 So, I'm going to take you through a couple cases to introduce this topic, and I've already kind of given you a background of the innervation and the anatomy. I'm going to take a patient right out of our clinic, I see this all the time, 32-year-old woman comes to the ophthalmologist for IP saying what's wrong, something's wrong in my eye. She has a history of migraine that used to be episodic, meaning less than 15 days a month, and is now chronic, meaning more than 15 days a month, and her eye exam is normal, except you notice that she has a reduced tear leg, and you smartly do a Shermer's test and you find out it's only four millimeters, and could these be related, and if so, how? Now this cartoon that comes out of Flugfelter's AGO article several years ago, I think it's just a reiteration of everything that I just was talking about, that of course the eye is innervated by the trigeminal system, and of course it has reciprocal innervation with the autonomic system, and that when the trigeminal system is stimulated, the autonomic system kicks in and is supposed to make more tears, et cetera, et cetera, but obviously this little trigeminal nucleus is not sitting in a vacuum, it's connected to that trigeminal nucleus caudalis, and all of the central brainstem components that I talked about earlier. So I'm going to tell you about how tear film dysfunction may contribute to migraine, and I'm also going to suggest that some of the symptoms of dry eye really may be a migraine or peripheral nerve symptom, and those of you who see a lot of dry eye and you test them and they test like they've got fine aqueous tear film production are going to be surprised that maybe migraine may be playing a role in this. So the first clue to dry eyes and migraine having some connection is in Shogren's syndrome, and it's been known for quite some time that almost 20 years that people, individuals with Shogren's have higher incidence of migraine, 46% of patients with Shogren's have migraine, and when you think of only 20% of the population, women and 10% of men, that's a lot, and that's been corroborated by a more recent study as well. And this is one of the very first study, only six years ago, okay. This study came out of Turkey where they took a group of migraine patients and they didn't specify chronic or episodic whatsoever, so we don't know at all, versus controls, and they did Shermer's test, they did a tear film breakup time, they did that lysamine green staining, the conjunctiva, they did the ocular surface disease inventory test, and low and behold they found that people with migraine tested had lower Shermer's, had worse tear film breakup time, et cetera, et cetera, et cetera. So this was one of the first clues, and I saw this about six years ago, and of course I've been interested in the eye in migraine all along, but this I thought was interesting. More recently there's been a plethora, there's going to be a lot of studies coming out, and I hope somebody from Cornius in the audience, but we really need to grab hold and understand this better, because this is a study done in a neurologist's office, Dr. Wong in Canada, these Canadians that are very ingenious, went and sat, they did osmolarity testing on tears in a neurology practice, and they found, first of all, you know, they did 34 patients, most of these were women of course, because of migraine runs in women, 76% of these people in this clinic were disabled by their migraine, almost half had daily headaches, over the third had dry eye symptoms, okay? Then they did osmolarity testing, and they defined abnormal as greater than 308, or greater than 8 million osmols per liter between eyes, and by that testing they found almost half had abnormal osmolarity testing, versus about 20% of the general population. And what they also found was that patients with migraine with aura had a higher level of positive osmolarity testing than those with aura who didn't have dry eye symptoms, and those with daily headache also had osmolarity. But what was really interesting was that the headache and the OSDI did not correlate with osmolarity. So in other words, you couldn't say how, if the headache was really, really terrible, the osmolarity would be terrible, or the OSDI would be terrible. It didn't correlate with that, yes, Judith. Did they test just the 35% who had the dry eye symptoms, or did they test everybody? They tested, so in this study the question was, did they test just the people with dry eye symptoms? They took 34 patients, and these were people who were, you were excluded from this study if you had a known dry eye, or you were told you had dry eye, or anything like that. Just in a neurology headache practice. So they didn't sort of stratify that way. Kathleen? Yeah. So the ocular surface disease inventory is interesting, because eight of the 12 questions are totally non-specific to dry eye. So painful sore, blurred, poor vision, difficulty reading, difficulty driving at night, difficulty with computer work, difficulty watching TV, and there's only really four that are more really dry eye-specific. So gritty, you know, painful eyes in windy situations, dry areas, or air conditioning. And so I guess it doesn't surprise me in the sense that it didn't correlate the severity of the headache, didn't correlate, but I should say it does surprise me a little bit, it didn't correlate, because I think most people with migraine, just because of the eight non-specific questions, would have a high OSDI score. Good point. That's good point. But I can just tell you that it's not just the OSDI score, it's the DEQ-5, and all of these scores are definitely elevated. Here's another study that came out. Looking at wavefront analysis on the cornea. And in this