Ventriculomegaly and corpus callosum abnormalities are relatively common fetal ultrasound findings involving the brain. Neuroimaging specialists at the UCSF Fetal Treatment Center illustrate their consult process, showing the prognostic range for these conditions and MRI’s potential payoff for patient management.
Refer to Fetal Treatment Center Hi, My name is Aaron Matsuda. Welcome to our fourth UCSF fetal treatment center. Webinar. Um, we are here and we're open and we're ready to partner with all of you and please do not hesitate to reach out to us. We'll have some information at the end on how to refer and how to contact us. Next slide, please. So we have the pleasure of having our feudal neurology team here today to present to us a new frontiers and feudal neurology. We are graced by the presence of Dr ARIC Glenn, who is a radiologist that sees pediatric adult patients with nervous system disorders at UCSF Medical Center in Benioff Children's Hospital. Her expertise includes using advanced M R technologies to diagnose fetal and pediatric brain disorders, as well as interpreting M R images of fetuses and newborn. In her research, she works closely with the M R scientists to develop and apply new techniques that will better evaluate brain abnormalities. Glenn earned her bachelor's degree at the Massachusetts Institute of Technology and her medical degree at UC San Francisco. She completed a residency and radiology and a fellowship neuro radiology, with a focus on pediatric neuroimaging. Both at UCSF before joining the staff in 2000 and one we also have with us today Dr Dr Don Goneau, who is an assistant professor of neurology and pediatrics at UCSF. She co directs the West Bay Fetal Neurology Clinic with Dr Sheer attends on the new NATO neuro critical services, and coordinates long term care in the neonatal neurology follow up program. Her research centers on the use of advanced neuroimaging to study preterm brain injury and euro development outcomes, as well as novel robotic technologies to improve motor outcomes. She obtained her degree undergraduate degree at In Microbiology immunology at McGill University's. She studied at McMasters and trained as a child neurologist at the University of British Columbia and completed her fellowship training in neonatology, neurology as well as a masters in clinical research methods at UCSF. In addition today, we're also joined by Dr Elliot Sheer, who is a professor in neurology and pediatrics at the Well Institute of Neuroscience is and the Institute of Human Genetics at UCSF. He directs the Brain Development Research Program, a group that studies the genetics and biology of autism and epilepsy. He cited the genetic disorders of brain development including a genesis of the corpus callosum. In this process is identified several genes that air mechanical is Stickley, linked in thes to autism. For his research, he was the 2006 were sitting in of the Philip are Dodge Young Investigator awards from the Child Neurology Society. He is board certified child neurologists and co. Directs the Comprehensive Center for Brain Development of UCSF. In this capacity, he cares for Children with narrow development disorders, including autism, intellectual disability and Phyllis epilepsy. He is a native Californian completely was undergraduate green philosophy and biology at Stanford University. He obtained his M D and Ph. D at Columbia University in New York and completed his clinical training in pediatrics and neurology at UCSF. Welcome and thank you. I'll turn this over to Dr Glenn now. Thank you, Erin. So during the course of this talk, we're going to discuss the role of fetal brain memory and illustrate its value. You'll then hear from Don Gaetano, who will discuss the causes and consequences of fetal ventricular Magalie on from Elliott Sherr, who will discuss the genetic causes as well as the prognosis of abnormalities of the corpus callosum. The current role of fetal Emory in prenatal care is really that of being a compliment to prenatal sonography. And it's done primarily in cases where we would like to diagnosis where we're concerned, actually, for a brace a brain abnormality, such as when there is something that's suspected in the brain on the prenatal ultrasound. But it's also done in cases where there is a normal prenatal ultrasound. But there are complications in the pregnancy that we know put the fetus at risk for developmental brain abnormalities. It's also used to guide genetic counseling and used in centers that perform a futile surgery to evaluate the fetus both before and after in utero surgical therapies and also to help plan delivery and peri natal care. Now the value of feudal Emery has been, um, pretty much shown throughout the literature. Predominantly initially, actually from many retrospective studies, many of which were met analyses. I listed some of the largest ones here, but then, actually, uh, recently there was a very large prospective study that came out of Paul Griffiths Group in the UK, called the Meridian Study, which actually really showed the value of fetal emery Um, in cases where they're suspected brain abnormality. And they found that additional findings were actually seen on M R um and changed prognosis in about half of cases. So that was very helpful, actually, to really illustrate the value of female memory and more specifically, within the Meridian study, it was showed that the diagnostic accuracy of feudal Emery for specific brain abnormalities is much higher than that for ultrasound. And when they looked at overall brain anomalies, the diagnostic accuracy of feudal emery was 93% compared with 68% for ultrasound. They also looked at multiple subgroups of different brain anomaly, different brain anomalies, which also showed increased diagnostic accuracy. And, um, one of the brain anomalies that we looked at to look at the diagnostic accuracy of fetal Emery was a critical malformation known as polymer Krige aria. And indeed, we have also shown that the sensitivity of fetal emery for Polly Micro Jarrah is relatively high. It's probably actually even