2024 Fetal Care Center Frontiers in Fetal Neurology Day 1 - Dr. Dawn Gano

Next up is Doctor Pero. Um, he will, he is a pediatric surgeon and fetal surgeon here at Cincinnati Children's, and I will turn the, uh, presentation over to him. Thank you, Doctor Kara Markham. Uh, yes, it's a pleasure for me just to talk about potential new treatments, uh, prenatal treatments just for fetal hydrocephalus. Uh, we are researching for many years in animal models, so I will show you what are our progress on that. So, So, we know that the circulation of the CSF that is produced in the colloid plexus, so, it's just going through the ventricle system, OK? Through the silvius and the fourth ventricles and go around the brain just for reabsorption. So, uh, it's, it's clearly important that when we have an obstructive uh problem like uh conductal stenosis, we obviously block that normal circulation and we start to build up fluid in the lateral ventricles on the third ventricle. So, this is a pure obstructive uh problem in the, in the, in the babies and also in the fetus very early in gestation. So, what happens is the ventricles are growing and growing and growing. So, it's an increase on the, on the pressure, increase on the uh cortical mantle thinning, it's a rupture of the septum pellucidon, and finally, it's a rupture of the denudation of the ependyma that produced many, many problems in these babies, mostly in the development of the brain, all right? So, also, we have a very good parental diagnosis, so, we can detect very early gestation, every single ventriculomegaly and hydrocephalus, OK? Depending if it's mild, moderate, or severe. And also, MRI is a very, very good tool to uh complete that study and also identify if it's a real and isolated aqueductal stenosis. Uh, with a genetic testing, right? So, we have some examples here of a severe, uh, ventriculomegaly, hydrocephalus, and also extremely severe. You can see here, the rupture of the septupellucidum. So, and the thinning of the brain, right? So, this is very understandable that the brain will be in trouble for a normal development. So, also, we know that uh many causes of fetal hydrocephalus, but the most important in, in, in obstructive congenital hydrocephalus probably is sarco ductal stenosis, right? And also, we know and we, we saw in the first talk that there is a potentially uh poor outcomes, OK, with intellectual disabilities, sometimes, plasticity, seizures, etc. So, knowing that, uh, and knowing that we have postnatal treatment almost consistently, these babies will, will need a CSF derivation, mostly with BP shunts, OK? With all the problems of the BP shunts from produced malfunction, infection, etc. etc. and also the alternative that uh Doctor Scott explained it perfectly well of endoscopic third ventriulostomy that We can do postnatally just to uh recirculate the CSF, right? So, knowing these treatments, right? So, we know that any of these treatment postnatally probably arrives late because during the intrauterine period, uh there's a progressive brain deterioration, right? And we know all the changes that are prescribed in these brains, depending on denudation, astro. Cytosis, microgliosis, etc. etc. So, what about to do something before birth, right? Uh, as soon as possible just to stop this problem in the brain development. What about do a prenatal fetal ETV, OK? You saw previously, this technique is very cool, but what about the possibility to do in the fetal period? Never did that, right? So, I had that idea a year, many years ago when I still was in Barcelona, like 20 years ago and I was developing the project. So, it was very nice just to meet with Dr Torsonodourus, a neurosurgeon, ve neurosurgeon from Turkey that joined me in, uh, uh, 10 years ago and also my PhD is a neuroscientist, Mark Arius. So all 3, we started a project just to try prenatal fetal ETB and we are still working on that and very close to our clinical trial. So, This is a new thing. No. So, there was like 40 years ago, right, that somebody tried to do introine treatments in the 80s actually. So, the first uh pro uh initiative was uh described it in this paper I published it recently where I uh described how the first strike was in fetal and monkeys, uh uh uh chip models. And, uh, using vesico, uh, ventricular amniotic shunts, right? So, just to put, uh, the high pressure of the CSF outside to the amniotic fluid and the first human case was described by, by Buleve, OK, also almost 40 years ago. But after very fashion time and doing uh uh basic uh uh ventricular amniotic shunts, uh, they There are collected 44 cases in our registry, but the results uh discussed in this important uh fetal uh medicine and surgery meeting uh in '82. So, make that the, the experts in fetal surgery decided to do a moratorium on this fetal intervention because probably the clinical outcome and the patient selection was not as good as should be. So, after 40 years, right, right now, and we have more technology, better imaging and genetic tools for better patient selection, so, it makes sense that