study, done by Shetty in Boston, these were all individuals with no aqueous tear film deficiency, and then he studied, and this didn't show up as well as it did on my computer, he studied patients with migraine, which is 60 controls, which was 80, and he found that aberrations in the patients with migraine, and these were chronic migraine patients, were higher than those with control. So there's something going on here that I think is interesting. So these dry-eye symptoms are not rare. You see these symptoms in your practice every single day, and 20 to 30 percent of patients, and maybe even higher in Utah, over 45 can have symptoms, but they don't always have low aqueous tear film production. There have been some very interesting studies that have come. One study came out of the VA population, and this Virhoff study came out of a group of study in women and dry-eye symptoms, and they looked at concordance, meaning that they looked dry and they were dry, and then people who said they were dry, but they didn't look dry at all or didn't test dry. And what was interesting was that these people who had this discordance had higher incidence of arthritis. They also had increased incidence of anxiety, depression, PTSD, and allodinia. So sort of a sensory disruption. Do you think they asked about migraine? I couldn't believe it. I wanted to write a letter to the editor and say, how could you take this paper without asking about migraine, and I mean more common than most of those other conditions. Now, many of you may have known about the study that was done by Krista Kinard when she was a fellow with us. She looked at chronic migraine and did look at corneal nerve fiber density and symptoms of dry-eye. And she took 19 patients with chronic migraine, most of them women, and controls, and she applied a dry-eye questionnaire, and I think in this case it was a DEQ-5. And then she did basal tear film secretion, corneal sensitivity, tear film breakup time, and they were all normal in all of our patients. But when she looked at the corneal nerves on the cornea, she found that the nerve fiber density was reduced and the nerve fiber length was reduced. The nerve branching pattern didn't seem to be that different. So we published this, let's see when was that, in 2015, and then this paper came out last year by Shetty again in Boston, and what they did was they looked at the same structural changes in the cornea in migraine, patients with migraine, chronic migraine, and photophobia and chronic migraine without photophobia and sex-match controls. They measured all those sub-basal nerve plexus changes in chronic migraine and looked for structural changes with and without photophobia and controls. And what they found was that the people with migraine and photophobia in general were the ones that seemed to have the biggest changes in their corneal nerve density. So the branching was different, their fiber length was different, their area was different, and so forth. So this is an area that really I think has, I mean, those are the studies that are basically out there on those corneal nerve anatomy and looking at migraine. So I wonder if there isn't evidence for some central sensitization that could be coming with this dry-eye symptom problem, and especially when dry-eye symptoms don't respond to a topical anesthetic where there may be a heightened sensitivity to pain. And sure enough, this article by Crane came out and showed that in these individuals who have these symptoms, not only do they have the dry-eye symptoms that they don't look dry, but they have the dry-eye symptoms, but they have bicutaneous allodinia testing if you touch their skin, and there's various ways of doing this test, they have a heightened sensitivity to skin testing as well. This would suggest that this is something more central, right? I mean, this has gone beyond the trigeminal system, it's now into the thalamus or into the brain itself. There's a central process going on, and this has also been corroborated by another investigator. This Perry Rosenthal in Boston also has lots of papers on dry-eye light pain, he's called it DELP, and neuropathic-like pain, and he's called it NOP, but these are varying degrees of dry-eye testing and looking at evaporated hyperalgesia, and he's shown associations with a lot of eye procedures, so the more eye procedures we do on these people, like cataract surgery, LASIK, and if they've got any sensitivity like this, you get into trouble, and he also noted that it's highly associated with fibromyalgia, chogrens, and even blepharospasm. And he also feels like there's probably a peripheral sensitization that takes place, and then that is followed with a trigeminal mediation into a central sensitization to a brain problem. And I thought this article was really interesting that came out saying, well, okay, so what am I going to do in my office about these people who've got this neuropathic eye pain complaint? And so they recommended first determining whether it's peripheral, you know, by putting a drop of anesthetic in, and if it is, goes away with that, then really work on ocular surface treatment. And if it's not peripheral in that, it seems to be more centralized pain. They say send them to a neurologist, but you don't have to do that. You can try a few things yourself. They recommended low doses of tricyclics or something like gabapentin. And then many of these are mixed, meaning there's both a peripheral and a central component. And then they recommend lifestyle and complementary therapy. I would say that in all our migraine patients and patients that have chronic pain, we should be working on lifestyle, sleep, and so on. So I think the dry eye and corneal findings are really interesting. I