 Okay, so today we're going to be talking about mainly retinal dystrophies. We usually don't have time to go through retinal and macular dystrophies, both macular dystrophies and retinal dystrophies in the same one. But for those of you who've been in my clinic, you know that I'm the main referral person for the Intermountain West, really, for retinal degeneration. So I'm going to give you my approach to how I deal with these patients and get them the care that they need. And you'll see that they do take a lot more time than an average retina patient. And when they come in the way I run my clinic, I try to have, I'm working on trying to adjust my clinic so that I see one new retinal dystrophy patient per clinic, not two or three as they sometimes try to put into my clinic. And you'll also see when you come into my clinic that we're trying to get them to come in early at the beginning of the clinic because typically their workup before they're even ready to see me can be three to four hours. And so they need to be, this is every bit as bad as neuroop clinic, I think. And they, so we have to really allow that the patients need to be aware. And a lot of the patients that are coming in to see me have already seen three, maybe four eye care specialists. They've seen their optometrists, they've seen ophthalmologists and a lot of, and they've gotten, by the time they've reached me, they've had, they have a lot of misinformation, a lot of apprehension. They generally have been reading on the internet already and reading a lot of getting, you know, seeing a lot of variability actually most of the stuff on the internet is probably pretty depressing for them to look at. And so we have to give them some hope and so I've tried to do that. Plus there's a lot of misinformation as we'll see on the internet too that gives them false hopes and can take their money and can take and give them essentially bad care and perhaps even put them at risk. So these patients just take a lot of extra time. When I came here 21 years ago, that was one of the reasons I was brought on is that I did have at least a reasonable expertise in the care of these patients and was willing to take them on as part of my reason for coming out here. So we'll get started here. And there are a variety of retinal dystrophies that I see. The ones that are the most common include retinitis pigmentosa and we will go into that more in detail. There are syndromic retinopathies which means that's retinitis pigmentosa or similar diseases plus other systemic manifestations. I would say compared to some of my colleagues at other institutions, I don't have as many as you would expect as other institutions have. That may be just the referral pattern here, it may be just the genetic population here but there aren't, most of the cases that we'll see in my clinic are pure ocular diseases. With the exception, unless you want to talk about things like Usher disease or things that have just one other manifestation like hearing loss. But in terms of real, uncommon, rare, multi-system diseases probably you're not going to see a lot of them in my clinic. The other one that I surprisingly see very few of are stationary retinopathies. This is things like congenital stationary night blindness and I'm kind of mystified at that. If I talk to my other colleagues, I don't see, I just don't get that many referrals. Don Creel is very good, is a very good electoretinographer and some of these have very characteristic patterns but I just don't see them very much and maybe I'm under diagnosing them or missing the diagnoses or people don't complain enough. But stationary retinopathies mean that they have some sort of manifestation similar to retinitis pigmentosa in terms of poor dark adaptation, other problems like that but they don't get worse as opposed to RP by definition, pure retinitis pigmentosa is a disease that will get worse. Then cone dystrophies which we'll get to later on in the talk, I would say are very common here in Utah but they tend to be macular cone dystrophies. I see a lot of these that are kind of hard to diagnose, they tend to not have good genetic diagnoses but they tend to be atypical here would be my impression. Toxic retinopathies you always have to keep in mind, I've picked up a number of those through the years where you just have to, where you see a retinitis pigmentosa or some other retinol degeneration that just doesn't totally make sense and then you do a little more of a history, make sure that you do occupational histories, histories of joint implants, other things like that, you may pick up some toxic retinopathies is basically what I'm pointing out and you also want to do a good drug history and then there are pseudo retinopathies which means that they look like retinitis pigmentosa or similar diseases but they don't have, but they're not inherited and they often are somewhat atypical in that they may be unilateral and they may be post-inflammatory or some other problem and we'll go into all of these in more detail. So retinitis pigmentosa is a disease that you will see if you spend a little bit of time in my clinic. The estimated prevalence in the United States and elsewhere and worldwide is about 1 in 3,000 people are affected so that means there are over 100,000 people affected in Utah and if there are 3 million people in Utah, we're talking about, I think, what is that, make about 1,000 people with retinitis pigmentosa here in Utah and this is the most common inherited form of blindness that is found and there's a large variety of inheritances, we'll go through that, essentially every type of inheritance has been described with retinitis pigmentosa type syndromes and they also have a very, they have a large clinical variety of clinical courses and genetic causes. So that's an important thing just