2024 Fetal Care Center Frontiers in Fetal Neurology Day 2 - Hour 1 Q&A

Well, thank you so much, Doctor Ritter, and also Doctor Urbach for those fantastic talks. Um, I'm actually going to start off with a question for, for Doctor Ritter. Um, the case, uh, the cases that you presented, specifically the twins, were there any signs, uh, I don't know if you've done, um, brain MRIs at this point? Do they, are they showing any intracranial lesions at this point? So, uh, for fetal MRI's for them, there was no, um, specific, uh, MRI findings consistent with tuberosclerosis on the fetal MRIs. Um, so they had them at 27 weeks and 32-ish weeks, I believe. Um, the, um, the more severely affected twin did have an extra NICU stay, uh, where there are concerns that there could be seizure. Um, and had an MRI at that point around 2 months of age, um, and there was one small cortical dysplasia on there. Um, both infants have had normal EEGs up to this point. Um, so we're feeling pretty reassured about their kind of neurodevelopmental progress at this point, but there's at least some findings of TSC intracrannially for the, the one. The, the less affected twin, we haven't done imaging yet and part of our goal is to kind of um delay imaging if we can um when we know there's not something severe like a, a Sega tumor that would be causing problems. And what is the duration of therapy postnatally for, for these infants? Um, there's no great answer, uh, for this. So, the, the first thing that we always look for is just, um, stability after birth. So, um, we want things to shrink and we know that these rhabdom moments will regress and shrink on their own without treatment. So, um, usually, um, it's a conversation with the family. So for this severe rhabdomyoma, the one twin, we've continued treatment because there is still some valvular displacement on the echoes that's caused by the rhabdomyoma. So we want to keep shrinking it um as we go. So we've continued treatment in that scenario and we don't have an end date. Per se. Um, that's true for many of our TSC things that we see this as a targeted therapy for the entire disease. And so oftentimes we're treating it as like, hey, we're continuing this unless you have problems. For, um, the second case I showed in which there's quite a bit of reduction before the, the infant was born, um, that family had said, hey, we're good, we just want to get to term and so we went down and, um, and so we haven't continued therapy after birth. Um, so it's really kind of a case by case discussion at this point. And it looks like based on the data you're sharing with use of MTOR inhibitors in pregnancy, there is such a wide range of dosing and wide range of just even checking, uh, you know, levels and so on. Are there attempts to try to standardize this and what are the sort of the future steps as we bring this, you know, uh, to, to a larger, um, clinical population? We, we use our, uh, pharmacokinetic uh consult service quite a bit. And so we will do that with the first levels that are drawn. Um, but we're just starting to figure this out. Um, I would say postnatally, um, and so I haven't done a lot from the fetal side. What I mean from the, the postnatal side is that the current clinical trials are actually making it so that, um, the physicians aren't deciding the dosing. It comes from the pharmakinetic team based on the infant's own dose. Um, and what I, so, so. Hopefully out of the, the current clinical trial, um, we, we get some of that information and we can create models, uh, but I think most of them is gonna depend on getting an early level or level within the first week of treatment. So when we looked at historically in our infants, we would get levels, um, but it took us two months to get to therapeutic range, um, and that's because of, you know, Delays in getting levels or not knowing how to adjust. Whereas now if we can get a level in the first week, we can get our infants into range within two weeks of life. Um, and so I think that will come for the fetal side as well, just with some extra complications because of the um increased maternal, uh, volume and change rapid changes that are even occurring at the time point, you know, 26, 28, 30, 32 weeks as we're finding these. Um, there's also rapid changes in the maternal blood volume. So I have a comment to share from the um chat as well as a two-part question myself. Um, so it's a comment from our colleague, Doctor Ford, um, that elevated triglycerides in the third trimester are not uncommon in general in pregnancy, so the serolinus effect on triglycerides may not be as, um, as severe as you might think. Yeah, we, that's what we want to say too. Uh, but we, the thing is we know, uh, triglycerides, we increase these with these medications. So it's definitely something that should be followed, but the Untangling what would be just from the pregnancy and, and from uh the treatment is, uh, I think a situation we may not be able to ever answer cause there's not gonna be a placebo necessarily in this especially when we're treating um severe rhabdomyoma. So my kind of second set of questions um relates to the fact that most of these fetuses are going to present with rhabdomyomas, but um does the study design allow for treatment if there's no evidence of a rhabdomyoma, but a CNS lesion? And I guess the first part of that question would be possibly to someone like Doctor. A garage, which is, you know, we see all sorts of brains for different reasons. Um, can you distinguish a TS lesion reliably on fetal imaging? Um, if the answer to that is no, then, you know, obviously, that's, that's not gonna allow for treatment. But if the answer to that is yes, then, um, you may be able to make a significant difference in the neuro outcomes for these babies by treating in utero. Yeah, so. I think the, the short answer is we don't uh have a great time to actually uh get fetal MRI's, um, repeatedly. That's usually if there's a family history of TSC. And so in those cases, um, we, we can catch brain lesions and be very convinced with subapendulal nodules and if there's tubers on the fetal MRI of yes, this infant has TSC. So we can pick up that, um, and you don't need rhabdomyomas at all to be in any of our studies. Kind of the risk of TSC enough is, can put us in, um, and then clinical diagnosis with the brain MRI can include you in treatment trials. There has been one case report of a congenital sega that was found on prenatal ultrasound and was also treated with um an MTOR inhibitor and had reduction in size. So there is signs too that if you have a clear brain lesion related to TSC that you can use MTOR inhibitors and treat them uh fatally as well. And certainly to add on to that, if we're able to, if we have a suspicion, and if this treatment really, you know, it seems from a side effect standpoint to on the, on the maternal side is minimal, uh, we can do genetic testing, right, and confirm because I think the very powerful thing is if we can prevent Epilepsy and we can prevent the neurodevelopmental, you know, disabilities that we see in this population early on. Um, and you add to that early genetic testing, this is really an, uh, a very, very, you know, nice therapy that we can offer to our patients. And, and that's our hope is that the current infant clinical trial is positive. We're obviously um have, see where that lands, but if that's positive, then yes, our next steps are talking about how do we find these fetal um and start prenatal treatment. Do you have better outcomes if you treat even earlier to prevent the epilepsy? OK. How far are you, um, how far are you following these babies? Um, so, in, um, so in our heart TSC protocol where we're following the echocardiograms and using that to study them, uh, we can start prenatally and then we go through, uh, 5 years of age. So trying to get a long time course cause um these really haven't been studied closely in the prenatal um or the, sorry, not prenatal, postnatal treatment trials, the kids are followed for till 2 years of age. Does it also include developmental. Yeah. It's fascinating. It's amazing for these patients. OK. Well, thank you very much, Doctor Ritter, um, and as he said, you know, I think, please feel free to reach out to him directly with any further questions or comments.