While surgical survival for complex congenital heart disease (CHD) now exceeds 90%, over half of these children still develop significant neurological dysfunction. New evidence suggests this often begins in utero, resulting from aberrant fetal circulation, rather than surgical trauma. Get to “the Heart of the Matter,” with Neil Friedman, MBChB as he discusses current understandings of neurological injury in CHD patients.
All right. Well, uh, good morning, everyone. Um, please let me know as we go along if you either cannot hear me or um not see the slides. So, um, I will be talking today about um our current understanding from a neurological perspective with respect to injury from congenital heart disease. Uh, this is a really, really big topic that's been 50 years in the making. And what, in order to understand where we are today, by necessity, we really need to go back and understand where we've come from, um, in order to better understand where we are right now and where the future lies. Uh, no conflicts and, uh, no financial disclosures. So just by way of overview, um, congenital heart disease is still one of the most common, uh, birth defects that, uh, that we see that accounts for about 300 to 40,000 children every year or 1% of births. Um, and this is including everything, all come as even things, um, sort of more simple like ASDs, uh, for example, VSDs which may spontaneously close. But the real area or the group of interests are what's known as the complex congenital heart disease, and there are about 65,000 children born every year with this. And The group that's been particularly studied and we'll go through why this group has been looked at, uh, for very good reasons, is the, uh, transposition of the great arteries, where the arteries are coming off the wrong chambers, and the hypoplastic left heart syndrome, which is essentially a single, uh, unihysiology, univentricular physiology, and about half of all the kids with complex heart disease fall into these categories. And these are the two categories that have really been studied over the last 50 years. So, um, what's changed over the years is that the repair of children with complex congenital heart disease has really become earlier and earlier. And now about 25% of all these children will have surgery during the first year of life and actually very often within the first weeks of life. One of the advantages of this is that there's less exposure to chronic hypoxia, um, compared to when children used to be uh, used to be repaired. And there's also less palliative surgery. The ability now to do more definitive repairs, uh, has also changed with experience and with time. So, uh, this is a, a slide, um, from CHOP, and what we see on the right side of the screen here are the various types of heart surgery. Staring at the top is the hypoplastic left heart transposition tetralogylo and BSDs with the decades along the bottom. And what's really dramatic, as you can see, BSD has always had very good survival, but now it's almost 100% survival, whereas hypoplastic left heart, when the surgery was first started in the early 1970s, the mortality from this was really incredibly high. Almost no, none of the children survived and certainly didn't survive long term. But right now the survival rates are really remarkable with more than about 90% of these children surviving. So survival is no longer really the key problem. In fact, we now have more adults alive with congenital heart disease than we do children. It's estimated there's about a million or just under a million children, and there's 1.4 million when this was last looked at, which is a few years ago, and this is only going to go up and up and up. And one of the problems we face within the neurology world is none of our adult colleagues are familiar with the kind of problems and the complications these children face. And this is a general trend overall when we see survivors of cancer, sickle cell disease, even some of the neurodegenerative diseases, the muscular dystrophies, etc. And what's emerged is that it's actually the neurological morbidity that's become the most profound problem of the survivors more than anything. And a significant number of these adult survivors are having trouble both socially but also with employment. And so it's very, very costly. So this is some data that came out a few years ago out of uh Canada. And what it shows you on the left side here is that back in the 1980s, the average age for congenital heart disease was age 11, with increasing survival with improved surgical techniques. By the early 2000s, the mean age of a congenital heart disease. was aged 17 and by 2010, more than a decade ago now, the average age for congenital heart disease was in fact 25. So it's really actually becoming an adult disease and an adult burden from the same authors plus Ophelia that later showed, you can see how the incidence is still highest amongst the children, but increasingly we are seeing this uptick in the adults and now even into the geriatric survivals. So the major extra cardiac complication from the congenital heart is the neurological morbidity, and this is really what's been plaguing the field for the last 20 to 30 years. And about 1/3, 25 to 1/3 of children that have congenital heart disease will end up with some form of either physical, cognitive, or developmental neurodevelopmental issues. But this isn't all even really children that have relatively mild congenital heart disease are going to do absolutely fine for the most part. However, more than 50% of children that have those critical congenital heart types that I alluded to earlier will end up with some disability or neurodevelopmental problems. So again, Gail Wolosky was from uh CAP, uh, published this a few years ago where if you look again along the types or the subtypes of congenital heart disease from mild all the way up to palliated, which is a single ventricle or syndromic. You can see that the numbers with no disability, which is the white column, really drops dramatically. So by the time you get into the severe palliated group, more than half of these children are going to end up with neurological issues and neurological problems. So the history of cardiac surgery in children is really very, very interesting. The earliest stages prior to the 1970s was really closed palliative surgery, and this stamp of Dr. Sir Brian Barrett Boyle's was really the pioneer that moved this field along more than anybody else did. In the early 1970s, he was initially doing lamb work and then subsequently moved it into human studies, where not only was he one of the early, um, Pioneers