 Welcome everyone to our first virtual grand rounds. We are honored to have a guest speaker for our visiting professor rounds. And Dr. Kathleen DeGree will be introducing her in just a few moments. You can all see in our in the chat below that Megan Johnson has posted the CME phone number and the CME code for anyone that would like CME for this program. Please also post any questions throughout this quick hitting talk. I'll be monitoring the chat for any questions and time permitting at the end I will pose any questions that Dr. Newman at the end. If you do particularly want a question answered if multiple individuals do pose the same question or just say they want to that question asked I'll make sure that those rise to the top and are asked. Again, welcome everyone who were joining us and I'll turn the time over to Kathleen DeGree to introduce our speaker. Yes, I welcome to the neuro ophthalmology grand rounds and we're just unbelievably thrilled to have Dr. Nancy Newman with us today. I've known Nancy for several years. She's a true giant in her field. She's not a physical giant but she is a giant in neuro ophthalmology for sure. She holds the Leo Dell Jolly Professor of Ophthalmology and she's a professor of neurology and neurosurgery as well at Emory University. She directs the neuro ophthalmology unit. Her background is she went to Princeton University. She also studied at the University of London on a Marshall Scholarship then she was at Harvard University. She trained in internal medicine and neurology at Mass General Hospital, and she was a chief resident in neurology and then did her neuro ophthalmology fellowship with Simmons LaCelle at Mass Eye and Ear. And she's a fellow of the Academy of Neurology, the American Neurology Association and of course of NANOS. She's the past president of the North American Neuro Ophthalmology Society. She was chair of the board of directors and now she is the senior vice president for education at NANOS. And Nancy has many, many claims to fame. She's written over 500 papers. She's written several books. I'll tell you that the sixth edition of Walsh and White, the big three volume tome was edited by Nancy Valerie and of course, Neil Miller. And then she and Valerie wrote a wonderful book that I have in my office and you can borrow it. And it's also in our library, the Bloomberg Library called neuro ophthalmology illustrated where she really goes through all of neuro ophthalmology and has illustrated several of these. She's an outstanding lecturer. She really is somebody that we've tried to get to come here and she gets to be the first virtual professor here at the University of Utah at the Moran Eye Center. And Nancy, thank you so much for coming to us virtually today. Thank you so much. My pleasure. So sorry I couldn't be there. I was really looking forward to it in my, my, there are these reminders that come up on your email and my flight from Salt Lake is due to depart to come back to Atlanta and a couple hours just wanted you to know I just got that email. My disclosures on the bottom. Not many of them are relevant to this so I am I am really delighted to be here and I'm delighted to be here for, for multiple reasons, even though I'm not here. And one of them is that Kathleen degree is is my hero and everybody's hero. And I would do anything that she asked me to do. Judith Warner is kind of like my baby sister since we both trained with the same wonderful person similes cell. And so I had was looking forward to this I'm enjoying it but it would been a lot better to be there. Anyway, I thought that I would choose this particular topic to talk on because it's just a multitude of topics and I've got lots of people out there I assume. People have different interests and to talk for an hour is a long time and so the way I get around it is I'm going to do basically all of neuro ophthalmology in about 50 minutes. And it's an update but I'll slip a little bread and butter in there along the way. And when you want to do something like this how do you construct it well when you're a neuro ophthalmologist. I always ask the question where first right first where then you get your what's and then you get your now what. So, in this particular situation, I am going to go around the eyes and brains that a neuro ophthalmologist deals with. Do topics with updates starting at the eyeball going through the optic nerves segueing into the brain the visual pathways back through the pupils and then the ocular motility and then we'll be done so fast in your seat belts it's a very fast paced lecture if you don't like or not interested in what you're hearing about just wait 30 seconds you'll hear something else. And we'll go from there. So, starting with the retina. And the retinas relates to neuro ophthalmology. What's what's new in that regard so the first thing is within the subject matter of acute retinal ischemia whether it be an ophthalmic artery occlusion central retinal or inclusion, or even transient monocular vision loss of retinal vascular origin. Although these entities all have different visual outcomes, they have the same systemic implications. And the reason is because they are all the result of a vascular problem with the anterior circulation to the brain or the, which is the carotid circulation. And so it has the same mechanisms and causes as cerebral ischemia, and there are now 12 articles in the past eight years, which you cannot miss and they all say pretty much the same thing. They basically say that if you take anybody with retinal ischemia whether it be permanent, like a CRO or transient like transient monocular vision loss from retinal origin, and you do an MRI on these patients looking for silent DWI positive acute areas of cerebral ischemia. You will see that in up to 53% of CRO patients 31% of BRO patients and 18% of transient monocular vision loss patients will have these silent DWI MRI findings, which are little strokes in the brain. And it identifies a subgroup of patients at an extremely high risk of major stroke, especially within the next week and within the next month. And