 Okay, welcome everybody to Grand Rounds. It is a privilege to have Ilya here with us today. Crazy to think I met Ilya as a fellow when he was a fellow. It's almost 15 years ago now. You see, he's got his new beautiful building. So he and his brother have started this new lane gold Institute for plastic surgery up in Meridian. It's awesome to have him close. Ilya is one of the leading experts literally in the world on corneal and neurotization. It is an absolute enjoyment to have you here. Ilya, I'm just going to we're going to turn things over to you and let you get going. Okay. Okay, perfect. Thanks, Doug. Really appreciate it. It's honor honor to participate in your Grand Rounds. Let me go ahead and share the screen real quick. All right. Can everyone see this? Okay. Can everyone see this? Perfect, Ilya. Working great. Oh, great. Well, again, thanks for the opportunity to present this. And I think this is an exciting topic. And there's a lot to talk about. I'll try to hit the main points and would like to open the discussion for questions after I finish just to make sure I address any questions or concern, you know, or inquiries about this procedure. So these are my financial disclosures. So in this talk, I'd like to go over the indications for the procedure, for corneal neurotization procedure. I describe the available surgical techniques, clinical outcomes of the surgery, and also briefly delve into other roles of peripheral nerve surgery in the treatment of other conditions, such as period orbital neuropathic pain. So as we are all familiar, neurotrophic keratopathy is a degenerative condition of the cornea characterized by decreased or altered corneal sensation. If you research the prevalence of the disease, it is approximately 5 out of 10,000. But I think it is underestimated. I think a lot of neurotrophic keratopathy is being missed. Until recently, with the development of this surgery, as well as recombinant nerve growth factors, we're paying a little bit more attention to the condition because we can actually do something about it. About 15% can progress to visually threatening disease where there's corneal melt, and even perforation. We're also familiar with the macchi classification of NK, with the first stage being characterized by punctate keratopathy progressing to stage two with persistent or recurrent epithelial defects, neovascularization of the cornea, and then the third stage being manifested by the corneal melt and perforation. The most common ideology that we see in our clinics is due to infectious causes such as herpetic infections, simplex and zoster. But certainly a close second is neurosurgical ideology or intracranial neoplasia. So these are proximal injuries of a trigeminal nerve. Another relatively common situation is where folks have had corneal surgery or they've had retinal procedures such as penretinal photocorrigulation, injuring their long-cellary nerves. So why does neurotrophic keratopathy occur? Well, this is kind of a simple diagram shows that showing a cornea with with corneal nerves. And in addition to providing reflex tearing, you know, being responsible for the reflex tearing and reflex blink, the corneal nerves are extremely important in providing nutrients to the epithelium. And in turn, the epithelium supports the corneal nerves. So this interplay is very important to keep healthy corneal epithelium. So how do we diagnose neurotrophic keratopathy? This is becoming more common now since since or the use of this tool called Cauchy Bonnet esthesiometer is becoming more common as we are learning and recognizing neurotrophic keratopathy more frequently. And as you may remember, the way you check corneal sensation with Cauchy Bonnet esthesiometer is by using this nylon monofilament. And the length of the monofilament is directly proportional to the amount of corneal sensation. So six centimeters is six to five centimeters is relatively normal corneal sensation. And as the monofilament becomes shorter, this correlates to decreased corneal sensation. Through sort of my experience and experience of my colleagues, it appears that approximately two centimeter of corneal sensation provides adequate protection to the corneal epithelium preventing persistent or recurrent epithelial defects. We tend to measure the corneal sensation centrally in four quadrants of the cornea. So currently, there are multiple temporizing therapies for neurotrophic keratopathy. And most recently, there's been development of recombinant nerve growth factor that has been introduced to the market a couple of years ago. But unfortunately, none of these therapies result in proven improvement of corneal sensation. And the durability of the success using these therapies is also questionable. So really, what we need to do is to address the underlying cause of the disease or the loss of corneal innervation. So neurotization isn't a novel concept. Neurotization has been utilized in other areas of the body. Essentially, the principle of neurotization is that the peripheral nerves can regenerate. And it's possible to use an expendable healthy donor nerve to reinnervate a target organ that has lost its innervation. We this this slide kind of summarizes the anatomy of a peripheral nerve. The nerve fascicles enveloped by epineurium. And the nerve fascicles are really the