Neonatologists have remarkably improved survival rates for low birth weight infants to approximately 90%. But of that 90%, roughly 25-50% later exhibit cognitive or behavioral deficits. Watch as Dr. Neil Friedman discusses the mechanisms underlying the selective white matter vulnerability of the premature brain to hypoxic-ischemic injury, the role of unique vascular supply of the preterm brain, and the role of pre-oligodendrocytes injury in PVL.
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Good, everyone. We'll get going. Um, so, um, I wanted to speak this morning, uh, a little bit about neonatal neurology. We don't do too much during grand rounds, uh, and I'm not, I don't think I've done this in the last couple of years, uh, certainly for our grand rounds here. Um, I did present a number of years ago at the, um, PCH's grand rounds, General Ps grow rounds. So I wanted to talk a little bit about current understandings in terms of PBL or perventricular leuka malasia, and what it is about the preterm brain that predisposed these children, uh, to it. So I don't have any conflicts of interest or disclosures as far as today's talk. Um, the objectives have been included, but basically look at some of the mechanisms underlying why there's this predilection for white matter vulnerability in the preterm brain, uh, to HIE. And then also talk about some of the vascular unique aspects about, uh, prematurity, uh, before the, uh, brain fully matures. And then finally look at the role of the preoligodendrocytes, which are the predominant cell type in the brain at this, uh, at this time. And I just wanted to start with an acknowledgement, um, to two of the mentors that I was extremely fortunate to have worked with, uh, in the past and really developed a love for me in, uh, neonatal neurology in particular. Um, on the left side is Victor Dubowitz. Most people will know him, perhaps a little more from the, uh, field of neuromuscular disease, and I spent some wonderful time in London working with him. Uh, his wife Lily Dubowitz, um, was also a very, uh, renowned neonatal neurologist. Uh, but going on rounds with them was quite phenomenal at Hammersmith Hospital, the two of them, and people are still familiar with the Dukewoods and Duwood school named after them. And on the right side is probably the doyen of modern day, uh, neonatal neurology, Joe Volpe, uh, from Boston Children's, who's written the sort of definitive textbook and probably most of the research around this area has come either directly from him or through his prodigges over the years. So, um, if we look at prematurity, uh, there's still about 60,000 infants every year born in the US. And although technically prematurity is regarded as less than 37 weeks gestation, in general, when we're talking about the PVL type of picture, we most commonly think about babies under about 1500 g, which translates into roughly about 32 to 34 weeks gestation. That's the group that's most most vulnerable, and the group in particular that we often see this in is around 28 weeks gestation. Um, the neonatologists have done a remarkable job with survival, and, uh, pretty much all of these babies will now survive compared to when I first started doing this work. Um, and what's quite remarkable actually, and as I'll show you, it hasn't changed very much, is that when you look at the survivals, only about 10% will develop cerebral palsy in its strictest sense. There is about a 25 to 50% incidence of neurodevelopmental problems, including some behavioral issues in these children, but true CP is only at about 10%. However, with the improvements in care, we are now, um, seeing the survival of younger and younger gestation and younger and younger weight. And so for those children now born under 1000 g, the survival rate's about 70%, which is also truly remarkable. Um, but we do see a slightly higher burden of neurodevelopmental, uh, issues, including cerebral palsy in this particular group. But the vast majority of my talk today is going to talk about the, uh, Uh, about that group, that's sort of the sweet mark around 28 weeks or so. This was an interesting study from a few years ago from Australia, but they have a really wonderful database around cerebral palsy, and they were looking at the motor impairments in particular in preterm children over about a 15-year period. And, um, if you look at the top part of the children born, um, uh, prematurely or extreme low birth weights, you can see that. The change in percentage of CP diagnosis over this 15 years really did not change very much at all. What did change, however, was the non-motor manifestations of cerebral palsy with a significant P value that almost doubled from the early 1900s uh into the uh mid-2000s. But the incidence of CP itself remained fairly constant. So we're all familiar with the basic pathophysiology for premature injury. The two broad categories are prairie ventricular leuka malasia or PVO, which is what I'm going to address today. And then the other really big group or pathology that this group of interns get is IVH or intraventricular hemorrhage, but I'm not going to really talk at all about that today. So I love using this quote from Charcott, the famous French neurologist, who basically stated that diseases from old and nothing about it has changed. It is we who change as we learn to