 Welcome back after Thanksgiving. I hope everyone had a wonderful holiday. I'm very happy to be here today. I know this year I was pretty happy on Thanksgiving to have joined the Marianne family. So I've really enjoyed the past six months that I've been here so far. If you haven't met me before, I'm Carolyn Craven. I am part of the medical retina team with UBI-DIS and ocular oncology and a little pathology on the side. Today is our annual retina grand rounds and so we're gonna split it into kind of two parts. The first part will be presented by our wonderful fellows. We'll start off with kind of a nice smattering of retina that you might find in my clinic with the side of genetics. So we'll start with Dr. Koehler. That's okay. Hi everyone. So this will just be kind of a basic introduction to what we do in our retina department when we get referrals for inherited retinal disease. I have no financial disclosures. Inherited retinal disease is a very broad topic and it's becoming more difficult every year as the number of genes that are identified for different inherited retinal dystrophies expands. In our clinical exams, while they are great, they can only get us so far. And that's because there's so much heterogeneity in the field of genetics where multiple genes can give rise to a similar phenotype or a single gene can give rise to several different diverse phenotypes, one being PRPH2. So ultimately we rely heavily on genetic testing when evaluating these patients and maybe the diagnosis of just like retinitis pigmentosa is not sufficient anymore for these patients. And to explore that idea, I'm gonna present a couple of cases. The first is this 23 year old male who was referred to us. He has mild nyctalopia and photophobia and he has two uncles who have some sort of vision problem and his brother seems to have problems with nighttime vision too. So already there's this theme of male predominance in this family. You think about an excellent disease with this patient. Vision's very good. He's 20, 20 in both eyes and he has some constricted visual fields to confrontation. And when we work these patients up we get a lot of imaging for many different reasons but optosimaging is extremely helpful in these cases. And you can see in this patient he has this blonde fundus but there's particularly a lot of choreoretinal atrophy in the mid periphery and encroaching on the phobia as well. And it's fairly symmetric in both eyes. This is also identified on his wide field fundus autofluorescence which you see these patches of hypo autofluorescence and also this ring of hyper autofluorescence in the macula of both eyes. And then OCT imaging is critical. We wanna look at the anatomy of the retina is particularly the outer retina and you can see at first glance it may look fairly normal but there definitely is easy loss and ELM loss temporally. There's also trace amounts of intra retinal fluid near the phobia in both eyes. And visual field testing is also critical for these patients. They may not complain of visual field loss but sometimes we find that they have only like 20 degrees of vision and they're driving. And so having this to just alert them and also to follow is extremely important. And you can see this patient has constricted visual fields in both eyes with various scatomas. So not surprisingly, we recommended that he get genetic testing and we'll touch a little bit more on this later but he underwent in vitay testing through a saliva swab and that showed a CHM mutation which is diagnostic for coridaremia which is consistent with his clinical picture. And that's a very critical point that we'll also talk on in the next case a little bit about the genetic testing being consistent with the clinical picture. So coridaremia is rare, excellent recessive as we expected from his family history. And it's this result of a CHM mutation which is involved in intracellular trafficking in the RPE and photoreceptors. And it typically presents in the first and second decade of life. And this is also critically important because these patients are young, they're starting to learn how to drive or they already are driving. They're also maybe in high school or getting ready for college and thinking about what careers they wanna have. And so having this knowledge of what sort of genetic disorder they might have and arming them with that so they can prepare even if it's for decades ahead so that they at least think about that when they're considering a career path because not all career paths are good if you're going to lose your central vision in a decade or two. But these patients can retain very good vision, 20, 20 vision even into their fourth and fifth decade of life sometimes. But there is hope for these patients. There are several clinical trials ongoing for coridoremia. One recently finished that was looking at a viral gene vector. And the FDA is always interested in visual acuity and improvements and not a loss of visual acuity but it's kind of hard to study that in these coridoremia patients if you only have a year or two of data because if they retain good vision for decades it may not be the best identifier for their disease course. But there are other clinical trials still underway one of which the Moran is a part of with a 4D-110 viral vector which is intravitual injection and we have a few patients involved in that trial. And then it's also extremely important to look at the natural history and that can empower patients to know what to expect. And so that's also why we get so much imaging when they first come in and we wanna follow them every year or two to see the changes and to at least describe to them and show them what's happening if they're not aware but oftentimes they have a general idea that they know each year their vision is getting a little bit worse. And there are other clinical trials going on elsewhere. So the highlights of this case is just that genetic testing can be extremely helpful for diagnosing patients. It also helps you identify family members that are at risk and for family planning for these patients whether they want to have kids or if they do not. And also the genetic testing is extremely important for identifying if they would qualify for any clinical trials. So our case two will touch on these topics a little bit more and go into a few other ones but this involves a 38 year old female who was referred for peripheral pigmentary changes. She's completely asymptomatic. She had just gone in for updated glasses and got a dilated eye exam. Her vision is 2020 and 2025 full visual field to