Michael A. Mahr, M.D ., an ophthalmic surgeon at Mayo Clinic in Rochester, Minnesota, discusses identifying and decreasing the relative risk of postoperative endophthalmitis in potentially higher risk patient groups.
Well, good, good morning, everyone, and welcome to Mayo Clinic Grand Rounds. My name is Mike Marin. For those of you who don't know me, I'm a cataract surgeon here in Rochester. Our main objective is 1, to review the current effectiveness of post-cataract surgery and ophthalmitis prevention at Mayo Clinic in Rochester, and 2 is to be prepared to identify and decrease the relative risk of post-cataract surgery and ophthalmitis in potentially higher risk patient subgroups. So our pre-test question. So patients with the following condition or or conditions have a higher risk of developing post-cataract surgery and ophthalmitis. 1, active uveitis within a 12 month time period of cataract surgery. 2, current systemic corticosteroid use. 3, current systemic non-corticosteroid anti-inflammatory use. Or D, all of the above. All right, so what's the basis for our current practice? Really, the, the summary of this is as follows. Trials started in Sweden showing that intracameral antibiotics decreased the rate of post-op end ophthalmitis, and in 2007, the ESCRS did a prospective randomized trial that established this is really the de facto accepted practice around the world. And since then there have been subsequent studies, including a big meta-analysis in 2018 of about a million patients. That showed that patients receiving intracamera antibiotics had an end ophthalmitis rate up to 3/4 lower than those not receiving intracameral antibiotics. Because we're talking about rare complications, it's even hard to establish what a baseline rate is, but in that pooled M uphemidas study, the baseline rate around the world was about 1 in 3000 cases. So then it begs the question before we get into anything else, how are we doing here at Mayo Clinic Rochester? So we looked at our data going back over 25 years and obviously cataract surgery has changed a bit over 25 years, and this is a busy slide. I'm going to try to go through it slowly. So in the beginning of this era we did approximately 34,000 cases in patients who did not receive intracameral antibiotics, and our suspected endophthalmitis rate, which is patients getting tap and inject for end ophthalmitis, was about 1 in 2600 patients, with the culture positive rate being 1 in 3000 patients. On the other hand, since that time period, we've almost uniformly adopted intracameral antibiotics at the end of cataract surgery with a slow initiation starting around the time of the study. So in the approximately 23,000 patients who've received intracameral antibiotics, we have an end ophthalmitis presumed rate of about 1 in 7,008 or 1 in 7800 patients. And ironically, if you look at this, even with these huge numbers, this is approaching, but not statistically significant yet. So to dissect this a little more, and I know this is busy. If one just presumes that the baseline end ophthalmitis rate for patients not getting intracameral antibiotics at Rochester is 1 in 2600, and if you apply this rate to the 23,000 patients that received intracameral antibiotics in Rochester, you can estimate an estimated or expected and optimized rate after cataract surgery in this subpopulation, the ones that got the antibiotics of 9 cases, but we only had 3. So our best guess or estimate is we may have avoided 6 cases of post-op end ophthalmitis with this intervention. So what did this cost? The cost has varied a little bit over time because the cefuroxime we compound ourselves, the moxifloxacin we receive prepared in the bottle, but it's about $10 per case. So we spent about a quarter million dollars or about $38,000 per avoided case based on our best estimate. So which antibiotics do we use? Here, we're lucky. We have a great pharmacy, so we have done the compounding of cefuroxime and for most surgeons, that's the baseline medication. And if there's any question of allergy or contraindication, then surgeons typically switch to the moxifloxacin. What about safety? We have no known safety issue that we had either with the compounded cefuroxime or out of the bottle moxifloxacin. So, this is great data. So the question is, big picture, where do we go from here? We've had success, but what else should we be doing now? And the answer is, is once you have a complication rate driven to very low number, the next reasonable step is to try to still look for subgroups where the relative risk of end ophthalmitis may be higher than the general population. Of course, the inherent challenge is we're talking about a case volume of teens over 25 years. How do you potentially subgroup these really, really rare events? And the answer is this is difficult to do as a center by yourself. So the question number one is, is in general, which patients have a higher relative risk of post cataract surgery and ophthalmitis. Probably the best answer comes from a big study in the UK looking at 1.3 million cataract surgeries where their baseline end ophthalmitis rate was about 1 in 4000 patients, which is actually fairly similar to ours. Patients with a higher relative risk of post-cataract surgery and ophthalmitis in a statistically significant manner or in ranked order #1, posterior capsular rupture, which intuitively makes sense. 