recognize what was formerly imperceptible. And there's perhaps nothing more true about this statement than PBL. Although we often think about things in modern terms and the discoveries in modern terms, when you actually go back in the literature, you realize that much of this was really describe described centuries ago. And one of the oldest areas that people did work in in the mid 1800s was in fact cerebral palsy of children, uh, although it wasn't noted that until the end of the 18th century end of the 19th century. So this young man really is the first that changed the world regarding CP and the knowledge of CP. And this is John Leto, an orthopedic surgeon, and I enjoy doing a little bit of the historic aspects to try and understand what we know today because again, a lot of the information we have today was really identified a long time ago. They just didn't have the tools necessarily at that time to make the diagnosis. And they're two really, I think, fundamental parts to the history of PBL. And the first starts with John Little, who was an orthopedic surgeon. He himself had polio and he had undergone as a child subcutaneous tenotomy, which gave him his interest in orthopedics, uh, orthopedic surgery, and he was really the first person to group a cohort of children and describe cerebral palsy as a clinical entity, although it wasn't named cerebral palsy at that time. And he had two really pretty famous monographs. Now the first of these was in 1843 in what he termed the nature and treatment of the deformities of the human pre I'm essentially referring to CP. And in that paper, he really emphasized the aspect of prematurity that the vast majority of the children he was seeing at that time were born prematurely, and he talked about asphyxia and the need to be resuscitated. This latter part is a little bit, which has led to even modern day, uh, litigation about that this is obstetric mishap, which we now know is not really true, and especially not true as far as the premature brain. And he noted two factors of uh etiological importance. The first was the poor maternal health. And certainly infection at that time was a really big deal, and that is very true even today. But the second was the, uh, he noted that with prematurity there was an inability of the infant to cope with the environmental stress, and that has really proved to be very pertinent. The second lecture he gave in London was in 1853 again on the nature of treatment, the deformities of the human brain, and what he noted was that the spasticity in these children was not always symmetrical and in particular made the point that the legs tend to be much more severely affected than the other. And this we know today is sort of the hallmark of prematurity, which is the so-called spastic diplegic presentation. And he also pointed out that epilepsy was a, uh, although he said occasional complication when you read the literature at that time, they really noted it at quite a significant incidence. And so towards the end of the 19th century, After work by Freud and others, um, and having classified cerebral palsy, the entity or the concept of spastic diplegia as a separate new nosological entity was described and really attributed to the early work done by little. And um also again, the emphasis being on both prematurity and on birth asphyxia. But perhaps the second and more profound change that came was with Betty Banker and LaRoche, and Betty Bank was a famous pathologist, married Morris Lichter, who was also a wonderful pathologist, and ultimately, They moved to Cleveland and there's a lot of legacy there from the work that they did, but this really remarkable paper from 1962 really talked about a name perioventricular leucomulation of infancy as being the synoqua no insult that these premature babies developed as far as the brain insult. The other thing that was really remarkable and got lost for many, many years and we'll come back to a little later is they talked about it as being a form of neonatal encephalopathy. So even though the pathology at that time was localized to the white matter, they did talk about it being a more extensive encephalopathy. They also made the point that the actual abnormalities themselves emerged during the neonatal period. It wasn't necessarily a perinatal or prenatal issue, that there was necrosis of tissue in the perioventricular region, which is what they, uh, which is why they named it the PBL, and they really sort of first were the first to identify this border zone in vascular supply of the premature brain, uh, which is one of the key concepts of prematurity leading to PBL and we'll talk about it in a little while. But more importantly, they did notice back then a diffuse loss of nerve cells involving the cerebral cortex. And for many, many decades, this aspect of prematurity and PBL got ignored. So if we look at the traditional thoughts around PBL perimventriculleu malaysia, as already mentioned, it's the classic lesion in a baby under 34 weeks of age, typically around 28 weeks mark, but the weight seems to be the most critical incident, and it's about 1500 g. And the uh neurodevelopmental problems occur in about 25 to 50% of these children. Um, it tends to involve a symmetric, non-hemorrhagic and ischemic white matter injury. This is distinct from IVH, which more often is unilateral, certainly