of open heart surgery, but he was the pioneer of neonatal open heart surgery and was the one that was advocating for these early repairs. The irony is he was an incredibly heavy smoker. He developed severe angina, but by the time he was 40. And actually, um, I actually remember he died at the Cleveland Clinic in 2006. Toby Cosgrove, who was the head surgeon, later became CEO of the Cleveland Clinic, operated on him for a valve disease and unfortunately he didn't survive, didn't survive that. Um, and the era of neonatal corrective surgery really was ushered in in the sort of mid to late 1970s, uh, and much of it attributed to, uh, Barrett boys. Um, what followed from that in the 180s and 190s at the time I was doing some training, was the issue of neuroprotection. We knew now that the children could go through the surgery relatively safely for the most part. We saw the surgical survivals doing better and better with the techniques they had. But we've started to see a lot of complications from a neurological perspective, both in the short term, but also the long term. And going into the 80s and 90s, really, the concept was for the most part, you had a, an essentially normal child other than they had a really severe congenital heart problem. That's at least what the theory was at the time. You then put them through this incredibly intrinsic surgery. Unfortunately, this video is not playing. Um, they're operating on the heart, which, you know, in the term baby is probably just a little bit larger than a walnut. Special equipment had to be developed that had very long tongues and uh Ability to be to be able to operate in bloodless fields. And at the end of the surgery, what you got back was a baby, uh, most typically with an open chest because of the swelling in the edema, often with pacing wires in the chest, sometimes needing uh dialysis post-surgery and intubated. And then the post-surgical course, at least for the 1st 40. 8 to 72 hours was incredibly complicated and really quite tough for these children, but this was sort of the original concern was that really the damage, the issue that was taking place was happening here during the time of bypass surgery. So to understand this, we need to understand just a little bit about cardiopulmonary bypass surgery. And I usually ask people, and we won't because we're doing this on Zoom, but consider what temperature we operate under for bypass surgery. And I think people will be surprised to know that when the original surgeries were done on bypass, they were actually operating at um at at core temperatures for the body of less than 10 °C. But with that, there were incredible complications and hemorrhage. But nowadays the sort of optimal temperature in order to get an EEG that is essentially isoelectric, that's not requiring a significant amount of energy or substrate utilization is between 19 and 22 °C. So, you know, when we cool people down to these, uh, the babies and, uh, the HIE babies and the ICU babies down to these 33, 34 temperatures, we really are not doing a whole lot as far as brain metabolism is concerned. So at the start of the bypass surgery, they come into a very, very cold operating room. The head generally gets packed in ice and sometimes the body in ice, but they have, they can get the temperatures down to the sort of 34, 35 degrees. But then they've actually got to go on to bypass in order to cool the temperature. And as I mentioned, they operate around about 19 to 21 degrees. Uh, there's a point where the blood flow stops, to clamp the aorta, and then they start to warm the child post-surgery. What's important to realize that even once the temperature recovers at the end of surgery after bypass, We know from a lot of studies now that the mitochondrial recovery, when you look at cytochrome oxidase using the infrared spectroscopy, the mitochondrial, the cellular recovery often will take another 24 to 48 hours to return to normal. But hypothermia itself is not without concern and without complications. The biggest concern we have at these sorts of temperatures is that your circulation, your cerebral perfusion becomes pressure passive, and what we mean by that is you lose the ability to auto regulate. So for most of us, the reasons we don't faint when we stand up is we have this capacity to auto regulate across, across a variety of mean arterial pressures. Um, if it's too high, we have hypertension. If it's too low, we become hypotensive and run the risk of stroke. At the top end here, when you don't regulate, you run the risk of hemorrhage. And when you lose this pressure passitivity, which is really what we see in the HIE kids as well, it's a really critical situation because any fluctuation in blood pressure is directly felt by the impact of the brain. If it's elevated, you run the risk of hemorrhage. If it's low, you run the risk of ischemia. The other interesting thing, although it's not fully understood why it's necessary, but when you go on to bypass and you have these suckers just pumping the blood around, you lose the pulsatility. And for some reason, neurons in particular need that pulsatility, the systolic diastolic variation. Not fully understood, but this loss of pulsatility when you see it on the EKG screen, uh, is a significant issue, uh, for these children. There's also increased blood viscosity. We'll talk about that a little bit more. And at these cold temperatures, there's an increased binding for oxygen at a cellular level. The other thing that was known early on, and there's some incredibly good studies at this, looking at this, is that the minute they go on to bypass, there's incredible disruption of the blood brain barrier with a massive inflammatory response. And almost all attempts to try to dampen this inflammatory response has been unsuccessful, but it's also still the basis that they use a lot of suppressive drugs, um, on bypass to try and damper this response. And then at the end of the day, the baby comes back, as I've already mentioned, um, often, you know, needing to be, uh, well, not often, but they are, they're needing to be supported, occasionally, they need to remain on ECMA if they aren't able to come off the circuits. Uh, they have the open chest. They've got a lot of hemodynamic instability, arrhythmias, um, and sometimes the need for dialysis. And so for the next 48 to perhaps 72 hours, you have a lot of hemodynamic instability. And so this was thought to be the basis for the neurological morbidity that we were seeing from these children with congenital heart disease, undergoing a tremendous amount of stress, incredibly complex surgery on artificial, uh, plastic