2024 Fetal Care Center Frontiers in Fetal Neurology Day 1 - Dr. Charu Venkatesen

OK. So moving forward, I am going to now talk about congenital aqueductal stenosis. I do wanna say many of the themes that I want to highlight in this talk apply not just for this diagnosis, but also to many of the neurological conditions that we see um in the fetal period. And I have no, no disclosures. Um, learning objectives, um, I want to communicate, um, uh, and, and, you know, have an appreciation for some of the difficulties surrounding counseling in this condition, um, highlighting the varying neurodevelopmental outcomes and introduce the concept of isolated congenital aqueductal stenosis versus complex congenital aqueductal stenosis. So let's start with ventriculomegaly, um, and which is the most common CNS abnormality identified on fetal imaging. Uh, fetal ventriculomegaly is measured or the, the ventricle size is measured at the atrium of the lateral ventricles. Um, and anything larger than 10 millimeters is considered abnormal. So 10 to 12 is considered mild, 12.1 to 15 millimeters is considered moderate, and anything over 15 millimeters is considered severe. By the time patients with congenital aqueductal stenosis come to a fetal care center, their ventricular measurements are typically in the moderate or severe range. What does this look like? So here on the left, I have normal anatomy, fetal MRI um of a 32 week fetus, highlighting some important landmarks. The white arrows are highlighting the corpus callosum, which appears normally formed. Um, the asterisk indicates a normal fourth ventricle. The dark black arrow here shows a normal tectum, and the white arrowhead is showing a patent aqueduct, where you can see the fluid that is going through that aqueduct, and the black arrowheads are showing the normal recess of the third ventricle. In contrast, this is a 33 week fetus uh with uh congenital aqueductal stenosis where the corpus callosum is very thin. You see a thickened tectum right here, and the fluid through the aqueduct is not seen all the way through, and you see that there is a narrowing and an obstruction at the level of the inferior portion of the aqueduct. And the third ventricular recess is quite large. So this is what defines congenital aqueductal stenosis on imaging, on MRI. The incidence ranges from 0.5 to 1 per 1000 births. The ideology, we can think in broad terms as either being acquired or due to a genetic disorder or syndrome. Within the acquired category, we can further think about them as intrinsic, meaning there's some kind of an obstruction within the aqueduct itself, most commonly due to a post-hemorrhagic insult or perhaps an infection leading to gliosis, or extrinsic, which is far rarer, where there is compression of the aqueduct externally, most typically due to a mass. With regards to genetic disorders, these are rare, but among the more common that we encounter include uh L1CA mutation. Um, which is an excellent condition. Rhombencephalosynapses, which is shown in this imaging, um, on the right, where we see, uh, a fusion of the cerebellar hemispheres, which is what defines rhombencephalosynapses. This is at the 23 week stage, and this is the same patient, uh, postnatal scan showing a few cerebellar hemispheres characteristic of rhomencephalosynapses. And we can also see it accompanying distroglycanopathies, such as Walker-Warberg syndrome. In the literature, um, there are wide range in, uh, reported with regards to postnatal mortality, ranging anywhere from 34 to 68%, and typical development is very wide range, uh, reported in the literature, anywhere from 4% of children being reported to have normal development up to 63%, and epilepsy risk is reported around 50%. So with these broad range of numbers that are reported in the literature, this is quite challenging, and the question becomes, well, how can we improve counseling? We did a study, um, here at Cincinnati, and I'm just gonna present just a little bit of data as it's, it's, um, has not been published yet. Um, and I'm going to review the study, uh, very briefly. So we had 140 cases of congenital aqueductal stenosis identified by a fetal MRI prenatally. Of those 140, about 16% um had early demise either due to termination or fetal demise, and we lost about 3% to follow-up. We had 113 live births, and in that, of that number, about 11% um died uh prior to hospital discharge, and we lost another 8% to follow-up. Um, so we had short-term neurodevelopmental data available for 86 of these patients. Um, from there, we, um, had, uh, a few, um, you know, demise after discharge from the hospital, about 4% and about 11%, um, who were lost to follow-up. And so therefore, of those, then we had a further long term data available for a subset as well. We reviewed this group into categories. We basically broke them down and said, well, let's think of the CAS as isolated or complex. So, isolated were if that was the only thing that was the anomaly found on imaging, um, meaning no other intra or extracranial findings. And complex was where there were any other kind of accompanying intra or extracranial anomalies or genetic abnormalities. Main findings, so at time of discharge, we found that um those with complex CAS, higher percentage, up to 95% required some type of CSF diversion, and in this series, all the children who had, had um CSF diversion was in the form of a ventricular peritoneal shunt, whereas isolated, about 70% underwent some kind of CSF