higher now since we published our study because now most of fetal Emery's performed at three Tesla bond with the increasing magnetic field strength with three Tesla m r. We can actually see a lot more details within the fetal brain. So why does final emery add value? What has higher soft tissue contrast resolution than prenatal ultrasound? And because of that, we can actually see a lot more details within the fetal brain, such as the folding pattern nurse location of the fetal brain, the developing brain Perrin coma and the corpus callosum. Andi, I'll show you some examples of normal fetal brain development. It's also not affected by artifact from the overlying Cal. Very, um, however, the exam does take quite a while upwards of 45 to 60 minutes, and the mother does have to lie still during the examination, ideally in the supine position. But if needed, we can put her in the left lateral to Cuba. Disposition. Now one of the structures that we look at when we evaluate fetal brain M R is the lateral ventricles. Um, and the lateral ventricles are relatively constant in their size During gestation, however, they do appear smaller with gestational age as the brain is forming basically and growing, Uh, just to show you here the 19 week axial image of the fetal brain on then 21 week a fetus just to show you how relatively, the lateral ventricles really look larger at 19 weeks, but they're not really larger. It's actually that the brain has grown pretty significantly between between 19 and 21 weeks now. We also look at the walls of the ventricles on day should be very smooth, and they're typically dark on T two weighted images because they're comprised primarily of germinal matrix cells within the ventricular zone, and it's the to many of the cells that will populate and form the brain. In addition, toe looking at kind of the overall shape in the walls of the lateral ventricles, we do measure the atrial diameter, as is done on prenatal ultrasound, as is shown here, um, through an axial image of the level of the body of the Cory plexus. However, it's important to note that the atrial diameter on Emery can actually differ from that on prenatal ultrasound by up to about a millimeter, even when the two studies were performed on the same day. We also look at the corpus callosum with fetal emery, and we can really see it beautifully on non oblique midline images as this curved structure above the ventricles. This is unexamined of a 21 week fetus. We can see it even more beautifully. A 29 weeks as the Colosseum has continued to grow and the fetal brain has continued to grow on. The Colosseum is always uniformed and thickness and hypo intense on the T two weighted images, which is a lot of what we use actually to make our diagnoses with fetal M R. However, in addition, toe looking for the presence of the Colosseum and its shape and its morphology, we also do by aama tree of the corpus callosum with fetal M R. In order, Thio better assess the length of the Colosseum, especially in cases where we think it may be too short, or where we suspect that there's Hypo Genesis of the Colosseum. And that's something that we typically measure in two ways. Either an inner inner by aama tree or an outer outer by, ah, mature the Colosseum, depending on the gestational age and there are references in the literature that we used to compare now, another advantage of fetal Lamar in terms of the detailed evaluation of the fetal brain that we can see is actually the multilayered pattern that we observed within the Brain Peron comma. And this was something that was observed on fetal autopsy specimens quite a while ago by Costa Vic on his group and on postmortem fetal M R. And we can see it on in utero or on in utero, fetal emery, which we do currently. Um, And it's very fascinating because this multilayered pattern that we can see within the brain prank Emma actually represents the different layers of the fetal brain. And in particular, when you look at the fetal brain prank Emma with fetal emery and I'm showing you here the t two weighted images that we use. And as I mentioned, that's the mainstay of most diagnoses, um, for fetal and mark imaging. We can see if we start with the walls of the ventricles on area of hypo intensity on these t two weighted images that represents the Germinal matrix within the ventricular zone. And above that, we could see an area that's brighter on the T two weighted images. And that represents the Perry Ventricular Zone, which is a relatively self sparse layer of the fetal brain. And then above that, we can see an area that's a little more intermediate you guys see everything okay? Perfectly a really. Excellent. So continue where I left off. I'm not sure what what I last said before I got disconnected, Um, but was talking about the different layers within the developing brain parang comma that we can see with fetal emery. Um And so I'm just showing here the bright layer within the sub plate zone, which is a transient layer within the fetal brain where there are important early synaptic connections that form. And this is a transient layer within the fetal brain. And then, um, above that See, for some reason, I'm not able to advance. There we are. And above that we have the cortical plate in the marginal layer. And this multilayered pattern is something that we expect to see on fetal Lamar until about 28 weeks gestation. Now, in addition to seeing the multilayered pattern with fetal m r, we also do by aama tree within the fetal brain. And it's a bit different from the ultrasound by aama tree because we do a cerebral by parietal diameter, which measures the actual, um, diameter of the brain Peron comma measured from the outer aspect for the outer aspect of the brain on one side to the outer aspect of the parietal lobe on the other side and also bone by parietal diameter, which is measured from the inner aspect of the Calvary, um, to the inner aspect of the calve area. The fetal brain is also very dynamic in terms of the folding pattern of location of the fetal brain. And I've just shown you some examples of a 21 week fetus 23 