2, and we're gonna get to this more, a history of uveitis. 3, a history of vitrectomy. 4, a history of recent anti-VEGF injections, which makes sense because that in and of itself is, is a potential influence or a creator of end ophthalmitis. And then finally, a history of potential glaucoma, corneal pathology, or diabetes. Now for the purpose of this talk, I want to drill in on that uveitis category. That's obviously a very broad grouping and the question is, can that be better stratified or understood in the context of end ophthalmitis? So yes, but again, going back to what we said before, volume volume wise, it's really not possible for any institution to do this themselves. Now there's a new in press Irish registry study in ophthalmology that's coming out this summer that actually looks at this and provides potentially some meaningful insights. And what they did is an EMR review looking at close to 10 million cases over 10 years in the United States. This is a busy slide, but basically what was done is patients, again, it's an EMR review, were stratified as a control group of having no uveitis, potentially having had a diagnosis of recent active uveitis within a year prior to surgery, and then the two other big variables were, were they currently on a systemic corticosteroid or were they currently on a systemic non-corticosteroid. Anti-inflammatory medication at the time of actual cataract surgery. So these variables were plugged in. A multivariate analysis was done, and here's what it showed. It showed that in statistically significant fashion, having had a uveitis diagnosis within 1 year prior to surgery created an odds ratio of 7, so a 7-fold higher rate of having an end ophthalmitis diagnosis after cataract surgery. On the other hand, A little lower rate but still statistically significant, having been on current systemic corticosteroids or current non-systemic immunosuppressive medications also doubled the rate of post-op cataract surgery and ophthalmitis in this pooled study. So of course there are caveats. This is an EMR diagnosis review, so of course it's plausible that uveitis patients are going to be more likely to have a risk of post-op inflammation that may be diagnosed as an end ophthalmitis or rule out end ophthalmitis, but it may not be an actual infection in the eye. On the other hand, the other thing to think about is the corticosteroid group is fairly straightforward, but the non-corticosteroid immunosuppressive medications, this is potentially a lot of different medications and a lot of different doses, and likely there's variation here, at least for the purposes of this study had to be lumped, which isn't ideal, but it is the way it is. So one then has to think about the things that we can actually control or do something about and the question really is then, is it plausible that systemic corticosteroid or non-corticosteroid anti-inflammatory treatments um actually increase your risk of post-op end ophthalmitis. So here are a few insights. Number 1, across the US, about 3% of patients based on insurance data are on a systemic corticosteroid or non-corticosteroid anti-inflammatory treatment at any one point in time. There's a study done in intravitreal injection patients, and it shows that the rate of post-injection end ophthalmitis can be up to 10 10fold higher in immunosuppressed versus non-immunosuppressed patients. And of course, if you look outside the ophthalmology world, there are multiple studies showing that immunosuppression is an independent risk factor for surgical site infection. So what does one take with all this, you know, somewhat messy and confusing data. One, our current Mayo Clinic, Rochester post-cataract surgery and ophthalmitis prophylaxis with intracameral cefuroxime. And or moxifloxacin appears to be clinically effective based on a historical or current international norm. If you have to go back downstairs. Specifically, um, now our current rate with intra intracameral antibiotics is about 1 in 7800, and then the estimated cost per case prevented is about $38,000 the way we're doing it here. Interestingly, there's a recent Irish registry study showing that patients with either active uveitis diagnosis within a year prior to surgery or those on current systemic corticosteroid and or immunosuppressive treatment may have a higher incidence of cataract surgery post-op end ophthalmitis versus controls. And then interestingly, there's studies showing in the intravitreal injection population that immunosuppressed patients, when they do get end ophthalmitis, they present earlier than the general population. This is a little bit of information to tuck away. And then finally, what's the bottom line? Why do you care? If you have a patient on transient systemic corticosteroid or non-corticosteroid immunosuppressive