to keep in mind. Patients who come in with the diagnosis of RP are going, they will have read on the internet and they will see RP as a blinding disease, they claim and I don't know if this is really true but they often say that their doctor said, yep, you have retinitis pigmentosa, you're going to be blind in five years and then just walks out, I hear that story all the time and so hopefully the people in this room will not do that and understand that there's a lot of variety and either you need to know what you're talking about or you need to show some compassion and refer them on to someone who knows what really is going on with the disease. And the problem has been and still is that there's very limited interventions that are truly effective and available for the patients. So patients with RP, when I take the history, their classic complaint is usually night blindness and that they can talk about, they often say that's been true all of their lives or since they were very young that they just didn't see as well as their compatriots at night and they tended to have more light on at night that there's just something different about and their parents may say that there's just something different about this child compared to other children that they have and it may not be all that bad but that's the first sign and then the next sign that the patients usually have if they have classic RP is that they start developing manifestations of decreased visual field loss or decreased visual field and if they have this they may have more trouble in sports, they may be bumping into people and things more than you would expect and then but on the other hand for pure retinitis pigmentosa, the central visual acuity and cone function is generally preserved until late in the course of the disease. So patients with classic RP typically will have 20-20 vision even into the, even at the point that they are legally blind with fields less than 20 degrees in each eye. So unless they have macular edema or other problems, the central vision is typically preserved but there's always exceptions and they may eventually have, they eventually will have loss of central vision plus they will also have, there are also things that are cone rod dystrophies, rod cone dystrophies where the cone system is also involved. And this is the scary part for the patients is that the end stage can include no light perception. So there's not a lot of diseases that we deal with, much more commonly in my clinic I'm dealing with macular degeneration where I can assure patients unless there's something really unusual, they're going to have their peripheral vision, they're going to be able to see the big picture of things, retinitis pigmentosa is a disease that has a very scary outcome if it goes to its end stage. And after you've taken a history and found out that the patient has symptoms, has at least symptoms that are consistent with RP, we take a look at the patient and look for the classic signs of retinitis pigmentosa. And the pigment of retinitis pigmentosa are bone spicules and that's shown, let's see if I can do this without, yeah. So these kind of clumpy pigment that doesn't necessarily, that can follow blood vessels but doesn't always, it's typically in the mid periphery here. There can be, there's a lot of different manifestations. Some patients have dense, almost confluent bone spicules here. Other ones may have just a few little patches is all that you'll see is manifestation of their RP. And there are some cases of RP where there's no pigment at all. So it doesn't have to be present. The other thing that you'll see is peripheral retinal atrophy, the pigmentation, the caroidal pigmentation that you see here just doesn't look quite as uniform as you would expect and you see down to the caroid a little bit better than you would expect. There is waxy pallor of the optic disc and occasionally optic nerve head drusen. So waxy pallor means that there's, it's pale and it just doesn't have the vasculature, it just doesn't have, just doesn't have a real normal look to it. And optic nerve head drusen can be found, I've heard it claimed up to 20% or so that if you really look for them to have that. And then there is classically vascular attenuation shown here and you often see vitreous cells. Now these are not inflammatory cells, this is often just little bits of degenerative tissue that gets off into the vitreous. But that can be confusing if you're worrying about an inflammatory disease that is doing the same process. Then posterior subcapsular cataracts are surprisingly common in these patients, that's the most common cataract that I see, they happen at a relatively young age in these patients. I often see them in their 20s, 30s with a posterior subcapsular cataract. And you have to be at least thinking about whether these are visually significant. Remember a patient with RP has a very restricted visual field, sometimes only 20 degrees. And a posterior subcapsular cataract that would be pretty much asymptomatic to a normal seeing individual may be visually significant if it's just right in the center, which they surprisingly often are. And it's been shown through many studies that patients with RP do very well with cataract surgery and so having RP is not a reason to avoid doing cataract surgery. They're not at any higher risk of complications or any other reasons to avoid doing cataract surgery. On the other hand you have to go in with the fact that they do have a problem in the retina and so you have to have the patients go in with reasonable expectations that you're not going to cure their RP, that there's a possibility you may be wrong and that it's not as visually significant as you thought. So there are a fair number of disappointed patients if you don't prepare them for that. Cystoid macular