so DWI MRI has been concluded to be needed to be performed within 24 to 48 hours of visual loss to allow for effective prevention of recurrent stroke. So what does that mean? That means that the people on the front line for these vision loss problems, which are the optometrists and the ophthalmologist need to follow guidelines from the American Heart Association, the American Stroke Association, and now the AAO, that these patients equal a stroke. Now it's not so hard for ophthalmologists to equate a CRO or a BRO with a stroke. It's a little harder for them to take so-called amaurosis fugax and know that there is a almost one-fifth chance that there's going to be this silent little cerebral ischemia, and there's no way to know who those patients are, right? And so we have to make sure that they have any neurologic complaints and equate that with a stroke. So we have been trying to get the word out. We're doing it through the American Academy of Ophthalmology publications. We have had it in the practice parameters. And I can't. Okay. I am now muted again. Am I unmuted? Someone is background noise. I'm going to briefly mute everyone. Okay, Nancy, you should be good to resume. Thank you so much. You're welcome. So we're getting out the word that any patient with an acute retinal ischemia should have an immediate referral to the nearest stroke center. So what do you do? Well, educate yourself and help your colleagues. Establish a network with the closest stroke center. You're lucky. You're in Salt Lake. I'm sure there are many of them. And find your favorite local stroke neurologist with whom you will work out that network. And here's the simple message. All you have to do is make the correct diagnosis and send the patient to a stroke center. Boom. Now, I often get the question, well, what if it's two weeks out instead of one week? Certainly within one week, they should go to an ED or a stroke center or whatever network you and your stroke neurologist have worked out. If it's not acute, make sure you cover yourself and cover that patient by talking to the stroke neurologist and they usually will get the patient into their clinic as an outpatient within the week. Are there any other retina things that are of interest to neuro ophthalmology? Well, it for decades, longitudinal population based studies such as the Blue Mountain study, the Eric study have actually included retinal photographs as part of their longitudinal analysis. And what they're looking for are not C.R.A.Os and B.R.A.Os. They're looking for retinal vascular changes as indicated here, subtle things. And then they read those and it turns out that these findings have predictive value for association for stroke, recurrent stroke, cognitive impairment, cardiovascular disease and peripheral vascular disease. Now that's on a population basis. Is there any way that we can translate that information into a single patient predictive value? And the answer is going to be in deep learning. Because if you can have somebody retinal image scanned and this added into the score for their predictive risk for vascular disease, it will be truly amazing and only something like deep learning is going to be able to do that. What about on the individual basis? How can we use retinal photography for that? Well, our group has piloted the use of non-migreatic fundus cameras in emergency rooms and in neurologic clinics and in pediatric clinics. And we showed as early as in 2011 in our New England Journal article that non-migreatic fundus cameras are easy for non-aphthalmic trained individuals to use. Take only about 10 minutes to train and then less than three minutes to take good quality photos. You don't have to dilate the pupils and the pictures as you see on the right are really beautiful. And it has shown that, not surprisingly, that things are being missed in the emergency room. We showed that it's feasible. We showed that it's feasible in children as young as age two. And we've shown that it's easily transferable with good quality images to smartphones, even old smartphones. In a lecture I gave at the American Academy of Neurology in 2017, it was like the Emperor's New Clothes where all the neurologists were elbowing each other and saying, you don't really use that aphthalmoscope, do you? Or do you ever see anything when you do? And the reality is these pictures are magnificent and certainly are a lot better than emergency room providers and neurologists. And it's not like you're doing it for nothing. In the ED studies that we did, 12% of patients who had these photographs had relevant findings on the photographs as diagnosed within 24 hours by neuro-ophthalmologists reviewing the photographs that would have changed the patient's management in the emergency room, such as bilateral disk edema like you see here. So there's an issue, though. We did these photographs. The second phase, we gave the ED providers the photographs. They did better at finding the abnormalities. They were up to 40% instead of zero. But they still were missing a lot of things. So they weren't interpreting the photographs as well as you would hope. So what's missing is that little piece like in the EKG machine, or not only do you get the EKG, but you get the automatic interpretation of the EKG. And it'd be wonderful to have that automatic interpretation. Now, tele-automology is doing that to some extent, but you still need an ophthalmologist at the end of the phone, and you need to transmit the images. But deep learning, artificial intelligence will likely allow, like an EKG machine, an immediate interpretation of these photographs in the ED, in neurology clinics, in other types of clinics. If you think that this is a complete Star Wars type idea, it's happening right now. And this article, which you see in front of you, which comes from the Banzai Group, brain and optic nerve study with artificial intelligence based out of Singapore, looked at 16,000 photographs from all over the world of the optic nerves and trained a artificial intelligence deep learning system to with accuracy of 0.98 and 0.96 to recognize