Brittni A. Scruggs, M.D., Ph.D., an ophthalmic surgeon at Mayo Clinic in Rochester, Minnesota, reviews routes of administration and discusses outcomes and adverse events related to ocular gene therapy.
Sounds great. Well, I'm Brittany Scruggs, one of the retina specialists at Mayo Clinic in Rochester, Minnesota. And today we'll be talking about viral gene therapy for inherited retinal diseases. All right, so the learning objectives for today. Number one, we're gonna review routes of administration and outcomes and adverse events related to ocular gene therapy. We'll talk a little bit about current clinical trials and use of gene therapy in the United States in 2025, including Lukturna, which is no longer a trial but is currently being used as an FDA approved medicine, and we'll discuss some barriers to clinical use to gene therapy for ophthalmology. Here are disclosures for the planning committee and for myself. Um, most of these listed under me are for research grants. Um, either I'm a PI or sub I. Um, for several of these companies for clinical trials. Multiple choice question, what is the prevalence of serious adverse events, SAEs associated with subretinal viral gene therapy? Is it about 1%, about 10th of patients, a little under half, or about 2/3? All right, so we're gonna start with a case. This is a 10 year old patient of mine who has profound night blindness, um, poor vision, and, uh, this is the fundus photo, and it shows pretty significant, uh, outer retinal atrophy, mostly in the periphery, but extending into the perifoveal region. And despite the optic nerve looking pretty healthy and the posterior pole looking pretty unremarkable, this patient is 2100 in both eyes. And she states that the vision is very poor and she has a hard time navigating. She uses a white cane, um, and is having a hard time in school. She says, when I look at a house at night, all I can see is the silhouette and sometimes the lighting coming from inside, but I'm unable to discern her words, for example, the color of the exterior. This is her OCT and I'm only showing the right eye, but this is a very symmetric exam, so the left looks very similar. So her foveal contour looks pretty good. Uh, inner retina looks fine, but the outer retina. Uh, the ISOS junction, the inner segment, outer segment, which is where the ellipsoid zone is, uh, looks pretty disrupted, um, throughout the center, and then you can see it's lost completely here with almost near loss of the outer nuclear layer. So the photoreceptors, um, are starting to succumb to the disease in the perifoveal region, um, but no intraretinal fluid. This is the Goldman visual fields of my patient. Again, a 10 year old, um, and pretty significant constriction. The 54E isopter is constricted to the central 40 degrees, um, and the 34E is, uh, centrally to 5 to 10 degrees. So she has profound ring scotoma. And when I asked about her vision centrally, since it's 2100, she said, you know, it's really frustrating to see. It looks like there is Vaseline smeared on my camera is how she worded it. I'm not able to participate in bonfires with my friends. It's really important to her and in her community. They do that often. She said, I can't play over at my friends' houses without someone having to assist me, and um when she goes home, she pretty much gets in bed and stays in bed. So, as a 10 year old, she's not living life to the fullest. Her mother said, I really knew she could not see from birth when she didn't look at me when breastfeeding. However, she's seen multiple eye doctors over the last 10 years and they do not have a diagnosis to date. So, At this point, the family is asking, is this inherited? Is it progressive? How do we optimize the vision? Is there a cure? And I would say these are the four more important questions and common questions in my clinic when we're dealing with a presumed inherited retinal disease. So first step is, you know, discuss genetic testing, explain what we're seeing, and offer the ability to explore this further. There are many targeted gene panels now for inherited retinal diseases, and this changes every year. So it's really nice to have genetic counselors and geneticists to partner with. Because they spend a lot of time, 30 to 45 minutes per patient, before we even get the genetic testing to discuss what the options are, the pros, the cons, the cost, um, and so I have listed here some of the targeted panels. This is not an exhaustive list by any means, but the My Retina Tracker is really an interesting program, so I wanted to discuss that. So the My Retina Tracker program is a Sponsored test that has 110 genes on its panel. It's a, a test that is really a partner with the Foundation providing Blindness, Spark Therapeutics, Johnson and Johnson. It allows, you know, genetic testing of these 110 genes. They provide genetic counselor if you need it. They, if the patient would like to sign up, they sign the patient up for an IRD registry, no cost to the patient. So in the future, if there's a clinical trial relevant to that patient, they would call the