membranes, pumps that you lose all the natural physiology of how the brain likes to receive oxygen, blood, and pressure. So when we look broadly speaking at the morbidities of congenital heart disease, we can divide them into the early complications, which for the most part are strokes and seizures, which may go on chronically to become epilepsy and more of a late complication, um, and then the neurodevelopmental disabilities. And what's been realized, it's this latter part, it's these late, uh, problems of the neurodevelopmental disabilities that really has become the signal biggest morbidity of children with congenital heart disease. There's certainly a significant number of children that have problems from strokes and seizures, but it's really the neurodevelopmental problems of late. So I'm not going to spend too much time today. I just want to give you some of the basic data around the strokes and the seizure aspect of it, but I'm going to focus a little more of the talk around the neurodevelopmental disabilities. So we know following the Fontain surgery, which is seen here where you have this fenestration between the uh uh infera vena cava and the conduit, this artificial conduit, that in the United States, anywhere from 3 to 20% have strokes following Pontan repair. And the question is why is there such a huge range between the 3 and 20%? Well, it turns out that it's a question of how you define complications. So when MRI is used as part of research studies to look for complications, the incidence of stroke is much, much higher. In the European series at about 16%, and in the American series at about 20%, whereas if you're just relying on clinical judgment in the postoperative period, which is fraught with problems given how sick these children are, the sedation they're on. The insensitivity of head ultrasound, especially in term babies for detecting stroke, the incidence is much, much lower. Um, Gabrielle de Viber and colleagues in Toronto looked at the, the, um, risk of stroke overall. So this was for all comers, not just the complex hearts, but this was kids that were undergoing ASD closures, VSD closures, things of that sort, and the total risk of all these children was less than 1%. So a small risk, but for the complicated kids, it's not an insignificant risk of stroke. The other thing from practice that you quickly realize that a lot of these kids have silent strokes. We see them when we're imaging them for other reasons, either to follow up on development, to they have seizures, etc. and you see, much like you do in the sickle cell population that there's a lot of small but seemingly were quiet strokes in this population. So these are just a list of some of the better series that we've done looking at the incidence of stroke. Uh andre du Plessis, this was out of the Boston group, uh, Boston Children's, but they relied just on clinical diagnosis, as did the Macquale Group. Uh, so you can see how small the incidence was, uh, of, sorry, yeah, 2.6%. Now, the interesting feature was when you looked at the preoperative scans. So this is before, after birth, but before they get to surgery, depending on the group. Dan Licht is a wonderful neurologist out of, um, out of CH, and McQuellan was out of San Francisco. Um, there's an issue about what gets classified as stroke, what size needs to be, that does need to be territorial. I won't go into the debate about that. Suffice it to say that there was clearly a significant incidence of stroke that actually preceded the operative. A period showing that the fact that you have this mixed blood, you have single ventricle physiology, you had shunting of blood, these children were clearly at risk before they got to surgery as well. Um, another really remarkable series was, um, done by Charma McClure, who was from Loma Linda with Steve, um, uh, gosh, uh, Ashwell, Steve Ashwell's group, where they did autopsy series looking at sequentially at 84 brains. Uh, this was a heart transplant, but they actually showed that about a third of these children ended up with really significant stroke on autopsy series. There haven't been a whole lot of um autopsy series, particularly focused on stroke, but I will talk about one in particular from Boston that looked at white matter injury, uh, a little bit later. Doctor Friedman. Yeah. There is a question, um, that is it from um one of the participants, and I wasn't sure if you needed this, the concept that in the face of midline developmental abnormalities involving the heart. The brain is normal, is probably not valid as many of these children have midline and other developmental abnormalities of the brain and other structures. Yeah, so, uh, thanks for that question. It's actually something I am going to touch on, um, a little bit later in this talk in much more detail. The truth of it is that it only accounts for probably less than about 25 to 20 to 25%. So for the majority of children with congenital hearts, even with the complex congenital hearts, Um, the brain often is normal in terms of its, uh, structure, but we'll talk about why we see the complications in a vast more, a vast large majority of these children. But, uh, but that is true that the genetics of congenital heart does have an implication here and we'll, and we'll talk about that. So, um, the second immediate or early complication of the seizures that occur, uh, in the postoperative group. Um, there's the usual culprits, things like electrolyte imbalance, infections. We spoke about the stroke risks and sometimes kids that have a rough uh bypass course and get uh develop post-hypoxic seizures. However, there's a very unique thing that occurs in children that are on these uh bypass pumps, and it's been referred to as post-pump seizures or sometimes referred to as cryptogenic seizures. And these are by far the best studied and the most common type of seizures that we see. They are very, very characteristic and very stereotypical. They follow a very typical course. They're incredibly difficult to treat, um, and often the treatment is a little bit Um, pointless because no matter what you do, these seizures continue for about 48 to 72 hours. They typically occur in the 1st 24 to 48 hours after bypass, but you may see them as far out as 72 hours. They're very abrupt and often said. They're often repetitive, and they frequently go into an electrical pattern of status epileptic epilepticus. Um, but they are confined to an immediate postoperative period and they tend to then quieten and dampen down. And the overall prognosis is clearly a lot better than with hypoxic seizures, although there is some debate in the