asymmetric, and there's a hemorrhagic venous in fact, whereas this is a small arterial ischemic insult to the brain. And not only do you see it in the premature infants, but you also see it in sick term infants. So you can get, although we typically teach PBL as being a premature lesion, in term babies that are really very, very sick and hemodynamically compromised, you may actually see PBL develop. So the two principal components of TBL, one is a loss of all the cellular elements, the so-called leuka malasia, and this is the cystic element of PBL, which fortunately these days is really much less significant than certainly 20-30 years ago where the cystic PBL was really quite a prominent feature, and this probably has to do with changes in the way we manage these babies or the neonatal neonatologists manage these babies after birth. The more common lesion though that we see is this diffuse white matter scarring or gliosis in the perioventricular zone, and it's really occurring at a time where the major cell type in the white matter is the preoligodendrocytes. And as I'll allude to later, these preoligodendrocytes are exquisitively sensitive to hypoxemia and become very, very resistant to hypoxemia once they mature into full adult oligodendrocytes. So if we look at the neuropathology, this is coronal section through the brain. Uh, we have the lateral ventricles, the acadium septum pollucidum, the corpus callosum here. What we see within the white matter is this diffuse pale, uh, areas on the H&E stain, particularly around the frontal horns. Um, and this is the diffuse form of pericentricular leucoalacia, but occasionally you will also see the cystic areas which may be isolated little cysts, they may be macrocysts or they may actually be a coalescing cysts. And this is more of a focal, almost a stroke like a picture where you get a loss of all the neuronal elements. And this is important because with diffuse PBL you have really the involvement of these preoligodendrocytes, and this is what gives rise to a lot of the complications that we now know as part of PBL. It's this macrocystic cystic lesions, particularly around the frontal horn, that gives rise to the so-called spastic diplegic form of prematurity and the um The focal areas can either be microcystic, these tiny little punctate areas, or more commonly these larger macrocystic areas. And this is again a pathological specimen just showing how severe it can be where you get this sort of cystic breakdown of the white matter. But as you can see, you also get quite significant gliosis and volume loss of the white matter with seemingly complete sparing of the surrounding cortex. And just more magnified view, showing complete destruction of that white matter due to the so-called macrocystic PVL, which again, just to highlight, it's fortunately a very rare complication these days of PVL. When diagnosing PBL, one of the biggest mistakes, I think, uh, that we still make is we rely on the ultrasound for the diagnosis, uh, in these babies. And ultrasound is really not very sensitive to the diffuse form of PBL. It's very, very good because of contrast, the gray white contrast scale, excuse me, of the, uh, focal PVL, the cystic PBL, but you can often miss the more diffuse PVL. And really, you want the MRI and in particular diffusion-weighted imaging, uh, to be able to help you with that. So this is a, uh, ultrasound and coronal view with the ventricles, the frontal horns up here. And what you see are these macrocystic areas within the white matter, making cystic PBL very, very easy to see on ultrasound. However, when we look at the MRI, the T2 images, because the, uh, the, the, the neonatal brain and in particular the preterm brain is so undermyelinated, it undergoes tremendous myelination during the first two years. The water content is exceedingly high in the neonatal brain. And so when you try and look at these T2 imaging, it can be really difficult sometimes to really notice any uh abnormality on it. However, if you do a DWI, you can see the extent here in this particular baby of the of the, uh, these more diffuse PBL that is going to emerge later on. And later on with ultrasounds, it may become more apparent, but early on, it can be really very difficult to see. And this is just an example, looking at a baby at 55 days of age and then 10 weeks later, and in the, um, in slides A and C. Um, you're looking at the T2 weighted images. And although you get the impression there's something going on in the white matter here, it's really a little bit difficult to see, although there has been a little bit of cystic breakdown in the white matter about 10 weeks. But again, if you look at 5 days using the DWI imaging, you can see how sensitive it is to the PVL that will later become apparent. So again, appropriate imaging in the newborn is important and all too often I see babies discharged from the NICU with a Ultrasound before they leave saying, you know, they don't recognize cystic PBL saying there's no obvious PBL and the baby's going to be fine. And you know, sure enough, we'll see them a few months later in clinic and they have signs of classic spastic diplegia. Um, again, just showing an ultrasound in the same baby. This ultrasounds at 7 days of age, and I think you'd be pretty hard pressed to find or to comment on maybe PBL in this frontal