kind of the workhorse of corneal neurotization. And what I mean by that is that the way this works is the distal target or the denervated target is innervated by releasing the nerve fascicles from the epineurium and essentially plugging them into the tissue, the denervated tissue, in hopes that the axons will eventually grow into the surrounding tissue and find their receptors and make meaningful connections with the sensory or motor targets on the denervated tissue. So that's kind of the the principle of the surgery. And that's why we find success due to this meaningful connection between the axons and the existing receptors within the denervated target. How do these peripheral nerves regenerate? We learned all of this in our neuroanatomy course. Once there is injury to the axons, there's essentially breakdown or degeneration of the distal portion of the nerve via valerian degeneration. And then Schwann cells and macrophages come in, macrophages clean up the debris and prepare the area for proper axonal regeneration. And then Schwann cells then guide axons from the proximal severed end to regenerate towards the target. Regeneration usually occurs at approximately one millimeter per day. But that can vary. You know, in pediatric patients, we see that the nerve regeneration occurs at a faster rate. And maybe in older patients, patients with a lot of comorbidities, this may be delayed. The surgery, the neurotization itself can be accomplished via direct or indirect methods. So direct neurotization basically imply or what that really means is you're taking an entire donor nerve, so the expendable nerve that's not critical to function, and you're transferring that entire nerve to the target. And once you transfer to the target, you release the fascicles and or your branches of that nerves that are bundled together, and then you plug it into the target tissue. With indirect transfer, the donor nerve isn't long enough to reach the target. And so you can use an interposition nerve graft, either harvested from your own body or you or taken off the shelf as allograft. And I'll get into that a little bit later in the talk to, to then allow the axons from the donor nerve to grow along that conduit to the target. So the so the interposition nerve graft really just functions as a bridge or a conduit to allow the the healthy axons from the donor to grow towards the target. So having kind of described that background, coronal neurotization essentially is exactly what we talked about is you take the healthy, expendable nerves. So in this case, it's, you know, this diagram shows a super trochlear and super orbital nerves from the other side of the of the face in this particular diagram, and transfer the these nerves to the cornea. Now, if the patient has healthy, intact donor nerves on the same side as the affected cornea, then you can do an ipsilateral transfer, you don't have to do a controller transfer. And this diagram, you know, assumes that the whole trigeminal nerve is out on the on the right side. And then so the left sided donor nerves are used. And so once once those nerves are transferred, then they're essentially placed in the subcontractival plane around the limbus and then eventually, the axons start growing into the surrounding tissue, you know, in all directions. And then some of the axons end up invading the corneal epithelium, corneal stroma and many making meaningful connections with the sensory receptors within the corneal epithelium and with epithelial cells as well. And that shows kind of the cross section of what is presumed to be happening within the cornea. So what are the indications and the preoperative testing for the surgery? So that's a highly debated topic. I'm going to give you my indications and what I you know, think through my experience is the reason to do the surgery. So I find that neurotrophic keratopathy is a very, very diverse disease process. So there are patients who may have herpetic ideology and their corneal sensation isn't uniform throughout the entire cornea. So they may have areas of hyperesthesia and areas of hyperesthesia. But their overall clinical picture is consistent with NK. And so even though not the entire cornea is denervated, and they may be some even some areas of hyperesthesia, that is still an indication for me to go ahead and perform the procedure if they're showing signs of MK, and the cornea isn't recovering corneal sensation with adequate medical management and follow up. Obviously, you want to have intact donor nerve. So whether it's contralateral, ipsilateral nerve, a sensory nerve that you can transfer to the cornea. So if there are no available donors, then you the patient may not be a candidate for the procedure. And certainly patients with certain comorbidities such as, you know, poorer health, those who are undergoing radiation, chemotherapy, have active, you know, ocular, periocular malignancies, or, you know, those aren't really great candidates for the surgery. Certainly patients with a lot of smoking history, etc, should probably be avoided as well due to poor nerve regeneration. So my my very first case was a patient that I saw in University of South Florida when I was my second year of practice. So that was in our third year in practice, like our second year in practice in 2013. And she was, you know, referred