Um, we are going to move on to the next hour of our talk, um, so I would like to Um, UCSF, who will be talking to us a little bit about, um, intracranial hemorrhage and some of the challenges we face, um, as neurologists, both in fetal counseling and as we follow these children after birth. Thank you and good morning, good afternoon, whatever the right salutation is in your time zone. I'm grateful for the invitation to participate today and speak with you about intracranial hemorrhage. I'm going to focus on 3 types of intracranial hemorrhage, germinal matrix hemorrhage, intraventricular hemorrhage, periveventricular hemorrhagic infarction, as well as intraprenchymal hemorrhage. And examples of these are shown in the schematic on your left and on the right side of the slide, I have MR images with representative illustrations of the severity of different types of fetal germinal matrix hemorrhage. We use the grading system developed by Pappe to score GMH in the preterm population and apply it to fetal MRI. Grade 1 hemorrhage refers to subapendinal hemorrhage. Grade 2, blood in the ventricles. Grade 3, blood occupying more than 50% of the lateral ventricle or associated with ventriculomegaly. And grade 4 is perhaps most accurately known as a perioventricular hemorrhagic infarction, whereas a complication of IVH or ventricular distention, or both, there is obstruction of the terminal vein, which lies underneath the germinal matrix, and there's infarction of the medullary veins. Often, there is no etiology identified for germinal matrix hemorrhage in the fetus, particularly when it's a low-grade hemorrhage. Commonly identified risk factors when they are present include complications of twin pregnancy, congenital anomalies, and intrauterine growth restriction. I show an example of a co-twin demise on the left. Where initial ultrasound imaging showed ventriculomegaly, fetal brain MRI at 23 weeks, demonstrated germinal matrix hemorrhage, as shown in the echoplanar coronal image in the bottom left. which is sensitive to blood products. There was progression of ventriculomegaly into a pattern of post-hemorrhagic hydrocephalus, and in this case, the neonatal MRI is sagitral T2 shown in the middle column, illustrating obstruction at the level of the cerebral aqueduct due to an adhesion secondary to hemorrhage. And when we look back at that fetal MRI, you can see clear imaging indicators of a high risk for progression. Again, borrowing from what we know about the preterm population, there's a very rounded appearance of the frontal horns with a wide anterior horn width, which is strongly predictive of post hemorrhagic hydrocephalus. Uncommon risk factors identified include congenital infection. As well as maternal trauma and coagulopathy. And here's a case of congenital CMV acquired late in the pregnancy on the far right, with the in utero imaging illustrating germinolytic cysts suggestive of a remote terminal matrix hemorrhage, as well as really dilated temporal horns, which, while this finding is not specific for CMV is often highly suggestive. And I think an important learning point from this case is that maternal serology was negative for CMV, but we know that it is not 100% sensitive for recent infection. And this speaks to the importance of postnatal testing unless it's been definitively excluded from amniocentesis. Turning now to fetal periveventricular hemorrhagic infarction, this case presented with unilateral ventriculomegaly on a 3rd trimester ultrasound obtained to monitor fetal growth. This coronal T2 weighted MRI shows asymmetric dilatation of the left lateral ventricle, associated with ipsilateral reduction in the periveventricular white matter volume. As well as reduced volume of the ipsilateral deep gray structures. And there's a rim of T2 hypointensity in the wall of the lateral ventricle, which strongly suggested PVHI. The patient delivered just a few days after this fetal MRI with the day one head ultrasound shown in the middle panel. And this illustrated a new right temporal hypeechoic lesion, which was confirmed to be hemorrhage on a same day MRI shown on your right. This is a susceptibility weighted image where blood products bloom. And it confirmed both the right temporal hemorrhage and our theory of the case in utero that there had been a germinal matrix hemorrhage and intraventricular hemorrhage complicated by PVHI. And this combination of findings led us to strongly favor a genetic vasculopathy with targeted testing showing an autosomal dominant de novo variant in cole 4A1. Cole 4A 1 and 2 encode the alpha 1 and alpha 2 chains of type 4 collagen. They form a heterotrimer to stabilize basement membranes of blood vessels expressed throughout the body with particular enrichment in the brain, eyes, and kidneys. So, these are the organ systems that need to be evaluated when this condition is suspected. Cole 4A1 can be associated with a broad spectrum of cerebrovascular disease, including hemorrhage of a range of severity at any stage of the life cycle, as well as small vessel vascular disease and aneurysms. Ophthalmologic findings can include coloboma, as well as microcornea, and there's a form of the condition called HANAC, which stands for uh hereditary angiopathy and nephropathy with aneurysms and muscle cramps, and you can see examples of extensive renal cysts in the bottom right. Here's my patient's follow-up scan at 2 years when he developed focal impaired awareness seizures. Sagittal T2 weighted MRI on your left shows numerous hyperintensities dotted throughout the supratentorial white matter. And in the middle panel, an axial T1 weighted MRI showing a new finding of insular heterotopia, mapping out to the region of right temporal hemorrhage diagnosed after delivery, and also correlating with the patient's focal epileptiform abnormalities on EEG. I think this case raises a number of fascinating points, chief among them, the role of prenatal diagnosis to inform the ultimate natural history study from in utero across the life cycle, which is vital to address the many uncertainties that these rare diagnoses lead to. And this is particularly important for a condition like Cole-FA where there's variable penetrance and variable expressivity, and we do not have good answers to many important questions that families have, including what cognitive aging might look like with this burden of white matter disease so young that's progressive, as well as the risk of recurrent intracerebral hemorrhage and how we might prevent that. We recently published our experience with fetal intraprenchymal hemorrhage here at UCSF. I share these data on