specifically papillodema from other optic nerve abnormalities and from normal optic nerves. And although I'm embargoed in one week, this will be published in a very major, very major journal. And so I think this is going to completely revolutionize what it means to re-put examination of the ocular fundus, which has been so enforced and pushed by Kathleen DeGree and others that it's important and has to be done. It's going to reintegrate the importance of that into clinical examination. So it begs the question, should we stop teaching ophthalmoscopy to our students and Kathleen, I think we're going to go through a few years where there's going to be a transition, but I honestly think the answer is going to be yes. Now let's move on to the optic nerve. And you know, you have an optic neuropathy for sure. If you have to get decreased vision and abnormal visual field, a relative affron pupillary defect, nothing in the media, a normal retina, ruling out retinal detachment and either a swollen or pale or normal optic nerve, if it's acute. And so there are all these categories of optic neuropathy that one needs to consider, just like any piece of tissue, but there's something specific about the optic nerve that allows you to think of two special categories, and that is an optic neuropathy due to elevated cellular pressure, which is glaucoma because the nerve inserts in the eyeball. And optic neuropathy due to the fact that the optic nerve is not really a nerve, it's a white matter tract of the central nervous system, as my mentor would say, it's a card carrying member of the central nervous system, and therefore it is covered by the same fluid and coverings as the rest of the brain, and therefore it is subject to the pressures in the brain, and therefore you can have an optic neuropathy from elevated intracranial pressure, if it is transmitted along the nerve to cause swelling of the optic nerves bilaterally, and that of course is called papillodema discadema due to raised intracranial pressure. And of course, it can happen for any reason that causes raised intracranial pressure. Unlike most other optic neuropathies which tend to have central defects and spare the periphery, papillodema like the other mechanical optic neuropathy glaucoma tends to spare central visual acuity until very late in the disease, but involves severe peripheral visual field constriction. And the causes can be anything that causes raised intracranial pressure from a mass lesion to hydrocephalus to a meningeal process which does not allow the fluid to passively resorb into the venous sinuses until the fluid builds up in the CSF compartment pressure or venous sinus thrombosis or anything else that would cause raised venous pressure which similarly would make the CSF pressure have to build up in order to passively resorb into the veins. And finally, if you rule all those things out, you have idiopathic intracranial hypertension and the mechanism for doing that, as you see here, everybody deserves good imaging, preferably MRI and MRV. And if it's normal, a lumbar puncture, and if the lumbar puncture shows normal CSF contents and the pressure is elevated to end up with IIH, of course, always reconsider cerebral venous sinus thrombosis and make sure you have adequate use of the venous sinuses. And the IIH diagnosis in 2020 is, of course, very infused by the important article written in 2003 by 2013 by Kathleen and colleagues, which gives new criteria for the diagnosis of IIH, making it not just a diagnosis of exclusion, but also including radiographic findings of elevated intracranial pressure, as you see here. Now, IIH is everywhere there are obese people, and I can tell you, shelter in place is not helping this. I personally have gained three pounds so far, and very concerned about this. The United States of America tops our most obese countries, and it is still growing, and we know that the incidence of IIH is growing almost completely in concert with the increase incidence of obesity. This was a very scary article written in the New England Journal of Medicine recently, which projected that in just 2030, the United States will have a 50% prevalence of obesity. It's really frightening. So, how do we manage these patients? The first thing is, we have recognized over the past couple of decades that there are certain characteristics of a patient and of a patient's presentation, which make them at particular risk for vision loss, and therefore, even though most IIH patients do okay, and you have time to manage them correctly, there are certain red flags that should make you be more attentive to certain people when you make that diagnosis of IIH. And those red flags are in the United States African American race, and this is beyond issues of access to care or socioeconomic things, and it's very interesting. Black race is also associated with a higher risk for glaucoma, not doing as well, another optic nerve disease. Male gender, we know that males get this disease much less often, only in 10% of cases. However, when they do get it, they tend to have worse visual function. Severe obesity, so morbid obesity over a BMI of 40 has worse visual function. Certain other characteristics like anemia, sleep apnea, and hypertension do not bode well for these patients. A rapid vision loss at presentation. So first of all, severe vision loss at presentation. The horse is probably out of the barn by then. These people have to be watched because they don't have much left to lose. And a rapid onset so-called fulminant IIH, where within two to three weeks they go from no symptoms to horrific symptoms, and these people usually end up needing surgical intervention. One quick word on headaches. It's like bringing coals to Newcastle with Kathleen there, but remember headaches are very common in the general population. They're very common in the IIH population. They're often severe and disabling, but there's no correlation with the level of the CSF opening pressure. And even when you get rid of the papillodema, you improve their vision and you have documented that you have lowered the CSF