week fetus in the 27 week fetus, just showing you kind of overall how there are many more in folding or sell side. Aziz, you increase gestational age, but also to show you, um, if we focus our attention on the Sylvian fissure, um, which we can see here on the axial image on the 21 week fetus, and here we can see it on a 23 week fetus and then on the 27 week fetus, we can say that the Sylvian fissure is already present at 21 weeks, and it's still there 23 27 weeks. But its morphology is changing. And so fetal memorize. Let's just look not just at how Maney soul side we have and obviously the number of salsa increases and the, uh, with gestational age, but also to look at the morphology and complexity of the sell side, which also increases with gestational age. And sometimes we'll actually recommend that we do a follow up fetal emery. If we're concerned that there is a location delay now, we, um, can also do advanced feudal M R imaging. And I'm just showing you unexamined you here. Or you can actually segment out areas of the brain and look at more detailed, um, aspect of fetal brain development. And as our post processing techniques of M. R I improve, we'll see more and more of that hopefully make its way into clinical care. Now, when you refer a patient for fetal Emory, it's It's very important, actually, to make sure that you let the team that's doing the fetal m r. Know exactly what the suspicion is, um, and so if it's being done because there's a suspected abnormality on prenatal ultrasound, then it's important for us to know exactly what was seen and ideally, actually be able to look at the images is that will help us to guide the exam and also our interpretation of the exam. Similarly, if the patient has had, genetic testing is very important for us to know that. And if there are conditions in the pregnancy that may affect the fetal brain and its development, also very important for us to know that because in reality the kinds of findings that we see on fetal M R can be very subtle on DSO if we know where toe look, we have some idea of what areas of the brain may be affected or maybe abnormal. It helps us to better diagnosis those abnormalities because the fetal brain is, I've shown you really is dynamic and changes on a weekly basis. It's very important for us to also know the gestational age of the time when we're doing the scan and also how accurate we suspect that the gestational ages. So, for instance, was their first trimester ultrasound and are we sure that her LMP dating is accurate? So now I'm going to spend some time just illustrating the added value of fetal M r. With some examples, and I know that Don Ghana is gonna speak to you afterwards about Ventricular Medley and Elliott share will speak to you about abnormalities of the corpus callosum. But those air to areas that I'm gonna focus on right now and really ventricular McGill is the most common referral diagnosis for fetal Emery. Additional findings can be seen on fetal emery anywhere from 5 to 15% of cases typically. And part of that range probably depends on the experience of those who are doing the ultrasound and those who are doing the feudal emery in the Meridian study it. Actually, uh, the feudal Emery findings led to a change in management in about a quarter of the cases. When a patient is referred to us for fetal ventricular Magalie, we're looking for, uh, really trying to figure out what the reason is for the ventricular Magalie. And so we're looking for the associated findings that may be seen, and fetal ventricular meagley can be seen with many other conditions, including malformations of cortical development, including areas of focal or diffuse injury to the fetal brain malformations affecting the posterior fossa as well as abnormalities of the corpus callosum. And so this is one such case where fetus was referred to us because there was ventricular Magalie seen on ultrasound. She was 23 weeks at the time of the feudal Emery. And when we look here, if the fetal brain on M R, we have an axial image on your left and to Corona images on your top right and the bottom images also an axial image on we can see that the Sylvian Fissure zehr really too shallow for 23 weeks of gestation. So we're concerned that there's a process involving the folding pattern of the fetal brain. In addition, post era Li, we can see that we actually see too many unfolding when we shouldn't see any in this area at this gestational age, we then look more globally of the brain Peron coma, and in addition to it being thinned from the ventricular meagley, we actually do not see a multilayered pattern. So now we're very concerned that there is, um, or diffuse global cerebral dis genesis that is occurring here that is affecting the migration of neurons. Looking below the territory, um, we could see that the cerebellum is small and also the brain stem looks very dis plastic and arse agile. Image nicely shows us the Z shaped configuration of the brainstem, which is characteristic of congenital muscular dystrophy. And this is an example of Walker Warbird syndrome confirmed post Natalie. In this case, there was a fetus that had isolated mild ventricular Magalie on ultrasound, and the fetal emery. 