confrontation and her macular fundus autofluorescence looks pretty normal overall as does her OCT. But you can see on Optos imaging that she has diffuse peripheral and mid peripheral pigmentary changes with a fairly hard demarcation line that's pretty close to infir arcade. And this is also evident on the wide field autofluorescence and her visual field testing showing significantly constricted visual field particularly in the upper field. ERG showed reduced amplitudes in both photopic and scotopic lighting. So for her, you know, not surprising differential inherited retinal dystrophy but you might be surprised that I put allergeal syndrome on there. And this is why the clinical exam is still extremely important for these patients. So briefly, allergeal syndrome, I know as a resident, this was always sometimes frustrating to get these consults in the NICU to evaluate and try to diagnose babies with this. But it's an autosomal dominant inheritance pattern. Jague one is one of the mutations that's responsible for greater than 90% of these cases but there's also this other mutation notch two that's present in about 7% of patients. And this encodes this transmembrane protein in the notch signaling pathway but these patients can have multiple systemic issues related to this disease as well as many different ocular findings. And so using the exam to identify some of these abnormalities can help you decide what sort of genetic testing to obtain. And I bring this up because looking at Dr. Bernstein was part of an article that looked at the systemic and ocular findings in allergeal syndrome. And you can see that the auto fluorescence looks fairly similar to what our patient has this hard demarcation between hypo auto fluorescence in the periphery and normal to hyper auto fluorescence closer to the macula. So we refer this patient for genetic testing and also to social work and possibly low vision if they are interested at this time but they don't always pursue that right away. But I bring up this example because there are so many genetic retinal panels that are available and we rely heavily on Emily Spoth our genetic counselor to choose the panels but it also is in discussion with us about our clinical findings and our differential. And so this just shows through blueprint genetics some of the various panels that they have available and there is some overlap between these panels but one of the panels is the My Retina Tracker program panel which comes at no cost to the patient and covers 351 genes including some mitochondrial genes and 351 gene sounds really good and might be enough but not always in every patient and they also get genetic counseling as part of this program. The print out this is not for our patient but just an example comes like this there's a lot of information here but it essentially says what mutation they have whether it's pathogenic whether it's a variant of uncertain significance and it gives you an idea of their clinical report the mutation it describes families that might have this the studies that have been that have undergone to determine whether it's pathogenic or why it's a variant of uncertain significance and the ultimate conclusion. And so most of the time our genetic counselor will go over those results with the patient but this patient she had previously undergone My Retina Tracker program paneling but that does not include the notch two testing she had a couple variants of uncertain significance which are seen in Usher syndrome but her clinical exam is not consistent with Usher syndrome and then she also had this SLC2 for a one mutation which is seen in congenital stationary night blindness but that's an autosomal recessively inherited disease and this would not be responsible for her findings. So her clinical exam given the thought that this could be allogial syndrome she needs further testing and we advise that she get notch two testing and we're awaiting those results but it just kind of highlights that even though we have great panels and they cover a lot of genes you still have to perform a really good clinical exam to evaluate these patients to determine what genetic panel would be best for them and also keeping a database of the community and these genetic mutations that are common in the community can be extremely helpful for knowing what patients would benefit from future clinical trials such as we have the Luxterne sub-retinal injection that's available for RP-65 patients and certainly there will be other gene therapies coming down the road in the coming decades. So with that, I'm gonna hand it over to my co-fellows and Dr. Craven who will build on these ideas as well but I welcome any questions, yeah. It's not been amazing to me people with such profound visual flip effects would be totally unaware that they have that problem. Yeah, I think support for us understand there's work needs to be done is but I'm confident that the brain it kind of fills in these gaps and it just kind of averaged out like it doesn't have a blind spot for instance and it takes a little from one side to the other. It's so we need to be aware that often these people don't have an idea how dangerous they are although suddenly we could get with that axi if they have a patient that happens once. I had no idea that suddenly this little kid showed up this little child showed up out of nowhere on a bicycle and he hit him and killed him and of course that was a horrible event. He had profound visual field defects. There was no way he should be driving. He had no idea. So patients often aren't aware of that aspect little macular change boy they see that immediately but a lot of peripheral fields until it's very advanced they have no idea that defect is there. I would agree 100% with that. I'll let Dr. Bernstein comment. Yeah, I'll just kind of comment and I think that there will be more in the upcoming talks but our genetic counselor is a really great resource and we really need to use her even more than we are. She keeps a great database, she's very knowledgeable and interact and most of her work is coming from retina but there's a lot of other genetic diseases out there and the other specialties and you just, she will help guide you through it. Now we're lucky in retina that these are covered by my retina tracker so it's, this is $1,000 worth of testing that they get for free and they, all they have to do is fill out some online surveys and that's about it and patients all wanna do that if they're interested but it has to be retina, they will only pay for retinal degenerations and other things. We