 good morning today we're going to have some fun facts about photophobia so I'm going to start off by talking a little bit about the clinical characteristics that are associated with light sensitivity a lot more about the pathology of light sensitivity than we did 15 years ago I don't think the atomic textbooks have caught up and then I'm going to talk a little bit about some clinical research we're doing using specially designed optical notch filters for treating light sensitivity so photophobia just means abnormal intolerance to light there are some other similar syndromes like photo oculodenia which is a syndrome of light sensitivity in eye pain following a eye injury or surgery and there's central dazzle that's more associated with tumors and strokes that are real they're both those are both relatively uncommon whereas I'd say relatively common so there are a lot of affowment conditions that are associated with light sensitivity but the thing is is that almost all of these have at least some other sign and or symptom associated with them that's going to help you as an optimal condition and then there are also some underlying neurologic conditions that are associated with photophobia but again almost all those have signs and or symptoms that are going to help you differentiate it from just plain old light sensitivity that doesn't seem to have an underlying cause that's obvious on exam so many of you know that I split my time between comprehensive ophthalmology and neuro ophthalmology and so I can tell you that in my general ophthalmology practice just whoever walks in the door practice that the most common underlying conditions that I have seen associated with patients who present with a chief complaint of photophobia are going to be migraine blepharospasm and TBI my grain out numbers those other two put together probably three at least so there was a very unfortunate paper that was published by the group at Emory a few years ago where they said where they said the sunglasses sign is a sign of functional vision loss and so they looked at 1300 new neuro ophthalmology patients that they saw over 13 months 34 of those 1300 patients showed up wearing sunglasses and the majority of them had turned out to have non-organic vision loss seven of them did have organic vision loss for which wearing sunglasses was an appropriate treatment and the take-home message from the paper was if you have a patient come in wearing sunglasses they're probably functional but that has not been my experience in neuro ophthalmology and it's definitely not been my experience in my comprehensive ophthalmology practice and I think the unfortunate thing is that people reading that article would extrapolate the results from Emory which is a tertiary neuro ophthalmology service to their comprehensive ophthalmology service or their cornea service and it's just not appropriate in my experience yeah I do have some functional patients that come in wearing sunglasses but most of the patients in my practice wearing sunglasses really have something wrong with them and it's usually migraine blepharospasm or traumatic brain injury so a brief review of migraine because it's so prevalent almost one in five women have migraine at some point in their life it's a huge number it's the far and away the most common neurologic condition it affects about six percent of men still very common and migraines I think especially a month away public have a rep as just being like a bad headache but they're really not they're really be very disabling for some people because of the light and the sound sensitivity nausea and vomiting they can last you know several hours end up missing work missing social functions not being able to enjoy time with your family and friends I mean it's really a serious condition it affects 31 million Americans or that have episodic migraine they're 14 million Americans roughly with chronic migraine chronic my brain is defined as at least 15 headache days per month for three months in a row at least that's that's a lot of headache we spend about two billion dollars and it's estimated sometimes it's not real helpful to ask somebody if they have migraines I mean sometimes they do when they say yeah but a lot of times they've either been either undiagnosed or misdiagnosed and so this is a really quick three questions you can ask about somebody's headaches more likely have migraine and less likely have tension headache or some other headache syndrome okay so now I'm going to turn away from talking about the some of the clinical characteristics of photophobia and talk a little bit more about the path this is not a for sure thing but a lot of evidence seems to be pointing toward the fact that these intrinsically photosensitive retinal ganglion cells these are also called melanopsin cells because they contain the photopigment melanopsin these cells are definitely responsible for circadian rhythm entrainment so your body has a natural 24-hour cycle if you stuck if you stick a person in a cave with no light no clock no access to any sort of clues to what time it is their body will still maintain a roughly 24-hour schedule of sleeping if you travel from Salt Lake City to Sydney Australia where they're about 12 hours