to me for a tarsorophy, because she's been treated with all kinds of drops and ointments for about a year and a half and continued to have a persistent epithelial defect. And so she was very, very resistant to the idea of having to have surgery to close her eye, and ask me if there's anything else I can do for her. And, you know, at that point, I said, I don't really have anything else to offer you, because you've tried everything else that exists. And so we'll have to close your eyes, at least partially. And but then I came home and started doing my research. And I found this paper is the only paper that I found published on this topic in plastic and reconstructive surgery journal in 2009. And this was a paper by a surgeon from Virginia Eastern Virginia Medical School, led by Julia Chorzes, who is now retired, but she's a was a well known nerve surgeon, a plastic surgeon and the peripheral nerve surgeon. And she partnered up with one of the ophthalmologists in the in the in that group. And they've performed actually six of these procedures on over a span of 16 years on average. And they reported very remarkable outcomes where when they transferred the contralateral super orbital super trochlorine nerves. All of these patients, except for one have had remarkable restoration of porno sensation, stabilization of porno surface with no recurrence of epithelial defects. And some of them progressed to improve vision. And these patients had, you know, proximal injuries to the trigeminal nerve, which with no hope of spontaneous nerve regeneration. So while these were impressive outcomes, you know, is a quite a quite an invasive procedure, you know, the essentially these patients underwent a coronal incision, some ear to ear incision, a scalp flap was reflected in the and the contralateral nerves were harvested and tunneled to the cornea. So I performed a similar procedure. And kind of talk to the patient about it. I got permission from my ethics board at the University. And the patient did great. And this is her at two years. And she at three, three months, I noticed improvement in her corneal sensation, as well as stabilization of her epithelial defect. And then from then on, she remained, she remained stable. She had no recurrent epi defects, her cornea cleared up. And she went from hand motions to 2025 vision. And I talked to her actually just about six months ago. And it's been gosh, nine years now. And she's still doing great. So so definitely, I was I was very impressed. But the question was, you know, is there anything that we can do to minimize the morbidity and the extent of this operation to produce and produce similar results? So there, you know, because, because there's certainly a number of issues that can arise, you know, from this type of approach, as well as patient and physician acceptability of this technique. Luckily, four years later, there was another paper that came out of sick kids in Toronto led by Gregory Borschel, who's a craniofacial trained plastic surgeon does a lot of peripheral nerve surgery. And then I'll see him Ali, who some of you may know, he's a cornea specialist pediatric cornea surgeon, published a lot on Cornell Neurotization with with Gregory. And they've described a technique where they use contralateral, or ipsilateral super trochanal nerves connecting an interposition nerve graft with an anto side fashion to this to the contralateral super trochanal nerve, or in or ipsilateral super trochanal nerve and transferring the nerve graft directly to the affected cornea. And again, the nerve graft was used to minimize the morbidity of the operation. And the nerve graft just served as a conduit to allow the axons from the super trochanal nerve to grow along and eventually reach the cornea. And they've reported excellent outcomes in four kid or three kids, four eyes, where the children showed improvement at around three months in Cornell sensation and and they've stabilized the corneal surface. And in fact, some of these patients even noticed improvement in some of the scarring, although that was variable. And a few of these and a couple of his kids were able to get a deep anterior lamella caratoplasty successfully. This shows the harvest of the sural nerve that they used as interposition nerve graft. And this shows the co-optation of the sural nerve to the to the to the super trochanal nerve. So this kind of is a schematic diagram. The only difference here shows and to and co-optation. But essentially, here, super trochanal nerve is transected about a centimeter and a half or so above the superior orbital rim through an upper eyelid or sub brow incision. And then a nerve graft is co-opted to the end of that nerve, and then tunneled under the nasal bridge to the incision below the brow or in the upper eyelid crease medially on the other side and then tunneled through the fornix in the sub tenons and eventually subconjuctival plane to the limbless. And then the ends of the nerve, essentially the fascicles are released here and then they're essentially secured or tunneled around the limbless. They've further modified this technique by doing a corneal scleral tunnels to bury the fascicles for increased or improved penetration of the corneal scleral junction. Although again, that's that's a controversial point, whether that helps or not. They