pressure in many of these patients, the headaches persist. And so you really have to get these patients to a neurologist to help their headaches and the help is not necessarily in further lowering their intracranial pressure. The treatment after the diagnostic lumbar puncture is in general acetylzolamide. You need to get them to lose weight. I often tell them that only not even 10% of their body weight is all they need to reverse the disease. This makes it a more tangible possible thing for them to do. Someone's 300 pounds, you're telling them they don't even have to lose as much as 30 pounds, and that helps them in this process. And you predict the prognosis with visual fields. And ultimately, if you end up having to intervene, most of the surgical therapies have about the same outcome, so you get what you can get. We tend to use the CSF diversion procedures and those who have more headache, we tend to use optic nursing fenestration, only in those patients who really, how are their vision is threatened. The new kid on the block is venous stenting. We don't have a lot of data on this yet. It appears to be effective, but we don't know what it means to have a stent in your veins for 40 years or more. And so it does work. It basically, whether it's the chicken or the egg, it opens the stenosis and that allows for the pressure to go down. I will say that these patients, nearly 100% of them, depending on how you measure it, will have transversinous stenoses just as a result of their race intracranial pressure. And so just because they have stenoses doesn't mean you should stent them. Don't treat the MRI. There is no correlation with the degree or presence of these stenoses and the ultimate visual outcome in these patients. Again, don't treat the MRI. Moving to inflammatory causes of optic neuropathy, we know typical optic neuritis, which can be retrovulbar or in one third of cases anterior. The optic neuritis treatment trial, my goodness, 1992. That's a really long time ago. That's when Clinton first got elected president. Look at that. That's a long time ago. Anyway, it showed us there was no difference in visual acuity between steroid and placebo groups at six months. And although the intravenous steroids might accelerate recovery, it was only for up to about two to three weeks and then everybody caught up. What it did show us is that oral steroids, at least at the dose of one milligram per kilogram is a bozo no-no, not only didn't help but it doubled the risk of recurrence in either eye. I think the most important part now about the optic neuritis treatment trial was the longitudinal portion of it that kept on going. What it showed, and it was the first really to do that, was it showed that, well, after a brain article by Reorden set up, teed up the idea is that even having one typical periventricular MS-like lesion on the baseline brain MRI when you show up with an optic neuritis puts you at high risk for the subsequent development of multiple sclerosis, approximately 75% at 15 years. Risk, whereas you have a normal brain MRI, you have about a 23% risk of clinically definite MS at 15 years. The other thing that the ONTT showed us, which brings the ophthalmologist back into the picture in a big way, as a gatekeeper, is that if you have even a typical isolated optic neuritis and you have a normal brain MRI at baseline and any one of the following five factors, you never get MS. And those factors are no pain, no light perception vision, which anybody can figure out, but for you, severe discodema, hemorrhagic discodema, and retinal exudates. And so if you have any of those things, this is a different disease. This is not the optic neuritis associated with multiple sclerosis, making again the fundus examination and the ophthalmologist input very important in this disease. I will mention the 2017 McDonald criteria, because I think it's important that you know two aspects of this. Remember, the McDonald criteria, it still is you have to have dissemination in space and dissemination in time to make the diagnosis of multiple sclerosis. And what the 2017 criteria did is it relaxed the criteria so that you could actually use the symptomatic lesion that they present with in order to get dissemination in space. And you could use the symptomatic lesion to get dissemination in time. In other words, if one was enhancing and the other lesion was not enhancing. And so you would say, wow, okay, here's my patient here. Does she have MS? She has isolated unilateral typical optic neuritis with enhancement, and she has one periventricular ovoid, absolutely classic, demyelinating, non-enhancing brain periventricular lesion. And the answer for everyone clinically out there, I hope, is of course she has MS. But according to even the new McDonald criteria from 2017, the symptomatic lesion cannot be the optic nerve. And so by those criteria, she does not have MS. And why? Why when we see people like Steve Galletta on here, why did that happen? And the answer is because people don't make the diagnosis of optic neuritis very well. And why don't they do that? They don't do that because there are other causes of inflammatory optic neuritis that are not related to multiple sclerosis. One is neuromyelitis optica, right? And it usually causes a bilateral severe, no recovery or recurrent optic neuritis. But now that we have a marker for it with the antibodies, we're seeing that sometimes the optic neuritis can be unilateral and it may not be that severe. We always check for it. The new kid on the block for optic neuritis is a new therapy that's been approved by the FDA. It's a lot more expensive than rotuximab, but it's very, very effective. It's now not the only new kid on the block and these other therapies are coming out as well. Maybe that'll drive down the price. The newest kid on the block is the MAG antibodies. Again, more likely than typical plain vanilla optic neuritis associated with MS to have a bilateral recurrent. There's more often discodema, usually mild, with these folds around the optic nerve head. There are more often cells in the CSF and