patient. Um, they also allow targeted familial variant testing for patients, um, in the, for the patients' families who are potentially at risk or potentially to go further and determine if the variants are in trans, so they would test the parents. So, this is a great program that we use often at Mayo Clinic. So while we're getting the genetic testing for this patient, we're also thinking about, oh well, how do we optimize the vision. And so in the meantime, we're getting refraction, glasses, contacts, magnifiers, referring this patient to state services, you know, potentially talking about guide dogs or mobility training, wearable devices, and then for a lot of my teenage patients, we're talking about whether or not it makes sense to drive or or if this patient really is not eligible and then getting them into support groups. Uh, we make sure that they, you know, see the low vision store if they want to get set up with the state services for the blind and get all of the resources they need for school. It's really important. And then there's just a plug for talking about guide dogs. Um, this is a recent podcast through Mayo Clinic, um, where we discussed this book, Have Dog Will Travel. It's a quick book. You can read it on a, on a quick flight. Um, I liked it very much and I learned a lot, um, about the process. All right, so back to our patients. Uh, this patient, the genetic testing came back after about 4 to 5 weeks, came back with two pathogenic variants in the gene RP 65. So this is consistent with um LCA. There are about 10 to 2000 cases in the United States um of LCA related to RP 65. Luxturna, which is Vetta gene Naparvavac, is one of the first FDDA approved gene therapies, not only for ophthalmology but for any genetic disease. So this is really exciting for this patient because not only do we now have a diagnosis, but potentially a treatment. And early treatment is ideal, given the progressive nature of the disease, and as we saw in the OCT there's still significant outer retina that could be treated. So this is the patient's microprimery. This is a 10 year old, and there are really only a few spots of retina real estate, real estate that is sensitive to light, um, and you can see how profound her ring scotoma is. And so at this point, we're talking to the family about AAV adeno-associated virus, and gene therapy in general. And so AAV is the leading candidate for gene therapy applications, um, long-term success for transgen expression, non-pathogenic, and it's a recombinant, uh, AAV that specifically lacks viral particles, but it contains the DNA of interest. So in this patient, we would be offering RP 65, which is not functional, uh, in her cells. So, to do this, uh, this procedure or any gene therapy, um, Uh, that is including a subretinal injection. We do a very small cannula, needle cannula, where we penetrate through the retina and inject the viral supnatin underneath the retina. So you can see an intraoperative photo here where this is a subretinal bleb, and then this is an OCT intraoperatively showing the solution under the retina. So Luxerna, again, being the first FDA approved gene therapy in all of medicine, is approved for for RP 65 specifically. It's administered under the retina. We do start, start a perioperative steroid regimen of about 21 days, and so far over the last 10 years, it's been very promising in terms of the long-term data. There's never been a person that's needed retreatment. And so now Mayo is a Luxurna center as of 2024, um, and the criteria for providing, uh, this type of gene therapy to patients is that they have to be genetically confirmed, two variants in trans, um, on the RP 65 gene. They have to be at least 12 months or older, and they have to have adequate outer retinal cells to treat, and this is to the discretion of the physician. So, in our patient, we decided to move forward with Luxurna, and this is the first case of Luxurna in Minnesota. And I just wanted to start by thinking, you know, the huge team that really got us to this point of being a Luxerna Clinical Center for Excellence, allowing myself and Doctor Starr to travel to Houston to get trained. Um, and, you know, the finance team, the formulary team, these are $450,000 surgeries per eye, so almost a million dollars total. So it takes a big effort to get there. And this is immediately after the first surgery. I did this with our, our prior fellow, um, Doctor Andrade. And so this is some pre-op and post-op imaging. So we've already seen this microprimetry of our patients, so very limited. Um, real estate right in the center, pretty decreased retinal sensitivity, and then six months after Luxurna really has amazing change. This patient is really a super responder, where the entire macula now has retinal sensitivity. The vision went from 2100 to about 2050. Um, we also did Goldbond visual fields before and so in the periphery, each eye had about 20 degrees, um, laterally on the horizontal. And after surgery, it kind of extended all the way out to 70 to 80 degrees. So the world really opened up, the clarity