further describe their outcomes, long term outcomes in, believe, 19 patients where they report a successful corneal transplantation and stability of the results over the average two years and as long as six year follow up. The one criticism, I guess, or downside of this technique is that there is a donor site. And so donor site can have complications such as persistent pain, neuroma formation, etc. persistent numbness, loss of protective sensation. And so when we looked at this technique, we were aware of the use of nerve allografts, which are off the shelf products from cadavers, essentially, it's a cadaveric nerve that's desalierized. And use those nerves to perform the same or similar surgery to see if these patients would achieve similar results. So essentially, what these nerve allografts are there, you can see that they have this the infrastructure of the of our source peripheral nerve, except they have no Schwann cells, they don't have any cellular debris. And you can see these are what's called these little openings called endoneural tubes, and they allow the axons from the donor to grow through these endoneural tubes to the target in a similar way that the nerve allografts do see the undergoes kind of a very elaborate cleansing and process of removing debris and growth inhibitors of the nerves. And a lot of animal studies have shown significant improved efficacy, meaning that there's actually external regrowth or growth through these graphs. Although there's a lot of debate whether they work to the same extent or if they're just as good as using the nerve autographs. They're available in different sizes, versus when you harvest a sort of nerve graft, you sort of, you know, have what you have. So if you get a two millimeter graph, that's what you have your three millimeter graph, that's what you have. But with the allograft, you know, you have different diameters in different lengths, I use the longest length possible. The one criticism of using nerve allografts is that you there are no Schwann cells, the Schwann cells that you rely on to guide the external regeneration of those that are derived from the donor nerve that you're using. Whereas in nerve autograph, the Schwann cells are populated within the graft itself. So this shows the this surgery here, I'm using the nerve allograft. And you can see this is end to end co-optation with a super orbital nerve that I've dissected through an upper eyelid crease incision, use 10 o nylon suture to do end to end co-optation. And then sometimes, you know, we wrap it also the amniotic membrane graft to protect this co-optation on your orophy. And then this is to seal glue, the graft is then tunneled, as we talked about, and then buried in the subtenon spleen here, and then subconjunctival around the limbus. And then you can create little pockets, and then essentially, bury the fascals here, I've modified this technique somewhat, I'll show you in the next video. But this is essentially kind of the principles of how we do the surgery. When we looked at these patients, and those average follow up of six months, the results were very similar to the paper that was published by Gregory Borchell, the corneal sensation in these patients were slightly lower because these were older patients, but the stability of the corneal epithelium was very, very similar. So this technique with neurovaligraph also did show promise and showed evidence that this actually does work. To further explore options for corneal neurotization, and to potentially circumvent the downsides of using nerve grafts such as donor site morbidity or relying on a nerve graft for axonal regeneration. We thought about other options, so other ways to perform minimally invasive corneal neurotization by using direct nerve transfers. And so this was my first patient where we performed a direct nerve transfer through an upper eyelid crease incision, so you're actually able to dissect out the entire donor nerve that you need for transfer through an upper eyelid incision. I used also a small incision, sagittal incision behind the hairline that was about a centimeter to put an endoscope in and then allow dissection of the nerve. That actually works very well. And so the patient, this patient did regain sensibility at three months and had durable corneal stability. And so we've performed more of these procedures. And this paper that we published in 2019 describes five eyes and four patients where we performed this direct transfer, all of these patients showing improvement in corneal sensation and corneal stability. So this shows the this technique. So this is a upper eyelid incision to harvest an ipsilateral super orbital nerve to transfer directly to the affected cornea. And I'm gonna maybe fast forward to some of that. So dissection essentially is carried to identify the super orbital nerve where exits the foramen or notch. And then the nerve is dissected further cephalod in the loose areola plane. So it's up on telus plane on top of the periosteum. And, you know, for ipsilateral transfer, you need about four centimeters of this nerve. And then any connective tissue fat is removed. And here, you can see we isolated two branches of the nerve. And then the nerve essentially is tunneled middle to the middle horn of the elevator muscle to the fornix, and then kind of buried