out of sync with us over several days your body will eventually adapt to the local light dark cycle and you'll be sleeping at night and eating meals at the same time as the Australians it's these cells that re-synchronize your internal clock to the local light dark cycle these cells are plugged directly into the suprachiasmatic nucleus and hypothalamus and they help keep your body synchronized to that 24-hour cycle keep you synchronized to the Sun coming up and the Sun going down they're also responsible for pupillary constriction so when light hits your eye both pupils these cells are plugged right into the pre-tectal nucleus in the brainstem and then to the eddinger Westfall nucleus so these cells constrict and there's very good evidence at least in rats that these cells are also responsible for pain so if you look at a light that's too bright it hurts it physically is painful to look at a light that's too bright and it's probably these cells that that the basis of that pathway that pain pathway so you know here's your good old blue and red photoreceptors your rod photoreceptors and the story that I was told when I was in medical school is that these cells connect to bipolar cells and then you've got amigrant cells and horizontal cells and eventually ganglion cells and the ganglion cells send their axons out through the optic nerve to the chiasm to the tracks and then to the lateral geniculate in the thalamus well it turns out that about 10% of them ganglion cells in your retina don't go to the lateral geniculate they go to at least three other places in your brain one of them is the suprachiasmatic nucleus that I was just describing for entrainment of circadian rhythms one is the olivary pontine nucleus in the pre-tectal brainstem that goes to the adenger Westfall nucleus and then constrict your pupils and there's a third pathway that appears to go to the posterior thalamus which is those are pain centers in your thalamus that it's wired to these cells the unique thing about these cells is not only do they receive input from the cones and rods they're also intrinsically photosensitive they contain a photopigment just like rods and cones contain a photopigment and you can stimulate these cells directly without any input from rods and cones and you can still get circadian rhythm entrainment cupillary constriction and pain and actually Dr. Diggory has a cohort of patients with retinitis pigmentosa who are exquisitely light sensitive these people are legally blind and yet they're light sensitive that doesn't make any sense how could the blind person be light sensitive well it actually does make sense because their photoreceptors might be wiped out but these ganglion cells aren't these ganglion cells still work they still entrain their circadian rhythms they still constrict the pupil and they still cause pain so this is a light sensitive pathway that has nothing to do with vision nothing to do with seeing nothing to do with image formation if you really want to get into the nitty gritty of photophobia and some of the other circuits that are likely involved with the sensation of pain from a bright light Dr. Diggory and Casey Brennan who's one of our headache specialists in the Department of Neurology wrote a review in J&O about three years ago and this is one of the primary figures from that article and the take-home message is that not only does do these intrinsically photosensitive ganglion cells which are abbreviated here as IPRGC transmit you know through the optic nerve eventually to the posterior thalamus but the posterior thalamus also gets some afferent input from meningial pain fibers it's connected very closely with the trigeminal nerve which of course is not only the nerve that supplies sensation to your eye and orbit and face but also the nerve that's implicated in the pathogenesis of migraine and there's also some other bizarre connections with the superior salvatory nucleus the tarot punting also some weird melanopsin cells that are in the iris there might be some pain pathways that are separate from the optic nerve that are transmitted directly through the trigeminal nerve and the trigeminal nerve innervation of the eye so it's probably not as simple as intrinsically photosensitive retinal ganglion cells there's probably some other circuits involved to involve of light sensitivity. So I think it seems pretty clear that this is a protective mechanism I think all vertebrates have this mechanism and it keeps you from burning up your retina by looking at a light that's too bright it's a it's it causes pain so that you don't ruin your retina but I think in some people especially people with migraine this system just has too much gain it causes light sensitivity and pain at light levels that are that most people find to be very comfortable and there's a funny thing that I've noticed over time about people with light sensitivity especially people who come in with a chief complaint of light sensitivity is that it's I didn't figure this out myself like they told me it's non incandescent artificial light that really bothers them they specifically don't like fluorescent lights they don't like those big gas discharge lights that you see in Lowe's and Home Depot and Costco and