Chapters Transcript Corneal Blindness in SSA: Diagnostics, Treatments, and Innovations Speaker: Ashlie Bernhisel, MD All right. Good morning, everyone. Welcome to Grand Rounds. I'm gonna get started here. Um, I'm talking about a little bit of the work I've done in corneal blindness in sub-Saharan Africa, so I'm excited to get going. Upon conclusion of this activity, I want you to be able to discuss the impact and prevalence of cornealpasses and keratoconis in sub-Saharan Africa. Describe the basics of the rapid assessment of avoidable blindness methodology, it's known as the RAAB. Understand the concepts of health system leapfrogging and innovation in low and middle-income countries as defined by the World Economic Forum. And explain the process of a prioritization study. We'll also define the primary, secondary, tertiary, and quaternary um prevention strategies. So our multiple choice question for today is going to be corneal cross-linking is what type of public health prevention strategy? A primary, B secondary, C tertiary, or D quaternary. So what got me interested in this topic, obviously background of being a cornea specialist, but really what got me interested in it was reading this, this paper that surveyed the entire globe in terms of what's being done with cornea transplantation and eye banking. And they found, authors found that there is a 70 to 1 ratio of need for corneal transplantation, compared to the number of corneas available worldwide. However, over half of the world's population does not have any access to cornea transplantation whatsoever, so there's not even that one, it's just a 0. no ability to get any kind of, um, surgery that way. And then if you look at sub-Saharan Africa, that actually makes up a good portion of that half of the world. Yes, there are countries in Asia and Central and South America that also do not have any access to the cornea transplantation, um, but there's just such a high concentration in sub-Saharan Africa. If you look at this map, it, it, um, this is, this is from another paper that got me interested in this. There is the highest concentration of corneal blindness, one of the highest concentrations of corneal blindness in sub-Saharan Africa, and yet, only 0.2% of publications on cornea transplantation and eye banking is coming out of the region. So let's talk about perennial blindness in sub-Saharan Africa in general. So the population is about 1.3 billion of all of sub-Saharan Africa. The World Health Organization estimates blindness to be about 1.3% of the population. And that corneal opacities represent about 4% of the blindness there. And then it's important to note that the WHO definition of blindness is less than 2400 in the better seeing eye. So that results in about 650,000 individuals who are age 50 plus, who are bilaterally blind from corneal opacity, or at least blind, the better seeing eye is blind from a corneal opacity. So this, this is a big number, but it also does not include unilateral cases. It does not include visual impairment, which the WHO says is from 2050 to 2400 again in the better seeing eye. This does not include keratoconis, and this does not include people that are less than 50 years of age. A corneal, as we, as we know, corneal opacities tend to affect those at a much younger age in their most productive years, and this can have a huge social and economic impact. If we look at this, we see that those with corneal blindness tend to have more disability adjusted life years and more years lived with a disability. And so why the over 50 estimation? So that's based on the rapid assessment of avoidable blindness. This is really the gold standard when we're looking at prevalence of different eye pathologies worldwide. It was designed though to look at cataract blindness. So that's why for the most part they look at people that are age 50 plus. They, and the teams that do this, so this is a pop, this is really a community-based survey, because if you look at these, these places that are lower middle income, there is going to be a huge portion of the population that does not seek care at a clinic or a hospital. So if you do a clinic or a hospital-based study, the selection bias is just too great. So this is why this is a gold standard going door to door, and the team consists of ophthalmic technicians and usually one eye provider. And they're diagnosing the cause of blindness with often a pen light and a direct ophthalmoscope. Sometimes they'll have an indirect, and sometimes they'll have a portable slit lamp, but that's not a standard. And, and that's, so that's also the reason why keratoconis is not included in that number because um you're really only, you're, uh, first of all, the categories only include um corneal opacities, you know, glaucoma, kind of these big um topics and does not include keratoconis, so it would probably go under other. OK, so that was kind of the background to that, that had me interested in this. So I decided I wanted to look at that 0.18% of publications coming out of sub-Saharan Africa. So a research team and I did a systematic review of the literature looking at what that 0.2% shows. And then, um, I wanted to take some action and was wondering if there are ways in which health system leapfrogging or task sharing can help move the needle forward in I banking and cornea transplantation. In sub-Saharan Africa and potentially