don't do it for AMD, et cetera. So just use her and I get more than enough referrals from all of the Intermountain West for all the inherited retina diseases. There's huge amounts but she really helps support what we have but for the patients that do come in, they have to be warned this is a half day to a one day visit. There's so much testing that's going on that they just have to be, they have to come in with reasonable expectations when they're coming in and we're not gonna solve everything but we can solve a lot. I just briefly wanna say like in regards to the other genetic testing, you can see like through blueprint genetics, a lot of it is retina but there are other subspecialties identified on here, even like a cataract panel for genetic testing. Oh yeah, it wasn't what I was gonna say but Paula, I mean I think in pediatrics we see a lot of patients who have these kind of vague complaints and then have some retinal changes for which we suspect a dystrophy and I have been sending these, a lot of these drunken families both and I feel like before her, I would sometimes try to find which panel to order which was kind of difficult to navigate and now I'm just having her not only select the testing, I mean I just simply just send them to her. Is that the right process or do you want me to send them to you first and then you guys kind of involve families both? Do you have any preference on that? Okay, I guess it's louder here, I don't know if that one's even working but online, okay, all right. She will just work with you. I don't think every retina, if you are a good, if you feel confident that there's a retinal dystrophy and you feel confident in your practice that you can manage this, you can order the testing with her. So because the wait list for me is three to six months now for a retinal dystrophy for an inherited retina disease slot and I'm trying not to get overloaded. I can tell you that a lot of your schedulers try to sneak them in and then I get three new inherited retina disease patients at one time in a clinic and no one's happy with that, so. If you're ready to share the burden. Yes, yeah, I'm ready to share the burden. So if you feel comfortable, she will guide you through and go through which panels and what can be done and the costs. She has enough time to do that. Okay, I feel like I'm sending her maybe one or two referrals a week because with the cataract, with the congenital cataract, I send those to her. A lot of the abnormal genetic congenital stuff that we see, I find she's been incredible for. Yeah, and she has the capacity and the desire to do more, so. Okay, and one other just kind of question or thought. I feel like the most sensitive screening question I've had for my pediatric patients for whom I suspect a retinal dystrophy is Nicolopia. And is that seem true to you? I feel like that's very, at least for classic RP that will be their first symptom. Gotcha, and what's interesting, just having had Halloween, I feel like I'll see one or two cases almost every year of parents who found their kid was blind on Halloween because they had actually never been out past dark. And then on Halloween night, they just suddenly are just lost and they can't, they can't see that, you know, because they just usually not letting them stay out till that late other night. So, interesting aside. To kind of follow up on that, I think there's a lot of kind of good points that were brought up here. One was what Dr. Wilson was bringing up is patient awareness. And when we have our patients who have developed symptoms as a child, they've really adapted and they don't really know what they've lost unless it's very profound vision. And so some of the patients are really shocked when they hear about their diagnosis and what they're trying to tell you. Our next case, absolutely, absolutely. That would be exemplified by this next case and this inability to really process and kind of claim these diagnoses. And it's hard because it's such a radical change in the patient's expectation for the next couple of years to decades of their life. And sometimes this requires multiple conversations with them. Sometimes it requires talking to their families and kind of the art of breaking bad news and kind of asking the patient, how do you feel about this? What's your awareness? Do you feel safe driving? And kind of get them to come to these conclusions to hopefully they will admit to themselves that yes, maybe they're not the safest or their spouse is saying, I'm terrified when they're behind the wheel to get them to genuinely stop driving and making these lifestyle changes. Emily is a phenomenal resource. I got my start in medicine actually working with genetic counselors at Ohio State and it's spending time with them and seeing all the work that they go into taking care of these patients is really impressive. And so a lot of times we think about making these diagnoses and it's getting to the point of just getting that test result. But what genetic counselors do is they do a lot of work upfront with the patients before even getting to the point of collecting the swab and sending off the sample. And so they really kind of brace the patient on what to expect and what type of results they might find and how that might be applied to their next visit and their future care. And so there's a lot of involved conversation with Emily and the genetic counseling upfront and then also after the results come back and in the future. That's very helpful and it's also helpful to kind of revisit genetic counseling with our pediatric patients once they become adults because some of these topics might have been discussed with their parents or when they're teenagers and they're not really paying attention but once they get into further into their adulthood some of these concerns might surface a little bit more. So with that, Dr. Fuller will present our next case. If you've lost the mouse. All right, thank you. Yeah, great turnout, great comments. You've all pretty much given every point I want to make in my talk, which makes it easy. We're also running a little bit behind so I'm just gonna try to get through my slides pretty quickly. And I guess one point I'd like to make on the front end is Dr. Bernstein's really busy with IRDs. He and the fellows and the residents on service all feel that's the text and all the staff. But this patient is someone that Dr. Bernstein saw and then also Dr. Craven saw. So I guess if there is some kind of maybe urgent need or maybe as also as another resource someone, I don't know how much you're wanting