in the sub tenons and subconjuctival plane in the similar fashion as I showed earlier. And I'm not here, I performed a limited pyritomy around the limbless and secured the fascicles with the seal of fibrin glue. If a longer length is needed, then you could use endoscope. And here, actually, we're putting the endoscope with a kind of the brow lift sheath to tend the scalp through the eyelid incision, and then you can dissect a more distal branch, and you need approximately eight to nine centimeters of this nerve to do the transfer. Let's see this dissection and then this nerve can be a transected distally, and then reflected inferiorly through this eyelid incision. You can see you can get pretty good length is a couple of my patients have had this done. And then essentially happens next you thin it out, and then you can transfer it to the contralateral side. And this shows after it's been transferred. And then this is these are the branches of that same nerve before they are covered by the congenitiva. Another option that has worked well. Patients who don't have intact V1 is direct transfer of the info orbital nerve. Now here, you know, you have to be careful. And you don't want to transfer the entire info orbital nerve and just transfer selected branches of the nerve. And again, this isn't my first choice. But in patients who don't have any other options, then this is a or don't have a good option. This is a this is definitely a possibility. This shows partial selective neorectomy and partial transfer of the branches of the inforbid nerve directly to the cornea. So again, kind of similar idea and similar technique I switched to using less sutures and more fibrin glue for fixation of the nerves around the eye. So these techniques are very nice. But you know, let's talk a little bit more about clinical outcomes. So really what we want to see in these patients, we want to see improvement in coronal sensation. Although I have to say that that's a surrogate measure that's not that that that usually correlates to success, but not always. Ideally, you know, we ultimately want to improve their vision. Although again, the coronal neurotization stabilizes the coronal surface and allows for secondary procedures to allow for vision improvement. So it may in itself not necessarily improve vision, but it will allow for, for example, someone to have coronal transplant or have, you know, a cataract surgery, for example, where previously there weren't candidates for those who definitely want to see stability. So we want to see that the recurrence or persistence of PED is is resolved or addressed. We talked about coronal transplant, we want to see that the morbidity of the surgery is minimal. We want to look at cost effectiveness of the surgery. And so before before I left Duke, we looked at a lot of my patients. So we included essentially 29 eyes of 28 patients for whom I performed this procedure, although I've done this already probably over 7070 cases. But these, these were the cases that were included in this study, because they met the inclusion criteria, such as follow up, etc. And so essentially, we looked at those outcomes to see how these patients did. So different techniques were used in the study. We used mostly mostly the process nerve allografts for indirect transfers. And then the the other 10 eyes were performed. I'm sorry, 11, I'm sorry, 10 eyes were performed with direct transfers. And one eye was the coronal approach that I described earlier. So various donor nerves were used. 24 patients only made it to the statistical analysis. But we did obtain subjective patient outcomes, such as kind of their subjective experience in all of the patients. And median age was 60 years, median denervation time was 28 months. And average follow up was just over a year. As you notice, the stage was kind of were distributed towards stage one, stage two, although had five patients in stage three of NK. So these are Mackey stages. So these are the outcomes. So 92% of patients achieved improvement in oculosurface quality, meaning that, you know, they they're persistent epithelial defect was resolved that their punctated fill erosions were improved, they're calling a new vascularization was improved, their tear filaments improved, and these were evaluated with myself and my cornea colleagues, colleagues, including Victor Perez, that you you may know. The 13 patients. So 13 of these patients who've had PDs at their last at their follow up, 11 of them did not have a PD and have did not have recurrence of PD. There were two who who did. Now, interestingly enough, after the study, one of these two patients developed complete resolution of his PD and maintain that throughout next two years. So I think in this one patient, the there was just delay in renavation. The other patient unfortunately did not and required a Gunderson flap. So that's the only one patient really who did not respond to the surgery. The median improvement of corneal sensation was 2.3 centimeters. And we did not find a significant difference between either technique using nerve allograft versus direct transfer in terms of corneal sensation improvement. There's a trend towards improvement in vision, but a lot of these patients have had some corneal scarring that required transplants. And three of those patients did undergo