you should think about MAG antibodies because it will change your management. You don't treat these patients with conventional MS drugs. And the take home message, I think for everybody and nearly every up neuro-neuro ophthalmologist that I know is doing this. And by the way, this tram track look on the MRI, classic perineuritis involvement, perineural involvement, classic sheath enhancement for MAG. So the take home message is obtain aquaporin-4 and MAG antibodies in all patients with optic neuritis. Let's move to just a brief note on OCT that again calls to Newcastle to an ophthalmology group. I don't need to tell you that neuro ophthalmologists like to look at the RNFL, but we've been really taken lately with looking at the ganglion cell layer complex in our patients. And these measurements, especially RNFL, have actually been used as endpoints in multiple sclerosis trials, treatment trials, because they correlate not only with axonal loss and visual dysfunction, but they correlate with brain atrophy and MS, disability and quality of life. I think it's in the compressive and infiltrative category, however, where our use of the GCC has become extremely important and helpful for our neurosurgical patients. Here is a patient with compression of the chiasm and the left optic nerve and you see the mass here, you see the visual fields here. Here is the GCC. If you flip it upside down and backwards, it's truly amazing because you basically see the visual field imprinted on the macula. Look at that. It's truly amazing. So it's very sensitive and very corroborative of the findings on visual field. Now, sometimes you don't see any abnormalities on the visual field. The MRI shows it compressing the chiasm and the patient may have asthma or be a little risky for surgery and the neurosurgeon says, is this tumor causing any problem? And so you get the visual field. It's normal. You get the RNFL. It's normal. Look at the GCC by nasal visual loss showing early chiasm compression. This patient got operated on. So the GCC is more sensitive and will show things earlier than the RNFL and even visual field testing. But however, we still need visual field testing. Look at this by temporal hemianopia, normal RNFL, normal GCC. What caused that? Well, likely pituitary apoplexy, something recent. Because remember, even the GCC takes a few weeks to become abnormal and will be normal in acute optic neuropathies and the RNFL will take usually six weeks or more to become abnormal. Looking at vascular causes of optic neuropathies, the main one being enteroschemic optic neuropathy, in which obviously you have swelling of the optic nerve head, presumed due to ischemia, usually in older patients. The substrate for this to happen is the disc at risk, the so-called crowded optic nerve with no cup. And as I mentioned in our earlier lecture today, yes, this is a tertiary care center where we did this study and it's going to be biased toward very atypical forms of naion or optic neuritis. This we're going to see strange cases, but nearly a quarter of our naion patients were less than 50 years old. So the age at onset doesn't necessarily rule out naion. And I showed this table where, yes, it's important to consider age, but if there isn't pain, there's dyscadema and things don't get better. And especially if on a good quality MRI of the orbits with gadolinium and fat suppression, the nerve appears normal. You need to think about naion in your differential diagnosis. And this is particularly important as you see in this study. Again, a tertiary care center where 122 patients were referred with optic neuritis turns out that only 40% of them ended up actually having optic neuritis. And amongst the misdiagnoses, non-arturidic enteroschemic optic neuropathy was very high up. And this is important because if you get an MRI and a patient referred to you as a neurologist as having optic neuritis and you see a Ditzel, you may be inclined to commit these patients to long therapy with immunosuppressive drugs when what they really had was an Naion. And this new Naion, I wish I could tell you a bunch. We do now feel very comfortable that obstructive sleep apnea is a risk factor for Naion. We don't know if treating it necessarily helps, but it is a risk factor. And we do know that there is indeed a higher rate of Naion in patients who have recently used the performance enhancing drugs, the results of this buried in this journal that everybody gets daily, I'm sure the Journal of Sexual Medicine, but there's about a three times increased risk of Naion. On the treatment side, unfortunately the quark study was halted. There is still ongoing the Regenera study which looks at patients with chronic optic atrophy having had Naion a year before and sees if this is helpful in any way for recovery. Just a note about giant cell arthritis obviously need to think about it in any patient over the age of 50 and be careful systemic symptoms of headache, jaw claudication are absent in about 25% of cases. The new thing for GCA is Tosalizumab as again New England Journal article which showed that it is quite effective in steroid sparing, steroid sparing. It allows you to get these patients off steroids faster. It's this population it was tested on was not necessarily the same population we see with vision loss and the recommendations worldwide still are not necessarily to use Tosalizumab acutely, but rather to use it as a steroid sparing agent in the more chronic phase of treatment of GCA. I promised a little note on toxic nutritional optic neuropathies and the note is simply this, think about them in any bilateral optic neuropathy. And the agents you should think about top of the list or a thambutol check the med list, linozolide which is an antibiotic often used in cystic fibrosis patients, amiodarone it looks a little like Naion it may actually be Naion that gets triggered by amiodarone involvement of the small vessels we don't know. But make sure you at least look at the med list, and if it's happened in one eye, speak to the cardiologist about is it safe to discontinue the amiodarone. The