edema is quite common in these patients and was probably underdiagnosed until we got into the OCT era. Now that we have OCT, it's pretty standard on that's part of the standard workup of all my RP patients is to do an OCT because I miss it clinically. But if a patient comes in with classic looking RP, say as a 15 year old kid and comes in with classic RP but has 2050, 2060 vision, think Cystoid macular edema in these patients and be sure to have an OCT because that can be treatable with either with dorsolamide topically or dimox orally and you can help them improve their vision. So yes, they generally are not and they're kind of whitish in what I see but you probably could see pigmented but they can be confused and sometimes some of these patients come in into the uveitis clinic and so they can be almost anything but I generally say they're not pigmented. And as we've mentioned the macula is preserved until late in the course of the disease. That's the last place that usually goes in RP. So when a patient comes in to see me, what do they have to do for their three or four hours before they see me? We're supposed to, you want to get a clinical history. Did they start with night blindness at a young age? Do they have, does the progression, if you have someone who's come in and says things have gone bad in six months you have to think about and that they had perfectly normal vision before that doesn't rule out RP but at least makes you think about something else going on. But typically the course is pretty slow that they say and this has been progressing. The average age that I would diagnose patients are in childhood or young adulthood but I have diagnosed newly diagnosed patients all the way up until their 70s or 80s. There's some patients that have mild enough disease that they don't manifest and don't complain about the problems until very late in life so it doesn't totally rule it out but the more typical patient coming in is school age or young adulthood. You want to get a good family history and this is, we currently don't have a genetic counselor anymore so I'm the one in my technicians that need to do this. It's hard to get a good, to take the time to get a good family history but at least I take a limited one and ask, do you have any cousins with NEI problems? Tell me about your parents, tell me about if you're an adult, tell me about what's going on with your kids and your siblings and find out just to see if there's anyone else with even vaguely similar eye problems within the family. You then need to do a dilated retina examination and photography. The basic imaging that I do for my patients coming in includes fundus photographs and I'm trying to drill into my technicians and the photographers that if there's a patient with RP it's useless to me to give me a macular photo and it's amazing how the photographers still don't get it after all this time but if it says RP on it that automatically means I want the peripheral shots whether with the optos or montage shots. I also want to get auto fluorescence routinely because there's often a lot of auto fluorescent abnormalities that can bring out some of the changes in the mid periphery versus what's going on in the macula. We'll get infrared, OCT, all of the basic what I call non-invasive imaging. Fluorescent angiogram is not typically something I would get unless until after I've seen the patient and really looked if there's something unusual then of course I would get that if there's evidence of other vascular problems or something else unusual. Visual field testing, this is done a little bit out of order but visual field testing is very important and in my opinion Goldman fields are the gold standard still. Manual gold fields, Goldman fields are the ones to do. The hump-free visual fields that we get don't go out far enough. You really want to know what's going on in the mid periphery all the way out on these patients and so that's important. We do have the Octopus 900 which is an automated Goldman visual field. These are usually kinetic as you know but it does both kinetic and static wide field. The technicians hate it and the patients hate it too because it takes a long time to do that test. It can be 30 minutes of testing per eye on these patients and so we got the Octopus 900 for clinical studies when we were doing some of our RP studies you need to have something quantitative and less subjective than a Goldman visual field but the machine and the machine breaks down a lot and it used to do especially in the clinical studies that would go through their 20 or 30 minutes test and then it would just burp and throw away the data and then they'd have to start again. So it's not a well-loved machine. We've mentioned already optical coherence tomography and then genetic testing is becoming more and more part of the general workup in my patients. The problem has been and I think I may have it some more on some of the slides. There's a huge number of genetic diseases out there and the genetic testing was intended to be very expensive up until recently and took forever. If you got the free testing through the IGENE project which is no longer accepting patients that was through the NIH we would draw the blood and you'd never hear anything back for years and I just have to tell the patients you get what you paid for you didn't pay for anything for this they will get back to you when they feel like it but I had to really go through a lot with my technicians and the schedulers here because until we had this long talk with the patients about what IGENE testing was about they would start calling after two weeks asking well what are the results of my test and then the schedulers would get upset and they'd start paging me and paging the resident on call why don't we have the result back and I finally had to tell