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.
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Hi, my name is Aaron Matsuda, Welcome to our fourth UCSF fetal treatment center webinar. Um We are here and we are open and we are 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 fuel neurology. We are graced by the presence of Doctor Erick 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 technologies to diagnose fetal and pediatric brain disorders as well as interpreting m. R. Images of fetuses and newborns in her research. She works closely with the mmr 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 U. C. San Francisco. She completed a residency in radiology and a fellowship in neuro radiology with a focus on pediatric neuro imaging, both at UCSF before joining the staff in 2001. We also have with us today dr dr dot Don Gaetano, who is an assistant professor of neurology and pediatrics at UCSF. She co directs the West Bay feudal neurology clinic. With Dr Sheer attends on the no NATO neuro critical services and coordinates long term care in the neonatal neurology. Follow up program. Her research centers on the use of advanced neuro imaging to study preterm brain injury and neuro development outcomes, as well as novel robotic technologies to improve motor outcomes. She obtained her degree undergraduate degree in microbiology and immunology at McGill University's. She studied at McMaster's 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 Neurosciences 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 studies the genetic disorders of brain development, including a genesis of the corpus callosum. In this process, he has identified several genes that are mechanical, mystically linked these to autism. For his research, he was The 2006 Recipient of the Philip Our Dodge Young Investigator Award from the Child Neurology Society. He is board certified child neurologists and co directs the comprehensive Center for brain development to UCSF. In this capacity he cares for Children with neuro development disorders including autism, intellectual disability and epilepsy epilepsy. He is a native California and completed his undergraduate Green Philosophy and Biology at Stanford University. He obtained his MD and PhD 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 M. R. I. And illustrate its value. You'll then hear from Don Gaetano who will discuss the causes and consequences of fatal ventricular Magaly and from Elliot share who will discuss the genetic causes as well as the prognosis of abnormalities of the corpus callosum. The current role of fetal MRI 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 diagnose, where we are 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's 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 fetal surgery to evaluate the fetus both before and after in utero surgical therapies and also to help plan delivery and perinatal care. Now, the value of feudal mari 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 M. R. I. Um in cases where there are 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 final M. R. I. And more specifically within the meridian study, it was showed that the diagnostic accuracy of fetal MRI for specific brain abnormalities is much higher than that for ultrasound. And when they looked at overall brain anomalies, the diagnostic accuracy of fetal MRI 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 MRI was a cortical malformation known as polly my crotch area. And indeed, we have also shown that the sensitivity of fetal MRI for polly microsurgery is relatively high. It's probably actually even higher now, since we published our study, Because now most of Fetal MRI is performed at three Tesla. And 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 fetal MRI add value? Well, it 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 or location of the fatal brain, the developing brain Perrin coma and the corpus callosum. Um And 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 awhile upwards of 45-60 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 um are 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 and 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 um and they should be very smooth and they're typically dark on T2 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 to looking at kind of the overall shape and 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 at the level of the body of the Corey plexus. However, it's important to note that the atrial diameter on M. R. I can actually differ from that on prenatal ultrasound by up to about a millimeter. Even when the two studies are performed on the same day. We also look at the corpus callosum with fetal M. R. I. And we can really see it beautifully on non oblique midline images as this curved structure above the ventricles. This is an example of a 21 week fetus. We can see it even more beautifully at 29 weeks as the colosseum is continued to grow and the fetal brain has continued to grow and the colosseum is always uniform and thickness and hippo 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 to 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. Uh in order to better assess the length of the callosum, especially in cases where we think it may be too short or where we suspect that there's HIPPA genesis of the callosum 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 close um depending on the gestational age. And there are references in the literature that we use to compare. Now another advantage of fetal um are in terms of the detailed evaluation of the fetal brain that we can see is actually the multilayered pattern that we observe within the brain peron comma. And this was something that was observed on fetal autopsy specimens quite awhile ago by costa vic in his group and on postmortem fetal M. R. And we can see it on in utero or feed on in utero fetal MRI, which we do currently. Um And it's very fascinating because this multilayered pattern that we can see within the brain. Peron coma um actually represents the different layers of the fetal brain. And in particular when we look at the fetal brain, Peron coma with fetal M. R. I. 