improved, the sensitivity improved, and on an electrical level, um, ERG, this is a multifocal electroretinography, um, pre-op versus post-op, there's definitely improvement of that central peak and, um, just the electrical signal of the, of the cells, um, has improved. So, we are now one year status post Luxurna for this, for this child. Um, she did invite my family up to where she lives so she could present to the Lions Club in her town, and it was really quite an emotional experience because she said things like, I can complete many new tasks by myself. I'm no longer dependent on my cane thanks to Mayo Clinic. My vision continues to improve, and she said that she's very excited for all other people who get the chance to try Lucerna in Minnesota. Um. The second, and then she wanted everyone to know that she can go to bonfires now, which is, you know, was one of her main goals, and so it's exciting for, you know, a preteen. The second case we just completed this summer, and I don't have a lot of testing because this child is 2, but I did ask the mom recently if I could share some things, um, with y'all about some improvements. And even though we're only a few months out, she said things like this. Um, this, this little girl now can run. She ran for the first time and down a Dark hallway, the dad added, she has confidence. She can play on her own at the playground. She makes eye contact during meals. She can go on swings. She looks at books and asks a million questions. Her mom added, it is a whole new world for her. So this is all really exciting. Um, however, uh, it's not. All positive. There have definitely been some reports recently that Luxurna is associated with periphoveal chorioretinal atrophy, severe atrophy, and then most recently in the last year, there's been some real-world data um in the perceived study to show that this is pretty significant. Um, and so you can see here, this is a bleb of the viral supnatent under the retina. 4 months later, there's starting to be atrophy. And then this atrophy is definitely progressing and it's getting closer to the phobia, making these large scotoma. And so this is problem number one, and it's been It's been documented several times now. Um, it's up to 25% of patients who have Luxsterna end up having this progressive atrophy. And our team, these are three studies coming from our team showing that patient age affects the pressure of the bleb, so it really requires a lot of pressure when the patient is younger. And I found that even between the two patients I treated, the younger 2-year-old, really, it was harder. To propagate the blood, and we know that this increased pressure leads to retinal damage. That's been studied by our team and we've shown that to be the case in animals. And then we've also recently, Dr. Ayezi, Dr. Marmstein, and myself found that Corio capullaris is lost. Um, when we debride the RPE. So, really, we're getting to the pathophysiology of this problem, and this is not what I'm gonna be talking about today. I wanna talk about this problem. So there's been no gene therapy approved by the FDA since Luxerna, and that's December 2020 2017. And so, why is that? We know that gene therapy can be administered under the retina or as an intravitrial injection. But Luxturna is literally the only one and as I told you, there, there are only 1000 cases in the United States, so it's not many patients can be treated with this. So there are some active gene therapy trials and I like to, you know, go through clinicalTrials.gov before I see most of my patients because this is an ongoing process where every day it's different. Um, we wanna know about the trials and Um, what the gene therapies are, so I like to inform my patients, but you can see this is a shortlist. There aren't many gene therapies that are currently being, um, tried, and RPGR, the ex-link RP is being, um, it, we're enrolling patients right now at Mayo Clinic. Um, but there are many, many more that have been closed, uh, because they've either not been effective or they've not been safe, and this list is not exhaustive for sure. Um, you can see even for chromatopsia, many companies, many drugs, many phases, um, have tried and none have been FDA approved. So, our team recently wanted to study this. So we studied gene therapy and did a systematic review and this was published just on Friday, so hot off the press. What we did was we, we did a systematic review of all subretinal injections and clinical trials, all the intravitrial clinical trials, and then all post-approval Luxerna. Cases, um, these are the amount of eyes that we reviewed for humans, and then this is the amount of eyes we reviewed for animals. And for the 20 clinical trials that involve subretinal injections, we really broke it down into what were the side effects. We found that about 11.6%, so that's, that's the answer to the question earlier, so 11.6% of patients who had subretinal injections ended up having a serious adverse event. And then we broke it down further into who got vision loss. You can see there's a significant percentage of