other low and middle income countries. My slides are not advancing. There we go. All right, so the methodology for this. We reviewed the last 30 years of literature regarding cornea transplantation eye banking. We looked at 4 different databases and excluded non-peer reviewed literature and gray literature. So this is a scoping review. Um, if it was a systematic review, you'd look at all years of publications. You'd look at every single database, um, and you would include non-peer-reviewed and gray literature. But just for time's sake, we, we, we, we did a scoping review. Oh, what's going on, my Slides are very slow. OK. So, some outcomes, uh, that I wanted to look at were capacity outcomes, um, corneal transplant quality outcomes, tissue sources, eye bank functions, economic and financial system details, public awareness, willingness to donate, and legislation. So, this is for nerdy people, this is our prisma flow diagram. We ended up with 41 publications. Only 17 countries were included. Um, Goodness gracious. So these are the 17 countries. The ones with the red dots are Ghana, Nigeria, Ethiopia, Kenya, and South Africa. And these are really the only countries that had more than 3 publications on the subject. So most of these only had 1 or 2. So again, just very limited data, and only Ethiopia and South Africa have functioning eye banks. So South Africa started their eye bank in 1975. There are 4 eye banks there. Um, they do have countrywide distribution. However, there is a big bias to go to private practice. Um, so there are some concerns that they're paying a little bit higher price to get the tissue. So obviously some ethical issues there, um, and there is a limiting factor in terms of tissue donation. Ethiopia established an eye bank in 2003, provides tissue for three teaching institutions. Institutions. The, the main limiting factor there is thought to be practice patterns of the corneal surgeons. So they're all rela you know, they've all been trained in the last they, in the, in the last decade or so, and so a lot of them are just, um, don't have the experience for more complex cases, and so that's thought to be part of the reason. Um, Nigeria, Kenya, South North Sudan have opened and then closed eye banks, and Rwanda would like to open one. So indications for corneal transplantation, we found non surprising, it's not surprising to be keratoconus corneal opacities, although a lot were still being done for Ebola keratopathy. So again, just showing that there's not developed enough to be doing lamellar transplants. Or at least the experience isn't there. Graph survival is actually quite good. If we, if we compare this to worldwide, 1 year graphsurvivals are um at 90% or above, and 2 years, not far behind that at 88%. So, if you, this is kind of a way to compare apples to apples, um, you know, there might be more complex corneal opacities done in Su sub-Saharan Africa, so they're all cause graft survival might be a little bit lower, but for keratoconus, um, it's quite good. Um There were really no results for the outcomes I looked for, for capacity, so no annual transplant numbers for, you know, for in terms of um The eye banks or institution. Um, tissue sources are, when they do not have their eye bank is almost exclusively from the United, United States. Um, there's really no publications on protocols or guidelines on eye banking, no economic or financial system details. Um, so just really a, a, a big gap there in knowledge and, and, um, what's being done. So, my research question number 2 is looking at leapfrogging innovation and disruption. Um, So basically, are there ways that we can bypass some of the traditional development of eye banking in sub-Saharan Africa? The World Economic Forum has this document that they created, this publication that looks at basically ways to do exactly that, and You know, as a, as a, if you look up what healthcare leapfrogging is, and it's basically again, just adopting more modern healthcare practices, looking at having the same outcomes by passing slower, more traditional stages, one of the examples, if you look at healthcare overall, is often the, is often Aravan Eye Center. So we'll kind of give some of those, I'll give some of those examples in a minute. Um, this is a matrix that's from that Health Systems leapfrogging project, and it divides on the left-hand side, the WHO health systems categories, and then along the top, different types of innovation. Um, and so let's look at some of those here as examples. So, if we look at medical products on the left-hand side here, and ways that technology, there can be innovation in this realm, um, they give some examples in general healthcare, but a really, I think, again, a really outstanding example is that at Aravi Eye Center, they have something called Aolab. Where they basically have their own factory where they design and make their own lenses. They can make a monofocal PMA PMMA lens for less than $1. Um, they also make their own sutures. They also make their, um, compound their own, um, antibiotics and then dehydrate them so that they can kind of be available on demand. Um, and they've also designed their own eco machine. So that's just a really great way to, to leapfrog and not necessarily have to just pay for these expensive, um, these expensive medical products that are from outside the country and just really have innovated