 Hi, I'm Kathleen Diggree, I'm at the University of Utah in the Department of Neurology and Ophthalmology. And I'm Brad Katz, I'm in the Departments of Ophthalmology and Neurology at the University of Utah. And we're both from the Moran Eye Center and we're excited today to try to give you a practical approach to your patients with eye pain and photophobia and particularly we want to look at the melanopsin pathway. My disclosures are that I'm part of Inventor on a patent pending, and I have some royalties from three textbooks, one on eye pain. And I hold two patents regarding the treatment of photophobia with optical filters and nanoparticles. I'm also CEO of Axon Optics, which is a company that sells eyewear for the treatment of photophobia. So our objectives today are to give you some ideas about the basic history and examination of eye pain and photophobia, and then be able to identify those causes of eye pain and photophobia and importantly, outline treatment options for your patients. And above all, we want you to realize that providers need to know how to evaluate and treat eye pain and chronic photophobia. So we're going to start with a case. This is a 34 year old woman with light sensitivity causing eye pain. She has a history of migraine with aura in high school, and she's been really relatively healthy until now. She began having some insomnia, and she started to develop pain over eyes and face and at first started with sunlight, then it progressed to indoor lighting. And now she's incapacitated at home with her lights off, not going anywhere. She's seen three neurologists, three ophthalmologists. Some have even said she's got a somatiform disorder. She has been diagnosed with dry eyes, but she's referred to you. And we've done an eye examination with the visual acuity and the fundus being normal. The neurologic examination is normal. Well, what is causing the eye pain induced by light, and how am I going to approach this patient? I think the first step is doing a careful eye pain, photophobia history. And that means taking a careful family history. Not only do you want to know about a migraine family history, but other pain disorders, like do they have fibromyalgia or an autoimmune background? Then you want a life history. Is this new, old, when did it start? When did it get worse? What life events happened along the way that may have been associated with stressful life events or something like that? Then we want to understand what it feels like now. What's going on continuously or intermittently, and how long does it last? Particularly, we're going to go after migraine symptoms, a headache that's associated with light and sound sensitivity, nausea and or vomiting that worsens with activity. We're going to really query about autonomic symptoms like redness, swelling around the eye or lid, tearing, rhinorrhea, nasal stuffiness, ptosis or meiosis. And we're going to look for things that make it worse. Eye movements, the position of the head or neck or the eyes, exercise or touching the face. And then, of course, the medical history is extremely important. A history of a traumatic brain injury could generate new photophobia and eye pain. Obesity, snoring, autoimmune disorders, malignancy, vascular disease, depression and anxiety are also important to ask about. And don't forget a medication history. There are many medications that can make dry eyes worse, like diuretics, antihistamines, anticholinergics, some antidepressants, narcotics, stimulants. Think about the medications that somebody is on and whether they could be affecting this story. So Dr. Katz, what do you look for when you see a patient who has eye pain and photophobia? So in addition to a complete ophthalmic exam, when you have a patient with eye pain and photophobia, there are some other specific things that I'm going to add to my examination that I wouldn't ordinarily do. And so I'm going to take an extra careful look at the pupils, and I'm going to look at the eyelid position to see if there's any proptosis or lid lag that would clue you into thyroid eye disease. Sometimes palpating around the eye, especially around the trochlea, could clue you into trochleitis, which is an uncommon cause of eye pain. You know, a neurologist's trick is to tap over the occipital nerves in the back of the head to see if that recreates some of the eye pain, because sometimes patients with irritation of the occipital nerves will have referred pain into their eyes or their eye socket. And then another trick you can do is you can do a superficial compression of the superficial temporal artery or the supra-orbital artery or the infra-orbital artery to see if that improves the patient's pain, because that can kind of clue you in that there's a vascular component, oftentimes migraine, that's contributing to their pain. And then at the slit lamp, looking for any signs of intraocular inflammation. The other trick that I will sometimes do is I'll take a cotton-tipped applicator, and while the patient's eyes are closed, you can just