they don't like computer screens and regular old light bulbs they're fine with that being outside where it's actually brighter doesn't bother them that much it's these indoor lights these artificial indoor lights that bug them and I think there's an explanation for that too although so if you look at the if you look at the the emission of the Sun you know using wavelength down here is your x axis the Sun emits at sort of a Gaussian curve across the visible spectrum going from infrared to visible light and then to ultraviolet and the human sensitivity to light also is sort of a Gaussian curve here just within a narrow range of light you know between red orange yellow green blue indigo violet that we're sensitive to and I I don't think this is a coincidence I think that vertebrate eyes have evolved under the Sun and they're sensitive at the same sort of wavelengths that the Sun maximally emits makes sense if you look at the emission over wavelength of a tungsten filament which is the working parts of the inside of an incandescent light bulb it also has kind of a Gaussian curve to it because it's a burning filament just like the Sun is a gigantic burning filament and it emits it's sort of a Gaussian wavelength function just like the Sun does but if you look at the emission of fluorescent lights they're very that's what's displayed here with these little spikes it's very spiky so fluorescent lights emit very strongly at some wavelengths and not at all at other wavelengths it's and it looks good and it works well but it's very if you want to say unnatural it's very unlike the Sun and I think there's something about this these it used to be thought that the reason that fluorescent lights bug people was because of the a little bit of a flicker they have in them but that's largely been gotten rid of with modern fluorescent lights and people are still don't like them and I think it's this spiky emission spectrum that bugs people some people sorry my slides got messed up there we go okay so how do you treat people with light sensitivities you want to treat the underlying condition so if they have dry eye or they have iridus or they have I guess can't really treat albinism but if they have migraine blephar spasm traumatic brain injury you want to get them treatment for that condition there are no medical treatments for photophobia at this time but optical treatments are available some of my blephar spasm and migraine patients come in wearing sunglasses and you really don't want to do that because dark adapts the retina and so when they do take off their sunglasses their light sensitivity is actually worse than when they put them on and so I really try to discourage that there's this tint called FL-41 which I'll talk more about that is really good for migraine and actually research from our group here at Utah has shown that it's effective in blephar spasm and this tint is light enough that it doesn't dark adapt your eyes but still makes people more comfortable and for some people the difference can be really dramatic it's this rose colored tint there's nothing proprietary about it there's a couple of companies in the US that manufacture this tint and any optical shop can get it but very few do carry it our optical shop here does and they know a lot about FL-41 and help them that's right here's proof you can also make this in a contact lens which wasn't available until very recently and we have that at our optical shop here so this tint was discovered empirically in Britain they had a cohort of patients that didn't like fluorescent lights and they just put out a whole bunch of different colored glasses and let people try on blue ones and green ones and yellow ones and red ones and just by trial and error they came up with this tint that seemed to help people with fluorescent light sensitivity a few years later they put these glasses on a cohort of school children with migraine and found that it seemed to reduce the frequency and severity of their migraine headaches and since that time Dr. Diggory's been prescribing it for a lot of her light sensitive patients especially those with migraine and blephar spasm and you know we put these glasses on a cohort of blephar spasm patients it's probably been about 10 years ago now and showed that it reduced not only their symptoms of blinking and squeezing but also with electromyographic recording we could show that wearing these glasses actually made them squeeze less and made them squeeze less hard if you look at the spectral characteristic of FL 41 which is plotted here in blue compared to just a pair of like neutral gray tinted sunglasses you can pick up at the drugstore you'll see that the gray is relatively flat across the visible spectrum whereas FL 41 has this dip around 500 nanometers now if you look at the spectral sensitivity of melanopsin the photopigment that's in those intrinsically photosensitive retinal ganglion cells it peaks at about that same wavelength and so up here I've taken from an article the maximum sensitivity of the red green and blue cones and then also rhodopsin is stuck in here and this OPN4 this is melanopsin this is the maximum sensitivity of that photopigment it falls roughly halfway between green and blue just off of