patients who have vision loss in the setting of these adverse events. We then looked at intravitreal injections and out of the 11 clinical trials, we could look at and identify the eyes and side effects, we found that um 11 had a serious adverse events. Most of them were severe inflammation. You can see there was some vision loss as well. Um, we did find that the inflammation was dose dependent. So for macular degeneration, LHO LHON, um, and ex-length retinoschisis, you can see that there's a dose-dependent amount of inflammation in these trials to the point where some of these trials were stopped because of their inflammation. So out of all of the studies we looked at, only one of the intravitreal studies had a secondary efficacy endpoint met. Now out of the subretinal studies, 5 met their secondary efficacy endpoint. So in general, um, we are having safety concerns and also efficacy concerns. So, we looked at Luxurna cases post-approval as well and we found that retinal degeneration is definitely the highest for serious adverse events. You can see that, you know, most of the patients, uh, 25% of patients who had serious adverse events, most of them had retinal degeneration and some had vision loss. We looked at all of the patients that had bilateral externa and we looked at the patients who had uh chorioretinal atrophy, and we found that if you're going to have chorioretinal atrophy, you're going to have it in both eyes. You can see bilateral is the vast majority of these patients who have this complication. And so despite the advantages of AAV, and I hope from my two cases you, you see that it's really exciting. Like this is one of the biggest advances in medicine to date. So despite the advances in this gene therapy, there's still some major limitations. One, limited coverage. So when you do a subretinal bleb, you're really only detaching part of the retina, maybe only 20% of the entire retina, so you're not transducing the entire real estate that you could. Um, you have this dose limiting inflammation, especially with intravitreal injection. You have these post-operative complications like atrophy, and then we're having inconsistent efficacy. And so, uh, I have one slide about our, our lab, and then we'll conclude. So our retinal regeneration medicine, regenerative medicine laboratory is really focusing on a, a way to do this differently. Instead of a subretinal injection, we're making a fibrin implant that has the gene therapy within it. We can stick it on as a sticky patch onto the retina. And you can see treated versus untreated pigs. The treated pigs have um pretty exciting uh transduction across uh the RPE there. And so, uh, we're also getting transduction all the way out to the far periphery of the aura. And, um, so I wanted to share some exciting next steps as a conclusion. So first, we have some gene therapy trials that are already, um, enrolling at Mayo. One is the VISTA trial for X-linked RP. Doctor Ayezi is the surgeon for that. And I'm one of the sub eyes. Uh, and then we have a few trials coming up that Dr. Ayazi and I will be a part of, um, the radiant trial for advanced RP, Stargaze for advanced Stargart, the Celeste trial for Stargart, which is a gene therapy, um, specifically for ABCA 4. We had dual vector that provides the, the protein, um, in two different AAV vector systems. Uh, recently, our team submitted two very large grants, an RO1 and a blueprint grant, um, to really study this, to study the immune responses to gene therapy, and also to study ex-link RP using this fibrin implant. Um, and then we are on September 5th being published in the Science Family of Journals. Science Advances is an open access journal, um, and so some of the, the work presented today will be in, um, in press, in prints. So I hope that you can, you can read through that. Um, so in conclusions, Lucerna is an FDA approved gene therapy that can be given by subretinal bleb. I presented two cases today, um, really some of the most exciting cases I've seen to date, um, in medicine. Um, atrophy, unfortunately, is occurring and it, it can occur perifovially. We know that there are serious adverse events and we studied that and up to 11.6% of all patients with subretinal injections, um, have pretty bad, uh, side effects and then intravitreal injections is lower, but it's mostly related to inflammation and inflammation seems to be dose dependent, um, whereas the subretinal injections leads to retinal degeneration. And then finally, out of all of the Luxurna studies that we looked at, about 25% of them have retinal degeneration. And so we have a large team, um, that, you know, sees these patients, sees patients who um are getting genetic testing, and then behind the scenes that are doing some really awesome work. And I want to thank the Department of Ophthalmology and also the um Dr. Waller and the careervelopment Board that uh has been, you know, funding some of these projects. I'm very thankful. So. Last plug, we have IRD clinic and rounds. Um, the first Tuesday of every month, it's hybrid, so if you wanna jump on and talk