really well in that, that arena. Um, also related to that, again, giving the example of Arain, I spent a month there, so that's why I actually visited our lab and saw some of this in action. Um, so, behavior changes, again, for medical products. There is some, there's, there's ways to incentivize some of the, um, the, the workforce to keep things in check. So, like, giving them a bonus at the end of 6 months if there has not needed to be, you know, if there's no major breakdowns in some of the equipment. The other way for behavior change that I've seen at Arabin. Um, is, they, they put up posters everywhere, everywhere about, um, you know, the more money that they save, the more people they can reach. So they actually use altruism a lot, um, to really motivate their, their workforce, which I think is pretty cool. So part of another type of this innovation, another, so another behavior change basically or operating model change is probably more where this fits, is that of task sharing. Um, so this is another public health concept. So within ophthalmology, it involves delegating certain clinical responsibilities traditionally performed by ophthalmologists to other trained health professionals such as ophthalmic technicians, nurses, um, to improve efficiency, efficiency and access to eye care. Um, And why is that? There is just a huge shortage of eye care providers, specifically if we look at sub-Saharan Africa. So in the United States we have somewhere between 30 and 50 ophthalmologists per million people. If you look at sub-Saharan Africa, that number is about 3 per million. And so that's why task sharing and, and task shifting has become a popular idea. So, the, the purpose of the second study was to collect and prioritize experts' innovations and task sharing ideas in the field of eye banking and cornea transplantation in low and middle middle-income countries with a focus on sub-Saharan Africa. So, this methodology is a modified Delphi survey, um, in which experts and stakeholders are selected, um, and in this case, they had to have experience in corneal transplantation and eye banking in low and middle-income countries. We purposefully selected 50% of participants to actually have lived experience, um, and be locals from sub-Saharan Africa. And, and, or low and middle-income countries to meet the ideals of community-based, um, participatory research and really actively avoid modern global health colonialism, um, because oftentimes we're going and thinking we have all the right ideas, um, without really asking the local community. So this was a two-round survey in round one, the stakeholders were asked for innovation, task sharing ideas, so they, they made a bunch of suggestions. These were narrowed into 41 unique suggestions, so just duplicates were removed. Um, some were more like opinion statements than actually actual suggestions. And in round two, participants were asked to rate the innovations and ideas in three areas, so feasibility, sustainability, and success. Um, and so these were collected, averaged, and a list of the top 15 suggestions were created. Um, and really, so these are, these are some of the top ones, and the top, really what came up on top are a lot of these task sharing ideas. So, for example, personnel trained in both grief counseling and as a tissue recovery technician. Um, and similarly, so number 2 is both physicians and technicians with the ability to procure corneal tissue. Um, I think tied here at the bottom of here for number 6 is an interesting technology idea. Um, so at least one country from sub-Saharan Africa as of March of 2019, had 106 penetrants of cell phone coverage, so implicating that some people have even more than one phone. Um, mobile health services may be employed, um, health as an example, such as smartphones, messaging applications to help with adherence. So, um, coming up back for their, their follow-up appointments, making sure they're taking the right post-op drops, etc. So in summary, there's a need for transplant and eye banking services in sub-Saharan Africa, and there's really limited data in the region. Outcomes for keratoconis grafts in sub-Saharan Africa are similar to those of other areas of the world, showing that if it is, you know, if, if cornea transplantation is done, it can really be successful. Um, there might not be a high-tech disruptive innovation or single like frogging event that solves the issue, um, but this is, you know, about knowledge sharing, um, and hopefully some of these ideas can be tested. Um, I'm, I'm running out on time, but I just wanted to say, you know, after doing these two studies, I really kind of took a step back and said, you know what, wow, there's, there has to be so much in place for eye banking to take place. You know, sometimes, some places don't even have legislation in place. They don't have cornea, they don't have cornea trained doctors, so you kind of have everything simultaneously. So there's this, um, this paper that That looks at readiness for cornea transplantation. First of all, you have to have, you know, the, the base prevention, um, eye care prevention in place. You gotta have good cataract surgery in place before you look at corneal surgery. And so this, this is a cardiogram, and showing, basically, the, where, where the highest density of Corneal blindness is, is really blown up in this picture of the