 here everybody. Welcome to Grand Rounds. We'll get started here. What our first presenter is Dr. Krista Knar. She's our Neurolofomology fellow extraordinaire. She did her residency here with us when we were super happy that she was able to stay for the fellowship and were able to work with her again this year. And as you all know she loves loves to present. And so she actually wasn't going to do a Grand Rounds, but she begged Dr. Warren to let her. So because of that we have the pleasure of hearing from her today. So she's going to talk to us about corneal nerves and migraine. Thank you Trent. Good morning. This is meant to be a brief overview of one of the projects that I've worked on this year and it is on a topic that is near and dear to Dr. DeGree's heart. She is always present even when she is not here. So just to provide some definitions, migraine is defined by recurrent headache. You have to have had at least five attacks in your lifetime. The duration of pain should be around four to 72 hours and this is untreated or unsuccessfully treated headache. And then you must have two of the following. A unilateral pulsating pain that's moderate or severe in intensity and worse with activity, nausea and vomiting, photophobia or phonophobia. And other etiologies for headache must have been excluded. Episodic migraine is migraine that is less than 14 days per month and chronic migraine is what we'll be focusing on which represents 7.7% of the migraine population. And these patients have headaches for more than 15 days of the month and eight of those days must meet criteria for migraine and it has to be present in this pattern for three or more months. According to the Migraine Research Foundation, there's approximately 36 million people in the U.S. that have migraine and it's one of the top 20 reasons for disability in the U.S. An untreated episodic migraine progresses to chronic migraine at a rate of 2.5% per year. So the trigeminal system is thought to be involved in migraine and basically when you get activation of the system there's vasodilation of the vessels which end up irritating the meningeal tissues and if we remember back to medical school those are pain responsive tissues. So for corneal pain you have nochiceptor, you've got C fibers and A delta fibers that are the trigeminal afferents of the cornea. They travel back to the trigeminal subnucleus caudalus in the brainstem, synapse, second-order neurons travel up the spinal thalamic tract to the thalamus and then from the thalamus they go to the somatosensory cortex where the information is decoded as pain and also simultaneously to the limbic system which is responsible for the emotional response to pain. An interesting fact just to go back, the cornea has the highest density of nochiceptor fibers of all tissues in the body. It's estimated 16,000 per square millimeter which is 20 to 40 times higher than dental pulp and like 300 to 600 times higher than the density in skin. So this is a montage because corneal confocal microscopy can be used to image the the sub basal nerve plexus as we all know and these nerves enter at the limbis and they radiate in towards the center of the cornea and then they form a whirl pattern just inferior to the center of the cornea and this is a dynamic structure that does change and remodel over several weeks and this is just another image from corneal confocal microscope and it shows how the nerves can look different whether you're looking at the superior and inferior temporal or nasal or central view and just to point out these those white spots right there are not nerves those are dendritic cells or lingeron cells that are thought to be involved with inflammation. So the purpose of the study are the trigeminal aphorines different in chronic migraine patients versus non-migraine patients that's what we set out to try and figure out. So patients were recruited all of the controls came from the cornea suite already so they had had an eye exam so they didn't have to have as much extensive testing the migraine patients came from headache clinic with a diagnosis of either chronic photophobia excuse me or headache so they had a more extensive exam and so at that exam they had to have a slit lamp intraocular pressure because we needed to rule out corneal disease they had to fill out the dry eye questionnaire which is the DEQ 5 the photophobia questionnaire they had to meet the criteria for chronic migraine and fill out that questionnaire and then corneal sensitivity tear breakup time and basal tear secretion were also tested and then of course both groups had corneal confocal microscopy done inclusion criteria for the study subjects they had to meet the International Headache Society guidelines for chronic migraine control subjects could not have any migraine and then exclusion criteria for both was any systemic illness or medications known to cause a peripheral or sensory neuropathy any corneal disease or any prior corneal or intraocular surgeries which could also alter the morphology of the corneal nerves so this is an image taken from one of the migraine patients on the left-hand side is a raw image and then on the right-hand side is an analyzed image and so this is where you know there's differences in studies arise because you have to trace this by hand on a bamboo tracing pad and so you the analyzer defines the major nerve the nerve branches so the red is the main nerve fiber blue are the branches and green are the branch points this information is recorded in pixels height by width and then it goes into the CC metric software and it's converted into microns per area and it gives you the data for the nerve fiber