corneal transplants, and which were all successful at their last follow up. And then we also performed in vivo confocal microscopy to look at renovation in selected patients, and all of those patients did show evidence of renovation by in vivo confocal microscopy postoperatively, starting between three and six months. So this shows kind of the graph, looking at change in corneal sensation as a function of time. And you can see it kind of has this rectangular hyperbola type of function where the corneal sensation stabilizes at approximately a year and kind of remains relatively stable throughout at follow up. So that's pretty much what we see is that about 12 months, an average patients reach kind of maximal corneal sensation and improvement. And then they kind of stay stable. Now, that's variable. I've seen people who folks who did not have much improvement for a couple of years, and then all of a sudden started showing significant improvement and these patients were denervated for, you know, 10, 15 years. And then there are patients who have earlier plateau of their corneal sensation improvement. So this is just an average. But there's a wide distribution of the results. Another thing that there is also a subgroup of patients who did not show much corneal sensation improvement, but their ocular surface really improves and stabilizes. And some of them, in fact, do report feeling the drops. However, objectively, it's hard to detect improvement and corneal sensation. We also surveyed these patients and 17 patients completed the survey, the grade, you know, they reported their pain was was relatively mild, postoperatively. And mostly, these patients did not have a bothersome numbness in the distribution of their donor nerve. Really, only one patient was bothered by it at one year. And peristhesia was also quite, quite minimal in these patients in the area of donor nerve harvest. And majority of patients were very satisfied with their outcomes. And, you know, interestingly, everybody said that they would do the surgery again if they had to do it over again. So it's also kind of interesting. Some of the interesting points here is that there were a number of patients who noted that they could feel the coolness of their eye drops, you know, most of these patients keep their eye drops in the fridge. And they could feel the coolness of the eye drops before any objective improvement in corneal sensation was noted. And then six patients had allosthesia where initially about three to six months after surgery, they felt when the cornea was touched, or or when they had any sensation or contact with the cornea, they would feel, feel the sensation in their forehead where the donor nerve was harvested from that changed over a course of several months. And then it was they were able to map it localize it to the cornea. This just shows these patients characteristics. And the main thing here I want to point out is that patients had very minimal adverse events. There's you know, this one treatment failure that we discussed, although this patient eventually succeeded. So really, there was just one treatment failure. And the one patient who had an infororbital nerve as a donor had delayed presentation of maxillary tooth abscess, which was successfully treated because of lack of sensation in his cheek. These are some of the outcomes. This patient is an older elderly lady, she's 87, came in with kind of a classic MK with persistent epithelial defect due to her disaster, which she had this PD for over a year and a half. This is five weeks after corneal neurization, you can see closure of PD. This is a three months and this is her 15 months maintaining corneal integrity with no recurrence of PD. This is one of my patients is a younger kid was a five year old kid and idiopathic onset of MK treated for about three years since age of two for this with persistent epithelial defect, probably like 20 different places throughout the world. And finally was referred and we performed a supraorbital direct corneal neurization. This is him at three years postop, three months afterwards, his PD closed and eventually his carting actually improved to the point where he has nearly normal vision in the side. There's a little bit of embliopia. That's his other eye, where we actually did infororbital neurization as well. You can see improvement at six months. That's the patient I showed you earlier. This is another gentleman. This this is interesting case because this is one of the patients who I described that for two years showed minimal to no improvement and then all of a sudden develop improvement in corneal sensation and improvement in his epithelial integrity surface. This is shows a successful corneal transplant two years. This is a patient who had a corneal explant of his neurotrophic corneal and simultaneous corneal neurization. You show there's no corneal nerves sustaining of control for corneal nerves. In his explant there's no corneal nerves. This is three months showing no nerves and then at six months showing nerve early evidence of nerve regeneration. And this is showing now healthy nerves within the stroma and sub basal area of the cornea at one year. So I know we're running a little bit short on time. I'm just going to briefly go through this last study that we just submitted to British Journal of