to like advertise yourself as an IRD referral physician but Dr. Craven's amazing. I've done practice in my fellowship training and I was very proud that at Groening Memorial Hospital I was able to kind of bring blueprint testing to this underserved population. And we found in our, in my general medical retina UVitis clinic over a dozen patients in a year that ended up having an IRD that really changed the course of their treatment and expectations. So I do have one IRD slot a week, not including the macular degeneration patients that gets the appointment. So it is an ongoing kind of balance like Dr. Bernstein was saying is that these patients take a lot of time to get through just imaging before you even start talking to them. But so I do see some IRD on the side. Yeah, and that's really the point of my talk is to highlight just the spectrum of imaging that we do for our patients. And also to highlight Emily Spoth, which we've already done but her contact information will be up here at the end for the community and even RAN people. And then also to highlight how genetic testing is useful, although not always I'm diagnostic. So I've no financial disclosures. I'm not talking about the Love Island show from Mallorca. Talk to this patients from Tahiti. You know, this is a book about Tahiti by Robert Langdon. But you know their name of Tahiti is the Island of Love. So this is a 65-year-old female from Tahiti she was complaining of as Dr. Dording said, Nick Tilopia, although she didn't notice it on Halloween. She also is having trouble seeing lines for the past year while driving other various, you know, visual functions or visual tasks. She has a history of diabetes, A1C controlled. She has a prior ocular history or diagnosis of age-related macular degeneration, non-exidative, she's taking IRDs too and last on outside ratness specialist a year ago. Her visual acutin the right eye is 20, 25 minus two, left eye is 20, 30 minus two, pressures are normal. No APD and anterior segment exam is unremarkable. The posterior exam, whereas, you know, James's case, two cases were kind of from the outside in, this one is clearly more from the posterior pole radiating outward. So you see this RPE changes and RPE loss and atrophy of the macular of both eyes as well as these, you know, yellow deposits in the posterior pole and then also mid periphery. This is an OCT scan that highlights the RPE loss and the outer receptor loss. You can see at the fovea, there's some preservation of the ellipsoid zone, which, you know, speaks to the patients relatively preserved central visual acuity. Here is the macular funnous autofluorescence which shows a patchy multifocal areas of hypo autofluorescence in the fovea and in the posterior pole extending to the outside the arcades as well as areas of hypo autofluorescence. This ERG, it's not gonna go into all the details but it essentially shows cone and rod dysfunction and definitely in the right eye and also signs of rod greater than cone dysfunction in the left eye. Dr. Bernstein also will sometimes get dark adaptation results or testing which just shows how symptomatic they are from their nyctalopia or if they're, you know, nyctalopia is a subjective experience for patients and so this gives a quantitative measure. If a patient's rod intercept is greater than 6.5 minutes then they have a positive or an abnormal dark adaptation test result and this patient didn't have that. This is mya microprimetry which basically tests visual field at very specific points within the macula. Most patients, if you can see my mouse on here should have their results being here in this bell curve but all these patients results are not in the bell curve and so this patient has abnormal kind of visual function in the macula as a result of the atrophy from her condition. This is a really cool scan. It's a high resolution OCT. So in comparison to the standard OCT that we get you can see a greater definition of the retina layers. You can see kind of more clearly how the RPE and the ellipsoid zone are preserved kind of right at the fovea there whereas here it's a little bit less distinct and yeah, just a really interesting scan to get and something we do for our patients. This is a fun test that is not a great result for this specific patient but this is macular pigment testing. So a normal macular pigment does not look like this and even this is not classically abnormal but except for the fact that the software is not able to get a proper standard deviation for the range of macular pigment for this patient the machine is trying to compare areas where there is macular pigment areas where there isn't in these rings and as you can see from all the blue and the green off to the left it's not able to really to get a good reading for this patient which makes sense because she has diffuse RPE loss. So her macular pigment testing is gonna be pretty abnormal. To Dr. Olson's point, this is a visual field where there's the central scatomas in both eyes but with both, sorry, in each eye but in both eyes, she's actually functioning pretty well. So I think these patients do compensate with both eyes open and do fill in the gaps by these little micro saccades. She had vitamin A testing which was slightly high so her vitamin A supplementation was stopped to avoid toxicity and she did get genetic testing which was inconclusive. She has pathogenic variants in PDE6C which is autosomal recessive and then she also has a surround sec, a pathogenic variant in PDZD7 which is autosomally recessive for non-syndromic deafness. So these are heterozygous mutations for recessive inherited rental degenerations. So looking a little bit deeper on the PDE6C this gene encodes the alpha prime subunit of cone phosphodiesterase and is mutations of this gene are associated with cone distribute type four. It's located on the QRM 23.33. If you look at the PDZD7, this gene encodes for a ciliary protein which is homologous to proteins which are mutated in usher syndrome patients. And if you look at the location it's on the QRM 24.31. So some usher syndrome patients can have an RP type phenotype. This doesn't classically look like that but is there some interplay between those two mutations? They're kind of closely together although I think chromosomally they're actually they've been out light years apart but probably on the order of something like that even though they look close on the screen. It's hard because these genetic tests they don't track all of the pathogenic variants. We're still learning about them. I'll kind of skip Dr. Craven kind