22 weeks showed additional findings that significantly changed the diagnosis. We can see that there's a large defect within the brain Perrin coma on the right, involving the temporal lobe and the parietal lobe. There also are areas of blood that we can see a lining. Um, the area of injury on the T one weighted image on your lower left and on the T two star image on your lower right which we use to be more sensitive to blood products. And so this is an example of a schism Suffo Lee, which results from an injury to the entire Serie role mantle all the way from the, uh, ventricular zone to the developing cortex. And in this case, we brought her back for a follow up fetal memory about 10 weeks later, which will sometimes do in order to better assess the extent of fetal brain injury. And we can see here that in addition to this large cleft within the brain. Peron, comma there are multiple abnormal unfolding involving the cortex along three areas adjacent to the citizens. A phallic defect. And so here we can see evidence of Polly Micro Jari that has developed because of injury to the fetal brain. It's important also to look at the posterior fossa, and this is a case of ventricular medley, where we look at the Verma's, Um, and although you could say the Verma's is normal in height, the tissue that we see there is probably not Verma's because we don't see the normal primary ver me in Fisher. We also look at the contour of the cerebellum on the Corona image here and on the axial image here, and we don't see a Verma's. And this is a case of Robin stuff alot synopsis, which can be associated with stenosis of the cerebral aqueduct and consequent ventricular Magaly. Now another common indication for fetal Marie and we're feudal Marie can add value is in suspected abnormalities of the corpus callosum, and you'll hear more about that from Elliot share. However, futile memory can detect colossal malformations that air missed by ultrasound, and in addition, federal memory has higher diagnostic accuracy than prenatal ultrasound, both for a genesis of the corpus callosum and for Hypo Genesis of the corpus callosum, which some people refer to as partial a genesis of the corpus callosum. And if we look at the Meridian study indeed, weaken. See that for a genesis of the corpus callosum, the diagnostic accuracy of feudal emery was 93% compared to 40% for ultrasound on For Hypo Genesis of the corpus callosum, the diagnostic accuracy was 87% compared to 8% for prenatal ultrasound. We also so look for additional abnormalities on fetal emery. And in our experience, we can see those in at least 75% of cases, most commonly abnormalities involving silk ation. But also the post, your fossa and hetero topia, Um and uh, we have found is well, as the Meridian study found that there was a change in pregnancy management based on feudal MRR findings in over 40% of fetuses with colossal abnormalities. And really, the findings we see on M R can suggest a specific diagnosis and affect counseling of current pregnancy, but also of future pregnancy. So recurrence risk. So this is an example of a 20 week fetus with colossally genesis and send actively on prenatal ultrasound were on fetal. Um, are we can see on the saddle image that the corpus callosum is absent, and when we look more carefully at other features within the brain, we can see that there's an abnormality involving the distribution of the subarachnoid. Space is seen on the upper two images, which are coronal images and also in the lower panel of images, which are axial images. And in particular, we can see that there's excessive CSF within the middle cranial fossa. There's also an abnormal shape of the Cal. Very, um, if you look at the profile of the frontal bone on the satchel image on looking even more closely now with the face, we can see that there's hyper terrorism. I'm looking at the inner ear structures within the temporal bone. We can see that there's an abnormality involving the inner ear structures. And so the constellation over these findings from fetal Emery led us to suggest the diagnosis of a port syndrome, and this was confirmed with genetic testing. Another case of a 22 week fetus where colossally genesis was seen, but also with an inter hemispheric cysts on prenatal ultrasound. Fetal emery here a 22 weeks shows that the Colosseum is absent. But they're also all these abnormal in floodings in the fetal brain. If you think back to that normal cell cation slide, I showed you there really should not be many soul side At 22 weeks gestation, we also look at other structures such as the ventricles for their shape, and we can see that the left frontal horn is very dilated. They're also hetero topia lining the ventricles post eerily and unilateral Sarah Beller hyperplasia. And that led us to suggest the diagnosis of a cardi syndrome. And all these findings were confirmed with post Natal M R. And then I just wanna show a very recent case that we had off a 23 week fetus where the cable was absent. But they could see parts of the Colosseum on ultrasound, but not the poster close. Um, and so we do a fetal M r. And we can see that there is some prominent CSF space in the midline. So we're suspecting that there may be an abnormality involving the close. Um, but When we look at our sandal image, we can see nicely that there is anti are close um, the on of the body of the Colosseum, which is absent. And so this is an example of segmental colossal a genesis. So I just wanna end the portion of my talk just reminding us that fetal neurology is more is really a multidisciplinary team effort with the patient, obviously, at the center Onda, hopefully I've illustrated to you the value um, the fetal m r and the neuro radiologist can add in evaluating and counseling these patients with suspected brain abnormalities. And now, actually, I'm going toe hand it off to Don Gano who will, um, speak to us about the, uh, counseling and evaluation of fetuses with ventricular Magaly. You, Dr Glenn, I really appreciate the opportunity to participate today to speak with you about both the causes and consequences of fetal ventricular meagley, but also to discuss the role that we, as child neurologist, play as part of this multi disciplinary continuum of care. Ventricular mega Lee is the most common reason for a fetal neurology consultation. We see a slight male predominance and ventricular mega Lee is unilateral and slightly more than one half of cases. It's defined as a Nate riel diameter of 10 millimeters, which is equivalent to 2.5 to 4 times the standard deviation above the mean ventricular omega lee that measures greater than 15 millimeters is classified as severe, which is often interchangeably referred to as fetal hydrocephalus. Next slide, please. There are a number of causes of ventricular Meagley, which Dr Glenn has already well addressed. So it suffices to summarize this slide by saying that each of these associated causes congee rise to ventricular meagley by virtue of one of three