diversion. And importantly, far greater numbers if you had complex CSF, uh, complex CAS required feeding support. Almost to 63% required some type of feeding support, um, as opposed to about 29% requiring an isolated CAS. No differences between the groups in terms of seizures or respiratory support. This was where the findings became even more um interesting when we looked at longer-term outcome. Uh, when we looked at their motor outcome and um divided them into three groups, whether they were fully ambulatory or they required some assistance to ambulate, or they were non-ambulatory. And what we found was that if you had isolated CAS, um, up to 93% were fully ambulatory, whereas if you had complex CAS, about 44% were ambulatory. If um you were, had isolated CS CAS, no, none of the patients were non-ambulatory. Whereas, if you had complex CAS we certainly had about 32% who are non-ambulatory. All to say, if you have isolated CAS you have very favorable motor outcome, and this is a very important counseling piece that we can provide to families. We also looked at feeding support and epilepsy. Again, if you have, uh, remembering that, you know, in the short term, there really wasn't much of a difference between the two groups, um, in the acute stage when they were still in the NICU. However, long-term epilepsy rates were much higher, almost 56% if you had complex CAS, but only about 20% if you had isolated CAS. With regards to feeding support, almost a fivefold increase of needing some kind of feeding support via a gastrostomy tube, um, if you had complex CAS versus isolated CAS. So, one of the big points that I also want to make is, uh, you know, we tend to operate in silos oftentimes, and for a field like fetal neurology, where we are, really have so many touch points, collaboration is quite important. So for this study, for example, a lot of that work and the data that I showed was carried out by a medical student at the University of Cincinnati. Uh, we had great collaboration from Doctor Usha Nagaraj and Doctor Beth Klein, both neuroradiologists at Cincinnati Children's, Doctor Moira Hay, a maternal fetal medicine specialist at at Cincinnati Children's and Good Samaritan Hospital, Doctor Karen Berrauer, uh, one of our neurosurgeons here at Cincinnati. And so where do we move forward, um, with CAS, but I will parenthetically add many of our prenatally identified neurological conditions. Well, we need international registries. These are rare conditions. Um, and as you saw, you know, we have 140 patients that we pulled and trying to get data, but we need hundreds and thousands of patients, and that can only be accomplished through collaboration with larger patient data sets. Many of the conditions that we see, not just CAS but other common conditions such as agenesis of the corpus callosum or vermian hypoplasia, we can really think of them as isolated or complex. But we understand that complex is a very heterogeneous category, and we need much better genotype, phenotype characterization. We also need more longitudinal studies to characterize that adult-lived experience, um, not just, well, how is my child doing, you know, at age 10. Uh, but much longer, um, experiences, which leads to outcome studies. Outcome studies thus far, even in the data that, that I just shared with you, are, are things that we can measure. We can see, are they walking, what is their epilepsy, but we need better patient family and patient-defined outcomes. What are the stressors that are posed on these families, um, their perception of pain, quality of life, and independence. And, and of course, we need more studies where we look at postnatal interventions to improve outcome, and you're gonna hear a little bit about that with our next talk with um uh Doctor Scooch, as well as fetal interventions to improve outcome, which you'll hear about with um Doctor Perro after um Doctor Scooch's talk. And in the spirit of trying to get more collaboration, I wanna highlight a little bit, uh, some of our own efforts. So, um, uh, we have a Fetal Neurology consortium. Uh, this was spearheaded by Doctor Sonika Agarwal, who will speak in the next hour from CHOP as part of the AAN. Um, initiative and it has drawn fetal neurologists from across the country and I just wanna name, um, go through them a little bit here. Doctor Dan Gano, who's gonna talk in the next hour from UCSF, Doctor Monica Lemon from Duke, Doctor Sarah Mulkey from Children's National, Doctor Andrea Pardo from Laurie Children's in Chicago, Doctor Thomas. Tarui from Hasbro Children's Hospital, Doctor Mark Scher from Rainbow Babies, Doctor Lisa Emrick from Texas Children's, um, and uh one of our first initiatives was really to get a sense of where the state of practice is for fetal neurology so that that will help guide our future initiatives. And then we've reached out to international collaborators. So our second, um, collaboration, um, and one of many that we're really doing is to provide and begin to think about the, the counseling in a much more systematic approach. And we, uh, we reached out to some of our international collaborators. ator s um, including Doctor Barbara Skelza from Italy, Doctor Tony Hart from the UK, Doctor Dadwal from India, and Doctor Woolmer from the UK as well. So we believe that these types of collaborations are really, really important to move the field forward from both an education as well as from a research standpoint. So I wanna thank you very much for your time.