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 M. R imaging, we can see if we start with the walls of the ventricles uh an area of hypo intensity on these T. Two weighted images that represents the germinal matrix within the ventricular zone. And above that we can see an area that's brighter on the T. Two weighted images and that represents the peri 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. Arena. Okay, excellent. So continue where I left off. I'm not sure what what I last said before I got disconnected. Um But he was talking about the different layers within the developing brain Perrin coma that we can see with fidel M. R. I. 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 let's 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 um Are we also do by on a tree within the fetal brain? And it's a bit different from the ultrasound by on a tree because we do a cerebral by parietal diameter which measures uh the actual um diameter of the brain. Perrin comma measured from the outer aspect, 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 into 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 a 27 week fetus, just showing you kind of overall how there are many more unfolding or cell site as you increase gestational age. Um but also to show you um if we focus our attention on the sylvian fissure um which we can see here on the axle 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 at 23 and 27 weeks but its morphology is changing and Sophie deliveries, let's just look not just at how many cell side we have and obviously the number of cell site increases and the uh with gestational age, but also to look at the morphology and complexity of the cell site, which also increases with gestational age. And sometimes we'll actually recommend that we do a follow up fetal MRI if we're concerned that there is a location delay. Now, um we um uh can also do advanced fetal M. R. Imaging and I'm just showing you an example here. Or you can actually segment out areas of the brain and look at more detailed um aspects 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 M. R. I. It's very important actually to make sure that you let the team that's doing the final 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 as 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. And so if we know where to look and we have some idea of what areas of the brain may be affected or may be abnormal, it helps us to better diagnose those abnormalities. Because the fetal brain, as 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 at 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 um Don Gaetano is going to speak to you afterwards about ventricular medley and Elliot share will speak to you about abnormalities of the corpus close up. But those are two areas that I'm going to focus on right now. And really ventricular McGill is the most common referral diagnosis for fetal MRI. Additional findings can be seen on fetal MRI 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 M. R. I. In the meridian study it actually uh the funeral MRI findings led to a change in management in about a quarter of the cases. And when a patient is referred to as for fatal ventricular Magaly, we're looking for uh really trying to figure out what the reason is for the ventricular Magaly. And so we are looking for the associated findings that may be seen. And fatal 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 a fetus was referred to us because there was ventricular Magaly seen on ultrasound. She was 23 weeks at the time of the feudal M. R. I. And when we look here at 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 image is also an axial image. And we can see that the Sylvian fishers are 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 eerily, 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 at the brain perama and in addition to it being thinned from the ventricular mega lee, we actually do not see a multilayered pattern. So now we're very concerned that there is a more diffuse global cerebral dis genesis that is occurring here that is affecting the migration of neurons looking below the territory. Um we can see that the cerebellum is small and also the brain stem looks very dis plastic and are, so. Original image nicely shows us the Z shaped configuration of the brain stem, which is characteristic of congenital muscular dystrophy. And this is an example of walker Warburg syndrome, confirmed post natally in this case there was a fetus that had isolated mild ventricular mega leon ultrasounds and the fetal MRI 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 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 succesfully which results from an injury to the entire cerebral 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 MRI 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 Perrin comma there are multiple abnormal unfolding involving the cortex along um the areas adjacent to the skies. And so phallic defect. And so here we can see evidence of pollen microsurgery 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 vermillion 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 the case of robinson buffalo synopsis, which can be associated with stenosis of the cerebral aqueduct and consequent ventricular magali. Now another common indication for fetal MRI. And we're fetal MRI can add value isn't suspected abnormalities of the corpus callosum and you'll hear more about that from Elliot share. However, fetal MRI can detect colossal malformations that are missed by ultrasound and in addition, final memory has higher diagnostic accuracy than prenatal ultrasound. Both for a genesis of the corpus callosum and for HIPPA 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, we can see that for a genesis of the corpus callosum, the diagnostic accuracy of fetal MRI was 93% Compared to 40% for ultrasound. And for a hip a. 