PDE five inhibitors as we spoke about methanol and ethylene glycol toluene or glue sniffing and then find out if they had a hip replacement in the early 2000s, a number of these patients their hip hardware disintegrates and they get cobalt toxicity cobalt chromium metallosis with bilateral optic neuropathies and peripheral neuropathies. A couple of notes on what's new in hereditary optic neuropathies. Most of the hereditary optic neuropathies are indeed due to mitochondrial dysfunction. That's why they're called optic mitochondria apathies. The two big ones are labor serratory optic neuropathy which is due specifically to point mutations in mitochondrial DNA, but autosomal dominant or CARES disease dominant optic atrophy is also a mitochondrial disease because it's involving a gene that is on a nuclear chromosome is abnormal and it makes an abnormal protein, which is usually usually transported into the mitochondria. To help with mitochondrial function. Um, just a note on labors. This is a bilateral sequential optic neuropathy occurs simultaneously and about 50%. It's more male than female. Um, and it is a devastating disease, usually legally blind. It is associated in 90% of cases with three primary point mutations in mitochondrial DNA and since they mitochondrial DNA disease, it is inherited maternally because all the babies mitochondria comes along with their cytoplasm from mom's egg. Um, what's new in treatment besides your usual genetic counseling symptomatic low vision health and the answer to things I debonone and gene therapy. I debonone is not FDA approved for the treatment of anything in the United States. It is approved in Europe for labors. The dose is 300 milligrams three times a day. Your patients will get it off the internet. So you need to know about it. It is not the penicillin of labor, serenity, optic neuropathy, but it does appear to help some, especially if given in the first year of onset of symptoms. What about gene therapy I wish I could tell you we have a slam dunk here we do not, but we may at some point so it's important just to know a few things. First of all, we're very good at getting DNA into a nucleus of a cell. We don't do not yet know how effectively to get DNA directly into mitochondria to complement mitochondrial DNA. So we have two techniques for gene therapy for mitochondrial DNA disorders. The first is nuclear transfer techniques. This is pretty extraordinary work. It's done already in England. Basically, you take mom's egg, which has mutant mitochondrial DNA. You extract her nucleus, you take a donor egg with normal mitochondrial DNA, you extract her nucleus, you put the nucleus into the donor nucleus, you do in vitro fertilization with partner sperm, and then bingo, you have a baby that you've cured the mitochondrial DNA disease. You've cured it in the germline. It will never happen again, never be at risk. And if you think that this is, you know, futuristic mojo, there's a three year old boy who is the product of a US doctor going to Mexico to help a Jordanian couple conceive a baby with three genetic parents. And he's doing great. He had the NARP mutation, not labors, but this is being offered in the UK, but I think it will be a long time before our government would ever allow genetic engineering like this to cure labors. So what do we have instead? All the studies to date have used something called allotopic rescue. Allotopic rescue takes advantage of the fact that most of the proteins necessary for mitochondrial function are actually coded for on nuclear DNA made in the cytoplasm and transported into the mitochondria. So what we do is we inject a AV vector, we get the good gene that's abnormal in the mitochondrial DNA into the nuclear DNA, the normal protein is made here, and we get it into the cytoplasm. And we have two finished studies that looked at this one looking at labors onset less than six months, one looking at labors onset of vision loss six to 12 months. And like I say, it's not slam dunk. However, there is an improvement after injection of the gene therapy in one eye, in both eyes showed improvement over what would be considered the natural history. This is the early patients, they're injected, they still worsen, but at some point less than a year, they start to improve. Is this just that we don't understand the natural history here the two studies put overlapping each other, or is there really a bilateral improvement that is beyond natural history which has always been felt to be poor for this disease. And most of us really were worried that we were just missing the natural history until we ended up doing a non human primate study in which we injected the gene therapy in one eye and then three months later sacrifice the animals and looked at all the places. You see there with yellow stars and found the DNA had migrated along the visual pathways and so perhaps that's the answer this is very early we really do not know. So leaving this topic I just want to say for any of you who are involved in rare diseases. If you think about a study I did in labors back in the early 2000s, it took eight sites to recruit nine patients and it took us two years. These studies we've done, we have over 180 patients recruited, and the Chinese have nearly 200 patients recruited of labors patients, and we did it within a year and a half. And the answer is because we have enlisted lay organizations who do not have HIPAA rules and they can keep registries and as soon as we have a trial. They click a button and not only do they educate and counsel and have support groups with these these platforms, but they are so helpful for clinical trials so so go go and collaborate with your patients. Getting back into the brain. Let's talk a little bit about homonymous hemiopias usually due to strokes. The natural history of these disorders is that if they're going to get better, the hemiopia usually does so is in the first few weeks, and will certainly have done so by three months. And so that's always good not only for prognostic value but good to know when you're trying to decide whether a therapy is