literature, whether these are just symptomatic of the surgery or whether they do portend developmental issues, and the studies sort of supporting both, uh, concepts. Part of the problem of the, of this is that they are almost always subclinical and You have to have really comprehensive EEG monitoring in order to pick these up. They tend to be very, very focal here where you see the phase reversal in the left central, central parietal front to central region. Um, and these will often be missed if you just, uh, looking at the amplitude integrated EEGs. And again, in these babies, they are so heavily sedated, if not paralyzed after surgery that they almost always are subclinical. So the first big series to look at this was Sandy Helmers, that some of you may know as an adult epileptologist that used to do a lot of work in the pediatric world, and Sandy was at Boston Children's and she published this very big series a part of the Boston Circulatory Arrest Study, the first really big series looking at children with congenital heart, and what they saw was that only about 15% of the seizures themselves were clinical. The rest of them were subclinical. And overall incidence was about 20% of electrographic seizures. In their study, uh, the presence of seizures was associated with an abnormal brain MRI, something either ischemic, structural, toxic in nature, and also associated with a decrease in the PDI at 1 year of age and a lower IQ at 4 years of age. But I'll come back to this. Um, a much bigger and better study that was done by Bob Clancy's group at CHAP really looked at this in a little more detail. And what they showed is that the overall incidence of seizures was perhaps a little low, around 20, around 12%. But the important thing in their study was that for the single ventricle physiology, the hypoplastic left heart syndrome, the incidence was really at about 22%. So incredibly 1 in 51 in 4 children postoperatively. But more impressively, the average number of seizures in that 1st 48 hours was 72, so essentially these kids were in status, but again, subclinical status, not a whole lot of hemodynamic change on, although they were, they were being, you know, maximally supported. But interestingly, unlike the Boston Group, they showed that there was no direct effect on the Bailey score. The problem with the Bailey score at a year of age is it's predominantly focused on motor development. If you think about babies going from essentially doing nothing to walking and more of the cognitive behavioral learning, speech language, those sort of more executive functions don't occur until later on, or you can't detect it until later on. Um, the same group, Clancy and William Gain or out of char, Gaoneski, uh, subsequently published longer follow-up data on these children and to my point showed that the executive function social problems at 4 years of age did appear to correlate with the presence of these post-pump seizures. So they're not just simply symptomatic of the surgery they've they've undergone, but does really portend later complications. And so who are the groups that are at highest risk for this we we already mentioned it's the hypoplastic left heart or a single ventricle physiology. In the black bars here, you see the risk of seizures versus no seizures, and you can see with the transpositions, VSDs, tetralogies, the risk of post-pump seizures are relatively low, whereas when he's talking about single complex two ventricle defects, especially the hyperplastic is very high. The other important piece they came up with contributing to the literature was the fact that these pumps seem to be associated with an arrest time in excess of 40 minutes. And so if your cardiac arrest time is less than 40 minutes or it's on low flow bypass, in other words, no hypothermic cardiac arrest, the kids had less post-pump seizures. Now, this talks to a lot of the changes that's taken place over the year with the surgeries. Uh, the surgeons of old that were incredibly, because there was just a handful of them doing it, had incredible experience, used to do surgeries or liked to do the surgeries under circulatory arrest. Again, you've got a really tiny heart. If you can stop the heart, you don't have any blood oozing into the cardiac cavity. Your visual fields are much cleaner, much easier to operate on, but you've got no blood going to the heart at temperatures of these 20 degrees, your basal metabolic rate of the brain is less than 10%, so we knew that the safety margin was about 40 minutes. So if complications arise or if you have a less less experienced surgeon, trying to get these complex surgeries done in 40 minutes is really very hard. So these days there's been a big shift to going to low flow and now what we call regional uh bypass surgery, where you have an extended amount of time, but now they're on the pump for longer periods of time and much briefer periods or no periods of circulatory arrest. So the rest of the talk I'm going to focus on neurodevelopmental disabilities, and this has really become the real big problem. When you look at children post-um, excuse me, post cognitary bypass, the average intelligence is really within a normal limit. It's less than one standard deviation from the mean. So if you look at the MDI, if you look at the cognition of these children, a little less shifted, but still within the normal range. However, when you look at the uh the PMD, the PDI, the Psychomotor Developmental Index, you can see there's a significant shift of more than 2 standard deviations to the left. So this is the area that has been dramatically impacted. And we know from a bunch of studies now that at least 30 to 50% of these children require remedial school services with a 15% of them actually in full-time special education. So half of these children really have a significant problem. And compared to the average pediatric population where ADHD is present in about 9% of children, there's a 3 to 4-fold increase of ADHD and executive dysfunction in these children, which really can impact on performance, behavior, and social, um, their work, the way they feel about themselves. So, time's not gonna allow me to go through the pivotal trials through the 80s and 90s, but I just want to highlight these three which I think most people would acknowledge as being the main pivotal trials sponsored by the NIH. And I'll start by saying if you look at the graph on the right, what you have in the yellow bars are the PDIs and then the blue bars or the turquoise as the MDI that despite millions and millions of dollars, major, major studies, there was essentially no shift in the outcome of these