about cold cases, ask questions, develop projects, um, we're the leaders of the rounds and we'd be excited to have you there. Here's some references. Multiple choice, uh, question for subretinal viral gene therapy, 11.6%. However, that number is about a quarter, about 25% of patients if you look at just Luxurna, um, cases. So, any questions? Britney, this is Wendy. Do you hear me? Yeah. Um, amazing, uh, presentation. Thank you. Um, the, the parafoveal, uh, RPE loss, um, Is that progressing to central vision loss? Do they know? Do they know? Yeah, in, in some patients it is. Um, so out of, out of our patients that we looked at, you know, the 428 eyes that had received Luxerna, about 25% of them had this and about 10% of those patients had scotoma. Is that we're encroaching on fixation. However, most of these patients are very young and so about 11, like preteens is when it's, um, are, are the, you know, the mean age of these patients and so they have their whole lives potentially for these to progress. So I think time will tell, but unfortunately, it does seem to be significant. Mhm. Yeah. If there are no other questions, I'll turn it over to Doctor Barr. Well, good morning everybody. Um, thanks, Doctor Sharks for that awesome presentation. Uh, we'll be talking today about a topic here. The title of this presentation is when it comes to the point, Zoster orbital apex syndrome. And our learning objectives. All right, so starting with our test question, what is the most common treatment for herpes zoster orbital apex syndrome reported in the literature? A, oral valeycyclovir and oral steroids, B, IV acyclovir and systemic steroids, C, oral valleycyclovir, or D, IV steroids only. So our first case here, we have a 74 year old male. Um, this gentleman had a history of baseline 2200 vision in his right eye due to macular degeneration. He presented to clinic with a 9-day history of a vesicular rash and new onset diplopia. Uh, 5 days prior, he had been seen in clinic, where corneal conge and anterior chamber involvement were noted, uh, but no posterior segment or retinal involvement, and no ptosis or motility deficits at that time. At the current visit, he had significant ptosis of the right eye. Uh, as well as esotropia and limitations in AB duction, A deduction, and introduction of the right eye. And then there was also a marked midriasis of the right eye. Um, in this little video here, uh, he actually had not been given any dilating drops prior. Uh, visual acuity was too poor to test color plates, but remained more or less at his baseline. Intraocular pressure was normal, and given minimal pupillary response of the left and non-reactive people on the right, it was difficult to assess for an APD, but otherwise, anterior segment exam was unchanged from his prior visit. So based on the strabismus exam shown here, there was concern for cranial 3 and 6 involvement. And given his prior ocular history, it was difficult to rule out cranial nerve two involvement. And so our differential at that time included inflammation or thrombosis of the cavernous sinus, or an orbital apex syndrome. So we sent him for urgent MRI brain and orbits, with and without contrast, and MRV. And so here are the results from his MRI and the impression from radiology, uh, which you can plainly see here on the right side, there's asymmetric enhancement of the right nerve sheath, um, and the orbital apex region compatible with optic perineuritis and orbital apex syndrome. And he had an unremarkable MRV. So the diagnosis in this case was orbital apex syndrome from herpes zoster, and after discussing with the neuro-ophthalmology staff, uh, we recommended continuing his high-dose antiviral therapy. He was already on TID valacyclovir. We did have a discussion with the patient of the risks and benefits of steroids. Um, given the literature, which we'll be reviewing later, uh, steroids do, uh, have an uncertain benefit, but there are known risks, so he already had poor vision at baseline. And given that inconclusive evidence in the literature suggests benefit. Um, he did choose to defer steroids and continue therapeutic Valtrex with close follow-up. He was doing a lot better about one month after presentation, after continuing on TID Valtrex, motility was stable. There was some improvement in the vertical deviation, in fact. Uh, the rash and anterior segment involvement resolved, and his retro bulbar pain resolved. And then about 6 weeks after that, he presented to the emergency department uh due to a fall he had at home, which was determined to be from orthostatic hypotension. Uh, the thought was this was from diarrhea from the Valtrex, and so he asked about stopping the Valtrex, uh, but instead we decreased it to 1 g daily. Um, Since he was doing well and it had been several months. Uh, at that time, he did come back, and there was worsening of, uh, His horizontal uh contracture. And also worsening of vertical deviation, which was not consistent with the normal course, and so we were concerned for recurrence. He also had a recurrence of deep orbital pain. And