region here. But looking at the DWI, it becomes very, very easy to see the deficit, the defect of what's going to emerge as PBL for this baby. So if we look at the classic MRI findings for PVL. There are really three components to it. The first is the scarring of the white matter or the gliosis. It occurs classically in three areas. The first is in the frontal, around the frontal horns, and that's important for the emergence of the spastic diplegia. The second area is the trigone region towards the back of the occipital horn. In the trigon region is really carrying the auditory and optic radiations and is responsible for a lot of the higher function, uh, visospatial, and some of the auditory processing difficulties these baby have. And then finally you get significant loss of the white matter. So you see the ventricles and the cortex almost abutting one another. Now, if the PBL is bad enough, the entire region of the perioventricular zone is going to be gliotic and scarred. One caveat I will mention is that you only start to see, um, mature oligodendrocytes to end up getting the scoliosis, um, in the microglial cells at around 28 weeks gestation. So when you look at PBL in a baby born at about 24-ish weeks or thereabout, You see the classic findings of PBL. It's just you have compensatory dilatation of the ventricles. You don't see a whole lot of gliosis in the white matter, and that's just because of the gestation at which it occurred. And you can see the obvious difference here. This is obviously a slightly older child with full myelination, but again, this is what it should look like. And you get a loss of the central white matter. So when you look at the corpus callosum, it is complete, but it's very, very thin and very, very narrow. And so ultimately what you see in these scans is you get the gliosis around the perioventricular zone, the trigon, the frontal region. You get corpus cephaly or dilatation of the occipital horn with loss of white matter and the cortex almost abutting the ventricles, and you get this thinning of the central white matter or the corpus callosum and this is sort of the more traditional classic findings of PBL. So what is the clinical correlates to PBL? Well, we know that the cystic PBL is really what's associated with the spastic diplegia and in particular, because it occurs around the frontal horns, which is where the descending leg fibers are, the diffuse PBL is really what's responsible for that 25 to 50% incidence of other neurodevelopmental problems, cognitive and behavioral, as well as learning, and, but not the actual CP component. Um, and this everyone's familiar with the so-called homunculus representation, and we know that the leg fibers are descent. I just, this should be more medially. And so when you get cystic PBL around these frontal horns, it's really going to be taking selectively the leg fibers. Now, often with PBL, you will see some involvement of the upper extremities, but proportionately, the legs are significantly worse, uh, than the upper extremity. And then The end result of it is this classic picture of a child with a scissoring gate, a spastic diplegia gait, but really good upper body and arm function to allow them to ambulate usually with the assistance of quad canes or other reverse walkers or something, uh, or some type of support. So turning then to the pathogenesis of PBL, there are really three components that are unique to the premature baby that results in PBL and we're going to talk about each of these, uh, very briefly. The first is the vascular anatomy, uh, that gives rise to a watershed zone that is actually in the deep white matter here rather than on the cortex, as you see in the mature vascular, uh, anatomy cases of an older child or or term neonate. The second is you end up with what's referred to as a pressure passive cerebral circulation where you lose the ability to auto regulate, and so blood pressure control becomes a key component and postnatally we are not really as good as a placenta and able to regulate and moderate blood pressures in these remedies. And then finally it's occurring at a time where the predominant cell type are these preoligodendrocytes. So if we look first at the anatomic factors, so if we, uh, we're all familiar with the, the term baby, the child, where the classic periricular zones are between your anterior circulation and your little cerebral circulation and your posterior cerebral artery circulation, and middle cerebral artery circulation and the so-called watershed pattern. And then you also have the internal border zone, which is Between your MCA and your lenticular strides. So you get this very classic so-called paracetamol watershed zone in term babies or children that undergo uh hypoxemia, but more particularly undergo hypovolemia or drop of blood pressure. Now, in the, um, preterm brain, uh, the vascular anatomy is set up a little differently. Until about 32 to 34 weeks, the orientation of the vessels are a little different. You have from the surface these short and long penetrators that are coming down towards the uh deep regions of the white matter around the perivventricular region. And at the same time you have these ascending basal penetrators or perforators that are coming up, so that you end up with a watershed zone that is in the deep white matter rather than on the cortex