Ophthalmology, which should be published hopefully soon. But this is looking at our patients at Duke, looking at Oxervate treated by Dr. Perez and his group there and cornea group there and my corneal neurization patients. And essentially we looked at, we try to match these patients by their by their comorbidities and their age. And we were able to find 15 patients in each group that we could match. And this is a retrospective study. But we're looking at we're looked at corneal epithelial defect closure, recurrence rate of corneal epithelial defect, patient satisfaction and cost consistency with patient expectations. This is their demographics very similar. There is more neurosurgical kind of intracranial ideologies for patients who underwent corneal neurization. Otherwise, otherwise, the characteristics were pretty similar. So you can see that this is preoperative. And the, you know, majority of these patients had epideffect without stromal thinning. And this is the black shows stromal thinning. You can see all of these patients had a persistent epithelial defect. And at three months, the neuralization showed statistically significant improvement in closure of epithelial defect whereas patients treated with Senate German did not at six months. Again, corneal neurization showed further improvement, you know, close to 80% improvement in closure PD, whereas Senate German showed at this point only 40%. And then unfortunately, did not really improve with Senate German at one year. And then at one year, the corneal neurization kind of maintained its outcome with 80% closure of PD in this in this particular subgroup of patients. Again, you know, this this group of patients, but likely, I would not deem them as failure, because again, it can take sometimes over a year to see improvement. And so if we were potentially to look to these patients, you know, year and a half or two years from now, we probably would see that this gray square would become a rectangle, I guess, would become even shorter. So or potentially absent completely, if all of these were successful. So rate of recurrence was also a persistent phyllo defect recurrence was also higher in patients with treated with oxervate. And there was only one patient out 11 who demonstrated recurrence of PD with corneal neurization. And also the amount of adjuvant therapies were much higher in patients who were treated with recombinant nerve growth factor, so higher cost burden to the health care system with with nerve growth factor drops. And most patients were more satisfied with portal neurization surgery when questioned compared to Senate German. So the key take home point here is that portal neurization is an effective, safe and definitive treatment option for neurotrophic carotopathy. I think this is still in its infancy. And as we learn more about it, and other, you know, eye care physicians learn more about it, I think this will become the standard of care for this disease. I'm going to stop here. I have another few slides describing the nerve surgery for pain that in the paper that we published on that. But I think due to lack of time, and to allow audience to ask questions, I'm going to stop right there. Thank you very much. If anyone wants to get in touch with me, this is our contact information, please might use my cell to call, you know, if I could be of any resource or assistance or email. So I was available for anything that we can do to further educate and about the surgery. Yeah, that was awesome. Thank you so much for being here. Can we give time for a few questions? Sure. Questions from the audience. There's probably 50 plus people here. So thank you. That's awesome. Questions from the audience. If not, I have a million for you myself, but I'll probably save those for I'll text you when I'm doing this. Yeah. So when we're starting to do these procedures, is it kind of a joint procedure with someone like a specialty like cornea or nerve surgery, or what's the first starting out to be kind of approach these as well? Yeah, did you hear that? Yes. Yeah. So, you know, I've done most of these myself, but that doesn't mean that that's how one should handle that procedure. I think it just depends on expertise and comfort level. I certainly think that the team approach is excellent. You know, the limitation is that we're all very busy. Sometimes it's hard to coordinate these surgeries. And one of the limiting factors essentially really is the need for combining multiple specialists to perform the procedure. And so, you know, ideally, you have someone who can offer most of these themselves to allow for to capture larger patients and to be more efficient. But I don't think there's a right or wrong answer. I think it's just depends on your comfort level and the desire to collaborate. So there's a question from the audience. I would agree here whenever I'm not the largest, have you done con focal? I mean, let me see. Let me try to go back to my crust to look at the nerves. Yeah, you've done con focal might cross me to look at the nerves. Yes. Yes. I actually showed that earlier slide. I'll show you here. I'll go back. We've done it actually a bunch. And this is just one of my patients. So this is a patient, one of my patients who had actually an X plant. So this is this denervated cornea, you can see that there's no