treatment, new evidence now supports the idea that you might want to risk mitigate by timing elective cataract surgery to avoid treatment overlap with the systemic immunosuppression. So again, the answer to the pre-test question is, is active uveitis within 12 months of surgery or current systemic corticosteroid or non-corticosteroid treatments may all be conditions that influence your, your odds of getting post-op cataract surgery and ophthalmitis. Thanks a lot. I'd be happy to answer any questions you have at this point in time. Hey Mike Keith Barrett here, that, that was a, a great presentation, really that so clearly presented. Uh, one question, what is, what are the potential side effects of our intracameral medications? Um, I know some intravitreal antibiotics have risks of, of, of vasculopathies, of macular edema, um, or also anything we inject in the eye has a risk of, of toxic anterior segment syndrome, which may or may not be diagnosed as endophthalmitis. And may or may not be retrievable on your, your, uh, diagnostic code search. What what do you have? What do you, what are your thoughts? The, the, the, the biggest concern is obviously with the self-compounded medications, and the problem is you can do everything right. I think the cefuroxime. But if you have one bad day where there's a problem from a compounding point of view and you have, you, you, you can have a lot of cases of bad things that will overshadow those six cases you potentially avoided over many years. So there's an inherent risk in doing this whole thing, I think, and even though. Our experience has been very favorable up until now. You, you, you really never step away from that risk, and that's why some surgeons are very biased towards using out of the bottle moxifloxacin, which, which really has a great track record, you know, around the world at many centers in terms of avoiding toxicity issues. And when you talk about retinal toxicity with these antibiotics, it's interesting in the retina surgery literature. There were toxicity issues when subcon antibiotics were used and sclerotomies were leaking and then higher doses of antibiotic ended up in the eye through an unintended route, but I'm, I'm unaware of any primary concerns with the intracameral antibiotics in the context of posterior capsule rupture or post vitrectomized eyes. I hope that helps. Yeah, yeah, um, have we had any cases of tests, or did you? I'll have to answer, not that I anecdotally know of here in Rochester. We, you know, I didn't specifically search for tasks in this. Usually when there is tasks, it's, it's a big commotion that everybody knows about. I know at other sites we've had that happen, but again, not that I know of in Rochester over this period of time. Hey Mike, this is Ray Azzi. Really, really well presented. Thank you so much. Great talk. You know, all the antibiotics you mentioned can cause hemorrhagic occlusive retinal vasculitis, and this is what Keith kind of alluded to. Um, that's a really catastrophic condition in many instances, and so, I, I think that the equation has to include these potentially blinding conditions that are not infections that wouldn't get tapped and injected. Um, because there's, there's There's definitely something that isn't, but we don't quite understand what causes horrors. But we know that it's That it's probably a hypersensitivity reaction to patients that may have been previously exposed to those antibiotics. And um And I, I, I suspect the cost with respect to Complications may may exceed that of just what is represented by endophthalmitis. But yeah, I'm glad you brought that up. The and then the million dollar question there is, is again, are there eyes or for sure you should be avoiding incamal antibiotics because the back of the eye is more exposed to the front of the eye from a dosing point of view and, and I don't know if anybody knows the answer to all this, but, but I think that's an important issue and, and I don't have a great answer there. Well, great. Well, I, I think I appreciate your time and I think we're gonna switch over to our next speaker now. Thank you. All right. Thank you, Doctor Marer for that wonderful presentation. So my name is Rachel. I'm one of the PGY threes here in Rochester, um, and I'm happy to be presenting a case of chikungunya-linked demyelination today, um, for migraine rounds. Today, our learning objectives are to describe the clinical presentation of myelin oligodendrotrite glycoprotein antibody associated disease, which I'll be referring to as MOGAD. Um, we'll review the current diagnostic criteria for MOGATD and the characteristic imaging findings, and then we'll define the current evidence-based treatment strategies for MOGADD. For our multiple choice test question, which of the following statements best reflects the current evidence-based management? Of acute MOGAD presenting with optic neuritis. Is it A, high dose IV corticosteroids are the first line treatment for acute MOGAD attacks with plasma exchange or IVIG reserved for cases refractory to steroids, B, maintenance immunosuppression should be initiated