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 M. R. I. And in our experience we can see those in at least uh 75% of cases most commonly abnormalities involving suffocation but also the posterior fossa and hetero topia. Um and uh we have found as well as the Meridian study found that there was a change in pregnancy management based on final 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 a future pregnancy. So recurrence risk. So this is an example of a 20 week fetus with colossal a genesis and sinned. Actually on prenatal ultrasound. We're on fetal. Um are we can see on this satchel image that the corpus callosum is absent. And when we look more carefully at other features within the brain we can see that there is an abnormality involving the distribution of the subarachnoid space is seen on the upper two images which are corona images and also in the lower panel of images which are axial images. And in particular we can see that there is 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 saddle image and looking even more closely now at 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 is an abnormality involving the inner ear structures. And so the constellation of these findings from fetal MRI led us to suggest the diagnosis of a Prince syndrome and this was confirmed with the genetic testing. Another case of a 22 week fetus where colossal a genesis was seen but also with an inner hemisphere exist on prenatal ultrasound fetal MRI here at 22 weeks shows that the colosseum is absent, but they're also all these abnormal info holdings in the fetal brain. If you think back to that Normal cell cation slide, I showed you they're really should not be many cell site 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 cerebellum 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 of 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 central image we can see nicely that there is anti R. Close. Um and they one 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 is really a multidisciplinary team effort with the patient obviously at the center um and 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 to hand it off to Don Gaetano 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 neurologists play as part of this multidisciplinary continuum of care, ventricular medley is the most common reason for a fetal neurology consultation. We see a slight male predominance and ventricular meagley is unilateral and slightly more than one half of cases. It's defined as an atrial diameter of 10, which is equivalent to 2.5 to 4 times the standard deviation above the mean Ventricular meagley that measures greater than 15 mm 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 can give rise to ventricular meagley by virtue of one of three mechanisms. The first being hydrocephalus, whether due to obstruction to CSF flow or 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 lifespan, including fetal e. Next slide please. The work up includes a comprehensive Sana graphic evaluation to assess for associated abnormalities which occur in anywhere from 10 to 75% depending on the referral population in the study, this can provide important clues to target the diagnostic work up. For example, growth restriction, hepatic calcifications in the cities 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 alpha 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 fatal 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 fetal MRI should be strongly considered in all cases of ventricular meagley, particularly when the cause of ventricular medley is not known. Or if the additional information that an MRI 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 MRI 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 MRI affords increased diagnostic accuracy compared to ultrasound. The most common additional brain abnormality identified is corpus callosum abnormalities. Um The meridian sub study of ventricular Magaly showed a strong concordance between um ultrasound and MRI measures of ventricular meagley. It showed a diagnostic accuracy of MRI. 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 meagley occurring in 6% of those with mild ventricular medley and a 10-fold increased risk amongst those with severe ventricular medley. 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, an anticipated improved outcome in two thirds. And based on a review of a panel of fetal specialist, this information changed clinical management in 86 significantly or decisively so in a quarter, which was defined as impacting the decision to offer termination. The last point I'd like to make on this slide is that fetal MRI was highly acceptable to participating women. Well over 90% said that they would pursue a fetal MRI in a future pregnancy. Were there to be a concern about a brain anomaly? Next I'd like to show you a few additional cases of fatal ventricular Magaly and share how MRI informed the care. The first is a case of congenital CMV. E. That was in fact diagnosed post natally initially presenting with mild ventricular Magaly With Fetal MRI at 30 weeks. Additionally showing evidence of sub epidermal cysts in the lateral ventricles as well as on the saddle 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 CMV. E. Based on the morphology of the temporal horns, invasive testing was declined. Serology showed that she was C. M. V. Big positive I. G. M. Negative and after birth as part of the work up the urine C. M. V. Did result positive. I show the post natal MRI 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 suburbs Chandimal 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 Belgian cyclo Here. Next slide please Along the same theme of pattern recognition on MRI. This was a fascinating case, presenting initially with borderline ventricular meagley that progressed to unilateral ventricular meagley, prompting a fetal MRI. At 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 to us um An in utero hemorrhagic infarction which when we see this type of injury in a preterm baby, we would call a grade four 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 imaging on the far right, showing all of the regions of hemorrhage and the germinal 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, specifically a collagen for a spectrum disorder