them you're likely never to hear anything from this test and so and the technician finally they stopped calling me about this and as emergency results that needed to be found the good news is that genetic testing currently is free now if you have a typical rod cone rod-mediated disease like RP we have a program that I don't know when it's going to go away but one of the genetic testing companies called Spark which is developing gene therapy is taking any and all comers so I can send tests for free and they haven't gotten back to me yet but they will get they think they will test for the common genes for RP and get back to us within a month or two so that's kind of nice before and now if you were to send your your testing to or your blood to somewhere like University of Oregon or Oregon Health Sciences where we send it or to the Carver Lab at University of Iowa they will also get back pretty quickly but they will charge anywhere from fifteen hundred to three thousand dollars and currently almost no insurance companies will pay for it so it's out of pocket to the patients and we'll talk about why we should do that in some of the future slides here so electro retinography is the is something that we recommend highly in the patients that's part of the baseline workup of the patients I'm sure Don Creel has talked to you about electro retinography so and I am no expert on electro retinograms that's that's his field but what we're looking at is you want to see the function of their rods and cones in typical RP the the scotopic system is going to be affected much worse much earlier in they will and in most cases of RP it will be abnormal before they have any major clinically relevant symptoms and it's very common in these patients when when you see them that they are that they're that the ERG may be already extinguished from the start by the time they're diagnosed even though they may be functional driving still working the ERG can be pretty difficult to can be very low typically the rods the cone system will have some minor changes and changes in implicit time but will be much more much more functional than the rod system and it's important to do electro retinography not only for baseline diagnosis but you can pick up unusual unusual ones like congenital stationary night blindness rod monochromatism you can all there were it can help distinguish cone dystrophies from retinitis pigmentosa and sometimes you'll see mixed you know they tend to be a cone rod or rod cone dystrophy so again this is just kind of the typical things that we would see I want to go back one I think and visual fields the Goldman visual field the classic things you're going to find is initially some generalized construction you will also see mid peripheral visual field loss these skatomas here that can form into what the classic rim ring skatoma and eventually as you can see in a patient this one is just autosomal dominant RP followed for 30 years I guess 40 years here you can go from a pretty functional visual field all the way to you know totally dysfunctional visual field but maybe still with 2020 vision the other thing that's important when I order a Goldman visual field and again it's surprising how the technicians just don't get this is that Goldman visual field in an RP patient with unless there's some unusual and some exceptions should include not only each eye and I don't really care if they're dilated or not you know it doesn't matter that much for for what I'm trying to get in the clinic because sometimes somehow a patient gets gets into my clinic they're already dilated I diagnosed well this really looks like RP I need a Goldman visual field I'm not going to send them back and bring them back a different day I just tell the technicians just go ahead and use what we have the other thing that's really important is to get a binocular visual field because these patients many of them are teenagers young adults they're out there driving or want to drive that's one of their major questions that they're asking me is can I still drive doc and if I don't if I have just monocular visual fields I can't fill out their visual field form on their driver's license form because sometimes that's the only way that gets them their driver's license is to prove that they have a binocular visual field of at least 60 degrees and so it takes the technician only an extra probably three minutes to do a 340 single binocular visual field but I would say it's still one-third of the time it comes back without without it there so it's just something to remember it's easy to do okay so now RP genetics this this is a disease that can have as I said almost any any inheritance and so it can range from autosomal dominant that's about I don't have the exact number so you can't quote me on this but it's reasonably common probably about 20 or 30 percent of patients coming in have some have an autosomal dominant inheritance pattern which means it's past 50% you can get large families they'll know that there are other a number of cousins siblings parents out there typically autosomal dominant is the mildest of the are of the inherited rps that you'll see these are patients that function pretty well may be driving but and then really run into problems and functional problems more typically in their 40s and 50s they know they have the disease especially since it often runs in the family but it's it's not as bad the autosomal recessive disease on the other hand tends to be much worse they these are often the kids that are affected in their in their before age 10 or 12 these recessive means that either their their parents are consanguinous which here in Utah and Intermountain West is very rare here if you're gonna go for my colleagues that have a lot of Middle Eastern populations they see this much more ours it now that