of mentioned some of these factors. She can talk about it later. There's several papers that get into this variance of uncertain significance and different rates of these and different racial and ethnic populations. And this study said that there are higher rates among Asian, black, Native American, Pacific Islander and Sephardic Jewish individuals. I do think Dr. Bernstein does a really good job of even when he has nothing definitive to offer like in James' first patient. He tries to help these patients have hope in future advances. And I think this is one thing for this specific my specific patient is that even though the genetic testing didn't find her pathogenic variants necessarily it did add her information into the pool of the database for these genetic these inherited rental degeneration patients. And so this paper highlights that the disparities are hopefully gonna be mitigated over time as genomes from our individuals from these different groups are sequenced through large scale projects and as laboratories continue to share their information through ClinVar. So, you know, this patient although she kind of fixated on and didn't really had to have she has made major cognitive difficulties and it was hard to kind of counsel her on her condition at the same time to her and the family members that accompanied her I think keeping her in this database that Emily's both keeps can hopefully help in the future if anything does come up. So again, I just wanna highlight that Emily's both is a tremendous resource. You know, Marianne please people please refer to her. Also, I've seen some people from the community send patients directly to her and that's completely appropriate and encouraged. Here's her email and her cell number. She told me to put this up there. She wishes she could be here but she had another meeting that she at this time that she can't move. I just wanna say thank you for the to Dr. Bernstein, Dr. Craven, Emily and my co-fellows for the care of this patient and just want to end with that. There any questions? All right, and I think Dr. Craven might mention a little bit more about the some of the specific nuances of the care for the specific patient. So I think this is an interesting patient for a variety of reasons. One, the exam is so striking and so kind of what was brought up earlier getting genetic testing outside of your like dedicated IRD clinic. When you see something that seems and feel acts like a duck, cracks like a duck, you can go ahead and test to see if you can find that answer. You don't necessarily need all the advanced testing. That can always be done at a later time once they do get to an IRD clinic but sometimes I find the most valuable test and image is just the fundosado fluorescence. If there's one test that I never wanna give up it's that fundosado fluorescence. And then with this patient, she really exemplifies how we still have a lot of limitations to genetic testing at this point. I'm very grateful for Blueprint to be offering free testing for these patients. It makes it more accessible but it also kind of widens the net to really help facilitate getting just more data points to expand our awareness. And then the last thing is this patient came in and she did a lot of research on her own and Google and these patients are really fearful because they're losing vision. And so we have to be wary of what they might do and on their own to try and kind of improve their vision. So she was really fixated on having a vitamin A deficiency. And I always test for that in Nectalopia if you can find a reversible, easily treatable cause of vision loss. It's always good to rule that out but she had come with four bottles of vitamin supplements and that could actually be harmful, toxicity-wise for her. So I think having these conversations, this was a nice patient to present. So thanks, Spencer. Presenting another classic patient that might come into my retina clinic as one thing and turn out to be something totally different. Yeah, so I think the case that I wanna highlight, hopefully just kind of put together some of these things we talked about about the importance of kind of all of your information, your clinical history, really comprehensive exam and multimodal imaging and genetic testing to sort of get at what a diagnosis is when you're considering on the differential inherited retinal disease. So this was a patient, a 29-year-old woman who was referred for anterior uveitis of both eyes. She had no past medical history but she was diagnosed at age 11 with retinitis pigmentosa, which was diagnosed while she was living in Colorado in the setting of chronic nyctalopia. She wasn't on any medication. She didn't have any sort of obvious notable family hysteria than a great-great-grandfather with blindness of unknown etiology. She was Mexican-native American heritage. She grew up in Colorado and had no other high-risk exposures. On exam, she was 2025 in the right eye, 2020 in the left with normal intraocular pressures, no afferent pupillary, no relative afferent pupillary defect. And then jumping to her exam, she did have some signs of chronic anterior uveitis. So she had mild AC cell and flare in her left eye while on topical steroids. She had some structural sequelae with posterior synechia in both eyes. And then she had a fair amount of vitreous cell, one plus in the right eye and two plus in the left eye without haze. So this was her fundus photo of the left eye, which just highlighting, kind of showed this impressive sort of lobular, multi-sort of lobulated distribution of coriorutinal atrophy with associated bone-specule pigmentation within the atrophic areas. And there was some waxy appearing pallor of the nerve and some vascular attenuation. And then also I'd highlight that more peripherally, you have some of these more punched out coriorutinal scars in the left eye, sorry. And then this was the right eye going in reverse in very similar sort of symmetric appearance, also highlighting that this patient had a PSC cataract. And again, the sort of lobulated distribution of coriorutinal atrophy with bone-specule pigmentation and these more peripheral punched out coriorutinal scars. The autofluorescence corresponded kind of to that distribution with hypo-autofluorescence within these areas of atrophy. And then the OCT showed what corresponding to that was just sort of diffuse outer retinal atrophy sparing the central sort of foveal distribution with a cystoid macular edema in both eyes. Fluorescine angiography showed essentially large window defects corresponding to these