as I've just alluded to. And as a result of this, you end up with a watershed zone in the region of the deep white matter. And this is the area that we classically see, uh, PBL, and this was work done a number of years ago. It's still some of the best papers for PBL still goes back decades, which is why you'll see a lot of these, uh, older papers referenced. And this is out of Pepe and Wigglesworth, um, wonderful pathology book. Uh, this is just a half of a brain here, the Sylvian fissure, the cortex and the dark red. This is the ventricle over here just to orient you. And here you see these basal penetrators coming up from the, uh, into the basal ganglia thalamic region, and then you see these long and short perforators coming down from the cortical surface. And what you see here along here is your ventricle, uh, along the frontal horn of your ventricle is this hyper-perfused area so that if there's a sudden drop in blood pressure for any reason that is common in these newborn babies, this is the zone of watershed injury that you're going to see. The second unique feature is the pressure passive circulation. And uh, as we all know that the perfusion pressure to the brain relies on your main arterial pressure driving blood in, less the difference of your intracranial pressure sort of trying to force blood out. And that's the difference of these two, which actually gives you your cerebral perfusion pressure. Now, in a child, we know that there's a reg there's an area, a range of blood pressures or mean arterial pressures. which the brain can auto-regulate. Through, uh, chemoreceptors, vasoreceptors, and you can keep the cerebral blood flow at a fairly constant level, despite changes or fluctuations in blood pressure. The same is true for the neonate. The only difference is this level of water regulation is much, much more tightly controlled, and it's a much, much narrower range. So the ability to tolerate difference is harder. However, when you get to a premature baby or when you get to a sick term baby, they actually lose any ability to auto regulate at all, and you now end up in this terrible situation of what's known as a pressure pressure. Passive circulation, meaning that for every change in blood pressure up or down, you see an immediate change in the cerebral blood flow and the pressures that the brain, the neurons, and the oligodendrocytes are receiving. So at the top end here, as the pressures go up, you run the risk of IVH and hemorrhage, and as the pressures come down, you run the risk of ischemia and so called PBL. And this was work done by Alan Rosenberg, uh, that was again a number of decades ago out of uh Volpe's lab. And, uh, they looked initially at asphyxiated lambs. These were term lambs. But again, if you look at the control, you could see there was a level that these lambs were able to auto regulate very, very easily. Once they became asphyxiated, you see they became pressure passive. And while this is true for the term equivalent of the neonat as shown on the right panel, where they lose the ability to regulate, uh, it is also true of the premature baby that is sick. And another remarkable study done by Perlman that also used to work quite a bit with Volk and Rosenberg in the early 70s, the late 70s, early 80s, and this led to one of the most significant changes in the way that we sort of manage the neonates these days was the response of the neonate to pain. And I think we heard a week or two ago a pain lecture about how neonates do experience pain. It's just often underrecoized. So what we have on the left side of the graph. This arterial blood pressure, and then they were recording cerebral blood flow velocity, uh, at the same time. And with arterial blood flow, you have the really nice sinusoidal systolic diastolic peaks, and you can see that that's reflected in the brain. And we know from some of the cardiac studies that this sort of, um, this sort of peak in valley, the systolic diastolic sort of swing is really important for the health, particularly of neurons in the term babies, but it's also very important for the preoligodendrocytes. All they did here was simply monitoring the children while they were getting deep suctioning. And this was again in the early 80s when the deep suctioning was done without any sedation. And this was really very distressing and uncomfortable for the babies, for the neonates. Uh, and what you see is this very erratic, these high peaks, these very low. Um, zones at the bottom of the valleys, but it was a really a very irregular pattern. And sure enough, the same pattern was reflected in the brain. And every time that it peaked, you run the risk of hemorrhage and every time it really bottomed out, you run the risk of hypertension and PBL. So the third component of this that became really important was the timing at which this started to occur. So if you look at a pre-oligodendrocyte, it has a very, very few. Um, uh, articulations and ability to communicate, uh, with the other cells. And what you see is that at about 28 weeks, the vast majority of cells in the white matter still comprise the pre-oligodendrocytes, and it's at this time between about 28 and 32 weeks. that they start to mature from pre-oligodendrocytes into the uh into the mature oligodendrocytes. Once they are mature, they become very resistant to hypoxia, whereas