world, and country readiness is demonstrated with various colors. So this was making the point that India has a lot of corneal blindness, and they're really ready to take it on for eye banking. If you look at Africa, sub-Saharan Africa, there's a lot of corneal blindness, given it looks puffed up, um, but maybe less ready. So when I saw all of this, I kind of took a step back and thought, well, is there a lower hanging fruit in terms of corneal blindness in sub-Saharan Africa? Um, and I had been hearing anecdotal reports of keratoconis being really high in the region. And so looking at some of these public health strategies, prevention strategies, I thought, well, actually maybe looking at keratoconis might be a better, you know, easier way to start. Um, so just briefly, primary prevention is our actions that are taken to prevent the onset of disease. Secondary prevention, actions to take to prevent complications and are the development of visual disability due to an existing disease. Tertiary is to restore function or reduce existing disability, and quaternary is service and aid to function despite disability. So, for kera, if you look at keratoconis, um, you know, it might be tried for primary prevention, might, you know, none of this is proven, but things like controlling environmental factors such as eye rubbing, um, um, treating atopy. For secondary, that would be more cross-linking. Again, you're trying to prevent further progression of the disease, and tertiary would be cornea transplantation intact scleral lenses. The damage is already done. We're just trying to help them see better despite that. And then Quaternary would be low vision services. So, um, we did a scoping review looking at keratoconis as well. Just briefly, we found that the, and, and thanks, Dr. DeSouza, shout out to you, who's helped with this study, found that the range of keratoconis to be 0 to about a little over 1% as a comparison to the United States, prevalence is about 0.05%, so quite high in some places. I suspect the reason why some places found 0% is a lot of these, again, these prevalence studies are using. Um, sometimes just a pen light, and you're only gonna get really, you're only gonna find really advanced keratoconis that way, um, and they're gonna potentially miss more moderate, um, and mild cases. So, um, and, and cross-linking is being done. I just was curious about that in the study, um, but only done in Kenya, Sudan, and Cameroon. And so, kind of next steps would be looking at, um, you know, the Ethi, Ethiopian eye banks are really good, would be a really good case study to see if that can be implemented, implemented elsewhere. It was a huge collaboration between the Ethiopian Ministry of Health, SightLife, Himalayan Cataract Project, Orbis International Academic Centers in the community. Um, and so just like you can do case reports on, um, uh, on different patients, you can do really case reports on successful, um, health system successes. So, that's something that I think can be done also looking at ones that maybe that didn't work. Um, and then I think a lot of implementation research needs to be done. So, Rwanda, I think. Um, if this, this comes about is to look at things like, are these task sharing ideas that were suggested, um, would they be even acceptable to staff? Would, would physicians, you know, a lot of places, um, you know, do physicians want to have technicians go in and, um, collect the eye tissue. And then you do pilot studies and scaling up studies. And then for keratoconis, um, there's just, topography and tomography is just so expensive. Um, and what I really like to do is look at some sort of protocol where people can have some diagnosis of keratoconis in the absence of topography and tomography. So just a lot of work needs to be done, um, but I, I find this obviously very exciting. Um, so the multiple choice question, again, cross-linking is what type of public health prevention strategy? Is it A, B, C, or D, primary, secondary, tertiary, quaternary? And the answer is secondary. Thank you. Thanks for having me. My name is Sabrina Punja. I'm the neurophthalmology fellow. It's a pleasure to be here. And uh I wanted to present a talk this morning entitled The Absence of Essentials, Introducing the Central Scotoma. And a big thank you to Doctor Chen for all of his help putting together this presentation. Let's see if my slides will advance here. Learning objectives for this morning include formulating a differential diagnosis for bilateral central scotomas, reviewing the diagnostic criteria for neuromyelitis optica spectrum disorder or NMOSD, and identifying features of nutritional optic neuropathy. The test question for this morning is which of the following statements is true about bilateral central scotoma? A, MMOSD is the most common cause of central scotoma. B, vitamins A&E are important to in a patient presenting with central scotoma. C, vitamin B12 deficiency can present with central scotoma and peripheral neuropathy. And finally, D, central scotomas are usually caused by arcuate bundle defects. So our case this morning is of a 34 year old female who's presenting with painless central vision loss in both eyes. She's otherwise healthy with no medications on board, and she has no family history of vision loss. Her story began back in July 2023 when she presented with daily nausea and vomiting as well as