children over a period of 20 to 25 years. So the early debate was, is it better to do low flow bypass versus hy deep hypothermic circulatory arrests. The very early data that came out suggested That the complications from circulatory arrest, which was more in the Philadelphia group versus the Boston group, had better outcomes. But by 8 years this difference disappeared and Chop sort of thumbed their nose back at Boston saying if, you know, if you just look at long term outcomes, there really is no difference between these groups. They changed the pH stat management, meaning at what, when you're operating at at 20 °C, should you warm the blood to correct the acidosis or should you correct the acidosis at the temperature you're operating at the 20 degrees, alpha stat versus pH stat. It didn't change outcomes in these children, but what it did significantly change. Those of you on the call today, they are old enough to remember that we used to see a ton of chorioapheosis after bypass surgery. It was a very common complication, and this is essentially disappeared once they changed the pHA management of these children. And the final thing was what, at what viscosity, what do you optimize the blood at? And it turns out that the optimal crit is 30%. But despite all these variations and refinements to the surgery, There was really no change in the outcome. So at the end of the day, what was obvious was that the intelligence is relatively spared, but we had a lot of executive dysfunction. We had a lot of language or amota phonological awareness, a lot of fine motor apraxic difficulties is very common in this group, visual spatial dysfunction, depth perception. And you sort of picked your poison with low flow bypass, which is much more common these days. It was a little bit more focused on the high-level executive dysfunctions. Circare had a little more of the hyper motor, the fine motor, um, motor a praxic, um, and language dysfunction. But what people started to realize that this profile, if you look at it, is very, very similar to the profile of what we see in premature babies, generally those born under 32 weeks and most specifically under 1500 g. And when you started looking at the MRI of these children, here's the preterm baby with the very classic perioventricular leuka malasia or PBL, the white matter bright signals that you see in the perioventricular region. And when we started looking at these children, Steve Miller's a wonderful neuroradiologist, was at San Francisco is now in Toronto, head of Toronto neurology, and Steve McQull still out from San Francisco. But what they showed was that you see this. Perioventricular white matter injuries, which is very, very similar to what we saw in the pre in in preterm babies. The second piece of evidence came from a really wonderful pathologist, Hannah Kenny, who was at Boston. Richard Jonas was the surgeon there at the time. Jane Neuberger did a lot of this work on developing neurodevelopmental complications. But what Hannah Kenny showed was that looking at tons and tons of brains and these children that died in the 80s and 90s following cardiopulmonary surgery, the biggest pathology, the most serious pathology, and most frequent pathology they saw was white matter lesions, not these big strokes or catastrophic malformations or things of that sort. It was really this white matter damage that was, that was being seen. And so ultimately, it was back to the drawing board, uh, for these, uh, on these children. And the question became why are these children with congenital heart disease, who I'll show you in a minute, are generally born at term, the average gestation is just shy of 39 weeks. Were we seeing a profile that looked very similar to a premature baby, but more importantly, through two decades of incredible study, refinement of surgery, there was no real change in the outcomes. So people started to question in the early 2000s of what were the mechanisms that led to disrupted brain development in PBL with children that have some kind of cardiac lesion. And to the earlier question, there's no question that genetic programming and and susceptibility is a very important part of this. I'm gonna talk briefly about it because this is a topic on its own. I could spend an entire hour just talking about, but I'm going to talk about some just very big broad overviews. But the one that's turned out to be perhaps more important for the majority of these children, including ones with genetic abnormalities or predispositions, is the aberrant circulatory pattern that occurs during fetal life, where you get impairment of flow as well as impairment of oxygen, glucose, substrate delivery to the fetal brain. So if we look at genetic susceptibility, um, if you look at the syndromic forms, that's been identified in perhaps 25% to just under a third of these children, of this, about 12 to 14% are chromosomal abnormalities. Um, but denova mutations account for about 10% of these children. And more importantly, it actually involves chromatin remodeling, so the methylation, um, profile of the gene itself. So rather than a chromosomal abnormality. And so again, if you look at the nature of the chromosomal abnormalities, roughly this is a really nice series done a few years ago, about 20-21% had some underlying identifiable chromosomal abnormality. Uh, the highest was with the sort of midline, uh, that the, the person that asked the question referred to is exactly right. The, uh, atrial ventricular septal defects, or midline defects, the char trunkal defects. And septal defects had the highest. But again, complex congenital heart was also associated with a significant underlying chromosomal abnormality. What's become more obvious since we started doing higher level genetic testing on these children is that pathogenic copy number variant we gains of more than 1000 base pairs also account for at least a significant percentage of these children, and you can see about 15% with congenital heart compared to 5% of controls. And that this was associated very clearly with impacted neurocognitive outcomes. So, um Some of the genes that have been associated that we've now learned over time, the so-called homeobox genes, the uh when the transcription regulated genes are important with directional development, not just of the heart, but of the brain as well. And there's some, a small group of these genes that are critical for both brain and for heart development. And so when you see these real major complications of brain and heart, almost certainly you will find some underlying genetic etiology for it. So unfortunately, in about 2/3, we still have not