helpful such as vision restoration therapy retraining, which I am definitely not going to get into today. But what I will get into today is a really cool couple of articles that just came out in the American Journal of ophthalmology, in which a computer takes a picture of the actual visual field maps the patients visual field defect and then squashes the entire picture into the residual visual field of the patient. Is that really incredible or what so we're very excited about this obviously the technology is going to have to get better and lighter. It's a little heavy and cumbersome, but I think this is really exciting for patients with visual field defects including homonymous hemiopias there's an altitude note here. Pupils. It's not new to remind you about aproclonidine as the way to diagnose a Horner syndrome, your neurology colleagues probably still think that you need to use cocaine. You don't aproclonidine working on the basis of super sensitivity of a denervated Horner lid and Pupil will reverse the anisocorrhea make the Horner people bigger and reverse the ptosis regarding ocular motility. I'm sorry for those residents who heard this already I think the most important thing to talk about here is the fact that non invasive vascular imaging whether it's MRA or CTA is basically 100% sensitive to picking up aneurysms big enough to cause third nerve palsies. And so don't be too complacent, however, because these aneurysms are still being missed. And the reason they are being missed is because either the radiologist is not told the right thing to look for, or the radiologist did not have training in neuro radiology or vascular diseases so please know your radiologist talk to them and get get somebody to look at your scans who knows what they're looking at. Quick note on the degenerative diseases so now I'm segueing back into the cortex and other areas of the brain. There's a lot of bruja out there a lot of interest in using OCT measures of RNFL and GCC to predict diagnosis to predict clinical course of patients with Parkinson's disease Alzheimer's disease. Here's this article that just came out in neurology and clinical practice that the eyes have it and you can you can predict dementia risk in Parkinson's disease. I would caution people to jump on this bandwagon too soon for the individual patient this may turn out to be markers that may be helpful in clinical trials etc. But where the ophthalmologist really can help people with Parkinson's disease PSP other disorders in which the patient has has facial freezing and has difficulty with cognition is ophthalmic stuff, specifically Parkinson's disease. It's not getting them more dopamine that's going to help their visual complaints their visual complaints are more ophthalmic than anything. So they have convergence insufficiency they have difficulty getting their eyes into the reading ad of their spectacles. They have dry eye they don't blink they have blepharitis at a higher rate. So what can you do get them the low vision get them single vision glasses for distance single vision glasses for for reading. In mono vision cataract lenses put some prisms in their reading glasses for their convergence insufficiency treat their dry eye treat their blepharitis and reassure them that the fact that they're having trouble with vision is not because their actual Parkinson's disease is worsening and eating more of their brain areas. This is not a new article but I always end with it because it's my absolute favorite. I don't think we can get away with doing this study now without getting consent which would give it away but basically we. I had noticed that for a lot of my malingering patients that they came into my exam room which of course is not sunlit and has no windows, wearing sunglasses. And I mentioned it to one of the residents who was rotating with me and he happened to be a pediatric neurology resident, and he said, Oh, you mean like the teddy bear sign and I said, What's the teddy bear sign. All neurologists know this by the way, I didn't. The teddy bear sign is when you have people come in for overnight EEG monitoring for seizures for possible seizures. There is a high correlation, especially in adolescents and adults that if they arrive for their testing carrying a stuffed animal that there will be a correlation with non organic non epileptic seizure disorder. So we did the study and sure enough, wearing sunglasses when you haven't just had cataract surgery or you don't have UVitis is very predictive of non organic vision loss. Well, I thank you. I did end with about seven minutes for questions. If you're not totally stunned. Just to give you a highlight of what I think will be emphasized next year when I do this talk somewhere. I think artificial intelligence with deep learning systems is going to revolutionize ophthalmology in so many ways from the neuro ophthalmic point of view. I think the the areas where it will have the most effect is with ocular fundus photography, as well as OCT imaging of degenerative diseases. For clinical trials. IH there is a clinical trial going on right now for stenting. Mog, anti ischemic optic neuropathy I hope and labor's hereditary optic neuropathy for sure. So at this point, I will excuse you all. It's been very hard for me to do this. I'm I usually feed off my audience find the person who's starting to fall asleep and really look at them. Get some laughs back from people. So I apologize if if I was off a little I don't know. But I really appreciate the chance to be here. And thank you very much. Nancy this was extraordinary thank you so much for doing this I can tell you, no one fell asleep. I've been watching all the videos at least so we do have a few questions if it's okay and then at the very end I'll just turn it back over to Kathleen degree just to say a couple of final parting words so first question came from Judith Horner the beginning, probably asking for my behalf and other others in the room. What parameters do you use to distinguish transient vision loss due to ischemia versus transient vision loss due to other factors. Well, see, this