we're finally doing genetic testing we see that there is some there is recessive but it's harder to it's harder to do the genetic diagnosis because there's so many different genes that could be that could be involved in recessive disease x-linked is moderately common here in Utah that means that it's past that the that the females generally are not affected but the males are affected so it looks like it's skipping various generations it looks but if you but you have to keep that in mind but we've learned now that we do genetic testing on this that it's sometimes very hard to distinguish x-linked from autosomal dominant mainly because we know that some women are affected with x-linked disease it used to be the dog mother they never are but but we have documented families in my in my clinic where occasionally a woman will show up with this and it's just has to do with x-linked in that the lionization is uneven enough that she's affected when you wouldn't normally expect it to happen x-linked also if you look at the women sometimes you can pick up the carrier state in them they will have maybe little segments of the retina segmental retinitis pigment osa they may also have mild disease that shows up when they're in their 50s and 60s they're starting to get a little bit of night blindness so it's something to at least think about and we know that there can be that's now that we look at this there are some mix-ups between autosomal dominant and x-linked mitochondrial is uncommon in my in my clinic they tend to have other neurologic symptoms that go with other other diseases you know that but there are some mitochondrial ones that you will see syndromic as we know there's things like senior locum syndrome other ones that will talk about usher syndrome that they can have varda beetle syndrome so you do want to ask about other systemic problems they're hearing those sorts of things and then finally probably still the the most common disease in my clinic is sporadic which means we just don't know there's no known no known family history there they they may be in they could have any of these mutations then that they may be if they're autosomal they could have autosomal dominant but they're the founder of the disease of a new line of of RP they could be autosomal dominant just with variable penetrance and only a few patients show up and that's all that you see within the family they may be x-linked again you know it may be it may appear sporadic and of course recessive if you just don't have enough large enough family that you may not have any known relatives in the family with the disease so with autosomal dominant RP as I mentioned the courses can be very mild there can be variable penetrance the most common the and this was the first gene that was found for retinitis pigmentosa actually for relatively early finding of any genetic disease is that rhodopsin is one of the most common targets of this disease most common sources of this and mutations you know and it accounts for maybe 30 or 40% of autosomal dominant RP the most common mutation is something called P23H which is a proline 23H mutation histidine substitution it's in some parts of the country 30 or 40% of dominant RP is just that particular mutation if you go to Europe the prevalence is zero it is a disease that is an American disease with an American founder effect they even know who the founder of the disease is they've traced that all back and very interestingly essentially none of them ever moved to Utah so I have none or I just actually I found the first one or two and they had moved here from somewhere else to Utah so it's a pure founder effect but because it's so common a lot of people have been studying the disease they've developed mouse models for this disease but there are many many others and they can affect not only transduction but a lot of them affect folding of the protein here they affect they can be they can have severe mutations at the site where the redot where the vitamin A chromophore binds in almost anything can happen but a lot of them are protein misfolding diseases as in rhodopsin another relatively common mutation that we see is in RDS peripheral which is a structural protein that's involved in formation of the optic disc of the discs the interesting thing about RDS peripheral is that its manifestations can be very different even within the same family so you can have classic RP and you can have something that looks like a pattern dystrophy so again if you just think about things that look a little atypical and especially if you see other if you've already seen other members in the family thing that have different looking disease RDS peripheral is often the culprit another set of does another set of problems and genetic defects are ciliopathies because of the psyllium connecting the rod outer segment in the inner segment is a very complex set of proteins there and there's about there's literally dozens of proteins in there that can be affected and once you mess up the psyllium and effect transport between the rod outer segment in the inner segment or affect structural problems you can get a retinal degeneration there people here like Wolfgang Bear and Jun Yang here that are on our research faculty that's all they study is ciliopathies and so and ciliopathies often tend to be syndromic to affecting kidneys affecting hearing other other problems that are other ciliated structures in the body another set of mutations that we often see are splicing factors and so these are RNA these are RNA processing proteins they're relatively common here in Utah why why that would be true and why it come why it affects just the rod cells when these are found in every cell in the body people the the thought is that photoreceptor cells are such specialized cells that they don't have backups I think