 All right, let's go ahead and get started. One of our own is going to be doing our grand rounds this morning, Dan Bettis. So rather than speaking about unexplained vision loss, which is one of the resident's favorite topics, I'm going to speak about a particular patient that I saw, a 46-year-old woman with unexplained vision loss. This happened in Dr. Katz's clinic. Turn the mic volume up. Oh, here we go. So I'm going to speak about a 46-year-old right-handed woman who presented with a visual deterioration in both eyes. She actually presented to Dr. Katz's general ophthalmology clinic for decreased vision. Four months previously, she was driving along and nearly hit another car, so that prompted her to realize that her central vision was highly impaired. Several days later, she was at a restaurant and was having some difficulty reading one of the menus and actually had to have one of the waitresses there help her. And interestingly, this only lasted about a week, and then her vision returned to her baseline. Reportedly, she went to an eye care professional at that time, although no records are available. She recalls that that exam at that time was normal. She presents because four to five weeks ago, a similar spell started, except this time it's endured, and she's having persistent symptoms. Again, it was an abrupt onset, painless, decreased central vision in her eyes. She feels that her vision is washed out during the day and is better under darker-light conditions at dusk. As far as past medical history, she's recently discharged from the hospital for pneumonia. She was hospitalized four days. As part of that admission, she was tested for tuberculosis, and that was negative. She has a history of depression, and then she gives a vague history of thyroid issues, which have certainly never been diagnosed and aren't being treated at the current time. She's adopted, so she does not know her family history. Currently not taking any medications. She's off of her antibiotics for pneumonia and has allergies to Sulfa. As far as review systems, she does endorse a 30-pound weight loss over the past year and a half. She's gained about 10 of those pounds back. She has a vague week-slash presyncable episode, which was worked up at an outside ER. Again, we don't have those records, but reportedly they did some lab work, EKG and whatnot, and it was all normal. As part of that, she did get a CT scan of the head, which was also normal, which we do have, non-intentional. As far as her exam, she's small. She has a BMI of 16.5. Her visual acuity is 2,200, and both eyes, no improvement with pinholding or refraction, no APD present, mildly elevated intracular pressures at 24 millimeters mercury in both eyes. Extracular motility is full. Color vision is decreased, three out of six plates in both eyes, and then stereo acuity is presumably, both of these are presumably decreased because we've never seen the patient before, but her stereo acuity is decreased. She's able to appreciate the fly in just one out of nine circles. But otherwise, her eye exam is fairly unrevealing. Interior segments are clear and quiet. Dalliophonoscopic exam is within normal limits. The nerve looks OK. Neurologic exam is non-focal. We review the CT scan from the outside ER, and it's normal. So what else does anybody want to know? There's some things that are conspicuously absent from the above history, social history, and that's great. So she lives here in Salt Lake. She's unemployed, no known toxic exposures, particularly to organophosphates or any some such. She has no new sexual partners, no known sexually transmitted diseases. She smokes a pack per day since she was a teenager, and she has two to three mixed drinks per night. No other IV or illicit drug use. So as part of the workup to define these central vision defects, we decided to get a perimetry. Since her vision was so decreased, we decided to do goldmine perimetry. So here you can see that there are fairly dense secocentral areas of vision loss. Pretty characteristic pattern, while the peripheral vision is relatively preserved. So what's the differential when you start to see central or secocentral scatomata? So one thing on the differential has to be amaculopathy, which the patient denies a lot of the concomitant symptoms that should accompany amaculopathy, like metamorphopsia, night blindness. Our patient said that it was actually better at dusk. Photopsias, macular photo stress, or glare recovery. So while that's a possibility, she also had a normal exam, and I would say it's lower on the list. Neurologic causes of impairment of the optic nerve can be mitochondrally inherited. Labor could present in a very similar fashion to this. There could be a dominant optic atrophy, which typically presents a little earlier in life than this. You can always think about demyelinating disease in particular that could have been missed on a CT scan, which he had at the outside ER. Compression or infiltrative disease of the optic nerves, which should have been picked up in part by the CT scan. Syphilitic optic neuropathy. And then toxic or nutritional optic neuropathies, in particular B vitamins. Certain drugs, like methanol, if she denied any moonshining or home-cooked booze. She also had not been on an amputee hall. They did not treat her for TB when she was in the hospital. They simply tested her for tuberculosis. And then lastly, tobacco alcohol, angliopia. And in this particular woman's case, that was the presumptive diagnosis or the working diagnosis was tobacco alcohol, angliopia, or nutritional optic neuropathy. We also got VEPs, which you can see are mildly delayed in both eyes, the right eye, more than the left. And the plan was to check a CBC, a folate, a B1, a B12, all of which were within normal limits. She was counseled