don't think we've got the whole story yet. We don't really understand. Is it the migraine process that's participating in changing the cornea? Or is it, or mediators? Remember the trigeminal nerve releases CGRP into the cornea and there's substance P and all kinds of metalloproteases that are present in the cornea. But also that's the same stuff that comes out into the dura, by the way. Could we somehow study that? Is continuous stimulation, because somebody has dry eye symptoms or actual dry eyes? Is that producing more chronic migraine? And is the dry eye symptom participating in central sensitization and our dry eye symptoms when you don't have findings really a form of alodynia like what we see in migraine? And we don't have any idea whether treatment with local artificial tears or cyclosporine or punctal occlusion or lacosamide or flaxseed oil or whatever is going to have any effect on this process. But I think it's really important for every ophthalmologist to be aware of this connection because you're going to see this every single day in your office. Okay, any question or thing about the dry eye before I move into just eye pain? Yeah. I just have a comment about being thank you for trying to address this incredibly common but even more question. But I think that we see every single day people in this mixed or combined category where there's central and maybe even cognitive kind of regulation of what's going on. In my practice I found that there's a huge, huge, huge spectrum of corneal findings. We try to find, we try to see things that we can observe on the cornea, your own breakup time, staining, etc. And dry eye is so complex itself in that almost every dry eye patient has blepharitis or a little allergy or whatever. That's one of the reasons things like tear osmolarity, just not a very reliable index. Staining is pretty reliable. I would just submit that it may be impossible but it's studyable. When I state a cornea, in other words, findings increase but the symptoms decrease and so certainly there can be a disconnect between what you see on the eye and so that makes it even harder sometimes to treat. Yeah, yeah. Well I want to challenge the corneal service to partner with us and try to work on this problem because I do think this, we can observe the corneal nerves. We can't go in and look at the dura, okay? No, not that I'm aware of. I mean I have a lot of literature but I'm not aware of that. Okay? All right, well let's... Okay, all right, well I'd love to partner on it because I do think that this is something that's overlooked by the migraine community but it's certainly overlooked by ophthalmology as well. I mean, yes, Randy? So I mean I marked pretty well covered the key issues but I think sadly dry eye syndrome is a garbage basket term for at least several different conditions that, you know, people have dry eye type symptoms, we look at them and there are those who certainly, this is more of a dysregulation as you're talking about than yet. Some of those, it's clearly just pure dry eye and that's part of the reason why all of these things, again as Mark said, is extremely difficult but whenever you have people severe dry eye and you give them top of anesthesia and it hasn't helped their symptoms any, you know, that's immediately something going on here that's way and then you'll have those in whom you'll work hard, cornees looking better and their symptoms are absolutely better. And I get others in which, as Mark has also talked about that frankly, we have pretty bad symptoms, we're perfectly fine. But you see, I maintain that we should be looking at the kind of person that gets these symptoms because if you're predisposed to migraine, you're predisposed to sensory dysregulation in your brain, okay? Sounds are louder, touch is stronger. It's you're dysregulated by your sensory system. It's a sensory system processing disorder. And so I think that we should be thinking about disorders that have sensory processing and migraine is so common. It's a simple thing to even ask about in your clinic. And these people with this dissociation as I showed before, you know, they have pain problems, they have fibromyalgia, they have arthritis, they have, you know, all kinds of other things going on that are part of this sensory processing disorder. So I just want to bring to your attention that this is a common problem. If your patient has migraine, you should pay attention because that may help you understand better the way their brain is working, the way they're processing pain better. And we don't know if some of these newer migraine treatments that we've got now, like the CGRP antibodies, are going to be helpful in people who've got these dry eye pain problems because maybe this will be helpful to them. I don't know. Just like gabapentin, we use a lot of gabapentin and headache and chronic pain and I know in corneal pains. But it's something that we should be at least aware of in ophthalmology. Absolutely. So I want to just mention about what Mark just said about emotional processing. So guess what happens when, and I'm not going to talk about photophobia today, but I think it's very analogous, okay? Guess what happens when you have chronic discomfort? And this has happened in laboratory animals. So they took laboratory animals that mice that are blind at birth and then they just shine light on them. And these little mice squeak and make noises like they're being taken away from their mother, so it's a stressful event. Well then when these mice are examined under the microscope, guess where all the chemical light-ups are in the brain? It's in the amygdala and in the limbic system. So what it means is that pain gets into our limbic systems and participates in creating