gently palpate over the globe at the insertions of the superior and inferior recti and the medial and lateral rectus muscles, looking for myositis, which can be a cause of eye pain, usually with eye movement, but not always. And then finally, some patients that have cervical paraspinal muscle spasm will get referred pain into their eyes. It's often seen after like a whiplash injury. And so I'll sometimes just ask the patient if I can palpate their neck muscles. And boy, you'd be surprised at how many tense, rock-hard cervical paraspinal muscles you can run into. And patients may not necessarily know that their neck is bothering them, especially if it's a chronic problem, but that can definitely be a source of referred pain into the eye and the eye socket. Thank you, that's very helpful. So red eye pain, we in general think this is usually an ophthalmologic problem. What kinds of things can cause a red eye that you would see in ophthalmology? Yeah, I agree. Like if you're not an eye doctor and you're seeing any signs of redness, inflammation or if the patient is reporting a foreign body sensation, these things should really be best evaluated by your neighborhood ophthalmologist because they really have the examination tools and techniques to quickly rule out this list of possibilities here like scleritis and keratopathy and conjunctivitis, which could be causing the eye pain and the light sensitivity. Great. But there are also some important neurologic causes of eye pain and photophobia, like a horny with a carotid dissection can give you referred pain into the eye. A cavernous sinus thrombosis could present with multiple cranial nerve, palsies, elevated intraocular pressure and a red proptotic eye. The Toulosa Hunt syndrome is a idiopathic syndrome of inflammation in the cavernous sinus that can present with abrupt onset eye pain and ophthalmoplegia. A carotid cavernous fistula, if it's traumatic and it's between the internal carotid artery and the cavernous sinus causes a very dramatic red eye bulging eye, ophthalmoplegia, redness, but a small, a low flow fistula between one of the dural branches of the men in gel arteries and the cavernous sinus can be very subtle. You can have just a little bit of ophthalmoplegia, a little bit of redness, a little bit of pain. So those can be really tricky. Those are typically in middle-aged women and they open spontaneously. They're not associated with trauma. And then lastly, the trigeminal autonomic cephalalges are a really important cause of eye pain that can be accompanied by autonomic symptoms like tearing, eye redness, hornar syndrome, nasal stuffiness or a runny nose. And they can often be confused with trigeminal neuralgia. Yes. And sometimes you'll find eye pain is accompanied by visual loss. And in those cases, you wanna think about optic neuritis like with pain with eye movement. Sometimes inflammatory diseases of the eye like iritis, uveitis, gluritis and intermittent glaucoma. Inflammatory orbital disease also can present with eye pain and visual loss as can sinus disease. Menogitis usually has fever and stiffness of the neck and other things that we might want to consider. Vascularitis like giant cell arteritis or polyangitis can present with eye pain and visual loss and it's usually an ischemic type. Don't forget about pituitary apoplexy and a pituitary tumors can just present with photophobia and orbital disease looking for the proptosis and other findings of orbital disease may be also important. And finally, vascular diseases like aneurysm, ischemic ocular syndromes also can present with eye pain and visual loss. The neurologic signs can also occur with eye pain and painful third nerve palsy can be a simple microvascular third nerve palsy and diabetes but it could also be the compression or even rupture of an aneurysm causing painful third nerve palsy with or without pupillary involvement. And again, pituitary apoplexy. Also tumors, pituitary tumors, meningiomas, infections, demyelination and inflammation can be very important. So it's important to do a careful neurologic examination looking at all the cranial nerves carefully. I think eye pain with a normal eye and normal neuro exam is sometimes the hardest, especially in ophthalmology, this is hard. So if you have somebody with that, you really wanna be thinking about migraine and asking all the questions about migraine, about cluster or the trigeminal autonomic cephalelges. But what do you think about other eye conditions that have normal eye exams and normal neuro exams, Dr. Katz? Yeah, dry eyes can be really tricky. They're very, it's a very common problem. And most people that have dry eyes, they go to the grocery store and they buy artificial tears. They don't come to the neurologist's office or the ophthalmologist's office. They take care of it themselves. But it's the people that have atypical presentations of dry eye like eye pain and photophobia that end up in your examination chair. And so you just have to be cognizant of that and realize that patients can