mechanisms, the first being hydrocephalus, whether due to obstruction to CSF flow or uh, increased CSF production. Um, the second mechanism would be malformation and the third atrophy. And these mechanisms are not necessarily mutually exclusive, and there may be more than one cause of enlarged ventricles in any given case at any phase in the life span, including fetal e. Next slide, please. The work up includes a comprehensive photographic evaluation to assess for associated abnormalities, which occur in anywhere from 10 to 75% depending on the referral population. In this study, this could provide important clues to target the diagnostic work up. For example, growth restriction, hepatic calcifications and societies would be suggestive of congenital infection. Diagnostic amniocentesis is offered in all cases to obtain chromosome A micro array, which has a higher diagnostic yield than non invasive cell free DNA testing. Amniocentesis also enables testing of Alfa Feto protein to rule out a cult neural tube defects, as well as diagnostic testing for infection, which accounts for approximately 2% of cases of fetal ventricular meagley, most commonly C, M V and toxoplasmosis. If amniocentesis is deferred, a serology for C M V and toxoplasmosis at least or helpful I think Phil Emery should be strongly considered in all cases of ventricular mega lee, particularly when the cause of ventricular mega lee is not known or if the additional information that an Emory might provide would help inform a patient's decision about the pregnancy or enhance their understanding of what's happening with their fetus. And regardless of whether Emery is pursued, follow up ultrasound is important to monitor for progression or regression of ventricular meagley. Next slide, please. We know from multiple studies as Dr Glenn has already addressed that Maria Ford's increased diagnostic accuracy compared toa ultrasound. The most common additional brain abnormality identified is, uh, Corpus callosum abnormalities. Um, the Meridian sub study of ventricular Meg Lees showed a strong Concordes since between, um, Ultrasound and Marie Measures of ventricular meagley. It showed a diagnostic accuracy of Emory for other brain abnormalities of 99% in all comers, about 10% higher than prenatal ultrasound. The likelihood of an additional abnormality increased with increased severity of ventricular mega lee occurring in 6% of those with mild ventricular mega lee and a 10 fold increased risk amongst those with severe ventricular meagley. This additional information led to a shift in the anticipated prognostic category in one quarter of cases, worsening the outcome in a third but importantly, um anticipated improved outcome in two thirds. And based on a review of a panel of fetal specialists, this information changed clinical management in 86% significantly or decisively so in a quarter, which was defined as impacting the decision toe offer termination. The last point I'd like to make on this slide is that fetal emery was highly acceptable to participating women. Well over 90% said that they would pursue a fetal Emory in a future pregnancy. Were there to be a concern about a brain anomaly. Next, I'd like Thio show you a few additional cases of fetal ventricular mega lee on DSHEA Rare. How Marie informed the care. The first is a case of congenital C M V. That was, in fact diagnosed post Natal E, initially presenting with mild ventricular meagley with fetal emery at 30 weeks, additionally showing evidence of sub dependable cysts in the lateral ventricles, as well as on the sagittal view in the middle panel except ation in the ventricle. And this combination of findings was suggestive of congenital infection. We were particularly suspicious of congenital C M. V. Based on the morphology of the temporal horns. Invasive testing was declined. Serology showed that she was C M V i g. Positive. I dream negative and after birth is part of the work up the urine. C M V did result positive. I show the post natal memory here indicating some normal interval brain development. Some patchy white matter changes with increased signal on this t two weighted skin, as well as a small hemorrhage in one of the suburb bendable cysts. This diagnosis was very important, not just to explain why there were these changes, but it had an imminent implication for treatment, which included six months of antiviral therapy with Val Ganciclovir. Next slide, please along the same theme of pattern recognition on memory. This was a fascinating case, presenting initially with borderline ventricular mega lee that progress to unilateral ventricular mega lee, prompting a fetal, um, a riot 32 weeks with a representative example shown on your far left showing enlargement of the left lateral ventricle with some abnormal signal in the wall of the lateral ventricle, which suggested tow us a nen utero hemorrhagic infarction which, when we see this type of injury preterm baby, we would call a great for intra ventricular hemorrhage. And this baby was ultimately born due to preterm labor a week later with post natal imaging on Day one shown on the three images on your right, indicating in addition to the known prior findings, a new right temporal hemorrhage well seen in the middle panel, as well as the iron sensitive image ing on the far right showing all of the regions of hemorrhage and the germinal met matrix, the occipital horn of the lateral ventricle on the left as well as the right temporal region. And this combination of findings was strongly suggestive of a genetic vascular apathy. Ah, specifically a collagen for a spectrum disorder, which was confirmed as a call for a one mutation which had implications for the family because it can be familiarly inherited with wide FINA tip IQ variability and variants and penetrates, and also has a significant impact for the baby, both in terms of a future recurrence, risk of hemorrhage and stroke, for which she will need to be followed closely. The next slide speaks to the concept of ventricular medley being on evolving process at the time of prenatal consultation and