refractory hiccups. She was seen by her local GI team and a good workup was done looking for any structural cause for her symptoms with no etiology found, and she was ultimately diagnosed um as being uh having GERD or gastroesophageal reflux disease and was therefore started on some omeprazole for that. By February 2024, she experienced gradual onset painless vision loss in both eyes, and within a couple of months, she developed length-dependent paresthesias, affecting her hands and feet in a glove and stocking distribution. She was seen by a neurologist locally and she had an EMG done which was normal and also got a lumbar puncture, which was unremarkable. By July 2024, she was seen by her local neuro-ophthalmologist, and infectious and inflammatory blood work was done including MOGG and Aquaporin 4 antibodies which were normal, and she was therefore diagnosed with seronegative MMOSD. Her exam at that appointment was documented as having visual acuity of 20/150 in both eyes, having bilateral central scotoma, and temporal disc pallor in both eyes. For that presumed diagnosis of seronegative NMO, she was started on an oral equivalent pulse dose of prednisone, uh, followed by an oral taper with no improvement in her vision, unfortunately. Appropriately along the way, she did get a couple of different MRI scans, including of the entire neural axis, which we'll go through together now. And so here's an MRI um of the brain. Here's an axial flare at the level of the basal ganglia and we can see normal healthy appearing white matter with no demyelinating lesions. Here are a couple of additional cuts um focusing in on the floor of the 4th ventricle and I'm specifically trying to point out the area postrema over here which is the nausea vomiting center of the brain. You can note that in our patient, this area appears normal without any hyperintensity or enhancements. Here's another patient just for comparison's sake, and this is a patient with antibody-positive NMO and hopefully, you can see the difference because the area postrema is enhancing, which is characteristic of area post trauma syndrome, which clinically presents in some ways similar to our patients um with nausea, vomiting, and hiccup. Here are some orbital cuts and you can see um that there is no enhancement of the optic nerves in the axial nor coronal planes. Here's an MRI of the spinal cord. Um, we've got both the cervical and thoracic cord which did not show any, uh, hyperintensities and no enhancing lesions. And so we'll add a couple of additional points here to our timeline. Um, by October 2023, due to the extent of her GI symptoms, she unfortunately lost her job and began using uh daily alcohol. And um about a year later, by October 2024 is when she presented to the Mayo Clinic for further evaluation. When she presented to us, her exam, uh, showed a visual acuity of 2060 in the right eye and 2050 in the left eye, with essentially no color plates in either eye, no APD and a normal anterior segment exam. I've got her fundus photographs up here, and you can see that she has temporal pallor in both eyes. Here are her visual fields, and you can appreciate these bilateral central scotomas and mirroring this, she's got a decreased foveal threshold in both eyes. Here's her OCT nerve, and you can see that she has a quote-unquote normal appearing RNFL and you'll remark that there is a disconnect between that um normal RNFL and the degree of diffuse bilateral GCL loss that she has. So there is a discrepancy there that uh is important to remark. And if you look closely, you may be able to appreciate some evolving thinning, specifically perhaps involving that macullopapillary bundle. And so, let's build our differential diagnosis for bilateral central scotomas. There is a really helpful mnemonic that can help us with this, and um I've got it up on this slide, MI. Uh, the M is for metabolic, toxic, and nutritional causes. The I for infectious inflammatory, T for traumatic, C for compressive, and finally, the H for hereditary. I've bolded the important categories to keep in mind when thinking about bilateral central scotoma, so that would be the metabolic toxic nutritional category and the hereditary category. The infectious traumatic compressive, um, as well as the inflammatory category, um, can be considered but are often less likely when you have a patient presenting with the bilateral central scotoma. For the hereditary group, uh, labors is a great example and important to consider, and, uh, there are some other conditions that we could keep on that list as well. We will, uh, tease apart that metabolic category a little bit more, and we can stratify that out into nutritional deficiencies as well as drugs. Nutritional deficiencies to consider include vitamin B12 deficiency folate. You can also think about copper and other B vitamins. And then for drugs, we've got an array of different antimicrobials including ethambutol and linezolid on our list. And so, we can think about what unites these uh nutritional deficiencies in drugs and their presence contributes to decreases in oxidative metabolism, which therefore increases reactive oxygen species. And this will be important to remember a little bit later on in our discussion. And so we'll take a pause from her story and talk for a moment about why this is not seronegative NML. I've put up the diagnostic criteria for NMO and you'll