so at that time, we increased him back to Valtrex 1 g TID after which he had improvement in symptoms within a few days. And at 5 months since presentation, we followed him up, and there was improvement in motility, midriasis, ptosis. His vision was back to baseline, and he was no longer in any pain. Now our second case. Uh, this is a very sweet 92-year-old, uh, female. Unfortunately, she was a pretty poor historian, just given her age and cognitive status, um, she wasn't really able to give much of an HPI, uh, but she was brought into the ED. EMS staff provided the information that she had had a fall at home a few weeks prior, and that was complicated by a large scale hematoma. Uh, but at the present time, the concern was a significant left facial rash in the Vmon dermatome, including the tip of the nose. There was mechanical ptosis from edema, but extraocular movements were intact, and there was no APD by reverse. And pupils were asymmetric, but this was thought to be due to anterior chamber inflammation. There were no signs of orbital apex syndrome at the time of initial presentation. Intraocular pressure was slightly increased on the left. Um, and this seemed to be just from soft tissue swelling. Uh, the retina appeared intact. There was no retinal necrosis and no, uh, posterior inflammation or vitritis. And her visual acuity was down, presumably from the ocular surface, uh, which was very poor on exam and consistent with her 2050 visual acuity. Uh, she was actually admitted to the hospital for 4 more days of intravenous acyclovir. One dose was given in the ED. Uh, given multiple dermatomes involved, she had a large eruption on her back, um, and then she had the involvement of the face. And so we also initiated topical steroid, uh, Predorte QID cyclopenolate, uh, Xergan for the surface, and hourly artificial tears given the extensive surface involvement, and I planned to follow her up in 3 to 5 days. So she was seen in clinic after discharge from the hospital. She felt vision was still a bit blurry on the left, uh, but maybe a bit better than it was previously. Uh, the ocular surface, soft tissue edema, mechanical ptosis, and anterior chamber inflammation had improved, uh, somewhat, and her pinhole acuity was more or less stable. However, at that time, she developed a marked new left esotropia. And abduction deficit. So we sent her for urgent MRI orbits with extended cuts through anterior brain just to look for a 6th nerve palsy, uh, or an etiology of 1/6 nerve palsy. Uh, but MRI was clean, and so it was assumed to be microvascular. Uh, eventually, we were able to stop the Zygan. Uh, we continued her on Predforte, and she was transitioned to 1 g daily Valtrex with a maintenance, uh, for maintenance with a plan for her to follow up with orthoptics in a week. So when we saw her one week later, at that time, she had worsening of her ptosis, uh, even though the soft tissue swelling had improved. Intraocular pressure was still normal. Visual acuity had worsened to 2150, and color plates were noted to be decreased bilaterally but very poor on the left, which was concerning for optic nerve involvement. Uh, the left pupil was non-reactive. Which uh was concerning for ciliary ganglion involvement, and she had an isocoria with the left larger than the right. So given this constellation of cranial neuropathies, there was concern for orbital apex syndrome and optic nerve involvement, and so MRI orbit was obtained. Uh, we also got some ancillary testing. Uh, so she had an OCT, uh, and this was normal on the right, but not useful on the left, uh, just because of all the segmentation artifact, and this was most likely from extensive peripapillary atrophy, and that had been present and unchanged since her initial exam. The visual field on the right was remarkable for scatter only, uh, but left was notable for, uh, nearly global deficits. And then here's that MRI. Um, so, maybe a little more subtle in this case than the previous case, but, um, on the T1 fat set, there's enhancement of the left optic nerve sheath. Um, there was no clinical suspicion for right-sided involvement, even though the radiologists did comment, uh, left greater than right optic perineuritis, but clinically, we had no concern for involvement of the right side. And so again, in this case, given the involvement of multiple cranial nerves, 36, and optic nerve, um, the concern here again was for orbital apex syndrome. Uh, so, we did, uh, continue TID dosing of valacyclovir. And that was actually started prior to obtaining imaging, or restarted rather, she had been on it originally, and then we restarted it. Uh, while we were waiting for imaging. Again, we had a risk-benefit discussion with the family regarding steroids. Um, with her being 93, having diabetes, heart failure, AFib, and poor baseline mentation, um, there was risk for worsening encephalopathy, hyperglycemia, worsening or heart failure. And interestingly, she was really not symptomatic at all. She didn't seem to notice any of the vision changes or any of the motility issues, so, um, really, it seems