large areas of atrophy without any sort of notable peripheral vascular disc leakage or active retinal vasculitis. Her goldmine visual field showed what one might expect with these sort of paracentral scatomas related to the coriorutinal atrophy and then full field ERG showed sort of generalized reduced rod and cone responses sort of generalized retinal dysfunction of both eyes. So getting more into sort of then digging into the clinical history. So again, this patient reported longstanding nycrolopia since childhood in which this diagnosis of RP was made. But she also had several other features that sort of lent itself towards a different diagnosis. So she had vitiligo involving her neck and her face. She had areas of poliosis of her eyebrows and eyelashes. She had prior instances of alopecia that were involving patches of her scalp and groin area. And she had chronic headaches with pretty significant high frequency tinnitus, all of which as far as she could remember started kind of after or kind of in the context of when her vision issues started. So this patient was referred for genetic testing which ended up coming back negative for any explanatory mutations for this patient's phenotype. She had two variants of uncertain significance, one of which associated with Usher type 1D and then the other one associated with cone rod dystrophy and retinitis pigmentosa. So this patient was actually felt not to have retinitis pigmentosa but actually sort of manifestation of chronic VKH or vote Koyanagi-Harada disease which is a bilateral granulomatous pan-uveitis that in the acute phase presents with these sort of multifocal exudative retinal detachments as well as typically other extraocular findings including neurologic and skin findings that our patient had. And it's more common in Asian, Hispanic and Native American ethnicities as consistent with our patient. And really the findings of it, again getting towards what I'll talk about is just sort of the differentiating features sometimes of overlapping with inherited retinal disease is that depending on the stage, the findings can differ. So in the acute phase, you get this, again these sort of acute pan-uveitis with these active multifocal serious retinal detachments and corral thickening, but in the chronic phase which is typified by sort of this chronic atrophy related to autoimmune destruction of melanocytes. You get this generalized retinal atrophy with a classic Sunset Clofundus and you get depigmentation elsewhere such as classically described of the peri-limbo region and then on the skin involving, you know, vitiligo-poliosis alopecia. And so this patient actually met complete criteria for VKH based on all these findings with her chronic choreorentinal atrophy with this numular choreorentinal depigmentation, RP, clumping and then her neurologic and skin findings which were all very consistent with VKH. So I wanted to sort of use that to sort of lead into just talking a bit about kind of the mimicers and things that one might think of on the differential with inherited retinal disease such as retinitis pigmentosa. So RP is a group of progressive inherited retinal diseases that's characterized by photoreceptor degeneration and pigment accumulation. And with that being a group of diseases it's characterized by a very large range of both genotypic and phenotypic diversity as we've talked about. And so patients can present a sort of variety of ages, rates of progression, degree of visual impairment and so forth. But the characteristic clinical exam findings are gonna be your bone specular retinal pigmentation, retinal vascular attenuation and waxy optic nerve pallor. So I think the first sort of instance in which it might be a bit more straightforward to think about a sort of the things that can mimic RP is this entity call of unilateral RP which is actually felt to be quite rare. It was sort of on the order of around a hundred cases that have been described in the literature. And it's thought that true unilateral retinitis pigmentosa as a genetic disease is felt to be from a somatic mutation during embryogenesis that ends up affecting one eye. And so this was a case describing one such patient in which a patient over 10 to 20 years developed progressive retinal atrophy loss of ERG responses and concentric visual field loss and nyctalopia with a completely normal other eye. But in most cases, there's an alternative explanation that can be found for these patients with described unilateral RP. And so the things to think of would be things like prior trauma and retained intraocular foreign bodies that can cause chronic inflammation and then sort of the other things to think of are again chronic uveated conditions, infectious ideologies and toxic exposures like medications and so forth. And so unilateral RP as an entity is again defined by the typical RP findings in one eye with a completely normal contralateral eye including examined full field ERG and then the exclusion of infectious inflammatory and vascular ideologies that also can cause RP like changes. And in addition to one time point, this is something that should be followed over time because some patients with RP can develop, can be just sort of asymmetric in each eye as a current. So one eye can develop findings later on that might actually be suggestive of true genetic disease. And so these are just some examples of that. So this is the left sides of perhaps more a clear etiology of a patient who had an intraocular foreign body that developed these characteristic sort of pigmentary degenerative changes, diffuse unilateral subacute neurorhetonitis or DUSIN which is related to nematode exposure can cause chronic changes simulating RP unilaterally in which case is only about 25% an actual worm or nematode can be found in the retina. And Azor is a common one as well as a uveatic or inflammatory disease that can both spread and involve a very large portion of the retina either from around the nerve or extending centripetally from the periphery and eventually developed these bone spiculite changes and coriorentinal atrophy. And typically at least to start 60% of the time will be unilateral. And so again, this is looking at kind of a table of a case series of patients that had other etiologies that were found in patients who had RP like presentations. Now just highlight this to say and to kind of go reinforce what we've already talked about which is the importance of clinical exam, your multimodal imaging and history. And so patients who present, for example, unilaterally a very late onset rapid