in all patients after a first MOGAD attack. Regardless of disease course or residual disability, C, oral corticosteroids alone are not sufficient are sufficient for acute management of severe MOGAD optic neuritis, and adjunctive therapies are not advised. Or D, randomized controlled trials have established rituximab as the preferred first line therapy for acute MOGAD attacks. So jumping into a case, um, this is a 65-year-old woman that I met in the ER, uh, for evaluation of acute severe bilateral vision loss associated with headache and eye pain. Um, and she described this as a sudden whitening of the vision that occurred two weeks prior, and overnight, she just worsened to no light perception, um, and has not seen anything, um, for the last two weeks. Um, prior history is she was visiting her family in Kenya for the last 6 months and had just, um, returned back to the States about 2 weeks prior. Um, and she was actually diagnosed with chikungunya virus in Kenya 1 month prior, um, but we didn't have any records, um, or confirmation of that diagnosis. Um, otherwise, she had no prior ocular history. Um, she was not on any current medications. In her medical history, um, she had diabetes, hyperlipidemia, and lightened TB, um, but otherwise nothing major. Um, so after she arrived to the States, she was actually seen at several hospitals over the last few days to try and evaluate this vision loss further. A week ago, we had reports from, um, images from the first institution she was, um, evaluated at with reportedly normal MRI brain, an MRA of the head and neck, and a normal venogram, um, and limited CSF studies were obtained, but those were reportedly normal as well. Um, her MRI orbits from two days prior though at a second institution was concerning for bilateral optic neuritis. And so she was empirically started on IV Solu-Medrol. Um, it looks like they had declined any further, um, lumbar puncture or serologic testing at the time, and she did have significant improvement in her pain, but due to the ongoing vision loss, um, elected to transfer her care here, uh, to Mayo. Um, so now I'm seeing her two days after IV Solu-Medrol. Um, her visual acuity was still no light perception in both eyes. Um, she did have very minimal reactivity though of both pupils under the slit lamp. Um, but she herself could not appreciate this light. Um, otherwise, her motility was full in both eyes, her pressures were good. Um, and her, uh, slit lamp exam, her anterior segment was really normal. There's no inflammation visualized there. Um, in her posterior segment, um, no vitreous inflammation, but she did have slight optic disc edema in the right eye and grade 2 disc edema in the left eye with hemorrhage. Um, and she was also evaluated by neurology colleagues in the ER with an otherwise normal, uh, neurologic exam aside from this eye exam. Um, so we repeated, uh, imaging here in RED and you can see, um, there's enhancement and thickening of the bilateral optic nerves extending from the intraorbital segment all the way back to the preachchismatic uh segment suggestive of optic neuritis. Um, not pictured here, but also on the MRI brain, there was lepto meningeal enhancement, um, and that was concerning for a possible, um, infectious etiology and an MRV was notably normal for no thrombus. So we did obtain further diagnostics. Um, notably, we wanted to get more CSF and serologic testing to assess for any alternative, um, infections given her viral prodrome. This was mostly concerning for a possible viral optic neuritis, um, but we also wanted to obtain inflammatory testing as well, um, just to make sure that there was no, um, other etiology to explain this, um, despite the history presented at this point in time. Um, so here are the results of the notable testing. Um, she did test positive for chikungunya, both the IgM, the acute, and the IgG, um, antibodies. She also tested positive for dengue, which, uh, we actually believe was just a cross reactivity with the chikungunya titer. Um, and interestingly, she had a positive, uh, MOG IgG titer of 1 to 100, which is, um, pretty high. Um, so what is chikungunya virus? Um, this is an arbovirus that's transmitted by the Aedes species mosquitoes. Um, it's endemic to tropical and subtropical regions in Africa, South and Southeast Asia, the Caribbean, and parts of Central and South America. And it's this rapid onset febrile disease characterized by really severe polyarthralgias, myalgias, headache, and rash, and symptoms can last uh weeks to months. Um, you can start to see positive serum antibody testing with the acute IgM antibodies within the 1st 3 days. 8 days. Um, and the IgG appears shortly afterwards. And the IgM can persist in the serum for the first few months. Um, so it's pretty, uh, good at detecting, um, acute illnesses, uh, if you have an IgM positive, but the IgG can last up to several years. Um, so what is MOGAD? Um, it is this acquired immune-mediated demyelination of the central nervous system. Um, you get pathogenic IgG antibodies, um, that target, uh, myelin oligodendrocyte glycoproteins, and these are