behalf of a number of collaborators, including Ulrik Glenn, the Chief of Pediatric neuroradiology here at UCSF, as well as our co-first authors, Elizabeth George and Rachel Vassar. In contrast to the other studies on fetal ICH in the literature, we restricted our study to confirmed intraparenchymal hemorrhage. And in contrast to those other studies that often didn't identify an etiology, we found an etiology in the majority of cases. Most commonly, twin twin transfusion syndrome, whether complicated by co-twin demise or uh treated with laser ablation or both. Another 25% of the cases were due to a variety of maternal and fetal complications and comorbidities. For example, 2 cases of congenital infection, and just 1 case of fetal neonatal autoimmune thrombocytopenia. About 18% of the cases were due to variants in CL4A1 or 2, and 11% of cases were due to in utero transfusion for severe fetal anemia. A quarter of our cases had no known etiology, but I do want to point out that half of those cases had no etiologic testing, and the other half had some degree of etiologic testing. One of our take-home messages from this study was the yield of genetic testing in those in whom it was obtained, which was 39%. When we looked at the relationship between the pattern of intraprenchymal hemorrhage and associated findings on fetal MRI with the etiology, some associations began to emerge. In Cole 4A12 related disorders, all of the hemorrhages were focal, stentorial, involving the frontal lobe, and the next most commonly affected structure were the deep gray nuclei. We didn't have any cases of infratentorial hemorrhorrhage or schizencephaly in the coal fora group, but these findings have been reported in the literature. The most distinct feature of cole foray was hemorrhagic porencephaly. In our twin twin transfusion cases, we tended to see bilateral multifocal hemorrhages, often with IVH. Um, this case shown here in the second image from your left, additionally illustrates diffuse injury with a failure to identify the expected multilayer pattern. You can also see significant scalp swelling due to fetal eye drops. Interestingly, our intrauterine transfusion cases all had infratentorial hemorrhage, whether in isolation or in association with stentorial hemorrhage, and this was a really distinct pattern in this group. And finally, in the other maternal fetal complication and comorbidity group, we tended to see diffuse hemorrhage and diffuse injury, again, often with IVH. I share here a more recent case that wasn't included in this study of a rare monogenic cause of intracerebral hemorrhage. This was a case of congenital Omegakeocytic thrombocytopenia due to homozygous variants in the MPL gene. This is an autosomal recessive condition. That results in successive failure of all bone marrow cell lines, often presenting with a severe thrombocytopenia at birth. And this case really highlights the demonstrable value of broad genetic testing to identify very rare causes of fetal intracranial hemorrhage, the diagnosis of which can help inform, Management and health surveillance, as well as understanding the recurrence risk. In this case, we had the very unusual and rare mechanism of inheritance of uniaral diesomy of chromosome one, where this gene is carried. When we looked at our outcomes of fetal IPH, over a third of the cohort terminated the pregnancy. There was a strong relationship between the maximal diameter of the hemorrhage, as well as the ratio of the hemorrhage to the biparietal diameter and an outcome of termination. Less than 10% experienced in utero fetal demise. And half of the cohort was live born, of whom 25% delivered at a preterm gestation. About half of the cohort had a postnatal MRI, and about half of those patients had new findings, and this really emphasizes the importance of repeat postnatal MRI to identify findings that can inform prognostication. For example, the image I show here in the middle. Panel, um, was a, a case where there was maternal cardiac surgery, multifocal diffuse hemorrhages on the fetal scan, and you can see on the postnatal scan, severe volume loss, bilateral polymicroggyrhea, and ex vacuoventricular dilatation. We had longer term outcomes in 13 children in this cohort. The vast majority developed cerebral palsy, but I do want to point out that the extent and severity of injury on fetal MRI was predictive of the topology and severity of cerebral palsy in the child, and none of the patients with unilateral injury had a non-ambulatory outcome. When we look at our outcomes from our fetal IPH cohort and compare it to the data from Mary Dunbar's meta-analysis on fetal intraventricular hemorrhage, we can see that, uh, epilepsy was much more common after IPH and motor disability was also more common after IPH. A very interesting finding that emerges when we contrast these different Uh, causes is the risk of prematurity, and I think there's something really interesting to dig into scientifically there. I want to focus very briefly on the rates of VP shunt. 60% reported after PVHI, 40% after GMHIVH. Those are much higher rates than we see in the preterm population, and this suggests that there's a bias in our literature through ascertainment. On the basis of progressive VM, so I suspect the rates of hydrocephalus after fetal hemorrhage are likely lower in the population. As Doctor Venkatessen mentioned, we have a global working group where we're developing practical recommendations for child neurologists managing prenatally identified neurologic conditions. I'm leading the effort on fetal intracranial hemorrhage with Mary Dunbar from the University of Calgary, and we anticipate these recommendations to be published in the coming months where we outline considerations for testing, surveillance imaging, and postnatal follow-up. Then this leads me to my last point. And I think this is a thematic thread that could unite all of the talks today, which is the incredible importance of multidisciplinary care over a continuum of time so we can address the uncertainties that arise in utero vis a vis diagnostic and ideologic uncertainty, as well as prognostic uncertainty. So we can follow each child and family to identify the impact in them. So, I wanna, um, summarize in saying, while there are many knowledge and practice gaps, to identify and address these gaps, there's a great need for multi-center collaboration so we can better understand ideologies and outcomes, as well as develop and evaluate management strategies to both improve outcomes as well as the family experience. Thank you.
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