anxiety and participating in helping to make people depressed. So I know that some people are resilient and some people aren't as much, but this is a brain processing problem too. And also hereditary, there's a hereditary component who's more at risk to get into depression and anxiety as well. So I think it's very complicated, no question about it, but I think that the cool thing is that we can start understanding this on a neuroanatomic basis and then that means we can study it. It means we can have hypotheses. It means that we can think about ways that we might actually start to understand and treat it. Yeah, Randy. So this actually fits somewhat with some of the things that I've done with dysphotopsia. Right. And my explanation to patients is that the brain is a very powerful analog computer with a variable gain and that you don't necessarily control the analog computer component, but you can control your gain. And what I've noticed are those who are overwhelmed by this just absolutely focus on these symptoms and those in whom it resolves don't. And I've actually had success with some patients who will follow it, which I've said every day I want you to say, this is just going to get better. I'm not going to worry about this. And you truly... Yeah. And you're trying and I'll get a call and say, it just disappeared. And it hasn't disappeared. They finally have gotten some brain. This is like most of us. These symptoms are there. There's all kinds of things that we're seeing and experiencing in our vision and the rest. You know, I think it's the same thing where you'll have people who have incredible floaters and you'll say, my gosh, you need floaters to buy. You'll say, what floaters? Yeah. And then you'll have others in which you can already find a floater. It's driving them crazy. And so we need to remember that. Right. There's a huge variation we can do. I remember I had a medical student and I showed him through his end-topping phenomena how he could see his vessels and he couldn't quit seeing his vessels. I know. That's pretty cool. I think because Randy brought this very interesting thing up, I'm just going to cut to the chase that when I was in Switzerland, I found this very energetic medical student. And then I found an energetic medical student here who actually went on to ophthalmology at the University of Wisconsin, Chris Bowen. And we looked at all these patients for eye pain to come up with what diagnosis was in our clinics and just going to cut to the chase so that an ophthalmology is no big surprise. Most of it was conjunctivitis, dry eye, and blepharitis types of things. And in neurology, it was really migraine that caused the eye pain. And I'm just going to go. So, you know, the traditional red eye into ophthalmology and the white eye into migraine. But I want to caution you that many of your eye pain patients are going to have migraine because it's a very common problem. But I want to talk, because Randy brought this up, I'm going to just skip to this one. And then this is, you know, if I said that the visual quality of life in migraine and chronic migraine is reduced and we talked about, you know, the pain problems and all this kind of stuff, why else could it be reduced? Well, migraine has a lot of visual symptoms. And we're all familiar with visual aura. And I'm going to talk a little bit about aura and how to distinguish it from persistent aura. But all these people with migraine often have, because it's a sensory processing disorder, have stripe-induced discomfort. Many of them also have photophobia. They all have photophobia when they have a migraine, but in between, many of them have photophobia. And then there's this entity called visual snow. And this was a patient that got sent to me for treatment of prolonged aura. So it was a 17-year-old guy who has a family history of migraine. He had his first headache at age six. He had his first migraine in the eighth grade. And then a few months later, he developed migraine with aura. And it was a blank spot in the center of his vision with flashing lights that progressed out into the periphery for 20 minutes. Then he got a very severe headache lasting nine hours. And now he has a migraine with aura about once a year. And he treated with Sumitriptan, which caused chest tightness, so he quit that. And the question was, he had this migraine prolonged aura. So I said, well, what are your symptoms? He says, well, I see silvery lines that are always present if I concentrate on them. I see floaty squiggly lines when I look at the sky or snow. And as long as I can remember, my vision looks a little pixelated or greeny. And the symptoms were not associated with the headache. He sees through the visual phenomenon. And his past medical history was negative. He's on vitamins. And he's a good student. And of course, he said, and it doesn't interfere with my driving at all. I want you to know that because his mom was going, should he be driving? And so he had good acuties, fields were normal, his disc was normal. He had a normal neuroexamine. He had an MRI scan. It was normal. His depression scale was minor, minor. He had no anxiety with the GAT-7. And so the differential diagnosis was, is this migraine with aura? Is this persistent aura without a correction? Is this migraine aura status? Or is this visual snow? So I wanted to go through these different types of visual symptoms because I think this is confusing to a lot of ophthalmologists. One, typical aura. And typical aura is a neurologic process. It's dynamic, meaning it changes. The visual symptom starts gradually and it develops and gets bigger and bigger over a period of time, usually less than an hour. It may or may not be followed by a headache. And it usually is