 Okay, so I think we'll get started with Dr. Swan here. So this is a momentous occasion. It's his last Grand Rounds forever before he leaves us to go work for the Restasis Lake in South Dakota. And this is also his Neuro Grand Rounds, which unfortunately Dr. Warner's not here, but everybody here is gonna vouch for him. This is his last Neuroophthalmology Grand Rounds. So he's gonna talk about dominant optic atrophy. Perfect, thank you, Reese. So just a quick case that I thought was interesting that I saw with Dr. Katz, and then a brief review on dominant optic atrophy. I think it's just good to remember that not all pale optic nerves are compressive lesions and not all sort of field defects are glaucoma, and so this just provides a nice reminder of that. So this was a case of a 14-year-old girl who was referred for evaluation of bilateral optic nerve pallor. She self-reported that she had had poor vision since about kindergarten when she was actually, it was picked up on screening that she had poor vision. She was evaluated at that time, given some glasses, which she thought improved her vision slightly at that point. But at this point in school, she was having difficulty with reading and still also some distance stuff on the whiteboard, and so had represented to her outside optometrist who then referred her in to see Dr. Katz for further evaluation, because she'd never really been given a diagnosis as to why her vision might be more poor. She didn't report any eye pain or history of eye pain or pain with eye movements. She had no color vision changes that she reported. She had no history of diplopia, no headaches, or any other visual symptoms, besides just generally feeling like her vision wasn't sharp enough to allow her to do things that many of her classmates were able to do. On further history, so her past ocular history, just a subnormal vision that was first noted at kindergarten, but really had become more symptomatic over the last year or two to her. Her past medical history, she did suffer from gastric reflex for about five years, which she was treated for, but then had since had her symptoms resolved and was no longer on medications. She lived at home with her parents. She denied any history of use of alcohol, drugs, smoking, she was not sexually active, and she had no family history of any ocular conditions and no autoimmune or neurologic conditions. She was not on any medications currently and she had no medical allergies. So on her exam, her vision was 2060 in both eyes, and that was with correction. We could not get her to correct any better in clinic. Her pupils were equal around reactive colitis and accommodation. Her extracurricular movements were full and confrontational fields were full to counter, to counting fingers. Her Isha Harplace, she got 11 out of 12, and then this 15 hue color test, which we'll talk, explain a little bit more why we did this in her case, but she has a pretty regular pattern. So basically there's 15 little dots of that are different colors. And you should, in a person who doesn't have any color deficiencies, they'll kind of line them up one, two, three, four, five, six, seven in order of as the hues change. And what you'll see is if a patient has certain color deficiencies, and in particular we were interested in whether she had a tritand deficiency, you'll see that they'll kind of jump from along this axis. So they may jump from seven to 15 and back to eight and then 14 and nine and 13, which indicates that there's some confusion along that color axis. And she didn't have any of that on our testing in clinic. Her ocular exam was unremarkable in terms of her anterior chamber. She had no evidence of inflammation or previous inflammation. Her lenses were clear. And her most notable exam finding was that she had bilateral optic nerve pallor that was most prominent temporarily with a cup to disc ratio of about 0.5 and that pallor was definitely more prominent than the cup to disc ratio. There wasn't significant cupping. And then her macular vessels and periphery were normal. This was her visual field. I'll show a representative picture. We don't have optic nerve pictures of her. This was her visual field that she took. And so what's most notable 24-2 is reliable on both the right eye and the left eye. And you just see that there's definitely, her foveal threshold is definitely less than what you would expect, particularly for a young 14 year old. So it's 29 or 28 here and 31 in the left eye. And it's just a generalized depression here. Maybe you could say that there's some sort of central or secocentral pattern to it, but it's hard to say that that's, it's not true central or secocentral scatoma as we look at it. This was her RNFL. And so again, what's most prominent, this you can appreciate kind of where the nerve is most affected in the picture. But then you can see there's just very prominent temporal thinning and as well some inferior thinning as well, which is quite prominent. So at this point, thinking about the differential, I put dominant optic atrophy on here, which is what we believe that she ends up having. But a lot of these other things are important to rule out and consider. And so normal tension glaucoma, I'll just kind of walk through some of these. Normal tension glaucoma, you obviously, you wouldn't expect at her age for starters, so that's less likely. And she doesn't have a classic sort of visual field pattern for normal tension glaucoma, so that's a little bit less likely as well. She also doesn't have known risk factors in terms of migraine, sleep apnea or other stuff. Libra's heretic optic neuropathy, again, this oftentimes will have a family history. It's more common in males and females, which makes it more likely. It also usually presents later and it's a more acute visual change. So again, the classically kind of 20s to 30 year old, relatively acute visual change that may decrease even to 2200 or worse count fingers vision and then followed by a sequential damage to the other eye. Compressive optic neuropathy, we wouldn't expect it to be such a bilateral process usually, but always want to rule that out with imaging. She didn't have any risk factors for infiltrative or inflammatory disease. We inquired about whether she had any abnormal diet patterns or anything. She didn't have anything to suggest nutritional optic