have atypical symptoms from dry eye syndrome. They don't always just present with the dry itchy scratch and burning. And then patients with eye strain because they've got the wrong glasses or because their eyes aren't converging properly on the printed material. It's kind of a, the term we use in ophthalmology is asthenopia. And those things are best evaluated by an ophthalmologist. And those can cause eye pain and headaches. And then finally blepharospasm. So these are patients that have unconscious, repetitive blinking and squeezings of the eyelid often times exacerbated by light. And sometimes they can present with light sensitivity as they're presenting symptom. So how are we gonna approach this? So we've developed an algorithm for you to evaluate eye pain and photophobia when your examination is basically normal. And so the first is you have to really do a careful history, physical examination and think about central processes like head injuries, chronic illnesses, chronic pain conditions. And look carefully on your exam for a Horner syndrome. So ptosis, meiosis, check those cranial nerves carefully. Look for an afferent pupillary defect. Look for proptosis. Look for papladema. Look for any neurologic finding. And if none of that is present, which our patient, she had a normal MRI scan, she had a normal neurologic examination. So we fulfilled this whole section and it was all normal. So what's your next step? The next step is to put a drop of proparacane into the eye of the individual with the eye pain and photophobia. And you can do this yourself or you can ask an ophthalmologist to do this test. Is there any reason that you can't do this test, Dr. Katz? The only place where I could see you could mess up would be if your patient's wearing contact lenses, you might wanna have them take the contact lenses out first. But other than that, you're not gonna do any harm putting a drop of the topical anesthetic in somebody's eyes. And then you ask them how much of the pain or light sensitivity is reduced. In our patient, it improved her eye pain a little bit but it wasn't complete. She still had eye pain and she was still photophobic. All right, Dr. Katz, take us through what you do next to evaluate further for dry eye. So if you're really suspicious that somebody has dry eye as the cause of their light sensitivity and or eye pain, the next test would be what's called a Shermers test. And it's where a small piece of calibrated filter paper is put just inside the lower eyelid for five minutes. And this, again, is a test that ophthalmologists commonly do. And if you're a neurologist, you can work with your community ophthalmologists to ask them to specifically do this test. And it's usually done with a drop of topical anesthetic. And then you set the timer for five minutes. And most people should be able to squeeze out 10 millimeters on the Shermer strip in five minutes. And if it's anything less than that, then you've got an aqueous tear deficiency. You've got dry eye that needs to be treated. So our patient's Shermers was one millimeter. That's dry. That's like Sahara Desert dry, right? Yeah, and it's really surprising. You would think somebody with a Shermers test that's that low would have more like dry. They would complain that their eyes feel dry, scratchy, burning, but it's interesting that this patient had more like pain and light sensitivity. Yes. So then the next step is to look for things like hemorrholeopia, meaning everything is too bright or nyctalopia, meaning you have trouble seeing in the dark or decreased visual acuity. So night vision or vision that deteriorates in bright light. And this I think we would all agree we'd send it to the ophthalmologists for a good retinal exam because certain retinal dystrophies can have a photophobia associated with them and a retina specialist should be able to tell you whether that person has anything wrong in the retina. And our patient did not have these symptoms or findings. And then I really think you never want to miss bluffer spasm. Bluffer spasm is that repeated blinking and sometimes squeezing and sometimes it's spontaneous and sometimes it only comes out when light is suddenly shined into somebody's eye and their lids will clamp down and be very hard to open again. It's really an involuntary eye closure and this can be treated on a botulinum toxin and our patient did not have this finding. And then at the end, you have to screen for migraine. You know, do they have headaches that have light and sound sensitivity, nausea and or vomiting and worsen with activity because migraine is so common. And if they do at the end of this screening for migraine you should also screen for depression and anxiety and we'll tell you about how to do that but also the importance of screening for those two things. Now our patient did have a migraine history. We knew that right off the bat and she does have some depression and anxiety. So in our, we did a study in University of Utah, Moran Eye Center and also the University of Zurich asking what