regarding smoking cessation and alcohol abstinence. She started on colon sign Q10, which, as you know, is designed to boost mitochondrial function. We'll talk about why. That's important in a moment as far as the pathogenesis of the disease. She's also started on antioxidants, vitamin C, vitamin E, and then vitamin B12 supplementation, which is an important part of the management of the disease. In addition, she was very impaired by her visual function. So we referred her to Julia Kleinschmidt and also to Low Vision, who were able to help her quite a bit. So this patient is interesting. I actually saw them in follow-up with Dr. Katz. But we have quite a bit of follow-up. So I'm going to go through some of her follow-up visits. At six months, the patient felt that her vision was variable from day to day and even within the day. But overall, stable. She enrolled in classes through the Department of Services for the Blind. At six months, her vision was overall unchanged, maybe a little bit worse in the right eye. Intracurricular pressures were a bit. She did stop smoking. She was able to stop. She was able to stop drinking altogether. We'll see how long that lasted here in a bit. Her color vision remains impaired. Her stereo vision remains impaired. And the only change on Slitlamp exam is that there's now a mild pallor of the temporal optic nerves, which was not noted on initial presentation. Here's her pherometry, which is almost identical to when she presented it. Year and a half later, she says her vision is about the same. This is somewhat ungratifying to ophthalmologists because you can see she's seeing 2040 plus and that 2020 minus 2. She does have a new diagnosis of Graves disease. So this kind of vague thyroid difficulty that she had initially came to fruition. And she's status post-thyroid ablation. Color vision remains almost exactly the same. Her stereo vision is maybe a little bit worse. And again, her dilated exam is unchanged. So I think we often forget that is a very high contrast visual fund. What we often forget is that for that person, and they have not had much improvement in their contrast sensitivity, that overall function, even though they don't receive difference in their function. That's a very good point. That is, that's what we see and that we have. But function, that's really a relative issue. That's very important. Also important, and most of us do a good job of this here, is to make sure that we're noting whether the patient's looking eccentrically or anything like that when we're noting the visual acuity. But those are all very excellent points. And finally, at five years, and this is most recently, so she notes no changes to her vision. She has resumed smoking, half a pack per day, two drinks per week. Fortunately, she is back up to maybe a more of a normal weight range, so she's back up 25 pounds. So she's gained back nearly all that. She lost unintentionally. She's finished classes at the Blind Center and is now a volunteer at the Literary Center. And her vision, her snow and visual acuity, is gross sand change from before. And then we felt like her vision was improved enough to where she could perform standard automated parametry, and so that's what you see here. Again, verifying that there's sound. So you just talked about that. How did that happen? So we'll talk about tobacco a little bit. It's widely accepted that Christopher Columbus, when he came, he was one of the first non-person not from the Americas to see the tobacco plant. In fact, some of the early explorers noted some of their interactions with the indigenous people. They noted that some of the shamans of the Hispaniola and certain Central American provinces poison themselves with tobacco smoke during curing seance. Perhaps that's a premonition. The vast expansion of tobacco used to really occur during the 16th century or the 1500s, where a gentleman named Jean Nico, who sent some powdered leaves to Catherine de' Medici. And if you know that de' Medici's held no small amount of power during that time for her incurable headaches, they worked. And it gained quick popularity. And it came to become the herb of Nico, which is, of course, the derivation of nicotine today. Today or at least in 2011, which is the CDC data for 2012 hasn't been compiled yet. But in 2011, 45.3 million people in the US are about 19% of all adults in the US smoke. We actually have the lowest rate of smoking here in Utah, which is 9.1%. And cigarette smoking at large, not just speaking about vision, is a big public health problem accounting for approximately 443,000 deaths or one in five deaths in the US each year. Perhaps it's not lost on those in the audience that about one in every five deaths is due to nicotine, about one in every five adults smokes. So tobacco and impaired visual function are kind of a long history. So the first relatively modern report of tobacco induced optinoropathy was by Joseph Beer, who is not studying tobacco alcohol ambiopia. He was an early European ophthalmologist in 1792. It appeared in a couple different texts of the time, one by William McKenzie in 1833, and then by John Lee Sars, The Use and Abuse of Tobacco in 1859, described visual deterioration in amaurosis as common consequences of smoking tobacco. And one of the most interesting accounts I've found was by Charles Drysdale in 1875, where he reported some of his experiences with tobacco poisoning. He writes, one of the symptoms produced in acute poisoning by tobacco is blindness, and chronic poisoning is a rise to similar symptoms. In one week, I saw two cases of tobacco amaurosis in young men. The first had chewed continually, and the other smoked the enormous quantity of one ounce of shagged tobacco daily. Both were completely and irretrievably blind. So its place in history