which was confirmed as a cold for a one mutation which had implications for the family because it can be familiarly inherited with wide Fiona typically 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 an evolving process at the time of prenatal consultation. And these contrasting cases both had ostensibly similar imaging In the early 3rd trimester, suggesting aqua ductile stenosis with enlargement of the lateral and third ventricles. The patient in the middle panel highlighting the value of post natal Fiona typing. This was a male fetus who was born with abducted thumbs and that pattern suggests excellent aqua ductile 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 MRI just a few days later, with pathology unfortunately revealing a very aggressive um and untreatable tumors. And finally the last case is one of a very complex co occurrence of structural abnormalities. Hello, pros in 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. Um This presented with an abnormal an atomic ultrasound with fetal MRI. At 23 weeks on the left showing an enlarged mono ventricle with abnormal prank coma and the ventricle lined by Henry topia. And the second image to your left. The satchel view showing the enlarged posterior fossa, cyst, vermillion, hyper genesis and upward elevation of the territory. Um um as you would expect from an MRI 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 MRI has tremendous value to inform clinical care but importantly the outcome of ventricular miglia 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 in 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 etiology 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 is 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, a lack of systematic fetal and postnatal MRI. 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. Yeah. 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 multidisciplinary neonatal intensive care nursery service and for those that don't require acute care. I think there is a great value to reconnecting post natally 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. Uh thank you very much Doctor Jan out of this. Um you've had the pleasure of having really excellent presentations, focusing primarily on the imaging findings and how that informs both counseling on 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 as we understand better how specific mutations impact the function of the protein in brain development um and how that yields a better understanding of the developmental outcomes that we will be counseling the patients. And so shown here is um These are 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. Um and the 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 in the upper right corner that we refer to as partial A. Cc. And then um the one on the bottom of a thin corpus callosum and we see all of these um easily in post natal imaging. 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 imaging. Next slide um We also um look for associated features and so in these two um corona images, the arrows are pointing out um what is happening to the fibers that don't form the corpus callosum. So these fibers instead run hips laterally um from the front of the cortex to the posterior regions. And these are referred to as probes bundles. Um And I'll show you in just a moment, there's actually some evidence um that in certain cases having uh these probes bundles as opposed to say not having them leads to a better outcome. Next slide yet not next slide but just um these images here. This shows what a normal corpus callosum looks like in the corona image crossing the midline. And then next image um you can see here the um gave them septum pollution um that we would see in a normal developing bring. The doctor Glenn has showed us before next slide. Another feature that we frequently see in closely genesis is referred to as culpo succesfully. Um And you can see 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 intervention. And um so 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 2000 and three is his work that we did as a team here at UCSF including Hannah class, who is one of our premier pediatric neonatal neurologists. Um And so that data from the state of California gave us an incidence of approximately one in 5000. Um and the way that that was ascertained, we expect that that would be um under ascertainment of the total available number. Um We then read it an analysis using insurance data Um and came up with the incidence of approximately one in 2000. Um so it's still quite a common birth defect that requires considerable attention. Next slide that so um work that um that my lab has been doing is trying to add those two pieces that I mentioned to augment the imaging. So if we have excellent imaging, can we use genetics and can we use um other features in the case here. 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 here is just looking at the burden of genetic mutations. Um And just for sake of brevity, I want you to focus your attention um on the the two bars at the bottom where it says loss of function or L. O. F. Um And what this is is looking at individuals who are either um corpus callosum malformation carriers or um um typically developing individuals without any abnormalities. And you can see that there is a significantly increased frequency of loss of function mutations. So again mutations that result in premature truncation of the protein um for lots of different reasons but that these are markedly more elevated um in individuals that have A. Cc 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 slide. And what can we say about the potential genetic overlap of A. Cc 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 are in both a. Cc cases autism cases as well as cases of developmental disabilities 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 only in A. C. C. And not in idiopathic autism or developmental disabilities. Um So even though those individuals will go on many of them to 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. Um and then 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 