neuropathy and no exposure history that made us concerned for a toxic neuropathy. Optic nerve hypoplasia, which can be associated with septodysplasia as well on MRI. So again, another reason to get scans, but again, usually that's more of a hypoplastic nerve and this seemed to be more of a regular sized nerve just with temporal thinning and pallor. And then previous demyelinating disease certainly could do that as well, but again, she didn't have any reported history that was suggestive of that. So our work up for this patient, we did a CBC, vitamin B12, B1 folic acid to rule out potentially any nutritional optic neuropathy which all of hers were normal. Got an MRI brain with and without contrast with certainly with any patient with an optic neuropathy that's unexplained. I think that's really pretty much necessary to rule out. One could maybe even argue, certainly in an adult that is probably potentially worth getting an orbital MRI as well to rule out a small meningioma or some other compressive lesion that might be difficult to pick up on the brain MRI. And then Dr. Katz did discuss with her getting genetic testing for this OPPA1 mutation which is associated with dominant optic atrophy. She had no family history and because of social economic issues, they elected not to proceed with that but felt pretty comfortable that that's probably what she had. So a little bit more about dominant optic atrophy. So this was first described in 1897 but really classically described in 1959 with a description of 19 families that were in the Netherlands or Denmark, Netherlands. And that was sort of really the first classic association that showed that it was a dominantly associated disease and that had this sort of classic bilateral temporal and paler. It's usually an insidious vision loss similar to our patient that starts in the first decade. The prevalence in Denmark is about one in 10,000 because of a founder effect but globally, most people will say about one in 30,000 to one in 50,000. And the penetrance is quite variable and so a lot of people feel it's dependent on the genetic mutation. Generally looking at the various review articles that I looked at, the sort of consensus was around maybe a 70% penetrance but you would get rates from 43 to 100% based on the genetic alteration or the genetics of it. In terms of testing, like I said, so this 15 hue color test, this is sort of the classic tritinopia blue, yellow axis difficulties. So instead of kind of coming around in a circle, you get this on axis which our patient didn't have and not all patients do. The optic nerve paler, usually about 50% of patients, it's a predominantly temporal paler, about 50%, it's a global paler. And then the hunt for visual field, the most common is a secocentral followed by a central or paracentral scatoma and it's very unusual to get sort of peripheral veal defects. The peripheral vision is usually preserved in these patients typically. The RNFL will obviously just show a reduction in peripapillary thickness that correlates with where the paler is. You can do a VEP which shows a prolonged latency but a lot of these other things are supportive enough that not everyone does that and that's not always available at all centers. And then the genetics, classically the first one that was described was an OPA1 gene and then OPA3 has also been associated with it. There's been over 200 mutations that have been described and associated at this point with dominant optic atrophy. So there's a lot of different mutations on these genes that can cause a similar clinical picture and is probably why the variability patients in terms of whether they progress and at what age they present is slightly variable. Also worth noting if you have a patient that you're suspicious that they might have dominant optic atrophy it's definitely worth inquiring about other sort of systemic syndromic features. About 20% of dominant optic atrophy patients will have systemic features and they're associated with the genetics of it because it's a mitochondrial disease in terms of the gene that's actually affected. A lot of them will have some of these symptoms that we often of which we classically associate with mitochondrial disease. So it's worth inquiring about these. The deafness one dominant optic atrophy with deafness is the most common systemic syndrome and these patients can benefit actually quite well from cochlear implants. So it's worth inquiring about their hearing which our patient had no issues with. For treatment there's not really great treatment options at this time certainly maximizing the vision that they have so getting them connected with low vision is probably a worthwhile endeavor particularly moving forward in case they continue to progress. Genetic counseling and possible testing to inform them if anyone else in the family might be at risk and what their risk for if they decide to have children would be as well. Sort of anecdotally avoiding tobacco and alcohol because this is a mitochondrial disease there's thought that you can reduce oxidative stress by maybe avoiding these. And then there's been one case series on the use of synthetic coenzyme Q10. It was a seven patients and five of the seven patients at one year they showed slight improvement in their vision but there hasn't ever been a randomized control trial on this. And so it's not widely accepted as a required therapy but it may be worth considering in patients because it certainly seems like it may be beneficial. In terms of the prognosis so usually the rates kind of vary depending on the study that you look on how many advanced to legal blindness. The most recent review paper that I looked at kind of gave this breakdown which is about 30% will be about 20 to 60 or better. About 50% will be kind of in the range of 2060 to 2200 and then about 20% will be worse in 2200 with long term follow up. And their visual decline is usually slow. So again a lot of these are gonna end up better than what you would see with like a Lieber's hereditary optic neuropathy. So the vision loss is not as severe and as quickly or profound as it is in Lieber's. And then like I said certain ones may have a faster rate. The thought is that it's probably based on what genetic mutation of the 200 that it is but that's not well described just based on the frequency of things right now. These are-