yet found a genetic underpinning or genetic reason for it. About 12% are chromosome or 15%, as I mentioned, copy number variants, um, and about 10% of these are denova mutations. So the group that has the biggest concern for us are the children with the single ventricle. If you've not seen the pathology of this. Here's the left ventricle. It's just a tiny residual labins of heart. The right ventricle is the major structure here, and this is the equivalent of our holorosencephaly or single ventricle in the brain. Excuse me. And one of the earliest studies people may recognize the name here, Tracey Glauser. Tracey was, who is a very well known pediatric epileptologist in Cincinnati and has done a lot of work. Around genetics and epilepsy, but his early work while he was a resident and a fellow at CHOP was looking at brain malformations in congenital heart disease, and they described about 1/3 of children with single ventricles had some kind of developmental brain anomaly. A lot of these were minor. However, 10%, 1 in 10 of the children did have major abnormalities, as is seen here with this child with herloroencephaly. They also made the note that about 25% of these children, I'm going to talk about this a little later, uh, had microcephaly. So there are a lot of common syndromes you're all familiar with the trisomies, especially Down syndrome, uh, the 22Q microdeletion syndrome, um, but there are a ton of syndromes that are very well described, very well known, that are associated with congenital heart disease at a very significant extent. Not 100% though, even those with velocardio facial. There are also a lot of other syndromes where there is an association with congenital heart problems, where it's more of a systemic disorder where the heart is sort of in some cases almost a bystander in this. The one I'd just like to highlight because we all see it at one, and I don't think people realize, depending on the series, about 5 to 15% of children with congen with a neurofibromatosis type 1. Do have underlying congenital heart disease, predominantly affecting aorta, often stenosis, and also pulmonary valves and other valves. So when you're faced with a child with complex congenital heart disease, um, there are so many genes. Fortunately, there are panels available these days, but if you know the type of cardiac lesion, you are able to really narrow down the type of genes that are involved with this, and more and more of these genes are being described, uh, every day. So you can either target genes if you know the cardiac lesion, but life's become easy these days by just doing these panels. So the real focus has been on the fetal circulation. So if you look at normal fetal circulation, you all know that it's the amlial vein that carries the oxygenated blood from the placenta. It passes through a special channel on the liver, deductsinosis into your inferior vena cava. And then from the inferior vena cava, uh, babies all have a PFO patent foraminal valley, and so most of your oxygenated blood ends up in your left ventricle. So the oxygen concentration in fetal life is around 68%. Once it goes out, um, of your, uh, left ventricle, um, it gets systemically distributed. So there's oxygen-rich blood, the highest oxygen-rich blood going to the vein, which you have your patent ductus arteriosis, which also takes blood to the to the pulmonary arteries. But remember, in fetal life, you don't need lungs. And so again, the oxygen in the right chamber is only at about 53%. So what about in hypoplastic left half? Well, here we have a numbance, we have no ventricle at all. And associated with it is you usually have hyperplasia, um, of the ascending aorta. And as a result of it, the oxygenated blood plus the blue bullet coming back from your inferior and superior vena cava mix, they all end up in the right ventricle. So you have significantly reduced oxygen concentration. Additionally, because there's no real left ventricular pump sending blood directly to the heart, uh, to the brain, the blood has to rely on the patent ducts in a retrograde fashion as it goes through the pulmonary arteries to get to the brain. So you have not just decreased oxygen and glucose, given the decreased concentration, but you also have this decreased flow. And the ascending aorta sometimes is incredibly small. If you've never been into cardiac surgery or seen this, it's really truly remarkable. So normally you would expect the inverse relationship here. This is the ascending aorta, which is really very, very small. Often in the children with hyperplastic left heart, it's 3 millimeters, 2 to 3 millimeters in size, and the pulmonary artery here is really, really very big. Now if you contrast that with the transposition babies, what we see in the transposition babies is that Oxygenated blood is getting into that left ventricle the way it should. The problem is the artery coming off of that ventricle is going to your lungs, whereas the blue blood coming back from the body and the head, uh, at 53% is going through a very normal sized aorta. So the forward flow is fine. It's just deoxygenated blood. So you have normal flow issues, but decrease in nutrients and metabolites. And so this is what it should look like. It's just, this is what your, um, aorta compared to your pulmonary artery should look like. It just so happens it's coming off the wrong ventricle. So to understand this, we have to go back one step and look at work done by Petra Happe, again, a wonderful neuroradiologist, actually a neurologist that did neuroradiology is now in Switzerland, and this was on premature babies. And what she showed is as the brain matures, the surface area of the brain through gyro formation. Increases substantially and it's almost in this linear distribution. So when we see premature babies back here, the surface area is really very small, and by the time they hit term, it's really, you know, 89, 10 fold the size in terms of the surface area. So work by Karen Lipopoulas and Audre Du Plessis, both now at Children's National. What they showed, looking at this is they just looked at the total brain volume, like I was just alluding to. In red, the squares are the control babies, and this is the development starting at the onset of the 3rd trimester and progressing over time to term, and you can see the total brain volumes. In the blue, the open dots, this is the congenital heart. And you can see at the onset of the 3rd trimester, there's this divergence in brain growth. And the children with complex congenital hearts, the TGA's and the hyperplaces. Their brain volumes start to fall off. Um, subsequent work confirmed