the result of cortical spreading depression in the visual cortex. Now, there is, these are definitions that are in, if you ever have trouble sleeping, just get the international classification of headache disorders. It's about this thick. It's like the DSM-6. You know, it just gives you every single kind of headache disorder that you could think of. Anyway, prolonged aura is an aura that lasts more than 60 minutes, but less than four hours. Okay? And that's a prolonged aura. A persistent aura without infarction is a typical aura, meaning it starts out, but it lasts for longer than a week and you've done neuroimaging and there's no stroke. And then there's a thing called migraine aura status, but this is a typical aura in a patient with migraine with aura that has at least two aura episodes a day for at least three days in a row. It's kind of like having status epilepticus. You know, it's happening frequently. That's migraine aura status. So these are the kinds of auras. So blurred vision isn't an aura, okay? And a spot in the vision may not be an aura. It depends on the tempo of it and what happens during it. Now, visual snow, the proposed criteria I worked with Chris Schenken and Peter Goadsby on this paper, visual snow is dynamic, continuous, tiny dots in the visual field for three months. But you have to have a couple other symptoms. And this study was done kind of by a crowd sourcing almost technique of getting all the people with visual snow and then studying them in San Francisco. Palinopsia, which is either a persistent image when you look at something and look away, you still see it. Or trailing images when you see something move and you see a trailer go behind it. Enhanced entoptic phenomenon, meaning that you see excessive floaters. Self light of the eye, that's that light that you can see when you close your eyes and are in a mellow mood sometimes and just watching your eyes. Enphotopsias, photophobia and nyctalopia are in paradise vision. And the symptoms are not consistent with typical migraine aura and they're not explained by another disorder. So I showed him these pictures and he said, oh, well, I got grainy vision just like that. I see floaters in the sky just like that. And this one you can see are little itty bitty teeny weeny dots that are just sitting there. He didn't have palinopsia, the kind that you look at an object and you still see it, or the kind of trailers at all or just this little light in the dark. So he met criteria for visual snow. He had the grainy vision since childhood. He had enhanced entoptic phenomenon and photophobia since childhood. And his symptoms were not typical. He does have migraine with aura, but this is not a typical aura. And so it was not a persistent aura that we needed to treat. This disorder is seen in women and men. Usually there's a history of migraine. Over 60% of the people have migraine, but almost 90% have some headache disorder. And that needs to be sorted out because I do think that this is a brain processing problem. Anxiety and depression, about 20%. Many people, a quarter of the people that have this say, I've had this since childhood. And in most, it's continuous from the beginning and there's a high level of tinnitus. Visual snow has sometimes been called the noise in the visual system. And tinnitus is sort of noise in the auditory system. It can be associated with hearing loss, et cetera. But these people have lots of other phenomenon. And so in your office, if you hear about some of these, you might want to think about it. So the palenopsia, floaters, the bluefield etoptic phenomenon, photopsias, photophobia, and ectolopia, trouble concentrating. Over half the people say this distracts them. And surprisingly in this series, 37% were disabled, which is really startling, right? Because this is a phenomenon that shouldn't be disabling. You wouldn't think. There is, of course, and this is a brain problem. So there's been shown to be hypermetabolism and the right lingual gyrus and the supplementary visual cortex as well as in the cerebellum. I keep asking all our visual snow people, why do you think the cerebellum? But I'm not quite sure about that one. And they've also seen a thalamic cortical dysrhythmia, so kind of brainwave abnormalities and a dysfunctional neuronal excitability as well as been seen. And this, I think, is important. It probably is an impaired epituation response, is the best way to explain it. And then there have been studies that have shown hyperexcitability in the primary visual cortex. So this is where the thought is that this is what's going on. And this visual snow is something that you've got to make the correct diagnosis. You can't just, you know, you have to think about this. In our clinic, in neuro ophthalmology, we see people who have these really weird visual symptoms all the time. And the one thing that I do worry about a lot is a retinopathy. Because it can look just like a retinopathy early on. You may not see anything in the retinopathy. And we have seen a few of these people who've got some visual snow turn out to have anti-retinal antibodies. So I don't, or anti-glycine antibodies that are present in the retina. So we do need to keep thinking about this problem. But many of, most of these are not something like that. Most of them are visual snow. You can treat the underlying migraine. We gave this guy Elmo triptan, which is a different triptan. He didn't have any side effects from it. Medications don't work for this. The best medicine has been lamotrigine, but lamotrigine is also used for anxiety and depression. And it's an anticonvulsant. It may be helpful. It's the only one that has had some success with it. Nortriptaline, carbamazepine, sertraline, which is Zoloft, has been