if you have in other cells of the body in your liver they've got other splicing factors that can take care of a problem if you have a mutation in a splicing factor but if you have one in in some of these but PRPF 31 which is one we see a lot here your retina degenerates and then as I also mentioned already that protein misfolding and of misdirection can cause a lot of problems in the in the rod cells and this has to do with the fact that our rod cells don't regenerate they have to last all our life and so for a hundred years and so if you've got things that that cause problems in the cell for and you can have problems that can accumulate over many years recessive mutations are relatively uncommon in cult unless you have a lot of high at all a high rate of consequently we we said they're often severe and early onset and many of the labors congenital amirosis diseases which is essentially congenital retinitis pigmentosa are these recessive diseases and maybe I don't see so many of them in my clinic but they probably are in the Peds clinics and just aren't seeing them seeing me the mutations are often in the transduction cascade and in the visual cycle so they tend to be more enzymatic problems going on in the eye and they may these are the ones that were also first some of the first diagenic diseases were were recessive RP so that's where multiple where you have a mutation in in one gene and a mutation in a different gene but somehow they're connected in the pathway and you get enough enough disruption of the of the normal pathways within the eye that you get that you get cell death many of these diseases when they're first found when they disrupt the visual cycle they cause high levels of cyclic GMP there's there can be accumulations of toxic products within the retina that eventually cause cause death of the cells X-linked is tends to be a little bit different in that the males are affected it's usually very severe a lot of these kids are symptomatic at age 7 8 it's pretty unfortunate and these patients don't do very well females can have milder late onset the most common mutations are in RPGR one of the in which is obviously found on the X chromosome but the other one that you need to know about and that shows up on boards is corioremia in that it's X-linked it has a very characteristic pattern here where you see massive corioreal retinal corioreal atrophy preservation in the center and they tend not to have a lot of bone spicules they tend to have more patchy clumps of pigment seen here and mitochondrial retinitis pigmentosa is relatively uncommon obviously there's maternal in inheritance and think of neurologic problems so think current seer me loss those sorts of things and then syndromic is usually recessive diseases multiple organ systems can be affected most common syndromic disease I see in my clinic is going to be usher syndrome and they tend to have can the important thing about usher syndrome is that the hearing loss is usually pretty severe and it's congenital okay so try to distinguish it from patients who come in with RP and say yeah I have a little bit of a hard time hearing and it's happened in the last five or ten years that's probably not usher syndrome I can't rule it out but the most common thing they say the most common typical usher's patient as it was diagnosed early on usually and they tend to have such severe hearing loss that there's a little bit there's some changes in their speech there's other things that you pick up they may be wearing hearing aids they may have cochlear implants so it's it's more severe happens almost and it happens 10 to 20 years before they even develop any vision loss a bardae beetle syndrome I have a few patients with this not a lot but they will tend to be obese they may have mental retardation they have polydactyly there's a lot of a lot of other issues I've had one come through relatively recently but they're they're not a lot of them senior locan Nico can tell you all about that he's written the the definitive article on it I think and I think on there and so that's that they have kidney disease often and I've often had kidney transplants already and so there's a few patients in my clinic and then you get into really rare diseases Apert's syndrome Goldman Favre ref some disease gyrate atrophy you can read about about them in your book most of these I have never ever seen in my life in clinic and I've been in this practice a long time so it's you can think about it but they I tried just ruling out another gyrate atrophy this week and came back still with a normal ornithine so it's just the way that and I've written an article one of my early papers when I was a resident was on ref some disease never seen it yet so I created a mouse model but it didn't doesn't happen very often and then finally there's sporadic RP no family history and we thought and you just have to think about other reasons when it's when there's no family history at least consider that this could be a new founder mutation it could be pseudo retinitis pigmentosa it could be an autoimmune retinopathy and really should be in the in the in the uveitis clinic also consider things like car and mar cancer associated retinopathy for late onset somewhat atypical disease and as other reasons for this and then this is where you also think about toxic etiologies I picked up early on when I was on the faculty here I had a patient that was coming in with ERG abnormalities other other things and was referred in from from and referred in from the neuro clinic and I saw just a little more notation of MS 222 as they had done a toxicology or just a history of what he was exposed to and probably none of you have ever heard of MS 222 have you but I happen to have done that was one of the things I did my PhD on is it's a fish anesthetic that has known