length nerve fiber density nerve branch density and tortuosity coefficient so the results of our study the migraine patient average age was 39 and the control group is 45 women were more common than men as you would expect in the normal population the average dry eye score is 2.7 in our group for the migraine patients most of them have symptoms of dry eye a score greater than 7 is indicative of symptomatic dry eye interestingly the tear breakup time the basic tear secretion and corneal sensitivity were all normal in the migraine group which I guess isn't that surprising because we all know that these tests we use them to try to identify dry eye but it doesn't do a very great job which is why they're looking at tear osmolarity and different things to try to define this all of the chronic migraine patients had photophobia and 18 of the 19 had chronic inner ectophobe photophobia meaning they have light sensitivity even when they don't have a headache of the 30 control patients 13 didn't even finish the questionnaire they said wasn't even applicable and 10 of them answered yes to one question which is bright lights or bright sunshine bothers me at time so they had intermittent photophobia but not chronic so these are the descriptive statistics that we looked at again the nerve fiber density nerve fiber length nerve branch density and the tortuosity index which is a measure of how curvy the branches are and so this is compared in the chronic migraine and in control groups and basically what we found is that the nerve fiber density and the nerve branch density is diminished in the chronic migraine groups compared to controls and this was statistically significant and the tortuosity coefficient is much higher in chronic migraine patients versus controls the nerve fiber length shows a trend towards decreased density in the migraine group compared to the control controls but this didn't quite meet statistical significance and this is interesting because this is exactly what's found when you review the literature looking at diabetic patients they all have decreased nerve fiber length nerve branch density and nerve fiber density and increased tortuosity which and that's a neuropathy so dr. degree was quite excited about this some limitations of our study corneal confocal microscopy is still used mostly for clinical studies or research is not widely used in the clinic and so there's still not normative data for different populations based on age gender ethnicity however you can find statistically significant difference between groups that have been studied there were two imagers and two individuals that did the analyses however we did have a massed observer that view the images and they did not find difference between the quality of images and there was no statistically significant difference between how the images were analyzed and again our sample size is small but this is actually quite comparable to what is out in the current literature most of them have like 18 in their study groups so what is really going on you know to cause this substance P and calcitonin gene related peptide are known to be released from corneal trigeminal afference and animal models on migraines show much higher levels of substance P and calcitonin gene related peptide and these molecules are responsible for vasodilation of the blood vessels activation of mass cells and release of cytokines so is it possible that there's a sterile inflammation that's going on that leads to a neuropathy or is this just a neuropathy that can trigger migraine or continue or add to the chronification of migraine basically we don't know this is just the start so there's lots of different areas that need further study for one is there a difference in the corneal nerves between episodic migraine patients versus chronic migraine patients we looked at normals versus chronic migraine is dry eye a confounder because people with dry eye are known to have sterile inflammation and higher dendritic cells in their corneas when you look at the literature so you know is that what is doing this if we looked at tear osmolarity would that correlate better with the symptoms of dry eye and you know again is this an inflammatory is all of this an inflammatory process so you could in further studies you can count the number of dendritic cells and the most recent like in the last year they've started to look at this but this is even newer than looking at the sub basal nerve plexus and so there's even less normative data on that but in the future that'll be something that's probably looked at more intensely and then you could try treating these patients with autologous serum tears which have neurotrophic growth factors or there are topical neurotrophic growth factors that you could treat these patients with then you could reimagine them and question them on their symptoms of eye just ocular discomfort or dry eye and see if there's a difference after being treated and then another question to be answered is do these patients have hypersensitivity normal corneal sensitivity or hyposensitivity most of the measures that we have in use for clinic right now like the Cospenaeus Thesiometer cotton tip applicator those are all very rough tests to tell us whether or not you have normal sensation versus hyposensation there's a few researches these yameters that have a wider range of pressure but those are not available unless you get special rights to it but that would be maybe helpful to find out if these migraine patients have hypersensitivity and special thanks to the neuro ophthalmology group and Dr. Gordon Smith in the Neurology Department and Meg and these are my references any questions