possibility to recapitulate these uh treatments, but in my opinion, not to put any hardware, any, any shunt, just to try the ETB, make a hole and go, right? So, for that reason, we started, uh started a, a study in the fetal. Right? So, we used to do that in a very nice uh uh facilities in Spain, in a, in a, in a perfect veterinary environment with all the resources. So, we did many cases of fetal lamps just trying to inject in the external magna. Uh, initially, we injected caulin. It's like a, it's like a talc that uh obliterates the four ventricle, all right, but creates, uh, uh, meningitis like reaction, like irritation. So, we didn't like that much. So, also, we try it in different ways, transcutaneous, transuterine, or directly in the head, as you can see here, uh, of the, of the fetuses, and we discovered that uh we can create in all the models. Uh, moderate hydrocephalus, OK? And we like it more the transuterine or the direct head, uh, injection in cisterra magna. So, we tried it on other agents. So, we compare it to another possible resins or agents and we try to do, uh, by the same way, transuterine or open uterus. You can see here the leak of the CSF after the needle is in the cisterna magna, so we can inject the three. Agents, Cain, Onyx, and Bioglue. So, after this study injected in StenraMagna, we determined that uh analyzing all these groups in comparing Kaoline, Bioglue, and onyx, we decided uh that Bioglue was the best, OK? So, we did controls on the ventricles by ultrasounds, all right? And we described a new scale of severity, not for human, just for, for fetal lamps, right? So, we know when it's mild, moderate, and severe in a fetal lamp. So, these are some examples of the MRI you can see mild, moderate, and severe in these fetal lamps just created with the bio glue and you, you can see the section of this, of the uh microscopic view of the brains with all severe, mostly severe hydrocephalus created by this and only the bioglue was Allow it to create severe cases, right? So, uh, that was by Bioglue was the choose on, on that and also the thinning of the brain was also more significant with the Bioglue. So, we did that, we analyzed it prenatally and postnatally with the MRI's and then We described the natural history and the histological changes in this model of severe hydrocephalus. So, basically, we see uh uh denudation of the, of the ependea, yes, probably because the distension of the ventricles. You can see here very well, all these uh denudations, lack of cilia in these areas and then with a special software, we calculated the areas of denudation comparing with the severity. You can see You hear the tracing of all the pendema and all the data. So, that demonstrated that the percentage of denudation is higher with the severe category. So, the more severe, the more denudation and the more problems for this brain, uh, actually. And also, that happens very early in gestation until delivery. So, in different points, point times of the delivery, we can see that still the percentage of denudation is worse in the grade 3, in the, in the severity. Right? And also very early, so, I think this is important because if we do, we can do any fetal therapy, we need to prevent the denudation or just regenerate that sependemma lining damage, right? So, this is a very cool images of minoflorescence of a normal and a denudated uh ependema here. Also, we know that the astrocytes goes to the, replace the pendemal uh cells and create like a scar, right? And also, we can see that is microglia. Activated microglia is neuroinflammation. You can see this round uh green cells in the area of the nation. So, this neuroinflammation, all the neuroprogenitor cells in the subventricular zone are in, in, at risk of uh maldevelopment. So, then with that, we have a good model. We have severe hydrocephalus, we decided just to try to fix, OK? By uh implementing ETV all right? So, first, we injected the bioglue as we described it and created very nice hydrocephalus. So, to Three weeks after we went back to the same fetus and tried to use different scopes, very thin scopes. We use it as yellow scope at the beginning, but finally, we finished with a 7 French rigid uh phytoscope or cystoscope just to go inside uh the, the distended ventricle. So, this is the, uh, the, the entrance in the cooker point in the right side, just trying to go in the, uh, 1 centimeter to the midline and enter in the ventricle. OK? You can see a microscopic view all, all the, the setting and also we can do transuterine, right? So, then we can put the camera and see inside the ventricles. You can see here the Fromen Monroe at the end, we can see the choroid plexus and the thalamus 3 veins there in the inside the lateral ventricles. And then you can see also we can try to go trans uterine, so we don't need to open the, the uterus, right? And to access to the ventricles. We did 3 groups, the fetal ETB, the co-twins that were normal, and another one, hydrocephalus without treatment, right? The anatomy of the brain in the fetal lamb is so different, it's