toxicity and he was a fish fish pathologist and what he did is he would take his fish and throw them into a big tank of MS 222 they would fall the fish would fall asleep and then he would reach in and grab the fish and then study the fish and I asked him do you ever wear gloves and he said of course not I just reach in and grab the fish and so through the years he was chronically ingesting just like the fish absorb MS 222 through their skin he was he was absorbing it through his skin too and I just told him wear some gloves and he got better so it was able we were able to write that up as a as an occupational hazard of the using that of that career and then also consider vitamin A deficiency some of you may have picked this up they often have low macular pigment I will get that on patients and vitamin A deficiency will have night blindness but they will have said that they had it's a new onset for them they if you take a dietary history they often are eating something very unusual or they've had bowel surgery or some other reason why they're malabsorbing and so it's it's an easy test to do and you don't want to miss it because that can be treatable and then there are stationary retinopathies there's no clinical progression night blindness is prominent but the visual field is often well preserved this is and it's diagnosed best by electro retinograms these patients can be very mildly affected or can have very significant manifestations of the disease one of the classic ones is fundus alve punctatus which has all these white dots here and it's RDH retinal dehydrogenase 5 mutation but the if you diagnose the stationary retinopathy the good news is that they they're not going to get worse I mean they may be they may be clinically affected but it's not going to be too their prognosis is better in terms of treatment the patients often want to know about this but so you also a me a when I'm meeting with them and their families they want to talk a lot they're gonna have to allow 15 or 20 minutes or so to talk to them all about what their future is like what the treatments are like what we can do genetic counseling can be very important and as I said we get we I tend to send genetic testing as much as I possibly can that does mean now that I don't have a genetic counselor I'm essentially the genetic counselor which is kind of painful and it takes a lot of time but you do have to tell them about what risk is for their for other children that may whether they're gonna have few kids or whether the parents are still having more more children you need to just go through all of that it's pretty it's it's not rocket science genetic counseling though so we as physicians should be able to do that nutrition they often ask about in my clinics and here in Utah basically we tell them a healthy diet is important there is some role of vitamin a taking high doses of retinoids has been proven in large clinical studies to slow down the disease but that was slowing down degeneration of the tiny little signals on the Coney RG clinically it probably didn't make much difference to these patients they ask about Lutine Ziaxanthin fish oil all of those have gone through some studies their effects are pretty minor unfortunately and then they'll talk about Bilberry coenzyme Q and just huge numbers of other things you just have to tell them we don't know what if that really makes a difference gene therapy is coming for certain diseases in fact probably within a year RP 65 will be approved for genetic for gene therapy it's it's injected by a subredinal injection of an ad no associated virus to reintroduce reintroduce the defective gene we do not have a single patient with RP 65 here in Utah we've been looking hard so we the companies are very disappointed when they say they're all excited to come here and I say it's great we'd be happy to be a site but I got zero patients for you and I would know because my PhD was done on RP 65 I'd be watching if anyone came in with that with that mutation but we just don't have it the next gene therapy that's going to be coming those Coroid oremia that's probably coming down the line that we've got plenty of patients for so it will be happening the problem is with the number of different genes out there 40 different gene at least 40 different genes hundreds of mutations every gene is a multi-million dollar project so there has to be enough funding and enough patient load to actually make it worthwhile that's that's the problem with gene therapy so other people have been looking at more generalized approaches that don't require specific genes this includes stem cells there's lots of information misinformation on the internet about how stem cells is going to cure RP it's not that's it's still a long way off even for Stargard disease and other diseases and other diseases but you know you know how technology and science can change maybe in five or ten years we'll have be able to introduce the cells safely get them to hook up and do the right thing but right now they don't we've been involved in the study using Velproic acid which is which had a reputation that it could slow down visual loss we it finally required a multi-million dollar study done by the Foundation Fighting Blindness that we participated in did nothing again it was kind of disappointing but without those clinical trials people were putting their patients on VPA it does have toxic effects and now we can say VPA does nothing for the disease at least the way it was done in the trial other ones that are being looked at include Tudka which is Toro-ercy deoxycholic acid so that's a bear bile a synthetic bear bile derivative again there was a lot of hope it would be helping but I have it's been going downhill again and then there's electro stimulation and which is true pseudoscience but a lot of people