more that the risk factor is increased. So just by way of an example you can see microcephaly or white matter volume reduction um correlating with a global developmental delay in a significant way and similarly MRI findings that are 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 trying to give advice to families next fine. Um and this um pathway analysis here where you can see that the mutations are linked in in different ways to different um domains of functions such as Exxon development, neuronal projection guidance, um 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 next time. Okay. I'd like to give you a specific example of a group of individuals that we've been trying to understand better. Um And these individuals all have mutations in the gene kIF. One a which is the main Kinison or the main motor protein that moves material from the cell body down to the axon terminals in the developing brain. Um And you can see here on the left that there are two different mutations that were highlighting. One that's a miss sense mutation that results in a switch from three inning to mckinnon at amino acid position 99. Um And then you can also see down below at position 2 16 a mutation that results in a switch from argentine to history. Um At the top right of this figure, you can see um normal um corpus callosum and a satchel image as 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, um A thinning of the corpus callosum and a reduction in cerebellum or volume. So you can see um The red arrows in the upper left are pointing out that sara bellum and you can see on the first one at nine months um looks apparently normal but by one year and five months um 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. Um we also see similar loss of volume when looking just simply at the size of the ventricles in the axial images that are right below that. So starting at 10 months um and going through to four years and seven months, you can see that there is 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 associated with um 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 are ginny to history 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 of, 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 findings so that for example, the three inning 99 to Metheny mutation is recurrent, both in its clinical outcome as well as in its brain imaging outcome, our next slide. And then finally, there's a third way to take a stab at trying to better understand what's happening. Um, and that's 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 are inside of axons. And another way of studying them is to do that in reverse where you take the kidneys and proteins that are the blue blobs with the black lines um, that are attached between the micro tube. You'll, that's in orange and green. And the the glass cover slip, which is holding the whole subject. And what we're going to do is create a situation where these um, Kinison molecules combined to the micro tubules and shuttle them along in this gliding ass. A So next slide please. Okay, so in the upper left, we're gonna see what a normal uh, Kinison looks like with the micro tubules. If you could just start that slide there. Um, and you can see if you look that all of these white lines which are essentially micro tubules in um um sped up view are moving along the surface of the glass slipper. And if we go to the one on the bottom the T. And N. M. So that has again this mutation from three in into my thinning. Um It looks like all of those fibers that are moving quite briskly above aren't actually stalled so they are not functioning at all. They're not able to move these micro tubules down. Um now if we can look at the 2-0 I solution bailing too, I solution that's a polymorphism, meaning that that's a variation that occurs in the general population. Um and you can see that there is considerable movement there as 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 scientific change like the three mean 99 within me. 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 and 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 in 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 for the normal micro tubules with a normal Kinison. Um And then the ones in the middle, all three, You know the two that I showed you, the 399 Metheny and the Argentine to once existing have essentially no motility. Um And um it probably is the reason why we see the clinical and imaging abnormalities that we do see next slide. And then um 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 for 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 kind of like the heavy lifting section of the protein. Um So this is occurring in a different region and are a priority prediction would be that this wouldn't maybe only show mild developmental concerns as opposed to the severe ones. So next slide. Um And then 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. Um and a year and a half to two years later. Um There's essentially mild to no additional um atrophy. Um and that actually corresponded with the degree of disability that the child had. It was much milder, the child was in regular school um and was doing fine with just a little bit of educational assistance. 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 Gan O. And I are the pediatric neurologists who are most regularly associated with um providing consultation to the parasitology team, Dr Foster, Barber and Dr Gardner have also uh stepped in and have some similar expertise to bear. And then um last but not least dr Gupta our colleague and neurosurgery, pediatric neurosurgery um uh can lend significant expertise on a number of issues. Um And so I think I would just say in summary 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 do on a research basis as well as on a clinical basis that we can keep you abreast of changes as they're actually happening in the um and thank you for your attention. Thank you dr glen dr 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 I'm referring. I'll bring this back up in a second for 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. Mm.