these contrast in cases. Both had ostensibly similar image ing in the early third trimester, suggesting aqueduct all stenosis with enlargement of the lateral and third ventricles, the patient in the middle panel highlighting the value of post natal FINA typing. This was a male fetus who was born with abducted thumbs, and that pattern suggests excellent aqueduct al stenosis and targeted genetic testing revealed a mutation in l one can, in contrast, the patient on the right demonstrated progressive ventricular medley in utero with follow up ultrasound suggesting a mass centered on the brain stem, which was better visualized on this emery just a few days later with pathology unfortunately revealing a very aggressive and untreatable tumor. And finally, the last case is one of a very complex co occurrence of structural abnormalities. Hello, pros and safely, or a failure of cleavage of the cerebral hemispheres as well as dandy walker malformation, an exceedingly rare combination that had only been reported in the literature a couple of times. Thats presented with an abnormal an atomic ultrasound with fetal emery 23 weeks on the left, showing an enlarged mono ventricle with abnormal prank coma and the ventricle lined by hetero topia. And the second image, your left the saddle view showing the enlarge poster of false assist ver me in hyper genesis and upward elevation of the territory. Um, um, as you would expect from an Emory, this, um with such extensive and severe abnormalities, this baby has experienced quite severe global developmental delay and disability. Next slide, please. Collectively, I hope these cases show two things. The first is that memory has tremendous value to inform clinical care, but importantly, the outcome of ventricular medley is strongly contingent on the cause and severity and related to that the progression, rate of progression and presence of other anomalies. There are a number of unique challenges for counseling fetal ventricular meagley both related to this very wide variation and outcomes, as well as the fact that we don't have all of the information at the time of consultation. Whether this will be a progressive problem or what the et ology, maybe next side please. In the scenario of seemingly isolated, mild to moderate fetal ventricular meagley. Meta analysis data suggests that the overall prevalence of developmental delay is similar to the population level risk. So there's great reason for optimism regarding a normal outcome. But there are limitations to this literature, um, chief among them different degrees of follow up lengths of time, different types of follow up investigations, ah, lack of systematic fetal and postnatal memory. And this means there is still some degree of uncertainty that needs to be addressed with both um, future research as well as clinical follow up next slide, please. And for those babies that we anticipate a high likelihood of surgical intervention or requiring critical care. We provide that postnatal follow up initially as part of our multi disciplinary, neonatal intensive care nursery service. And for those that don't require acute care, I think there is a great value to reconnecting post natal E to address ongoing unanswered questions, determine the need for additional imaging as well as enable referral for developmental surveillance and early intervention services. And on that note, I will transfer it over to Dr Share. Thank you. Thank you very much, Dr Dan. Out of this, you've had the pleasure of having really excellent presentations focusing primarily on the emerging findings and how that informs both counseling, um, and a better understanding of prognosis. And I'm going to include some of that approach to thinking about how the understanding the structure of the corpus callosum might impact our understanding of clinical outcomes but also recognizing that we really need a three pronged approach where we think about imaging genetics and then even Aziz we understand better how specific mutations impact the function of the protein in brain development. Onda how that yields better understanding of the developmental outcomes that we will be counseling patients. And so shown here is, um, these air post natal images obviously of the corpus callosum in these mid sagittal t one weighted images and you can see here the one on the lower left is the normal corpus callosum Onda one. Right above it is the complete absence of the corpus callosum, a genesis of the corpus callosum. But there is also smaller ones in the upper right corner that we refer to as partial A C c. A man, Um, the one on the bottom, a thin corpus close. And we see all of these, um, easily in postnatal image ing. However, sometimes the thin corpus callosum that's fully formed, um may not present itself in that manner in a in a prenatal fashion. And so we may miss the opportunity to detect that even with the best available image next slide, Um, we also look for associated features. And so in these thio coronal images, the arrows were pointing out, Um, what is happening to the fibers that don't form the corpus callosum? So these fibers instead run hips laterally from the front of the cortex to the posterior regions, and these were referred to as probes bundles. Um, and I'll show you in just a moment. There's actually some evidence that in certain cases, having thes probes bundles, as opposed to say, not having them leads to a better outcome next slide. Yeah, not next. Like, but just thes images here. This shows what a normal corpus callosum looks like in the coronal image crossing the midline. And then next image you can see here the gave them septum pollution, um, that we would see in a normal developing bring that Dr Glenn has showed us before next slide Another feature that we frequently see in closely Genesis is referred to as culpo successfully on Do you concede that in the axial, um, image that's displayed on look like ventricular omega Lee in the form of, um, obstruction or some other form that leads to hydrocephalus? But these are indeed, um, normal findings to be seen in closely Genesis and don't