rhodopsin and it peaks right at about 480 nanometers very close to the wavelength that FL 41 blocks and that when I saw these data in early 2000s I was like well maybe that's why FL 41 works because it blocks the same wavelength of light that these pain cells are maximally sensitive at so prior to that there was really no science behind FL 41 right it was just discovered empirically trial and error and it really never got much traction I think because it just seemed like magic glasses with no science behind it and I think doctors especially were very skeptical of its efficacy and it just never it never caught on and that's why most people haven't heard of it most off shops don't carry it but now I think there is some science behind it and when I saw these curves I was like well now that I think or I know I think I know why FL 41 works I can make something better I can look I can take this transmission curve of FL 41 and if I can make this minimum transmission here lower sorry I don't know why my cursor keeps disappearing I can make something better so I hooked up with oh this is a little side topic before I go on to the glasses I actually think this is the most fascinating part of the whole story but clinically it's less relevant. If you look at a vertebrate photoreceptor and how it works you have opsin it's transmembrane protein that's coupled to a retinal molecule and when light hits it the 11-cis retinal is summarized to all trans-retinal and that causes a conformational change in the opsin which then activates a G protein phosphodiesterase is activated which hydrolyzes cyclic GMP and then you have this transmembrane ionic channel that gets closed all right that's how vertebrate photoreceptors work. If you look at an invertebrate eye it's actually very similar you have a similar not very similar opsin that's coupled to the exact same retinal molecule light isomerizes it from 11-cis to all trans-retinal but then some of the intracellular machinery is different but ultimately it also results in closure of a transmembrane ionic channel so vertebrate and invertebrate photoreceptors work in a very similar fashion with very similar molecules and there's now genetic evidence like if you look at genes that are expressed in an invertebrate photoreceptor and the genes that are expressed in a vertebrate photoreceptor there's very good evidence that these that are photoreceptors even though they look like if you look at an invertebrate eye and a vertebrate eye they look completely different but there's very good evidence that the photoreceptors evolved from a common ancestor and not only that the better part is that the rods and cones and bipolar cells all have very all share a common ancestor and share similar gene expressions whereas amicron cells, ganglion cells, horizontal cells actually look like they evolved from a slightly different ancestor that's a lot more like the invertebrate photoreceptors so all of the cells in your retina evolved from a common ancestor but at some point there was a split where the rods and cones and bipolar cells kind of had their own sort of development amicron cells, horizontal cells, ganglion cells had their own development and then specialization and that set of cells is a lot more like our invertebrate common cousins. These melanopsin cells, the intrinsically photosensitive retinal ganglion cells, if you look at the genes that are expressed in that cell it looks a lot more even though it's a photosensitive cell and it's in a human retina it looks a lot more like an invertebrate photoreceptor than it does look like a rod or a cone and the melanopsin molecule itself looks more like an invertebrate photopigment than it does look like a rod or the cone. So in your human retina is this vestige of a common ancestor that we share with invertebrates. Okay so now I'm back from my digression so I was thinking okay if I know why FL41 works I can make something better. So I got in touch with an engineer in electrical engineering here on main campus and he said you know I don't, I think as far as tints go, organic dyes I think that FL41 is as good as you can make it. If we're going to make something that blocks more strongly at the wavelengths that you want to block we're going to need a different technology and so what he recommended were called thin films and so thin films are very, very ultra thin layers of metal oxides that are applied to the surface of a spectacle lens and if you apply the layers in a certain order and there are a certain thickness and a certain composition you can get all kinds of optical properties and it's that thin film technology that we use to make anti-reflective coatings that are almost ubiquitous on spectacle lenses. Thin films are what are used to make mirror coatings like on sunglasses but it turns out that you can make a notch filter. You can make a filter that just blocks 480 the same wavelength that stimulates melanopsin cells by using this technology. So here's just a schematic diagram of an example of a thin film notch filter where you've got on the substrate surface you've got titanium dioxide that's 165 nanometers thick and then a layer of silicon dioxide that's 40 nanometers thick and then titanium again and silicon again