progression who have associated risk factors such as medication exposures or cancer history or patients that you would want to think about potentially an alternative explanation especially if the clinical exam findings are not typical for an inherited retinal disease. And then the last thing just to talk about is that there's interplay. And so there's increasing amount of literature looking at the inflammatory and autoimmune mechanisms that are associated with inherited retinal diseases. And so you can imagine that as cell photoreceptors might be degenerating or related to genetic process that you have a secondary autoimmune or inflammatory response that then might contribute to some of the findings that you see in these patients. And so there can be a lot of overlap with uveidic patients. And so this is just another case series looking at patients with bilateral RP like changes that were found to be related to ultimately uveidic conditions. In most cases intermediate or posterior pan uveitis. And I think just to take away again is that there's several features that are just really important to think about and the importance of these very extensive kind of comprehensive evaluations for these patients. So history-wise differentiating between the two the degree of vitritis tends to be more prominent in uveitis as opposed to IRD. But vitritis or some amount of vitria cell can be seen in up to 40 to 50% of patients. It tends to be low grade without snowballs or snow banking. But can overlap between the two. Retinal vascular leakage can be seen between the two but tends to be more severe in true inflammatory or uveidic disease. And then as in our patient the distribution of pigmentary changes which in contrast to a genetic or kind of classic inherited retinal disease in our patient being more multifocal he's punched out lesions and multi-lobulated and then your genetic testing. And so genetic testing doesn't exclude the possibility of an inherited disease but can help confirm a diagnosis if you're between if it's unclear and if the clinical picture is consistent. So that's everything that I have as far as our patient. So this patient again with a suspected VKH diagnosis was started on immunosuppression and she had a significant improvement in her headaches and tinnitus and her active intraocular inflammation supportive of that as our diagnosis. One thing I wanted to bring up for our first years Marcus did a really nice job about highlighting the importance of history. And for our first years I wanna make sure you know how to kind of elicit some of these symptoms with a patient who has a raw dystrophy and nyctalopia. They're not gonna necessarily come in saying oh, I can't see in the dark. They might come in and say, oh, I can't drive at night and it might kind of sound like cataracts. So some of the classic questions you can ask are if it's a clear night, are you able to see the stars when everyone else would be able to otherwise see stars? Or if you're in an unfamiliar environment like a hotel room and the lights are off would you be able to navigate that? And a lot of patients will sometimes even volunteer that description of oh, I'm at a friend's house and I can't navigate in the dark. The same thing with kind of day blindness and cone dystrophy is people might not always complain of things being washed out or having light sensitivity. You might see kids that are squinting a lot and it might actually be that they finally get better vision from limiting the light entering their eyes and recruiting more of their rod function. So if you kind of really listen to these kind of descriptions that your patients are giving you that can really start leading you down the road of considering an IRD or something else. Okay, so in our last 10 minutes I'm gonna kind of switch gears. I thought it would be good to address where we stand with geographic atrophy. I know that a lot of patients are starting to come in and ask about these new injections and this might be something that our comprehensive doctors and our optometrists and everyone in between might start getting patients asking questions about these. So I thought it would be good to kind of address kind of the changes that have been happening in this landscape. So you're a little bit more aware of these questions and answers. I do have some disclosures. I'm a sub-investigator for some studies that don't really are not relevant here. Just to start off, I have this patient came in. I was told by another doctor, maybe I should consider having that new medication that they're seeing on the TV commercials. So the next photo is not gonna be any surprise to you. It's geographic atrophy. It was a 65-year-old white male who'd been following with his local eye provider for a long time for a couple of years and he had started to notice his central vision. He was declining, but he had never really seen a retina specialist because he was always told there was nothing that could be done for this. And so more recently, things have changed. And so with the recent developments in medications, he came in for a second opinion. And so here the OCT really demonstrates the geographic atrophy quite nicely with the darkening around the main lesions and then the hypotransmission defects in his central macula that are affecting his fovea. So he had 2,100 vision in his right eye and 2,070 vision in his left eye. So we discussed these new medications. And so 2023 has been really exciting. It's been the year geographic atrophy has had treatments finally come to market. So we have a peccidicoplane and a vasin captain. And so this is really exciting because over the past 20 years, we've not really been able to offer our dry AMD or geographic atrophy patients anything more than a rut. We have seen some exciting advances in our wet AMD medications and treatments that have come a long way. And so although these are the first drugs that we have out to treat geographic atrophy, we have had some trials and tribulations with them. There have been some concerns and some risks that have come up. And so I talk about these with patients and be very cautious in who's going to be a good candidate for these medications. But I also use the example that we have to start somewhere. And so we started back in 2004 with our early anti-vegeth agents and look at us now. And so hopefully this will continue to develop these medications for geographic atrophy. And so these are acting on the complement pathway. Like I mentioned before, these patients aren't necessarily being followed in the eye clinic because they have