expressed on the outer surface of the myelin sheath in the central nervous system. The disease course can be monophasic or relapsing. Um, and those at increased relapse risk, um, have onset in adulthood, um, folks who are female, um, those who have a polyphasic first attack or a non-transverse myelitis attack, um, or those who have early relapse, and about 50% of patients do relapse, uh, with MOGAD. And again, the diagnosis, uh, we'll go into this a little bit in a couple of slides, but it does rely On detection of these MOG IgGs using a cell-based assay. Um, so it can really affect anyone of all ages, but you do see a bimodal peak, um, in children and young adults at the ages of 8 and 33. Um, there's no known predisposition in regards to sex or ethnicity. Uh, it's the most common demyelinating disorder in children, making up over 20% of demyelinic attacks in kids. Um, and it does represent about 6% of all optic neuritis cases. Um, in adults, it most commonly presents as an optic neuritis, whereas in kids, um, it presents as an acute disseminated encephalomyelitis. Um, and other presentations include transverse myelitis or a cortical encephalitis. Um, and MOGAD is considered, um, in this bucket of atypical optic neuritis in contrast to a typical MS related optic neuritis. Um, so 20-40% of MOGAD cases are actually preceded by infections. Um, this suggests that there's probably an environmental trigger that may initiate or amplify the autoimmune response. Um, but interestingly, there have been no documented cases of, um, MOGAD after chikungunya virus infection. Um, so this is really, um, uh, unique, um, in that case. Up to 60% of chikungunya cases though do have reported neurological complications. Most commonly, those are gonna be an encephalitis or a myelitis. Guillain-Barre syndrome has been reported as well, among others. Um, and these can occur either during the acute phase or even as a post-infectious, I mean mated phenomenon. Um, so characteristic imaging features of MOGAD on MRI you will see longitudinally extensive optic nerve enhancement like in our case. Um, it's also frequently bilateral and up to half of these cases can also have enhancement involving, um, the optic nerve sheath, um, in the perineural fat. Um, the optic chiasm is less frequently involved in MOGAD, which is in contrast to NMOSD. On OCT, um, this is a study by Doctor Chen. Um, you can see marked thickening of the peripapillary retinal nerve fiber layer, um, kind of a sign of the severe optic disc edema that you can see in MOGAD. Um, using a cutoff of 118 micrometers, um, it was quite, um, sensitive, that 74% sensitivity. Um, for detecting MOGAD, um, and distinguishing this from MS in the acute phase, uh, whereas a cutoff of 175 micrometers was very specific, but then you do lose some of the sensitivity. Um, and this is important because it can be, um, used as a sensitive myo marker in the acute setting. And while you're awaiting serologies, um, in the early phase, this can take anywhere from 1 to 2 weeks to result. Um, having this biomarker can be quite important for an early diagnosis that can guide therapy in the acute setting as it is different. Um, and here, um, is a picture from that study by Doctor Chen, just a representative of, um, the optic nerve of the optic disc edema. Um, so here on the left, you see an eye with MAD. That left eye, um, you can see the disc edema and the associated, um, RNFL thickening to 215. In contrast to the typical MS related optic neuritis eye and the right, um, really, um, you know, barely any difference from the fellow eye with a thickening of only 109. Um, so other features of Moge optic neuritis, um, despite the pretty poor visual acuity on presentation, the recovery is remarkable. Um, at 3 months after acute onset, 91% of patients have been reported to receive, um, a full recovery of 20/20 vision when steroid treatment is initiated within 10 days of symptom onset, and the more you delay treatment, um, the worse outcomes, um, are. Um, the median final visual acuity has been reported to be 2025 and only 6% have a final acuity of 2200 less in either eye. Um, so some patients still can develop this significant disability if not treated properly or even if treated properly, and typically this comes from the initial attack. Um, so this is, um, uh, the, a slide from the 2023 International MOGAD Panel criteria. And essentially, um, this essentially states that, um, you need three criteria to really, um, solidify diagnosis of MOGAD. One, you need a core clinical demyelinating syndrome. Um, two, you need a positive serum MG IgG result, um, based on a validated cell-based assay. Um, and if this is a clear positive, you don't need any additional supportive features. Um, but if it's a low positive, um, or negative, um, serum but a positive CSF, um, then, um, you need some further imaging or clinical features. Um, and again, this just emphasizes that, um, a low titer by itself or a CSF only positive is not enough, um, to confirm a diagnosis. Um, so this is a busy slide, but um we'll focus on the middle column here, um, just looking at