more elongated, so, there are some difficulties like a narrow foramen moor uh and uh different other problems, but, uh, we were able to do it. So, it's feasible. And here, you can see a sequence of the image on, on the lateral ventricle go through the monro to the, uh, to the floor of the third ventricle, so we can create a hole and go through the other side and see the, uh, The subarachnoidal space. All right. Here is a short video, OK? Hopefully, it's running. Yes. So, we are here in the lateral ventricles. You see, there is no septum pellucido, so we can see both sides of the ventricle. This is a very nice view of the atrium and the cho and the choroid plexus, then the narrow uh Monroe. So, we try to go with the scope. It's, uh, the other side is the same, all right? So, we go from the right side, all right. This is the double speed, uh just to make it shorter. So, we can go through this narrow Monroe, we can find an interthalamic addition very, very, very large, so it makes a little bit different and then go through the third ventricle. So, once in the 3rd ventricle, we can identify the mammal bodies, all right? It's a good reference to see the two scenario, this is the bluish area in front, all right. So, we pass a very rigid, uh, plastic fiber. Actually, it's a laser, but without energy. So, we can make a hole there, right? So, it's a blunt opening, OK, of the, of the membrane just to avoid any energy or any damage on the basilar artery, all right? This is a fetus, usually, it's a fetus in mid gestation. So, we can just make the hole and make it larger. We can use a narrow balloon just to make it bigger as you saw before in the last talk, but also, we can use the scope to go to the other side and just make it bigger, bigger hole. So, now, we are just progressing inside the hole to the other side, right? And where we can see the liquid membranes, OK? And uh uh oculomotor nerve and uh sometimes the basilar artery. OK. So, what are the results of this technique? So, this is a very good example, right? So, we have MRI of two twins, OK? In the same month, both with the same degree of uh ventricular omegaly and you can see here, right? So, a delivery, you can see that fetal ETB treated have a thicker uh brain, OK? And a smaller ventriculomegaly compared with the twin that still have a very, very, uh very, very thin brain and a large ventriculomegaly. So, this is a good example. So, we did in Many, uh, animals and we can see here that when we do ETV we can go from, uh, the moderate, uh, well, in general, to, to a severe to a moderate mild, so we can reduce the size in the red, uh, uh, sites and also if we divide in between moderate and severe, so we can put the moderate category to, uh, to either the severe to moderate to mild, and the moderate, we can go to normal, right, in these animals. You can see here, also for the compression of the brain, we can achieve the same, all right? So, we can improve the thickness of the, of the brain in these animals. Also, you can see in the last column that in these cases, and most of the cases, we recover the denudation. We don't know if we prevent denudation or we are regenerating after recirculation and deflation of the ventricles, but we are working on that and discovered that. So, in conclusion, we, we can see that even the Abi model, it will be more difficult than human. Uh, we can increase the size of the brain and we can decrease the lateral ventricle size and we are just working more in the, uh, in other aspects of histology and also trying to go for a clinical trial. Just shortly, There's a surgeon, a fetal surgeon in Brazil that started to do it in humans, so he consulted finally to us. I was one month ago in, in Sao Paulo looking at the procedure. It's really cool. It's doing all percutaneously, all right? So, with, with a sharp tip uh uh cytoscope, can go inside the lateral ventricles and perform this procedure in humans. He published 10 cases, all right? And the least we know it's feasible. All right, in the fetal lamb and also in the human and also it's safe because there is no death in at least in this, in this series so far, all right? We will see the, the efficacy in a larger series. So, I think we are ready just to start in USA, all right? So, probably join it with another hospitals and lead this, this this clinical project. So, there is many uh big names in, in fetal medicine like Cyprus nicolaitis and depress. Uh, Houston as well and us just to join efforts, all right? But our plan initially will be a phase one in 10 cases of human cases with safety and feasibility. If that filter is passed, we will go for phase two of efficacy, probably in a 50, 60 cases, all right, and go forward. Hopefully, that works and we can, and we can implement that as a new solution for fetal hydrocephalus, mostly in the cultural stenosis. And I would like to, uh, uh, thank all the people working hard in my lab, OK, in our collaborations in Madrid, in Chile, in also in Spain, in the Center for Research. Thank you very much for your attention. Happy to answer any question.