always been kind of just dismissed and said, there's nothing to be done until you convert. But geographic atrophy, some patients, it can be kind of slow, but in other patients it can progress quite rapidly over the course of a year or two years. And so these medications can really make a difference for these patients when it starts to approach their fovea. And so we're finding with C3 and C5 complement inhibitors, we might actually be able to slow this rate of progression. And so we talk about, I know Taylor Swift might be having her era of her chief's era, but I think we're more excited that we're in her complement inhibitor era here as I try and follow Spencer and her up-to-date findings. So AMD, it's a complex disease. There's many things that contribute to it. And so we're starting to really appreciate the inflammatory component. So we know diet smoking exercise, but we also have the lipoprotonaceous deposits that are sub-rentinal and sub-RPE that can be inflaming the RPE and causing accelerated damage and causing overlying damage to the RPE and photoreceptors. And so this is a target that we've found in cadaver eyes and testing changes in complement levels in these layers of the retina. So looking back at the complement cascade for medical school at a really basic level, the complement pathway is part of our innate immunity trying to attack and protect us from outside invaders. So it's trying to light cells, it's trying to kind of take care of damaged cells, it's trying to incite inflammation to help attack an outside infection. And then it also wants to clear these complexes. And so when this goes awry, it can be causing damage to the RPE and photoreceptors. And this is why this is a potential target. These three different pathways of this innate immune system kind of converge at the C3 convertase as well as the C5 complement. And so going through, we have Pixita Copeland, which was the first medication to come to market of note. Both of these medications are injected a 0.1 milliliter volume of medication. And so it's a little bit higher volume than we're used to. This medication can be dose every four weeks or every eight weeks. It has had some adverse events with endophthalmitis, intracular inflammation, ischemic optic neuropathies, and then a higher level of CNV conversion to wet AMD. And so I'll revisit this in a minute, but the second medication that's come to market is Avacin captain. This is the C5 inhibitor. This is also a 0.1 milliliter injection. So far it's been dose every four weeks for the first 12 months, but there's been recent announcements. I don't know if they've been formally published that we're still seeing a effect at every eight weeks of dosing. We're also seeing at 24 months that the slowing of progression in these patients, that benefit is actually doubled as time goes on. And so although these injections will kind of have to be done forever in these patients, there might be an acceleration of benefit as time goes on, but there's also data that says if we stop them, we can very quickly over six months lose any benefit that we have gained. With this drug, there has not been any endophthalmitis reported with it or any significant intracular inflammation or any ischemic optic neuropathy at 12 months. At that 24 month mark, there was one endophthalmitis and a mild intracular inflammation that was not vasculitic. And so a little formatting issues here. So a couple of months after Pixita Copeland came to market, there was an alarm that there were initially six case reports of a retinal vasculitis that there were initially six and now that there's been eight, five of these have been inclusive vasculitis. Three of them have been not inclusive vasculitis. We didn't really see these in the studies, but of course this is something that we fear, especially as we might be treating our patients better. I, these have been all seen within the first one to two weeks after the patient's first time injection. Overall, this has been a fairly low rate, but still very much in the front of our minds. That we have to look out for. In review, there's been no change in formulation between the study supply and the commercial supply to explain these cases. The company did stop distributing kits with the 19 gauge filter needle. They were distributing both 18 and 19 gauge filters. It's not unsure if this is the cause, but something we consider. Overall treatment considerations for our patients, these drugs can increase the risk for conversion to wet neovascularization. We can't necessarily do planned injections. We still have to monitor for this conversion. We also have to monitor the optic nerve with these higher volume injections that might be stressing the optic nerve. We can monitor with OCT, RNFLs and auto fluorescence more than we would with our wet neovascular degeneration. It's okay to continue injections if you've seen mild inflammation once it's quieted. And if they do convert, it's okay to treat them with anti-vegetation currently. And so as we kind of navigate these risks, we look to our patients who are gonna be at higher risk for fast progression, especially if they're at an early age. If they have certain characteristics of their geographic atrophy or features on imaging that might pretend a more aggressive course, they would be good candidates for this, but we do have to make sure that they have proper expectations that this slows progression, but it does not stop it. And so they still will continue vision loss and then otherwise need these injections long-term. Future therapies, kind of just real briefly, we're trying to do a wide variety of treatments. There's other modalities that are being tested, targeting the complement pathway. There's also genetic therapy that's both targeting optogenetics and trying to kind of restructure and repurpose working parts of the retina, but there's also gene therapy to help incorporate instructions on making some of these inhibitors to prevent the need for ongoing injections. And then there's also kind of repurposing oral medications that are widely available and easily tolerated. So we have a lot of exciting kind of potential in the future. Some of these studies are being done here at Marianne, but hopefully we will see as much advancement as we've seen in what AMD that we'll see in geographic atrophy, but we do have something to offer our patients with very specific considerations. So I don't know if anyone has any other questions or comments that I know we're a couple of minutes over, so I appreciate everyone's attention. This is great, thanks.