this, but also showed that this fall off in brain volume again, the solid lines are normal, the cash lines of congenital heart kids, what it showed, it had to do with every part of the brain, the developing whitepa and the cortical plates, the subcortical gray, all of it had the same issue. And so getting back to the microcephaly, what they were able to show, this is Shillingford, who is still, I believe a stiletia, what she was able to show is that if you look at the transverse arch, which is generally normal in these children with hypoplastic heart, usually about 3.5, 4 millimeters in diameter, um, the head circumference is normal. But if you look at the ascending aorta, once it gets below the mean of about 3 millimeters in size, so around 2 or below. These are the children that are born with microcephaly, and these are predominantly the children with the hypoplastic left heart and If you look at just the Gaussian distribution of head circumference, you can see this incredible left shift where about quarter to 50% of these children with complex hearts are shift shifted to the left and have microcephaly. Perhaps one of the remarkable, most remarkable studies done again was through Dan Licht in the group at CHAP. What they did is they looked at these brains and said, well, the brain is a little more complicated. Instead of just looking at total brain volume, let's look at something that they refer to as TMS or the total maturational score. And this was a score of I forget 8 or 10 variables looking at white matter ventricular sizes, cortical core, a bunch of different, uh, things, myelination patterns. And they assigned a score to it. And what they showed was that at term 38 to 43 weeks in normal babies, normal fetuses, the TMS score was 12, the total maturation score. You can see the incredible change over just the space of a week. If you looked at babies at 30 normal babies at 36 to 37 weeks, the TMS score was 11. However, when you looked at children with congenital heart disease, they are born at 39 weeks. So they were born at term. But if you look at their TMS score, it is significantly lower, below 36 weeks, and it's much more consistent with a 34, 35 week break. So what they showed us was, despite the fact that these babies are a turp, we have this fall off of brain growth, brain development at the onset of the third trimester. And by term, even though the babies are chronologically term, brain development is still very immature. It's at the 34, 35 week mark. And so if you look here, you can see a normal term baby versus the hypoplastic left heart, and their heart, their brain looks much more similar to a 30, 34 week kind of brain. So this started to explain why these babies were manifesting features that were much more common to immature brains. And the next remarkable piece of work was out of Steve's back lab again in Boston in the early 2000s where he was working on prematurity, but the same applies to these children with congenital heart. What he showed was that oligos uh oligo um, uh, the precursor oligodendrocytes, excuse me, pre-oligo, uh, uh, Precursor oligo uh oligodendrocytes, which are the precursor cells to the development of the neurons, and they are all the other uh uh stem cells as well. These oligo precursor cells are very highly concentrated at around 23 to 32 weeks. And as they get towards term, the, the number of precursor cells has matured and they are now, uh, oligodendrocytes. The importance of this is that These precursor oligos are exquisitively sensitive to hypoxemia. Once they mature, they're very, very resistant. And this is why children babies with HIE, we see selective neuronal necrosis, we see neuronal injury, children with strokes, adults with strokes. You can get white matter injury, but it's either secondary or with really prolonged hypoxemia. Whereas in the premature babies, the neurons tend to be spared and it's these preonicodendrocytes that are exquisitively sensitive. To hypoxemic and ischemic injury. And so these babies, even though they're at term, the brain is much more mature and it's got a significant amount of these precursor oligodendrocytes. And these are the cells that will go on to eventually cause myelination. And the last piece of evidence came from Karen Lupoulos and Steve Miller, who basically showed that if we did fetal MRIs and we did MR spectroscopy, which became available in the 2000s, you would see that these brains and the kids, especially with the hyperplastic left heart, had lactate peaks, showing that this at a cellular level these brains were very, very unhappy. So if we sort of do a quick summary of the fetal causes of neurodevelopmental disabilities, one, at the onset of the 3rd trimester, you've got this failure of brain growth. Uh, not only is it a failure of brain growth, but even though the babies are born at term, it's a substrate that is preoligodendrocytes in the brain that are very susceptible to decreased arterial, uh, in glucose concentration, but also towards flow. And these maturation dependent vulnerability of these oligodendrocytes plays a critical role. So I'll talk a little bit less about the neonatal onset, and this is the neonatal onset prior to getting to surgery, in other words, before the issues of surgery, and there's a lot of evidence that before they get to surgery, there's ongoing issues with these babies. Cranial ultrasound, which is not very good or very sensitive, even though they see abnormalities in 40 to 60%, some of these are very minor abnormalities. So I don't think this is a very useful. There's been a bunch of these studies. I don't find much reliance on the ultrasounds. Pre-operative MRI, however, has shown anywhere from 25 to 40% abnormalities. Often these are these white matter abnormalities, sometimes it's more significant developmental stroke. More than 50% now in the postnatal course, but before surgery, we'll have elevated lactates in the brain again showing uh the, the stress or the consequences of hypoxemia. And now with DTI we can also see patterns of abnormal brain development. So, The newborns that have the single ventricle or the cytotic heart disease, um, show disturbances in their perfusion by using ASL. So all of the stuff that we sort of assumed was happening because of a lack of blood flow, a lack of, um, oxygen and the subrate delivery has now been shown with newer techniques like ASL. Now, this study, uh, from a decade ago, the importance of it, so these are abnormal fetal MRI findings and these are abnormal postnatal preoperative. You can see that abnormal fetal uh MRI findings as a whole were seen in 16%, but Postnatal, these are all