kind of diagnoses come into the eye clinic and the neurology clinic. So we had almost 2,400 patients and we said what were the diagnoses of the people coming in with eye pain? And they really were conjunctivitis, keratitis, dry eye was right up there and then keratopathies, uveitis, post-surgical findings and even migraine in the eye clinic. In the neurology clinic over half of the people had migraine, optic neuritis was also really common and then the cranial neuralges were also common. I'm sure that the eye clinic missed the migraines and I bet the migraine, the headache clinic and neurology clinic missed the dry eyes because those are way more common and probably were more represented than were tested for. Now there are lots of causes of photophobia and we've talked about all these anterior causes like iritis and corneal abrasion. Corneal neuropathies I think are really important to be aware of and these can happen with dry eyes, they can happen with all kinds of other corneal problems and posterior causes. We talked about retinal dystrophies, albinism, achromatopsia, retinitis, pigmentosa can present with severe photophobia and then brain causes like meningitis as well as pituitary tumors can also present. Even psychiatric conditions can present with photophobia so depression and ADHD and there's a whole host of other conditions and even medications that have been associated with photophobia. But the most common causes of photophobia are gonna be migraine, blepharospasm, traumatic brain injuries and especially blast injuries are going to be your most common causes of photophobia. And I think this is really an important study done by Tom Buchanan in our group late earlier many years ago where we took people who came into the eye clinic with photophobia, 100 people and men and women. One of the highest causes of photophobia was migraine. The next highest cause was dry eyes and then several other ocular conditions and then trauma also occurred as well as well as progressive super nuclear palsy depression and then there were some undiagnosed types. So our patient had a history of migraine. We found that she had dry eyes and we think that the history of migraine, dry eyes were really driving her eye pain and photophobia. So then we have to ask the question, well, could migraine alone affect your vision and your visual quality of life? And in this study done by one of our previous fellows we took 29 patients with chronic migraine, 37 patients with episodic migraine with or without aura and controls. And we did several validated questionnaire instruments like the HIT6, which is a migraine severity score, the migraine quality of life score, the visual quality of life VFQ25 and the NEI supplement. And we found out something very interesting that migraine alone was almost a dose response curve. Chronic migraine had the lowest quality of life, visual quality of life, episodic migraine had lower quality of life than controls. So our visual quality of life in chronic migraine was similar to optic neuritis, idiopathic endocrineal hypertension and even thyroid ophthalmopathy. So we showed that chronic migraine really has a profound effect on visual quality of life. And in this graph, we charted on the Y axis, you can see the NEI VFQ score, and remember high is good and low is bad. And the HIT6 score, which is sort of a how bad is your headache? Where 80, this end of the graph on this axis is the worst and 40 and less is better. You can see that the chronic migraine in the black here have the lowest scores, followed by the episodic migraine, and then of course the controls were better. But as the HIT6 got worse, their visual quality of life also got worse. So what do you think Dr. Katz is driving this decreased visual quality of life in migraine? Well, to answer that test, to follow up that last study, we took 54 patients from our headache clinic with chronic and episodic migraine. We gave them the visual quality of life survey from the NEI again, the headache impact test and the ocular surface dryness index, the OSDI, as well as an instrument that we developed at the University of Utah called the Utah Photophobia Symptom Impact Scale. And we found that the thing that was most highly correlated with increasing severity of headache and light sensitivity was the dry eye survey, the OSDI. So if you look at visual quality of life, again on the Y axis, a bigger number is a better quality of life. And then put it next to on the X axis, this ocular surface dryness index, which is a measure of dry eye symptoms with worsening dry eye being a higher OSDI score, that gave us the tightest correlation of all those instruments that we checked. And so what we think is driving the reduced VFQ, visual quality of life scores in patients with migraine, especially chronic migraine, are dry eye symptoms. Yeah, so dry eyes can affect both eye pain and photophobia. And we've just shown you that the visual quality life is reduced in chronic migraine, that it's most closely correlated with these dry eye