require any any surgical interventions. Eso having a sense for that early on allows you to provide better counseling next slide. So what do we know about the incidents and epidemiology of a C. C. So the top data showing data from the state of California from 1983 to 2003 is work that we did as a team here at UCSF, including Hannah Class, who is one of our premier pediatric neonatal neurologists on DSO That data from the state of California gave us an incidents of approximately one in 5000 on, by the way that that was ascertained, we expected that would be another ascertainment of the total available number. Um, we then redid an analysis using insurance data. Andi came up with a incidents of approximately one and 2000. Um, so it's still quite a common birth defect that requires considerable attention. Next slide that so work that that my lab has been doing is trying thio add those two pieces that I mentioned toe augment the image. So if we have excellent image ing, can we use genetics? And can we use other features in the case here? Well, I'll show you some data on protein function, but all three together, we think, will give the strongest understanding of what is happening during brain development and how that might influence outcome. And so the first year is just looking at the burden of genetic mutations on, But just for sake of brevity, I want you to focus your attention on the the two bars at the bottom where it says loss of function or L O F. Onda. What this is is looking at individuals who are either, um, corpus callosum, malformation carriers or, um um, uh, typically developing individuals without any abnormalities. And you can see that there is, um, a significantly increased frequency of loss of function mutations again mutations that result in premature truncation of the protein for lots of different reasons, but that these air markedly mawr elevated, um, in individuals that have a C C versus normals. And this kind of data is important because what it allows us to do is to take the data that we're collecting on individual cases and extrapolated and say that most of the cases of loss of function mutations will be pathogenic and have clinical consequences Next line. And what can we say about the potential genetic overlap of a C. C with other nerve developmental disabilities? And does that put on these patients at risk? And you can see that there is a significant overlap for genes that Aaron, both A C C cases, autism cases as well as cases of developmental disabilities. Um, in a sort of broader perspective, however, you can still see that there are many genes in this particular grouping 173 where we find those Onley in a C C. And not in idiopathic autism or developmental disabilities. Um, so even though those individuals will go on, many of them toe have, um, delays and development, they won't be coming at it from the same angle. And again, understanding those implications will be important for families and prognosis generally next slide. And then, um, we've been, um, looking at a number of an atomic features on our brain imaging on Ben looking to see whether that will impact our ability to predict outcomes. And you can see here that all the individuals that have a global developmental delay, um, in the fourth column over from the right that many of them have other features that increase the risk. So the larger the circle and the darker the circle, um, the mawr that the risk factor is increased. So just by way of unexamined, you can see microcephaly or white matter volume reduction. Um, correlating with global developmental delay in a significant way and similarly Marie findings that are, um, robustly abnormal also correlates strongly with global developmental delay. So, again, all of these features that we're seeing here give better credence to our interpretive, um, capacity when we're tryingto give advice to families next. Fine. Um, and this, um, pathway analysis here where you can see that the mutations air linked, um, in in different ways to different domains of functions such as Exxon development, neuronal projection, guidance for brain cell migration, nervous system development. More generally, all of these are allowing us to understand the global function or the global category of function that these different genes are involved in. And again, when we see these, we can have a better understanding of developmental outcomes. Excellent. Okay, I'd like to give you a specific example of a group of individuals that we've been trying to understand better. Andi, these individuals all have mutations. Um, in the gene Kif one A, which is the main kindness in, or the main motor protein that moves material from the cell body down to the acts on terminals. Um, in the developing brain on Do you concede E here on the left that there are two different mutations that we're highlighting one. That's a miss sense mutation that results in a switch from 3. 18 to meth anin at amino acid. Position 99 on Ben. You can also see down below at position 2 16 mutation. That results in a switch from Argentine to history. Um, at the top, right of this figure, you can see, um, normal corpus callosum in a satchel image Azaz. Well, as in the axial image to the right. Um, but what we also have observed in this cohort is progressive loss of white matter volume, a thinning of the corpus callosum, and a reduction in Sarah Beller volume. So you can see, um, the red arrows in the upper left are pointing out the cerebellum and you can see on the first one at nine months Looks apparently normal, but by one year in five months, there's already significant loss of volume, and you can see that repeated below in a second patient who also has the exact same mutation. We also see similar loss of volume when looking just simply at the size of the ventricles in the axial images that air right below that so starting at 10 months, Um, and going through to four years and seven months, you can see that there's a gradual increase in the size of the ventricles, which is indicative of worsening of cerebral volume loss. And not surprisingly, these features of