kids that had fetal MRIs, but then went on to have an MRI in the newborn period before surgery. It was 32%. So there's very clearly it was specifically the, this group of double outlet rights, the dextro the uh papoplast and the, uh, transpositions. And only 9 of the 33 studies that were done had abnormal, um, with abnormal, uh, neonatal findings actually had an abnormal fetal finding. So showing that damage still continues to occur once the child is delivered, even before they get to surgery. And this is a study by Hansen out of Germany. They use the WISC for IQs and this is called the CETI, which is a cognitive score. And what this shows is this is the preoperative on the left side and the full scale IQ and the CET score in red versus green. And again, what it showed you was with these children with complex congenital heart. This is where the problem arose. Once they had surgical correction, it wasn't a significant difference in terms of the outcome for the children. And 2/3 of them had this problem going forward. And there are lots of other lines of evidence, um, and I won't in the interest of time, go through all of them. The neurological examination is incredibly helpful. The problem with this is that these kids are usually very heavily sedated preoperatively to try to assist with the ventilation and the arrhythmias and the cardiac function. Uh, the microcephaly if I've alluded to, EG abnormalities, preoperatives are also very, very common. It's much, much more sensitive. To ischemic injuries of the brain, even asymmetries and malformation of the brain, and a head ultrasound in these babies, but we still predominantly rely on head ultrasounds. Here at Phoenix Children's, we do have a protocol where the babies all get 24 hours, the complex parts of 24 hours pre-operative EEG and then post-operatively, we go for 72 hours. Because of that COP study. Um, and you can see a lot of the post-operative stuff, the status remained unchanged. So most of this was pre-surgery, post-delivery. Um, and then the last bit of, uh, information which I talked about briefly when I talked about PBL for a few weeks or perhaps a few months ago. I was certainly always under the assumption that brain migration ended by the end of the 2nd trimester and really was brain growth after that point. However, what we have subsequently learned is that there are a couple of progenitor stem cells in the subventricular zone, particularly around the frontal white matter, which is the susceptibility area for these children with PVL and these cardiac kids. Where these cells undergo migration after birth, and these cells are responsible for what I'm referred to as the interneurons. So in other words, the communication from neuron to neuron rather than a descending axon. And these interneurons are thought to be very important for executive function. And these pathways end up, um, these pathway, I'll show you a picture of this, it's easier to see. Uh, this is sort of a coronal view of it. Um, if we look at, sorry, this is the coronal view here. So if you look, this is where these progenina cells are around the frontal horns of the ventricle, and what they're doing is they migrate for the most part into the supplementary, uh, motor cortex through a medial migratory stream, and there's a second stream from the subventricular zone, but also a rostral stream that goes down towards the temporal bone. So, again, this group of um neurons is thought to be the reason we see some of the problems these babies have with executive dysfunction. And I didn't focus on that today because I talked about that with PBL. You see that same reason that we didn't understand for many years is why do these small white matter lesions end up with a neurocognitive profile. So at this point it's really a continuum of what we look for antenatally we talked about the genetic syndromes, altered blood flow and oxygen delivery, and especially delayed maturation of the brain. So even though born at term, they have a very immature brain. There's certainly a ton of preoperative stuff that takes place, stroke in anywhere from 3 to 20%, PBO and up to 20%. I didn't even talk about surgical stuff today where there's a ton of issues that take place during surgery. And then post-surgery, we see new strokes and up to 10%. We see PBL increase from about 20 to 50%, and we've talked about the seizures depending on the type of heart lesion. So, the last, you know, 2, 2.5 decades has been looking at neurological protection. There are tons and tons of studies going on. Unfortunately, we still don't have a holy grail. We still are battling to find ways to protect the fetus. And if you look at the next frontier, we're starting to see some fetal intervention in the cardiac world, what we're seeing is that for critical aortic stenosis, which you can think about is the severe hyperplas where there's no blood getting antegrated into the arch to the brain. They are now doing balloon dilatations of that aortic valve to allow better blood flow. But this starts very, very early on. Some people have even talked about perhaps during the 2nd trimester, uh, but certainly at the onset of the 3rd trimester. But I think this is in part where, where we're heading, and the question is what can we do in the maternal environment to try and help these brains. So neurological morbidity is still the major complication, as I've illustrated. Developmental disabilities is by far the single biggest group as a whole. I didn't even talk about the persistence into adults, the loss of employment, and problems that adults are facing now when they get to college and beyond to the and into employment. Um, and these prenatal and preoperative, the postnatal preoperative factors can be just as important as the surgical factors and certainly the genetic vulnerabilities are important. Once again, it's partly because of the developmental problem of the brain that these babies, even though born at term, have a high population still of preoligodendrocytes, and even then, the fetal life taking place, it's the prioligodendrocytes that are very vulnerable to any hypoxemia because of the placental uh related issues and the uh and the uh perfusion of the brain. But stroke and seizures still take up and play a really important, uh, part of this. So, um, I've left a few minutes for questions. I'll stop the sharing. Um, and I'm happy to take any questions if anybody has any. I'll just quickly check the chat. Um, Thank you. Well, no questions. All right. Well, um, I guess thank you all for joining early this morning and I have a few minutes to get to clinic. Take care. Thank you, Doctor Friedman.
