRI showed a bunch of lesions within follow-up imaging a bunch more. So one of their conclusions was people tend to get worsening lesions even up to a year later, and then a lot of times it kind of stabilized, exacerbated lung. This one is interesting, it just looked at, this was kind of a review in PubMed of about 15 patients with optic neuritis who had gotten either influx and abs, the tannercept or adelining abs. So this was looking at the results a year later. So following these patients for a year, all with optic neuritis, nine out of the 15 of things complete resolution, no new demyelinating lesions and near complete, back to their baseline with their vision who had partial resolution with some problem, but then four continued to have new lesions and new symptoms a year later on in the MRI. So their big conclusion was to treat it like treatment and stopping the, so one of the big questions still that everybody talks about is do they cause direct demyelination or do they just unmask worse than previously undiagnosed or even subclinical multiple sclerosis in people that are susceptible? So a lot of people have come up with ideas about tumor necrosis factor, alpha, having to have this kind of balance to make the pro-inflammatory regulation either way stable. And so either overproduction or excess of blocking of TNF alpha, they say can give rise to this imbalance. And the thought is if there's too much TNF alpha, like known with MS or these other disorders that actually just allows cells into places they shouldn't be like the CNS. Whereas if you have too little it doesn't initiate myylation but it makes it so that it just cannot stop the demyelination. But it sure appears to cause de novo, occurrence of demyelination. And there's no long-term data to really see if people are worsened or if they continue to have MS after they're exposed to this. So the only cost effective way to really look at people it's such a low incidence is really just see if they're at risk of the family history and then kind of an MS history rather than getting an MRI. And then the workup should be the same as for like a clinically isolated syndrome or an MS flare. And as we saw, the TNF alpha is definitely associated with multiple sclerosis and it worsens EAE. And then the other thing to kind of just watch out for is as all these new TNF alpha blockers are coming out and are being approved and used for more and more things. There's been no reported cases in literature on the Golanumab or the Sertilizumab that came out in 2008 and 2009. So these don't even have a label. They're so similar to Adelumumab. So all the other ones do have warnings against demyelination, but those ones don't. And so we'll probably end up seeing something like that in the future. All right, our next speaker is gonna be Dr. Katz.