volume loss are also associate ID with, with progressive decline in cognitive and motor function. And we can see similar features. Um, in the three samples that I showed you in the Argentine Tosto mutation on the bottom left. Mm. Okay. Next side. Okay. And I think that I've summarized this well, but just to say that there are many examples off of these mutations, this was the first grouping of these cases. But now, over time, not only from our group, but from other groups. We continue to see a, um a replication of finding, so that, for example, the three inning, 99 to Metheny mutation is recurrent both in its clinical outcomes. Well, as in its brain imaging outcome on next slide. And then finally, there's a third way to take a stab at trying to better understand what's happening on bats to study the function of the protein, either in cells in vitro or in the case that I'm going to show you here, actually, just a protein biochemistry essay and so many sins are again the motor proteins that moved down the micro tubules that air inside of Exxon's. And another way of studying them is to do that in reverse, where you take the kindness and proteins that are the blue blobs with the black lines, um that are attached between the micro tubules that's in orange and green and the cup of the glass cover slips, which is holding the whole subject. And what we're going to do is create a situation where these, um, Keynesian molecules combined to the micro tubules and shuttle them along. Um, in this gliding ass, A. So next slide, please. Okay, so in the upper left, we're going to see what a normal kindness and looks like with the micro tubules. If you could just start that slide there on, do you concede if you look that all of these white lines, which are essentially micro tubules in, um sped up view are moving along the surface of the glass slip and if we go to the one on the bottom, the T and N m so that has again this mutation from three million to defining. Um, it looks like all of those fibers that are moving quite briskly above are actually stalled, so they're not functioning at all. They're not able to move these micro tubules down. Um, now, if we can look at the 2 to 0 I salute seen bailing toe, I salute scene. That's a polymorphism, Meaning that that's a variation that occurs in the general population on. Do you can see that there is considerable movement their asses Well, um, and so that allows us to measure in a meaningful way, a difference between a healthy, um, change. That's just a random change and a significant Tina typical change, like the dreaming 99 with dying. And then if we can look at the 216 c on the far right. Um, this is again the other one that I showed you with the volume loss Onda again that this also has essentially no movement. So you have very, very strong correlations between clinical outcomes imaging features. And in this particular case, changes and imaging feature over time, as well as clear biochemical abnormalities that we can measure next slide. Just Yeah, there we go. Perfect. And then we can then quantify this, um, in this essay and measure the degree of speed of these micro tubules. And so the one on the left is the wild type of the normal micro tubules with a normal kindness. And, um and then the ones in the middle, All three. You know, the two that I showed you, the 3 1999 thinning and the Argentine two unsuccessful ing have essentially no motility on board. Um, it probably is the reason why we see the clinical and imaging abnormalities that we do see next line. And then, you know, we're obviously going to encounter um, differences over time, and we may see mutations that we've never seen before. And can we understand the potential for outcomes based on that? And so here's a mutation that occurs, um, at position 4 84 changing a glazing to a Syrian. So first off, a glazing to a Syrian is a milder genetic mutation. Secondly, that mutation is not in the motor domain. So the motor domain is the green on the left, where it says kindness and motor. And that's as you would expect. That's kind of like the heavy lifting section of the protein eso This is occurring in a different region and are a priority prediction would be that this wouldn't maybe Onley, um, show mild developmental concerns as opposed to the severe ones. So next slide on Ben. This is the same child who we consulted on. This was not a prenatal visit, but this was a post natal visit. But we could see already at four years that there was a slight volume reduction in the cerebellum Onda A year and a half to two years later, um, there's essentially mild to no additional atrophy. Andi, that actually corresponded with the degree of disability that the child had. It was much milder. The child was in regular school. Andi was doing fine with just a little bit of educational systems next side. Okay, um, I'm gonna just summarize here. So here here is our team. Um, Dr Glenn is our pediatric neuro radiologist. Dr. Gano and I are the pediatric neurologists who are most regularly associated with providing consultation to the parent Vitalogy team. Doctor Foster Barber and Dr Gardner have also stepped in and have similar expertise Thio bear. And then, um last but not least, Dr Gupta, our colleague and neurosurgery and pediatric neurosurgery, um, can lend significant expertise on a number of issues on DSO. I think I would just say in summary that that our team is able to both, um, give you the most up to date evidence that's in the literature. But also because this is really what we dio on a research faces is Well is on a clinical basis that we can keep you abreast of changes. Has there actually happening in the Andi? Thank you for your attention. Thank you, Dr Glynn. Doctor Gano Doctor. Share very much. Appreciate your time and coming and sharing with us. Uh, just up here right now. It's just a side on referring. I'll bring this back up in the second everybody to see, but thank you to all of our physicians for taking the time and thank you to our physician liaisons who also helped to make this possible in organizing and bringing everybody together