symptoms. But the question is how could this even happen? And Dr. Katz, take us, or I'll take you through this. So let's just talk about the anatomy of the tear film. So to orient you here, we do need to understand the trigeminal system. So we have a trigeminal nucleus. And remember the trigeminal system is the pain system for the eye. But not only do we have a nucleus that lives in the brainstem, but we have the caudal, the trigeminal caudal nucleus or the trigeminal complex, cervical complex. And these two systems are also connected to the autonomic system, the superior salivatory nucleus, which is in the parasympathetic system. And then don't forget that we also have a sympathetic system that comes up from the carotid, goes into the orbit and also has a supply to the lacrimal gland and participates as well in our tear film function. So the cornea is innervated by this trigeminal system and it can set up pain signals that go back through V1. And it can then connect with the autonomic system through the superior salivatory system to create more tears. And there's a reflex arc here that it can send a signal and then you're supposed to get more tears. Well, sometimes you don't get more tears either because the autonomic system isn't working right, the trigeminal signaling isn't working right, or the coupling of these two isn't working right. And so it's an integrated system of the autonomic system coupled with the trigeminal system. And the cornea and dura, remember, are innervated by the first division of five. And so that means that both the dura that participates in migraine and sends microscopic, has microscopic inflammatory changes that go into the trigeminal system can also have corneal input into that same system and set up almost a sensitivity that could just be maintained by the trigeminal system. So Dr. Katz, what do we know about the corneal nerves with chronic migraine? So this is kind of, we've got the whole ball rolling was, because we know that the first division of five innervates the dura and is strongly linked in migraine pathophysiology and it's also what innervates the cornea. We kind of thought that confocal microscopy, which is a specialized technique that we can use to look at the corneal nerves, could be affected in patients with migraine. So we took this cohort of 19 patients with chronic migraine and 30 controls, we gave them the dry eye questionnaire and then used confocal microscopy to look at the nerves, the nerve endings from V1 and the corneas of these patients. And we found there were some very definite structural differences, which are highlighted on the next slide. You can see the control nerves in the top picture and then a patient with chronic migraines in the bottom picture. The pictures in the right hand column are from a software package that outlines the corneal nerves, looks for branching of the corneal nerves, measures the density of the corneal nerves in a specific slice. And we found by testing all these different patients that nerve fiber density, nerve fiber length and nerve fiber, I'm sorry, nerve fiber density was very significantly affected in patients with chronic migraine. Nerve fiber length looked like it was a little bit different in chronic migraine, but it wasn't statistically significant, nor was branching. But the most significant finding was this finding that nerve fiber density was less in patients with chronic migraine. And these findings have since been confirmed by another group outside of university. We don't know if this is a chicken or an egg issue. We don't know if people with chronic migraine have abnormal innervation of their cornea or if abnormal innervation of your cornea leads to the development of chronic migraine or both. And it's interesting that in our patients, they had normal shirmers and tear film breakup times, et cetera. So even though they had those normal studies, they still had these abnormalities on the microscopy. So it means that we have to add, besides the typical drawing that we use with the dural input into the trigeminal system and connecting with the autonomic system, we have to add the eye into this whole arc where the corneal afference for whatever reason can be abnormal in chronic migraine, but also in patients who have a lot of eye pain and photophobia. Other groups have hypothesized that there's a shared pathophysiology between dry eye, migraine and traumatic brain injury because there's a shared trigeminal, phylamic pathophysiology that alters, is altered and it could be mediated by calcitonin gene related peptide or other mediators that we really haven't quite identified yet. So the next question you might ask yourself as I wrote down that you should ask about depression and anxiety. So is there a possible psychiatric component? For sure, many people for years thought anybody with photophobia, oh, these people are completely crazy. Well, people aren't crazy. Photophobia has been associated as a symptom of depression and some patients with migraine also have increased incidence of depression