staining. This is a control. You can see these control stains very nicely with PS for cornel nerves. And this is the control. Now, the new this is the and this is the confocal my cross field, the new cornea. This is a three months. You see no evidence of renovation. This is at six months, you can see the kind of this one fast bill here. And then this is sort of a snapshot. And you can not start seeing healthy nerves in the anterior stroma. Now I have a number of patients who I had similar outcomes, doing, you know, confocal my cross before and then months after we usually start seeing nerve regeneration at three to six months. There's been also probably at least five other papers showing similar outcomes with, you know, showing showing nerves within the stroma and sub basal plexus region of the cornea. Other questions. Jeff. Elias Jeff petty, just congratulations. This is this really extraordinary, you know, having seen patients with you know, severe, you know, severe neuropathy and then not quite knowing, you know, what to recommend. I'm curious now as you're receiving referrals, which patients are you recommending for Senate German versus NK? Yeah, so thank you, Jeff for your kind comments, by the way, I really appreciate it. You know, I think I don't think these are mutually exclusive treatments. I think I think that Senate German is a adjunct treatment, just like autologous CMT areas, for example. But I don't, you know, in my experience, especially in patients who have central injuries to the trigeminal nerve, meaning, you know, neurosurgical injuries with irreversible trauma to the nerve. I don't think Senate German has a long term role in terms of, you know, definitive definitively addressing the issue. So I think a lot of these patients could benefit from both therapies. So I've had a number of patients who have had perioperative treatment with Senate German. So for example, they started two or three weeks prior, and then we continue them throughout the treatment. We're looking at, you know, gathering these patients and publishing a report. I think I have about eight of these patients now. And so we're going to look at their outcomes, comparing to the control who just had coronal neurotization. But I do think there's something to that. And especially, especially maybe even in patients who had partial veneration, you know, less patients in, you know, ocular surgery, or patients who've had, you know, herpes infections, because there may be a role there for Senate German to improve nerve regeneration in those patients as well. Other questions? Yeah, I have one for you. So if all things are equal, what is your favorite approach now? What do you use? How do you do it? So my favorite approach now is for ipsolateral transfer, I do direct transfer of supraorbital nerve. And then for contralateral, I use a nerve graft. You know, because I can do direct transfer with contralateral approach, but it just takes me longer. Maybe I'm lazy, but I don't want to spend five hours in the OR. So now my procedures are, you know, ipsolateral is about 30, 40 minute procedure and then contralateral is about an hour. So they're actually relatively fast procedures. I mean, they're not a cataract surgery, but you can do it pretty fast with this, with this approach. So again, thank you so very much. I look forward to seeing this for a very long time from you. I can't thank you enough. Any other questions before we let you go? Just really give a teaser about pain, doing it for pain. Can you summarize that in one minute? Sure. Yes. I'm going to just show one slide. Okay. I know everyone has to go at private clinic or surgery at nine, but so there are really a couple of types of patients that we deal with. We deal with patients who have post-heropatic neurology or patients of trigeminal neurology. And these are patients who have these palcitrant pain that is very difficult to manage. And so what we've done for these patients is we've isolated the offending sensory nerves. So let's say in V1, these are generally super orbital, super trochlear and infotrochlear nerves. So you can see these here, and we connected them together. So you create a closed circuit. So they're not firing in the skin. And so they're kind of talking to each other. And that closed loop of circuitry kind of creates a situation where the pain on the skin is now gone, and they just have numbness, but the pain is gone. And then for patients who have neuroma or traumatic pain, what I've done for these is removing the neuroma and then either bridging the gap between the healthy distal nerve or proximal and proximal nerve, or directly neurotizing the skin, like when neurotized the cornea. And again, we published a paper on this kind of summarizing our outcomes and OPRS just a few months ago came out. And they're pretty remarkable outcomes. And these patients who were able to get off all kinds of drugs that were previously on. Anyway, I don't want to take up more of your time. But you know, if you do have a chance, you're interested, you want to look that up. You know, that kind of goes over the details of the techniques and why we do it and what these patients can expect. Fantastic. I think that's it. We'll let you go. I'm sure you have a very busy day. Thank you again so much. Thanks, Doug. And I look forward to catching up soon.