used. We've had some luck using the FL-41-10 for blue-yellow spectrum filters. For some of the people, it seems to dampen their sensitivity a little bit so that they can ignore it a little bit better. So I hope I've convinced you that migraine is intimately and integrally related to the eye and division and that we really have to be looking at this dry eye story. Because I think that there may be some important things that we could do to improve migraine, but also maybe help our headache colleagues understand about pathophysiology of what's happening peripherally. Eye pain is in your clinic. Most of the time you're going to see it. If you don't see it, be thinking about migraine and be thinking about cluster and be thinking about optic neuritis and if you don't see a red eye. And then I think this visual snow is more common than previously really recognized because a lot of people have it. At NANOS, we ask people to raise their hand if they have visual snow and I mean about a quarter to a third of the population raise their hand. So neuro-optimologists have a little visual snow. And I think this also means that we have to address that visual quality of life because visual quality of life is just as bad as people with Graves disease, IIH and optic neuritis and it just tells us that this is something worthy of our attention and our study. In the novel library, if you need a handout for your patients, you can go to the patient portal and get a handout on migraine and it's in about 15 to 20 languages so that you can hand out a thing about migraine. And I want to thank, I didn't do any of the work that I talked about here was never done solely by me, believe me. But I want to thank all the students, the army of students that we've had the pleasure to work with over the years. Our fellows have been amazing and I can't ask for better colleagues than I've had at the University of Utah, University of Zurich and Rami Burstein in Boston listened to me about photophobia and then went to the lab for a little bunch and then Peter Goatsby and I have been collaborating on visual snow. So with that, I think I've got a couple more minutes. I've got five minutes for questions. Yes, Randy. So, hard to keep me from asking questions but anyway, so these are very, very common as you know and so if we have patients with dry who also have migraine symptoms I agree, there's a fair amount of correlation. I mean, do you want to see these in a clinic? I mean, I'm just telling you if you guys, you're already hard to get into a headache clinic and these people come through very, very commonly. I would just say an ophthalmologist if they aren't comfortable starting something for somebody with migraine send them to a neurologist. They've at least been trained in headache and their primary care should be able to do it too. But you could partner and say, I'm worried that this dry eye problem is worsening their migraines. I'll work on the dry eyes. How about if you guys really work on the migraine symptoms and get, because I think if you get the migraine under control the dry eye symptoms might be a little bit better too. Especially in my practice I see if I can do both and kind of get them kind of working together then they may do a little bit better and especially these chronic migraines. These are people that have migraine more than 15 years ago. Well, often as you control the migraine really a lot of their symptoms with their dry eye go away even though as Mark said the actual clinical signs are getting worse. Yeah. So that makes it very interesting. Yeah, it is. So would you say something about hormonal regulation? I have a patient who had chronic migraine she got pregnant, no migraines two weeks after delivery your migraines come back. It's a two-story. So Bryce has a patient with migraines with pregnancy got completely went away and then two weeks after being pregnant they got their migraines back. That story is textbook. Hormones do play a role in migraine there's no question about it it's usually the falling estrogen that seems to be the trigger for migraine it's falling estrogen and so after pregnancy which is a very high estrogen state the falling estrogen they can go right back into the migraine and interestingly during pregnancy people are almost immune to migraine I've got some patients who've got like seven or eight kids because they felt so good when they were pregnant that they decided that's what they were going to do. So if you want a lot of kids marry somebody with migraine, no. But you would treat with hormones people have done that and there's some literature to suggest hormonal manipulation but in my experience the problem is you know there's a week before a period there's a week of the period, a week after that's three out of four weeks with ovulation going on in between there it's so complicated that to mess with hormones you end up in a mess there are a few people who really do respond to hormonal therapy and steadying state things out and these are people who would truly have like menstrual migraine but that's not very common I have to say most people have more than just the headache around the time of menses. It's a pretty massive dose as well to try to duplicate pregnancy. No you don't try to do pregnancy you just try to get to a steady state you don't try to get that high that would cause more trouble so we low dose especially in migraine oral contraceptives that are high dose are contraindicated especially in migraine with aura and there's even controversy about anybody with migraine taking oral contraceptives so that we don't like to do but low dose steady state sometimes has been studied and does work for some people not everybody alright and I even finished on time so thank you