and anxiety. And we asked the question, is there really an emotional component to photophobia? To answer that, we took migraine individuals with migraine with and without aura that had interictal photophobia. That meant their photophobia was there all the time and ictal photophobia, which meant that they just had episodic photophobia with their migraine only. And then we had controls who had no migraine and we did a back depression inventory and a back anxiety inventory. And this is what we found. We found those people who had interictal photophobia had a much higher depression score than those with ictal photophobia. And that was similar to controls. Ictal photophobia was just like controls, but when they had interictal photophobia, they had a much higher depression score. And similarly with anxiety that their anxiety was also elevated with interictal photophobia versus the ictal photophobia, which was again similar to controls. And since our study was published, another group has also confirmed this finding. And so to answer the question about eye pain and photophobia, what is it that we need to get this to happen? Well, we need the trigeminal system. I've already taken you through how important the trigeminal system is for dry eye, the trigeminal system is for migraine and so on. But we've got to explain something else. We have to explain what the mediators are. CGRP is an attractive mediator for photophobia and eye pain because when mice are given CGRP, they demonstrate photophobic behavior. They try to get into the dark. And if you give them a CGRP monoclonal antibody, you can attenuate that response. Similarly in humans, photophobia can develop within 30 minutes of a CGRP infusion. It comes in ahead of the actual head pain. So that would suggest that photophobia, there could be a mediator here. And certainly we know in the cornea, there are many polymodal noceoceptors that are activated in dry eye for sure. There can be up regulation of the TRIP-V1 channel and CGRP and TRIP-V1 are also connected. So this is an attractive mediator to look at for photophobia and eye pain. But how could we get light sensitivity? We have to explain an important conundrum. Do you need vision to have light sensitivity? And that question has actually been answered. Nozata and others identified 20 migraine patients with either no light perception or light perception type of vision. So they were legally blind. And those with light perception and migraine could still be light sensitive. And to answer this question, we really need to turn to the intrinsically photoactive retinal ganglion cells and the melanopsin story. Dr. Katz, can you take us through what this story is all about? So many of you will remember from medical school that in your retina, you've got different layers. The innermost layer has the photoreceptors, the rods and cones, rods for night vision and cones for day vision and color vision. And they synapse with another class of cells called bipolar cells, which then synapse with ganglion cells. And it's the ganglion cells whose axons actually leave the eye through the optic nerve and head back to the lateral geniculate nucleus where they synapse and then eventually send information back to occipital cortex. But right around the end of the 20th century, a subclass of ganglion cells was identified that's intrinsically photosensitive. In humans, it makes up about 2% of the population of ganglion cells. So these cells do not need input from rods or cones in order to be activated. If light hits them, they will start firing on their own. And the other thing that's unique about these ganglion cells is that their axons don't go to the lateral geniculate. They go to other parts of the brain and other parts of the thalamus where they innervate pain centers. They go to the hypothalamus where they regulate the circadian clock. And they also go back to the brainstem where they innervate the Edinger Westfall nucleus responsible for pupillary constriction. So it's the subclass of ganglion cells that have nothing to do with seeing or with vision but that are very light sensitive. And we think that these cells are still active in our patients that have photoreceptor degeneration. So these patients are blind, they don't have any useful vision, but these ganglion cells still work and can still send pain signals back to the thalamus. If you look at the a vertebrate photoreceptor that contains rhodopsin, it looks like the diagram over on the left and like polymerizes rhodopsin from its 11-cis to its all-trans configuration and that causes a cascade of enzymes to open up sodium channels. I'm sorry to close sodium channels in the photoreceptor, but if you look at the physiology of these intrinsically photosensitive retinal ganglion cells, they don't contain rhodopsin, they contain melanopsin, which is also a light sensitive molecule. It's isomerized by light. And if you look at the ion channels and the cell membranes of these cells, it looks more like an invertebrate photoreceptor than it looks like a