are really into that here in Utah and because people can sell it and you know how to their their acupuncture clinics and and try to help them at least claim to help the patients and then artificial vision which I think we'll be talking about next okay and then artificial vision is the is the Argus 2 chip implant it's very primitive but it is it is approved and I think we've already had a talk on that earlier I think at Grand Rounds when when Nylon Grigori was here and we will start offering that to very limited number of patients but it's for end-stage disease they have to be hand motions or worse I think maybe even worse than hand motions but you'll we have some patients we're already lining up to have this done and it'll be an interesting surgery five hours to do and then months of rehabilitation afterwards and a hundred to two hundred thousand dollars then in the last couple minutes we'll cover cone dystrophies there's a wide range of manifestations I see them a lot I find them pretty the a lot of them are these atypical macular cone dystrophies we don't have good genes for them it's hard to predict how the how the disease how they're how much they're going to progress there are some of them obviously the most common cone dystrophy we see is color is excellent colorblindness 3% of the male population has that problem but that's a stationary that's a stationary disease it's really the progressive ones that may happen in the severe cases you can get acromatopsia but that's relatively uncommon the cone dystrophy signs and symptoms include loss of color vision loss of central visual acuity they tend to be much more photophobic than rp patients they tend to pure cone dystrophy they may have preservation of their visual field and they often have an astagmus bullseye maculopathies if they're if they're really severe and the way we diagnose cone dystrophies is just like rp you know the clinical history family history dilate examination full field electro retinogram and multifocal may also be very useful in these patients and it's important again my technicians tend to forget about doing color vision testing but that's how we pick up some of these and genetic testing is moderately good not nearly as good as retinitis pigmentosa but we can send those out and similar similar we're looking at gene therapy stem cells there's even some companies that are trying to develop gene therapy for for just regular color blindness in males and whether that that one is a little bit questionable whether you want to put you know pretty normalized under have them undergo gene therapy but it is coming and then I think the last thing we'll just go through a few slides always remember that these could be toxic effects and you want to keep that in your mind there are numerous agents that can have toxicity often they will develop these crystalline deposits and they will have signs that are just atypical like crystalline deposits this is canthazanthin maculopathy lutein maculopathy will be in the news in two days because that will be our first case of that has been is going to be published in JAMA ophthalmology and so that's that's possibility the can't tamoxifen we've published one report here of tamoxifen deposits again they're crystalline deposits that tends to give you macular holes so other maculopathies can give you problems and then don't forget things like chloroquine hydroxychloroquine that's why I do a drug history of what they've been taking tobacco alcohol ambial amblyopia a thambutol all these other things can cause problems that can be confused with inherited retinal diseases and can be potentially treated by just by just changing their toxic exposure and then other things that we see digitalist toxicity is I think less common I don't but that color just because it's not used so much but that can cause disturbance of color vision Viagra and similar compounds they definitely can cause some color vision problems they are contraindicated or at least patients with RP sometimes asking I take Viagra and the answer is it's probably okay unless you happen to have the same mutation in the phosphodiesterase pathway but it's something to at least be careful about in those patients and then there's the other things like amiodarone and methanol that you just want to consider so I think oh and then the last thing is remember not everything that looks like RP is RP it can be post inflammatory post traumatic and it used to be you're not seeing it so much anymore but when I was when I was a resident we still would see a Rubello retinopathy because people Rubello wasn't was a disease of the 1950s and some of those patients would come in with salt and pepper retinopathy and other changes so the clues are that they don't that they're they may be unilateral they may be atypical they may have relatively little symptom on symptomatology they may not have night blindness even though they have something that looks like this they tend to have more of a salt and pepper configuration they have atypical electrophysiology and visual fields and they may the Rubello ones often they were deaf at the same time but they didn't have usher syndrome so I think that's it so any any questions at this point yes I haven't ever picked up a mutated you know I think that I'm gonna tell them it's rare you know the main thing I guess you would worry about is it's inhibiting other visual pathways and effecting the visual symptoms the visual pathways so in a patient who already has compromised you basically just have to tell them take the lowest dose and if you notice any symptoms you probably should stop I think that the chance that I'm going to pick up a phosphodiesterase deficiency in one of my patients is gonna be less than 1 percent so you know it's not it's not attacking the same pathway all right I'm very good