the pre-oligodendrocytes are exclusively sensitive. Now, this was incredible work done by Steven back uh in the early 2000s and Stevens's now in Oregon. Um, but the work that, uh, that he did was again, just to confirm and show that at around this time of prematurity, 24, 28 week range, the predominant, uh, cell population in the white matter are these uh oligo precursor cells and that the sort of switch over to them becoming mature myelinated cells occurs at around 35 weeks. And again, using a variety of different stains, we can sort of differentiate that. So initially, we have these preoligo progenitor cells and the preoligodendrocytes that uh migrate, proliferate uh into the white matter, and then they start to develop the synapses, and then, uh, you get the immature and finally the mature oligodendrocytes with multiple synapses. But it's this population that's really abundant at the 24 to 28 week mark. And this is just again showing a lot of these prioligodendrocytes, it's 28 weeks, but not really communicating well with the sort of neighbor prioligodendrocytes and synaptogenesis is still very, very immature. So why is this important? Well, again, work that was done back then showed the effect of hypoxemia, which was represented in these studies by introducing free radicals. So what these graphs show is percentage survival of cells in a petri dish. If you look at mature oligodendrocytes first, once you put in a free radical, Uh, into the culture medium, you could see that the survival between the mature oligodendrocytes that either had free radical added or those that did not have any free radical added was essentially unchanged, basically telling us that free radical hypoxemia didn't have much of an effect on these mature oligodendrocytes. However, with the preligodendrocytes, when free radicals was introduced into the medium, you can see that the loss of cells in the survival was reduced significantly. I'm sorry, the wrong way around. When there was no free radical, the negative means no free radical. On a free radical was introduced, survival rates were only at about 20%, whereas in the matureligodendrocytes with or without free radical, there was really no difference. And so a lot of the early work we're looking at scavengers for free radicals and vitamin E at one stage was very popular. And what it showed that you could add vitamin E at 12 hours after the insult, 15 hours after the insult, and in this case, birth of prematurity, and you saw an incredible increase in the survival. So once you had a free radical scavenger added into it, you could see even as much as 15 hours, it was quite good survival of these oligodendrocytes. However, If no free radical scavenger was added, you had only about a 15-20% survival, and this led to in the early, um, sort of the early 2000s it was people using these really incredibly high dose vitamin E. There was a time that people were using Topamax to pyromate as a pre-radical scavenger because of the amper receptors. And as always, what goes from in vitro into a beaver really had very little to no effect in real, in real life. And in fact, we learned that these high doses of vitamin E actually made the retinopathy uh prematurity significantly worse, which resulting in significantly impaired vision for these babies. And that's why these sort of super high doses of vitamin E are not used, and I'm not sure vitamin E is given more to the premature babies. They just showed it again. Um, so adebenone is just a synthetic form of, uh, is a natural form of coenzyme Q10, uh, which again, works in the mitochondrial chain, uh, for complex 12, shuttling enzymes to complex 3. And, um, if you gave vitamin E or you gave adebione into a culture medium. Where you introduce free radicals, the control group that did not get any salvage had again the 15 to 20% survival, whereas if you use either adeenone or vitamin E, the survival was really very, very good at 92, 95%. Once again though, the reality of this was that the use of adeenone in the premature babies had absolutely no effect. It was also used for HIE, by the way. Um, so this led to an evolving view of PBL over time, and the question became, we could really explain very well based on the white matter location of these lesions just on an anatomic basis why they got the spastic diplegia. But the question started to be asked, well, why do we see such a high percentage of cognitive behavioral and other neurodevelopmental deficits in these premature babies that were not motor were not CP related? Again, the concept at the time was it was this premature lesion, which was symmetric, ischemic, and was a white matter injury. And this led to a complete change in thinking in the early 2000s. And there was a realization at that point through a number of studies which I'll go through quite quickly showing proof of concept that it was in fact not just the oligodendrocytes, but you would have a dying back of the axons. So this was almost reverse the process and then infecting the neurons themselves. So that in fact PBL was not just purely a white matter injury, but actually involved the neuro the neuronal exonal axis as well. Getting back to that Betty Banker, uh, who sort of alluded to this in the early 1960s and showed pathologically that the cortex was involved. Now, um, the reason that this was missed or neglected