rod or a comb. They're in term from an evolutionary standpoint, really interesting cells. Now these cells shown in the schematic here is the IPRGC's at the bottom, the purple cells. As I said, they send their axons to the suprachiasmatic nucleus where they help entrain circadian rhythms. They go to the adenger Westfall nucleus in the back of the brainstem where they help the pupil to constrict and they also go to some pain centers in the posterior thalamus. And we think this is the photophobia pathway. We think it's these cells are sending their axons into pain centers in the thalamus. So when you look at a very bright light, like it hurts, like if you look at the sun, it physically hurts. And we think it's these cells firing that cause that pain. And it's interesting to know that these cells still do receive input from rods and cones, including the red, green and blue cones, but they do not need input from those cells in order to be activated by light. And also something that distinguishes these ganglion cells from other ganglion cells in the retinas is that once they're hit by a pulse of light shown in the left diagram, when the light turns on, these cells start firing like crazy. And even after the light is shut off, they keep firing. And that's a unique property of these cells that distinguishes them from other ganglion cells. And if you look at the spectral sensitivity of these cells, they run in that red line there. They sort of fall between green cones and blue cones and their sensitivity. They're maximally sensitive around 480 nanometers, which is a wavelength that's sort of a blue-green part of the visual spectrum. And actually, we've known for more than 20 years that a particular tent called FL41 can be helpful in patients with migraine, blepharospasm, traumatic brain injury who exhibit light sensitivity, but we really never knew why. And if you look at the spectral characteristics of this tent, which sort of like is a rose-colored tent, it is maximally attenuates light right around 480 nanometers, the same wavelength almost exactly the same as the wavelength at which the intrinsically photosensitive retinal ganglion cells are maximally sensitive. And we think, we don't know for sure, but we think that's why this tent is so helpful to people is because it helps shut down the light that's exciting those intrinsically photosensitive retinal ganglion cells that are then sending their axons back to the posterior thalamus and causing pain. And so this article that came out really showed how melanopsin co-located with the trigeminal system. And that's why we think that with melanopsin going with the trigeminal system, photophobia can occur and it can even occur in people without vision. Animal models do help us understand the emotional component. For example, newborn blind mice only have melanopsin cells or the intrinsically photosensitive retinal ganglion cells active up to post-datal name nine. If you shine light on these mice, they'll produce vocalizations that are similar to being taken away from their litter or giving an oxious stimuli. But if you knock out melanopsin from these mice, they don't have this aversive behavior. So we know melanopsin is definitely involved in creating this vocalization. But what I think is so amazing is that then when they've taken the mice and looked at their brain, they see early gene C-foss expression in the posterior thalamus where we expect it to be from the melanopsin cells, but also activation of the amygdala. And the amygdala is part of our whole emotional limbic system and suggests that this contributes to this emotional component. And so that leads us to understand eye pain and photophobia is somewhat of a circuit disease. We have the trigeminal system both from the cornea, but also from the dura feeding into the trigeminal nucleus caudalis which integrates then with the melanopsin system or the intrinsically photorentinal ganglion cells in the thalamus, there's some integration there. And this system has a connection to the amygdala and the limbic system accounting for the depression. And there's even a sympathetic component to photophobia that we did not cover that may also be important. But I think it helps us start to think about photophobia and eye pain as part of a whole circuit of disease. Now the most important thing for all of us is how are we gonna treat people like this? Because if she's really disabled and not leaving her house, what can we do? And the first step I take is I explain why do you have these symptoms? This is a real deal. This is not a made up symptom. People have a reason for having it. All of people who throw on five pairs of dark sunglasses to close all their blinds, get in the dark, they need to come into the light because the more dark adapted you are the worse light sensitivity is going to be. And then what about treating dry eyes, Dr. Katz? What do you think about that? You know, for patients with dry eye symptoms, even if you're not an eye doctor, you can't go wrong with over-the-counter artificial