recall that they're stratified into seropositive and seronegative varieties, and we'll go through that together. It's easy to get lost in some of um the words in these diagnostic criteria, and so we'll simplify things a little bit by considering serropo NMOSD as necessitating one core characteristic and presence of aquaporin foreign antibodies. In terms of those core characteristics, you have to have one out of the following. Either longitudinally extensive transverse myelitis, optic neuritis, area postrema syndrome, which we spoke about earlier, and then there are 3 additional presentations which more commonly would present to the neurology clinic, including a brain stem syndrome, diencephalic syndrome, so involving the thalamus or hypothalamus, and interestingly can even mimic narcolepsy. And then other symptomatic cerebral syndromes with typical of hearing lesions. And then finally excluding other reasonable diagnosis. We'll also spend some time briefly discussing the serum negative eneO given it's pertinent to our case. And so by definition, this is of course um necessitating uh the absence of aquaporin 4 antibodies. And then you actually require two core syndromes, one of which must be the longitudinally extensive transverse myelitis, optic neuritis or area postrema syndrome. Not only do you need a clinical syndrome, but you actually also need MRI criteria which um are included on this slide but we won't necessarily go through in detail. And needless to say that our patient does not meet this diagnosis because she didn't have any MRI correlates for, um, you know, longitudinally extensive cord lesions, optic nerve enhancement, or hyperintensity or enhancement of that area postrema as we saw earlier. And so hopefully you can see why she does not meet criteria for serone negative animals. Given that, we did some additional lab work and we can look through some of her results to get, get some additional clues. And so you'll note that her vitamin B12 came back low, and her methylmalonic acid or MMA returned back elevated, and we'll talk more about that shortly. We also completed the rest of the nutritional workup including homocysteine, folate thiamine, as well as genetic testing for labor's hereditary optic neuropathy, all of which returned back normal. And we can even look at her CBC going back to kind of foundational principles, uh, to garner some additional clues, and you'll note that she's got an elevated hematocrit due to hemo concentration, presumably from her degree of dehydration, and she also has an elevated MCV illustrating some macrocytosis from her B12 deficiency. And so hopefully, I can convince you that our clinical picture is very much in keeping with vitamin B12 deficiency, characterized by bilateral optic neuropathies, as well as peripheral neuropathy. And for her, I suspect that this was a small fiber neuropathy, which would be a cult on EMG which only tests large fibers. And so for treatment of her B12 deficiency, she was started on oral B12 supplementation and was ultimately transitioned to intramuscular injections in order to more effectively replete her stores. And since being supplemented, she clinically has remained stable. And so we'll take a moment to briefly discuss the role of MMA and homocysteine. And you can see over here, um, that B12 is plays an important role in um helping convert methylmonic acid and methylmolanylCA as well as homocysteine and folic acid to succinyl-CA and methionine respectively. And so in our case, it was um perhaps obvious once we got back that B12 level, which was low, but in many cases, the B12 level can actually falsely appear normal. And then what we need to do is look at some of these factors upstream in order to be able to diagnose a functional B12 deficiency by looking at the accumulation of products upstream in this reaction. And so when presented with a normal B12 level, of course, if you have a normal MMA and normal homocysteine, well, simply that means that you have a normal B12, but if you have a high MMA plus minus a high homocysteine, that could illustrate that you actually have a functional decrease in B12. Interestingly, if you have a normal MMA and a high homocysteine, that would actually be more illustrative of a low folate level. Briefly, I'll touch on some of the causes of vitamin B12 deficiency. I've got some of them listed on this table, and you need to think about this in anyone presenting with gastric abnormalities, small bowel disease, restricted dietary intake, or medications that can block or impair absorption. And so contributing factors in our patient include nausea, vomiting, um, her alcohol intake, and poor nutritional status, as well as her omeprazole use because it decreases the production of stomach acid, which is important in absorption of vitamin B12. There's a myriad of clinical manifestations of vitamin B12 deficiency ranging from ophthalmic and cerebral manifestations to spinal cord and nerves as we alluded to earlier. Um, but systemically speaking, you can also get cutaneous. Changes. Um, we alluded to some of the hematologic malign uh kind of changes that we can see including the macrocytosis, but you can also get anemia and thrombocytopenia. And finally, uh, macroglossia, uh, can also be a sign seen in these patients. And so going back to the eyes, let's speak briefly about why the macullopapillary bundle is disproportionately