MOGAD, um, and contrasting it to NMOSD, uh, versus MS related optic neuritis. So again, it's often bilateral, but it can be unilateral. Um, it can affect folks of all ages, uh, whereas MS-related optic neuritis typically targets young adults, um, while NMOSD can also target, um, folks of any age. Um, MOGAD, you'll have a moderate to severe edema quite commonly. This is seen in 80% of cases. In NMOSD this is variable but usually less severe than in MOGAD, whereas in MS related optic neuritis, optic disc edema, um, on exam is often absent, but 33% can have mild disc edema on exam. Um, the disease course, about half is monophasic versus half is relapsing. Versus an NMOSD, uh, greater than 90% relapse, um, but less commonly so in MS-related optic neuritis. And like we saw in our case, the vision loss on presentation is quite severe in MOGAD, so often NLP, uh, which is similar to NMOSD, um, but in contrast to MS-related optic neuritis where vision is not as severely diminished at presentation. Uh, like we mentioned earlier, um, recovery is quite good in MOGAD, um, but you do need to treat early with, um, steroids. Um, versus an NMOSD, um, recovery is quite poor, um, while an MS recovery can be quite good, um, with or without steroids. On MRI like we saw in our case, um, long segment involvement of the optic nerves as well as, um, sheath involvement is common in MOGAD. Um, and again, you'll see the MOGG IgG positive serology, which is critical to the diagnosis. Um, so treatment wise, um, usually for acute attacks, you want to treat with high dose IV methylprednisolone, and this will be 1 g daily for 3 to 5 days, followed by a prolonged oral steroid taper. Um, there was a large multi-center cohort study, um, from JAMA that it's highlighted here, um, and it found that patients receiving corticosteroids within a median of 4 days from symptom onset. Um, and those that received treatment earlier, uh, were more likely to have improved recovery and, um, a higher likelihood of MOG IgGsro negative conversion. So again, emphasizing the importance of early treatment. For cases that are refractory or very severe, um, plasma exchange is the most common, um, second treatment, and early initiation has also been associated with better outcomes. Um, and if not doing plasma exchange, IVIG has also been shown to be quite affecting. And for those who do have relapsing disease, immunosuppression will be required. Um, this is another study published, um, by Doctor Chen and his team, and this is a retrospective multi-center cohort study of adult patients with MOGAD looking at the association of maintenance IVIG with the prevention of disease relapse in adults with MOGAD, um, and it found that the median, um, annual relapse rate, uh, while receiving IVIG was lower than prior to IVIG treatment. And disease relapse based on IVIG frequency in people receiving 1 g per kilogram of IVIG every 4 weeks was lower than those receiving either a lower dosing or less frequent dosing of IVIG and this was both significant. Um, so in summary, this kind of supports the fact that maintenance IVIG is associated with the reduction in in disease relapse and less frequent and lower dosing of IVIG can be associated with treatment failure. So looping back to our case, uh, we did continue a total 5-day course of 1 g of IV methylprednisolone. Um, her vision did improve, but only the hand motion in both eyes by day 5 of treatment. Um, and so we transitioned to oral prednisone taper, um, and after long discussions with the family, we did, um, initiate plasma exchange a few days later. Um, due to the ongoing severe visual loss. Um, and six weeks later, um, she did have visual acuity improvement to 2017 in the right eye, 2015, the left eye, um, and we are seeing her back later this week, um, to obtain some further imaging, um, in the ophthalmologic clinic. So in summary, MOGAD-related optic neuritis is characterized by bilateral involvement, severe vision loss, and marked optic disc swelling with frequent perineural enhancement on MRI. Viral infections can trigger MOGAD through immune dysregulation with a post-infectious prodrome reported in up to 40% of cases. Um, it's less likely to result in permanent visual disability compared to other atypical optic neuritis. And early treatment with high-dose corticosteroids um has been associated with improved visual outcomes and it is really important. Um, so the answer to our question today is A, um, high dose IV corticosteroids like we mentioned are the first line treatment for acute attacks, uh, with plex or IVIG reserved for cases refractory to steroids. Um, I just wanted to thank, um, our team here, um, especially Doctor Poonja who, um, finished her fellowship here already but was really key in, um, helping with the, uh, managing this patient in the interim, um, Doctor Tashrez and Doctor Chen and the entire neurology team, um, that was really instrumental in the multidisciplinary care of this patient. Um, these are my references. All right. Um, well, if there are no questions, um, I hope everyone has a great rest of their Monday and thank you for listening.