kind of continues, and this is one of the things that I found very interesting about this disease was how it continued to crop up, particularly in wartime. So in Havana during the Spanish American War in 1898, there was an epidemic of optic and peripheral neuropathy. Not very well studied at the time, but two more which are better studied occurred, one during World War II and Southeast Asia among prisoners of war. They noticed a symmetric vision loss in some of the POWs several months after capture, especially in those who were malnourished and forced to exercise. They had associated peripheral neuropathy, bilateral nerve deafness, painful superficial keratopathy, and smoking was very common at the time, and tobacco use was implicated in some cases. Early dietary supplement, they found that early dietary supplementation, especially with B-complex vitamins led to a good visual recovery. One thing I'd like to point out at this point is the constellation of other neurologic symptoms points to perhaps other underlying nutritional deficiencies, particularly dry berry berry from thiamine deficiency and the like. And then finally, probably the best studied occurred in 1992 to 1993 in Cuba again, where greater than 50,000 individuals were found to have a bilateral optic neuropathy. This is when they had a acute downswing in the economy. There were famine and malnourishment was rampant at the time. They had other neurologic symptoms, as we saw, in Southeast Asia, including peripheral neuropathies, myelopathy, spastic peresis, deafness, all these in various combinations. They did a lot of epidemiologic studies on these patients, and they found wide-age range, age range, male predominance, and they looked further into the use of tobacco and by what means the people did consume tobacco, and they found that vision loss was particularly associated with cigar smoking and also pipe smoking, as opposed to cigarette smoking. They also found that it was associated with weight loss and also increased cassava intake. So cassava is almost pure carbs. It doesn't have a whole lot of protein, but also it contains naturally occurring cyanogenic glycosides, glucosides, which poisoning has been well-described with a lot of cassava. And we'll talk more about the proposed pathogenesis of tobacco, alcohol, and gliopia in a moment and talk about why cyanide might be important. And they noticed a partial to complete recovery in these patients in Cuba with parenteral and oral viadmins. So to speak about nutritional opting neuropathy, you know, many have proposed this change in nomenclature. You know, even though we're still used to hearing tobacco, alcohol, and gliopia, just to underlie, you know, obviously we see a lot of patients who drink and who smoke, who never get any vision loss. And so many have proposed that this underlying nutritional deficiency plays a large part. And so they have proposed putting that into the name. Typically affects heavy drinkers and smokers who are also deficient in protein and B vitamins. Males are more affected than females. And again, as I already pointed out, it appears more common, particularly with a cigar smoking or a pipe smoking. The pathogenesis at this point, you know, remains fairly poorly understood as far as things go. But it's likely multifactorial with underlying genetic susceptibility overlapping with toxic environmental influences. This has been particularly difficult to parse out, you know, one because of the ethical difficulty in putting together randomized control trials. But also with trying to parse out people who do tend to smoke and drink at the same time so you can't really take the two apart. It has been proposed that smoking in genetically susceptible patients might affect sulfur metabolism, which is very important in the detoxification of cyanide, leading to a chronic cyanide intoxication and deficiency of vitamin B12. You know, and this may be collaborated by that observation that they had in Cuba with increased cassava intake. However, in most of these patients, including our patient, a specific vitamin deficiency is rarely found. At times it can be barely below the normal limits, you know, and certainly not a profound deficiency of a vitamin. And so many have proposed that there's a relative deficiency of a vitamin. And in particular, there may be a relative deficiency of multiple B-complex vitamins working in concert. And so they recommend, you know, treating all of those vitamin deficiencies empirically. Given the similarities, as we pointed out in the differential of the presentation to labor-serratatory optic neuropathy, many have proposed whether there's an impaired oxidative phosphorylation and mitochondrial energy production, which would be that predisposing genetic factor to these patients who smoke and drink in developing optic neuropathy. Now interestingly, this was studied during that Cuban outbreak. They actually looked at mitochondrial DNA haplotypes and they were not able to find any association, to my knowledge, that's the largest study in this regard. And certainly it's open for more study, but to date this has not been found to be true. One of the interesting things, you know, this was very, very common, you know, even 100, 200 years ago, at least it was a commonly evoked diagnosis. And it's been decreasing in incidence over the years. And so number of authors have commented on this as to why this could be, because we have in general better nutrition nowadays than they did 200 years ago. Could it be due to a change in tobacco consumption, whereas more people are smoking cigarettes as opposed to cigars or shag tobacco and in pipes, versus an initial midst diagnosis 200 years ago, labors didn't exist, you know. A lot of multiple sclerosis didn't exist. All these causes of optic