tears. We do prefer to use artificial tears that are preservative free, but they do tend to be a little bit more expensive. So other kinds of artificial tears are good. And the worst thing that can happen is nothing. So if you prescribe artificial tears to your patient and it doesn't help, then you need to send them to an eye doctor to try to go to the next step, but you're certainly not gonna hurt anyone by using these over-the-counter preparations. For patients that need more serious dry eye treatment like the patient discussed, presented earlier today with a shimmers of one, they might need things like serum tears. So this is a treatment where the patient's own serum is spun off and put back in a sterile bottle and handed back to the patient. We sometimes use anti-inflammatories and some other in-office procedures that we can use to maximize dry eye treatment and try to cool off the trigeminal system that's being stimulated by chronic dry eye. And for sure we can treat underlying migraine. We've got excellent preventative and acute treatments for migraine. And if the patient has that, we need to maximally treat the migraine symptoms. Some of the treatments that have been proposed for photophobia and even eye pain are on a botulinum toxin. Dr. Katz had a patient where he did on a botulinum toxin just for photophobia and a sensation of dryness in a patient who'd had a post-traumatic brain injury. But also this has been reported in other cases. Anticonvulsants have been reported anecdotally to be helpful, gabapentin and pregabalin. CJRP monoclonal antibodies, anecdotally, anecdotally have also been found to be helpful. Sleep is really important for migraine and any pain disorder and melatonin is an easy fix for somebody who's having a sleep problem. And I don't think we should forget treating depression and anxiety because depression can kill people every day. And it's really important that we identify it and treat it. And then sometimes sympathetic blocks can also help with photophobia and eye pain, chronic eye pain, especially if there's a regionally, if this is a regional pain syndrome-like disorder. What about devices, Dr. Katz? Do you know of any devices that can be helpful? You had mentioned FL41 earlier. Right, so as we mentioned, FL41 seems to block the wavelengths of light that stimulate these intrinsically photosensitive retinal ganglion cells. And we have some good evidence that these are helpful in patients with headache. We here at the university have shown evidence that it's helpful in patients with blepharospasm and we have some anecdotal reports of it being helpful in patients with traumatic brain injuries associated with photophobia. It's important to know that these are not blue blocking lenses. In fact, if you look at the little blue arrow in our diagram here, FL41 actually transmits blue. It allows blue light to get through. That's not what's hurting the patients. It's this blue green light that's falling between the blue and the green cone photoreceptors. It's important. So the blue blocking lenses that you find on sale, on TV, in the early hours of the morning, that's not gonna help these people. There are some supra orbital nerve stimulators. The cephalyde device is now available, I think, without a prescription. And we can try it on at home and see if it helps their light sensitivity, their eye pain, their headaches. And TENS units can also sometimes be inexpensive and used around the eyes can help patients with eye pain syndromes. So I hope that we've told you that photophobia and eye pain are very common symptoms. Everybody has a reason and you have to make the diagnosis of what these symptoms are coming from, whether it's migraine, dry eye, blood for spasm, a retinal problem, pituitary tumor from the brain, et cetera. So you wanna make the right diagnosis as with any neurologic symptom. It has a real anatomic pathway. People aren't making this up. And we definitely need more studies to explore the complex interaction of melanopsin and the pathways of photophobia. And the trigeminal system is integral to the pain that people experience. And I think we've been very clear about showing you how cornea and dry eye symptoms can contribute to this. And then don't forget this emotional component. We have to treat depression. We have to treat anxiety because these can lead to deadly consequences and it's really important that we do that. And finally, boy, do we need some better treatments for this irksome condition? And the more research that we can do and the more that we can share what works for our patients, the better. Dr. Katz and I would like to thank all of our collaborators over the years. We've been lucky enough to work with students, residents, fellows, our colleagues at the Moran Eye Center, colleagues at the University of Zurich. And we especially wanna thank funding sources and especially the Mastigal family for their help in coming up with treatments and ideas for diagnosis and treatment of photophobia and eye pain. Thanks for joining us. Bye.