and then at the top you've got this layer of mag fluoride. These are all metal oxides, very, very thin layers and it just turns out that this combination of layers and this order with these thicknesses gives you a notch filter at 480. So we developed a clinical trial to test these out and see you know can we really make people with migraine better and so we designed two notches. We designed a 480 nanometer notch and as a sham we developed a 620 nanometer notch. The reason I picked 620 is because if you look at the maximum sensitivity of the human eye it peaks right here around 540 nanometers. Our notch filter at 480 kind of landed over here and so I said let's pick something that's on the complete opposite end of the human light sensitivity spectrum. We had two filters and this is what they looked like. The one on the right is the 480 filter. It has kind of a little bit of a bluish reflection on it and the one on the left is the 590 notch or the 620 notch which has more of a green kind of a green and yellow kind of reflection on the surface. We randomized 48 subjects with chronic migraine to wearing either the 480 or the 620 lenses for two weeks then they wore nothing for two weeks and then they switched. So each patient served as their own control and they wore the other lenses and then which lens seemed to help their migraines and their light sensitivity better. The headache impact test, that's a six question instrument. It's a lot, clinicians like this test, clinicians that take care of headaches like this a lot better than just asking people to keep a diary of their headaches because it really gets at how are the headaches affecting your life. We're less interested in how many headaches you're having or how severe your headaches are or whether or not you wound up in the emergency room we're more interested in how do these headaches affect your ability to go to and enjoy your family, enjoy your life really. The hit six questions are all scored on a scale of 6 to 13 each question. So the minimum score is 36, the maximum score is 78 and then you interpret it if your score is 49 or less then your headaches are having little impact and then 50 to 55 is some, 56 to 59 is substantial and then if you score 60 or more that's considered to be evidence that your headaches are having a very severe impact on your life. And it turned out of the 48 patients that we randomized with chronic migraine I think 90% of them were in that category of very severe. It turned out that both the 480 and the 620 lens were helpful and if you look at the compound effect of the two lenses over the time of the trial so the average hit six score in these 48 patients was about 65 at the beginning of the trial when they were wearing either the lenses that dropped by about 4 points during the washout period it popped back up a little bit and then during the second trial it went back down again and then when they took the glasses off it went back up so I thought this was pretty good evidence that the glasses were having some sort of an effect but what wasn't clear when I initially looked at the data was why my sham lens was working as well as my placebo it turns out that it was my ignorance of invertebrate photoreceptor physiology that may have affected the trial. So you may remember, if you're an ophthalmology resident and taking the OCAP you'll hopefully remember that in order for you to get that all trans retinal isomerized back into 11 cis retinal so it can be ready for the next photon it has to leave the photoreceptor be transported to the retinal pigment epithelium recycled over a number of enzymatic steps and then transported back to the photoreceptor. Invertebrate eyes don't have a retinal pigment epithelium at least I don't think they do. It turns out that invertebrate photopigments are bistable and that one wavelength of light that's lambda one isomerizes the molecule from its 11 cis to its all trans form and then a different wavelength of light, lambda two, isomerizes it back to its active form. If you look at mouse melanopsin it's 480 nanometer isomerizes melanopsin from its active state to its inactive state and activates the cell and it's 590 nanometer light that isomerizes it back from its inactive state to its active state and so I think this is why we got an effect from the lens that I think was that I had designed as a sham and there's actually clinical evidence who was a guy a couple of years ago he took a bunch of people and he had him take a test and he was interested in the effect of different wavelengths of light and how it affects your test taking ability and he showed that if you had people under 590 light 590 light that they did better on this cognitive test and so there is something magic about that wavelength of light apparently and of course if you think about the ganglion cell where it is in the retina there's no way it can send its melanopsin to the retinal pigment epithelium it's hundreds of microns away so it has to have some way to isomerize its photopigment back and forth between its active and inactive state so I think that's the plausible explanation for why my sham lens seemed to be an active lens and actually these data were just accepted by the Journal of Clinical