affected in this condition. And so the macullopapillary bundle has the highest density of retinal ganglion cells and small diameter unmyelinated axons. The result is that this is a region of incredibly high metabolic demands. In order to understand why the macullopapillary bundle is disproportionately affected, we also need to pose a second question of what is the role that the mitochondria play. There's been some incredible work done by a number of clinicians and scientists including um a wonderful neuro-ophthalmologist, Doctor Alfredo Cedo, and um I can't do their work justice in the limited time that I have this morning, but we'll graze the surface of some of the work that they've done which has helped, uh, significantly to better understand conditions like nutritional optic neuropathies, as well as labor's hereditary optic neuropathy. And so, as I mentioned earlier, these conditions are characterized by an increase in reactive oxygen species which leads to increases in apoptosis. Now, if we try and understand this better using this little schematic, um, we can zoom in on the level of the lamina rebrosa because there's some really interesting, um, clinical correlates, uh, based on the anatomy that we see. And so posterior to the lamina rebrosa, you'll note that fibers are myelinated whereas anterior, the retinal ganglion cells um are unmyelinated. And so, if you remember what the purpose of myelin is, it helps to speed up transmission along an axon due to saltatory conduction. And you'll recall that between those areas of myelination, we have our nodes of rhombier. And while there are some mitochondria situated at the nodes of rhombier, really, There's a paucity of mitochondria in these areas relative to the more anterior areas relative to the laminarobrosa, which are really rich in their mitochondrial load. And the perfect example of this is the macullopapillary bundle due to that high density of retinal ganglion cells, as I demonstrated previously. Another way to visualize this is using this graph, and you can see that as the distance along the optic nerve increases away from the retina, myelination decreases, and our axonal mitochondrial load also decreases. And so if we were to situate our macullopapillary bundle on this graph, it would be somewhere over here, and you can appreciate that it's gonna have an incredibly high mitochondrial load reflecting its uh metabolic, uh, needs and demands. And so a good clinical correlate for this is labor's hereditary optic neuropathy. Here's a patient that I saw earlier this year and you can see um in this patient with genetically confirmed labors, um, that there is this pseudoappilledema, uh type of appearance The correlate on OCT illustrating an elevation in the uh OCT RNFL thickness and a pattern perhaps similar to the OCT we looked at in our case earlier with this disconnect and evolving GCL thinning um alongside there. And so really what you're looking at in that uh picture is first of all, this web-shaped defect, which is an area of denuded RNFL but then also engorgement and uh swelling in those um remaining RNFL fibers, um, those fibers with a high mitochondrial load and the ones that are under such significant stress and strain in a condition like labors. And so, a couple of takeaways just as we wrap up here. Remember that when you have a patient with central scotomas, think Mitch with the focus on the metabolic and hereditary categories. Remember that the diagnosis of seronegative NMO is uncommon and has a specific and stringent set of diagnostic criteria. for good reason. Um, vitamin B12 deficiency occurs in patients with poor intake or malabsorption, including alcohol use and with certain medications, and that serum B12 levels can be falsely normal and in the context of high clinical suspicion, this really should be confirmed with an elevated MMA and a homocysteine level. And so just to finish off with our test question here, the answer is that vitamin B12 deficiency can present with central scotomas and peripheral neuropathy. Thanks everyone for your attention. Um, if there's a couple of minutes remaining here, I'll turn it over to the group in case there's any questions or comments. Thank you. Mr. Marina, this is uh John. Wonderful presentation. I think you made it just so clear, uh, in terms of how these patients present, but as you know, in our clinic, there's just so many patients that get referred for, and they always call it seronegative NMO for these patients who come in with bilateral central scotomas. And if they come in with these bilateral symmetric central scotoma just like your patient, it's never gonna be optic neuritis or inflammatory ischemia. And yet those are the most common causes of optic neuropathy, so I think that's why they always kind of go that route. But you've seen, we've seen so many cases together and, and you've astutely picked them up every time as a fellow coming in saying, you walk out and you say, Doctor Chen, this is not erroneg mininomo, and you've made that diagnosis and over and over and again, so I'm glad you were able to share this with the group in terms of kind of how to approach these patients. So thanks so much. Thank you. All right. Thanks everyone. In the absence of any other questions or comments, um, thanks everyone for your attention and I hope that you have a great rest of your day. Published May 19, 2025 Created by