is where I think the ophthalmologist are the gatekeepers. And there is a list longer than the tallest person I know is arm, regarding all the ocular things that can give transient monocular vision loss. And since your word is going to be taken in the ED, you are the one who's going to have to figure this out. In general, transient monocular vision loss due to retinal ischemia. Will not be painful. It will be fairly sudden in onset, it can take whatever pattern it wants, it can be colored or non colored, it can be black, it can be gray, it can be altitudinal it can be constrictive. It rarely would be anything less than a minute. It rarely would be anything more than 10 minutes. But the main thing is doing a excellent eyeball exam to make sure you're not missing one of the things pigmentary dispersion glaucoma angle closure glaucoma. And the AI, all the many things that can cause ocular reasons for transient monocular vision loss. Our next question is how do you go about encouraging the emergency room to purchase a non midger attic fundus camera. The hardest thing is to change behavior and the hardest among physicians and the hardest thing is to change behavior. If it wasn't something you learned in your residency. So the younger folks in the emergency department at Emory have uniformly been begging, begging for a camera in the ED because we have to take it out when the study was done. And I'm embarrassed to say we still don't officially have one there, although because the higher ups have not put it in the budget. And when you look at how much is budgeted when you build an ED, they all have that of thalmoscope and otoscope hanging on the wall. One camera would do it for a busy ED. And it's cost less probably than a couple of EKG machine so you really have to work within your system. I'll tell you what happens in Australia, where there is more of a uniform health system so people making decisions can make it for everybody. They had a horrific lawsuit regarding missed papal edema in a full minute IIH who went blind who had gone to emergency rooms like five or six times and didn't have their fundus looked at. And if you think you're, it doesn't happen here. I personally must be involved in at least 10 individual lawsuits like that. If you think that one of them would pay for probably every camera needed, given the amount of money that a lawsuit costs. So in Australia that happened now every hospital in Sydney has a camera. That that that makes sense. Hopefully we're going to take. So is it going to take a bad event to make it happen in in your setting I don't know. I hope not. I think what's really going to change things is this article about to come out in this major journal next week. Because once we test that with non medriatic photos and once we test it in EDs and neurology clinics, etc. You're not only going to obviate the need for tele ophthalmology. You're going to have immediate interpretation of a fundus disc appearance. It's not going to keep you from consulting ophthalmologists when you need to consult them. But it's going to make you feel a whole lot better that somebody is normal when they're normal, and a whole lot more concerned if something's abnormal, so that you'll get a console. We have one last question from Brad cats go ahead Brad. So I actually had just two questions. One quick one is your, are you using high dose oral steroids at Emory. Yes, our neuro immunologists will offer patients very, very, very high dose, like having to swallow hundreds of pills a day. In order to do the bio equivalent of IV salumetrol. They were doing that when patients really did not want the bother of IV steroids because in many cases they still would have had to come into the hospital, although there are at home arrangements. With the COVID, they do exclusively that. That unless they're worried that someone is aquaporin four or Mog and therefore needs not only IV steroids but possibly plex. They're trying to keep them out of the hospital. So they're doing it uniformly with very, very high dose oral. Yeah, and just for the benefit of the audience. Dan plague our excellent Moran ice center pharmacist is keeping 50 milligram prednisone pills in stocks so that if you do have a patient that needs high dose oral steroids for optic neuritis. You know we have it on hand whereas like otherwise you'd have to go to like three pharmacies to get enough pills like Nancy says hundreds of pills to treat somebody for three days. I would point out though I mean this, there are very few studies they basically show it may not be harmful. They don't necessarily show that there's any more efficacy than frankly what we know with IV steroids which is that the outcome probably still is the same it may affect the MRI slightly but it's it's not. You don't have to treat people with high dose steroids period if they have a run of the mill optic neuritis and they don't want to be treated. Sure. Yeah, no I usually give the patient the choice I tell them what the, what the outcomes are going to be and let them pick. The final thing I wanted to say is that you know Salt Lake City is the capital for photophobia. And so I just wanted to make a point out about the sunglasses sign is that sometimes that can be a sign of somebody that has severe problems with photophobia for reasons that haven't been treated and sometimes those patients will have functional vision loss and but oftentimes if you treat the photophobia sometimes the vision loss gets better or if you treat the underlying cause of the photophobia. So I wouldn't. Yeah, I would just be careful about patients with sunglasses sign doesn't mean they don't have something wrong with them, but it can mean they can have functional vision loss. Fair point. Thanks Nancy. I just want to say this was a tour de force through neuro ophthalmology. We're so grateful that you were our first virtual E ran round speaker. You did an outstanding job and just wonderful from retina all the way to the brain. Thank you so much for just an outstanding. Thank you so much for coming. Thank you. Stay well everybody. Yeah.