Neuroscience and revising it right now and hopefully it will be published later in 2015 Okay, so getting back to treatment we also, Krista Kinard, our neuro-automology fellow two years ago and former resident she did a study while she was a fellow of corneal nerves in patients with chronic migraine using confocal microscopy and she showed that not only do these chronic migraine patients have some alterations in their corneal innervation but every single one of them had dry eye symptoms which was something we were not expecting and so I think that dry eye is going to be very is probably universal in patients with chronic migraine and certainly migraine that's bad enough to have them come to the eye doctor with photophobia so treat their dry eye and we all know how to treat dry eye FL41 tint is commercially available that's that rose-colored tint I've had so many people over the years ask me where can I get this tint, where can I get this tint, where can I get this tint and some people could mail things into the Moran Eye Center but it's hard like if you live in Sydney, Australia to get FL41 glasses from the Moran Eye Center and so I founded an online company, Axon Optics we sell FL41 glasses online we ship all over the world, we ship contact lenses we do prescription, non-prescription we have a variety of frames and it's not like if you have a patient here in Salt Lake you want to send them to the optical shop because they can fit their frames properly and they can get it just right whereas if you have a patient that lives far away it's really a lot easier to work through the internet and get them through Axon Optics the thin film coatings that I described for that clinical trial are not commercially available we are now going through the FDA approval process because I want to market them as a treatment for migraine so you can't buy those but we are starting a clinical trial a new clinical trial soon we do have a pediatric and adolescent migraine study going on next door at Primary Children's so if you happen to know somebody, a kid 18 or younger, 8 to 18 I think is our age inclusion group with migraine they might be eligible for the study it's listed on clinicaltrials.gov so photophobia is a common accompaniment of some common ophthalmic neurologic conditions many of us forget to treat this facet of the disease I mean, optical treatments are currently available they're very cheap and they seem to work and they don't have side effects and I think some newer optical treatments are on the horizon that might provide better treatments for light sensitivity, migraine, blepharospasm, and traumatic brain injury okay, thanks for your attention yeah, baller yes, exactly so there are not FL-41 tinted computer screens available we're actually working on a nanoparticle filter that you could put on a computer screen that's another patent and another R&D project but I think eventually we will be able to make something that has the same notch filter effect computer screens and TV screens are really interesting because they primarily use blue LEDs and that blue wavelength is very close to the maximum sensitivity of null and option and that's why these screens, these modern screens are irritating to people and also I think it's why a lot of us are having trouble sleeping because we're all on our screens at night when we're in bed and we're stimulating these cells and we're telling our super-chiasmatic nucleus it's time to be awake and it's actually time to be asleep so the new trial, yeah, the sham filter is going to be a neutral density gray filter that has the same darkness across the visible spectrum so obviously another area of interest is is this whole pathway blue light, yeah, dramatic and there's actually a group here in Research Park that's interested in using blue light as a treatment for Parkinson's disease and I'm sure that and what you're saying are connected somehow and SAAT also sees it in that trend of course, yes it's classic that show yeah, so we haven't been tracking depression we are tracking hours of sleep each day but I hadn't thought about tracking depression yeah, yeah, it's very new sorry, I think Paul had a question yes you know, it's really hard to say because like fluorescent lights and computer screens and these gas discharge lamps all emit at different wavelengths across the visible spectrum and I'm not sure and I'm not sure it matters actually because let's say it's just blue light that bugs you blocking the 620 light is still going to have an effect because if you're not reisomerizing the melanopsin back to its active state if you're photochemically blocking it from being enzymatically restored to its original active state you will still get a therapeutic effect even if that's not the wavelength of light that bugs people yeah, I'd like to see that I'm sure that's true it is not somewhere that I've spent a lot of research time on and probably even more about it yeah, you know, I haven't just because it's such an uncommon condition but I think it's a great idea and it might very well be very effective for them I was looking at, yeah I'm sorry, I'm going to have to cut off questions so we have time for our last speaker but I'd be happy to talk to you in a bit yeah oh yeah