that there would be more risk of doing harm than good by starting steroids. So after that discussion, the family and the patient chose to continue, uh, Valtrex, um, and, uh, no steroids. And then 4 months from presentation, she felt her vision was still fine. Her visual acuity and motility were almost back to baseline, just a little uh intermittent ET there, um, and the visual acuity had improved significantly. She did have a a recurrence about a year later. Um, after she was on TID Valtrex for about 1 year, uh, we went down to 1 g daily, and about 1 month after that decrease, she did have a recurrence. Uh, there was a recurrence of midriasis. Um, and then on MRI there was, uh, again demonstrated optic perineuritis on the left. So after, after that point, we increased the Valtrex to TID dosing indefinitely for her. Uh, so her outcome at about 14 months, pupils returned to more or less equal, although the left was still, uh, minimal reactive, but, uh, the anisocoria improved. Her motility, uh, was essentially ortho, that's not shown here. Uh, the left optic nerve was relatively stable. Um, the segmentation artifact makes it difficult to compare OCT over time, uh, but visual fields significantly improved, uh, compared with the global deficits we'd seen previously. All right. So, uh, one of the objectives here in this talk is lesion localization and differentiating orbital apex syndrome from other lesions, um, and that involve the cranial nerves, uh, in the skull base. So, orbital apex syndrome can be differentiated primarily by involvement of the optic nerve, cranial nerve too. Um, you can also see ophthalmoplegia, any combination of cranial 36, and also V1 involvement, uh, but this is not specific to orbital apex syndrome. There are other syndromes that can have ophthalmoplegia. Uh, ciliary ganglion involvement is also, uh, something that can happen since that's, um, on the, you know, right on the optic nerve sheaths there. Close to the optic nerve sheath, and then cranial nerve 4 is less commonly involved, uh, but could still be involved in overlapex syndrome. And then there's superior orbital fissure syndrome. So the structures that pass through the superior orbital fissure, notably exclude the optic nerve, that is not one of the structures that passes through the superior orbital fissure. And so you can again get ophthalmoplegia, V1 sensory loss, but the main differentiating factor here is there's no involvement of cranial nerve too. And then there's a cavernous sinus. So often there will be signs of venous congestion, chemosis. You can also get involvement of V2, which is unique to involvement of the cavernous sinus. And then also a Horner's syndrome, due to involvement of the carotid plexus, uh, since the carotid does loop through the cavernous sinus there. So the mechanisms of Zoster orbital apex syndrome, uh, one thought is that VCV reactivation in the trigeminal ganglion can spread along the nasociliary branch of V1 into the orbit. Uh, necrotizing inflammation at the apex from lymphocytic infiltration and granulomatous inflammation can concentrate around the annules of sin and cause compression there. Uh There's also um some reports of a zoster induced vasculitis, uh, with angitis of the small and medium vessels in that intraconal space. And then of course, there's the possibility of extension from orbital or cabinar sinus inflammation, so maybe it can start out as one of these other syndromes and then progress to apex syndrome with involvement of cranial nerve too. In the literature, uh, there are not very many reports of orbital apex syndrome from herpes zoster, uh, but there was a review recently. In 2022, a paper by Chuu et al. they reviewed the prior literature going back to 1968, and this group found 21 total cases in the literature, 18 of which were treated with steroids, uh, 3 were not treated with steroids. And then since 2022, I was able to find 8 more cases published later, and all of those cases were treated with steroids. And uh in general, you know, it's kind of all over the place, how people do, uh, visual acuity, for some stable, for some significantly worse, and for some significantly improved. Uh, but there didn't seem to be a huge pattern comparing the two. Uh, here are the three cases that were not treated with steroids, um, and, and really, you know, there's, there's some that are stable, some that are worse, uh, and in our current report, we actually found improvement, uh, in the visual acuity compared with the time of presentation with the apex syndrome, not necessarily presentation with Zoster ophthalmachus, but once they presented with the apex syndrome, uh, we did find improvement in final visual acuity. And of note, this is with uh with oral Valtrex rather than IV. So just reviewing the overall outcomes in these two cases and the timeline. For case one, baseline vision was about 2200, and that was measured in clinic prior to the onset of the zoster. Uh, orbital apex syndrome. Uh, was noted 10 days after he first presented with herpes zoster ophthalmachus. And envision at that time