neuropathy or decreased central vision loss were not understood entities. And so if a patient shows up with decreased central vision loss, you know, they're smoking a pipe, then in drinking, then maybe you just call them a tobacco-acoholyan bleopia. This is just an interesting graphic that I found, just talking, just kind of illustrating of the change in tobacco consumption. So the solid line is the increasing use of cigarettes and then the dashed line representing the other forms of consumption of tobacco. So briefly, you know, part of why I wanted to talk about this was I felt that the historical background was very interesting, and too I wanted to refresh our collective memories about this disease because it is so rare. So to summarize, the presentation is much like our patient. An insidious onset of bilateral symmetric visual impairment with associated decreased color vision, particularly red and green color vision. And the signs are often subtle as they were in our patient. On presentation, we weren't able to see anything on bimicroscopy, but there may be subtle temporal pallor, splinter disc hemorrhages, mild disc edema. This has been described in literature most recently as people are using OCT on these patients. They'll find that maybe there's some thinning temporally but then the rest of the optic nerve head remains mildly swollen, you know, which they have proposed this due to underlying metabolic injury. As we saw, they can have a number of visual field effects, but the most classic being a bilateral symmetric seco-central scutoma. In our patients, this may be easier to plot using a red target than a white target. And then treatment predominantly is based on nutrition and lifestyle modification. So we treated our patient orally, but some have proposed using weekly B12 injections for 10 weeks, a multi-vitamin, including B-complex vitamins like thiamine and folate, well-balanced diet, and then absolutely abstaining from tobacco and alcohol. Understanding that this may be one of the most difficult parts for our patients in the treatment of this disease. It's become clear in the literature that abstinence from smoking is more important than abstinence from alcohol for visual recovery, perhaps coming back to some of the proposed pathogenetic mechanisms that we already discussed. And then it's important, you know, if you do find a vitamin deficiency to rule out other causes, you know, for that vitamin deficiency in particular, if you find a deficiency in vitamin B12, you need to look for pernicious anemia, and sometimes we may need the help of our colleagues in that. As we saw with our patient, the prognosis is good. So for patients who are seen early, you know, provided they can comply with treatment, although that visual recovery may be slowly you'll recall that in our patient, we didn't appreciate increase in the snow and visual acuity until 18 months, you know, after the initial insult. And Dr. Olson makes a very good point, you know, that even though we feel good and pat ourselves in the back about the visual recovery in our patient, they may be left with quite a bit of functional impairment due to the color vision loss and decreased contrast sensitivity. Unfortunately, you know, if these patients come to us in advanced state, there may be, you know, permanent vision loss due to artery from the optic nerve. And so they have a more guarded prognosis. So in summary, we should think about nutritional optic neuropathy in our patients who present with gradual painless progress and a vision loss, particularly in those who have secro-central field defects, which indicates a dropout of the imbed-about-cli-active petrolynecular bundle, temporal pallor of the optic nerve. And in the work of these patients, make sure you check for vitamin deficiencies, in particular B12 and folate, rule out pernicious anemia, rule out compressive lesions with a CT or an MRI. And then always think about labors, you know, particularly if there's a family history which our patient wasn't able to give since she's adopted, but if there's any form of family history, if they present a little bit earlier in life, you may think about dominant optic atrophy, particularly with a family history. And then again, think about labors if you do see particular signs on physical examination, particularly telangiectasis about the optic nerve. Time flies when you're having fun. So last year I gave a grand rounds the day before my son was born. And so this is the picture that you got to see at that time. And so now he's 14 months old. He loves new news, as you can see here. And he also likes to play doctor from time to time, but no pressure, no pressure. Thank you very much. Yeah. That's a very good question, Bryce. And one that I don't know the answer to, you know, in my reading for this presentation, I did not come across, you know, what was a safe amount of smoking? You know, I think that perhaps other people in the room know, but, you know, particularly, I think we should counsel complete abstinence for smoking, particularly if you do feel that it is related to their very own smoking. Yes. So the epidemiologists were looking at that very carefully on the proof of their answer. Yes, Dr. Harry. That's a great question. That's great. You know, and we're fortunate to have excellent, you know, resources here at the university for helping our patients to quit smoking, you know, but it's important for all of us, you know, particularly if we're going to be practicing elsewhere to find those resources, to be able to provide the patients when they come to us. Dr. Warner. Yes. Acute and onset. You're right. Oh, okay. I think it was Prisoners of War in Southeast Asia. Yeah, that's right. That's right. You're exactly right. It was a terrible economic time. Okay, thank you. Thank you.