was 2300, and he had significant ET hypertropiat ptosis, and midriasis of the right. In about 3 months, uh, in despite some initial improvement, there was a recurrence on, uh, 1 g daily, so we increased him back to TID valacyclovir. And then at 5 months, uh, vision had improved back to baseline, EOM deficits were improving, and ptosis and midriasis were improving. And then in case two. Uh, baseline vision was 2050, at least when she first presented to the ED before noting orbital apex syndrome. Uh, two weeks later, the orbital apex syndrome was noted, and visual acuity was 2200, um, and she had esotropia, hypotropia, ptosis, and midriasis. And then by 11 months, uh, she did have one recurrence after stopping the TID dosing of Valtrex, and so we brought her back to TID. And then at 14 months, visual acuity was back to the original baseline of 2050, with resolution completely of her motility deficits, ptosis, and midriasis. So our conclusions, um, herpes zoster ophthalmus orbit lapex syndrome is pretty uncommon. There are less than 30 cases that have been reported in the literature based on this review. The most common practice in the literature for treating this is IV antivirals and systemic steroids. Uh, but in a in a cohort of patients with limited baseline vision or at risk of harm from steroids, we found that antivirals alone were a good option with acceptable outcomes. And in the same patient population, oral administration of Valtrex had acceptable outcomes, and the benefit here was these patients did not require hospital admission for IV therapy. Uh, however, there were recurrences for these patients after de-escalating from TID dosing. And so, for these two patients, we did elect to continue long-term therapeutic dosing of 1 g Valtrex. Um, and something that I found notable in the literature, there was the ZEDS trial, uh, which is the first large scale investigation of prophylactic Valtrex for herpes zoster in general, not just apex syndrome. Um, although findings were not strongly supportive of prophylaxis for herpes zoster recurrence, uh, it was noted by the authors, the authors, um, That there was reduction in patients with multiple recurrences, suggesting there might be a benefit of prophylactic valacyclovir in a subset of patients, um, and so perhaps these kinds of patients with Apex syndrome might fall into that subset. So test question answer, the answer was B. The most common reported treatment is IV acyclovir and systemic steroids. And I'd like to acknowledge Doctor Chen, who's been my mentor for this project, and also Doctor Tajruz, who was kind of there along the way for um staffing these patients initially. And I'll take any questions. Hi, doctor Barr. This is Doctor Wagner. Thanks for it's a great presentation. Um, you know, I think it's really nice to see that they can, um, Improve even without steroids. Um, I, just a good reminder for everyone to think really carefully about the risks and benefits and true indications for steroids when we see patients with, um, inflammation of the orbital apex. I'm sure some of you were involved in management recently of a patient that was admitted with um clinically orbital apex syndrome of unclear etiology. There wasn't, um, A diagnosis of uh uh zoster, there were no skin lesions. That patient was uh treated empirically with steroids for some presumed inflammatory syndrome and actually um deteriorated, got a lot worse, lost vision in the eye, and eventually was diagnosed with invasive fungal disease, and for these patients, starting them on steroids can really, um, can really eliminate their last chance of recovery with invasive fungal disease. So just a good reminder that, It's not an, it's, it's not a totally proven um benefit and we just have to be cautious about using steroids and, and look at all the risks. So I thought that was really great example even in these zoster cases. Thank you, doctor Wagner. Uh, Doctor Barr, nice presentation. Um, I completely agree. There's so few of these cases that, you know, it's one of these things where we, we do IV antivirals and we, we do steroids because that's what's been done, but as you said, there's less than 30 cases and Uh, it's just hard to know, do the storage truly help or not. I, I think the biggest concern really is, um, if it goes to the orbital apex, that's the highway back to the brain, and there are fatalities of, of zoster. And so, you know, in our minds, it's get the antivirals as much as possible and then try, and then we can try steroids to try and decrease the inflammation and improve visual outcomes, but really, The number one is get the antivirals. If it's zoster, if it's obviously fungal, get the antifungals, you know, essentially, this is um the track back to the brain. Anytime it goes through oral apex, it can be fatal and there's certainly cases. Um, so, yeah, Doctor Bar nice job presenting this, and again, there's a lot of uncertainties in medicine. All right. Well, thanks everyone. We're at 8 o'clock here, so, um, we'll go ahead and wrap up, but, uh, everyone have a great rest of your day.