for so long is when we look at these children with PBL. It's very easy to see the loss of white matter. It's very easy to see the corpus cephaly and the gliosis. But remember, the cortex in the babies in the child even, and even as an adult, is only 5 to 6 millimeters in size. So to see a dropout of neurons is going to be very, very difficult if you have a dying back of the axons. And the, um, MRIs are sort of 2D imaging of the, of the brain. So you really can't get a volumetric of what the entire volume of the cortex involves. So this was incredible work by Terry Inder, uh, which was a fellow still in Petra Happe, who was a wonderful Swiss neuroradiologist again working in the BolP lab. This was really a, um, one of the most powerful papers to come out in the late 1990s, which really showed that if you look at premature infants, there was actually a significant reduction in the cortical gray matter. So if you took, uh, children born at term without PBL, obviously, The volume of gray matter was roughly 218 mL. If you took babies that had, uh, that were premature but did not have any evidence of PBL, there was a reduction in gray matter, but really wasn't that significant. But then if you looked at the volumetrics, if you looked at the amount of gray matter. In children born prematurely with PBL, there was really a striking significantly significant difference between the volume of gray matter on average from 2018 down to 157 cubic milliliters. So this was the first time in real time that PBL was shown to be impaired or to impair cortical development, even though, as I say, in retrospect, this ZANU probably should go back to Betty Banker. And this is just a different way that they illustrated this a few years later. So if you took premature infants that did not have any evidence of PBL or white matter injury, quite a large number of them. You can see that the average in terms of the gray matter was around the 200 mark, and that if you looked at the ventricular size of the CSF volume, it was just below 40 mLs. On the other hand, when you looked at these premature infants that had PBL, the total gray matter was significantly reduced, as I just talked about. And then obviously because you have a reduction. In the white matter and in the gray matter, you've got to have compensatory dilatation of the ventricle. And so it would show that the ventricular fluid volume of ventricular size if you like, was increased. So again, just proof of principle. The second really uh large uh support for this came in the mid 2000s from Hannah Kenny, a wonderful neuropathologist also out of Boston Children's. And what Hannah showed was that Um, when you look at PBL in addition to the gra, in addition to the, uh, classic white matter injury, you do get significant neuronal loss, uh, as well. So you get significant gray matter injury, again, just really confirming what had been known decades before, and that it's occurring at sites that are really important for cognition bone uh, memory and learning, including areas like thalamus, basal ganglia, hippocampus cerebellum. Um, and then again, a subsequent work by, uh, by Hannahin showed that there was at least a 3rd drop in density layer 5. So this sort of selectively was involving the parameter layer 5 neurons in these cases. Again, not a big series, but subsequent work has really confirmed this. And so again, if you look at the areas of brain involvement, although we think about it as white matter, by all these little white dots that are all these little red dots or pinkish dots that are illustrated, there is a significant involvement of gray matter as well. And so when we look at PVL, It's really a more comprehensive disease involving the whole neuronal axonal oligodendrocyte axis. So in addition, uh, to the white matter injury that we talked about, you also start to get damage to the slate neurons, to the deep gray structures, the cortex, cerebellum, including the brain stem. And again, particularly around the inferior olive, uh, was one of the areas most uh significantly hit. And there's been a lot of work over the years that has really confirmed this, uh, this work. So these days we talk more about encephalopathy or prematurity, which is kind of going back to the Bank, uh, Betty banker, uh, uh. Um, and so rather than talking just about PBL prematurity, uh, we sort of all correctly now talk about encephalopathy of prematurity because we do know that it really involves not just the white matter of the brain, but also the gray matter, but deep gray as well as cortical gray matter, um, involvement. And then there's been some really interesting work in the last decade to show, you know, the concept was that, you know, you had full brain migration by the end of the 2nd trimester, and then the 3rd trimester was just growth of the brain, the growth of the white man of the cortex taking place. But really some really uh interesting words from Paris and Morton that came out showed that even by the time of birth and for several months after birth, There's still ongoing neuro neuronal migration, and this may be an area of importance, not just in prematurity, but also in the congenital heart kit to show a very, very similar neurocognitive profile to the premature babies. And the reason for it is though the congenital heart children are actually born at term, uh, with a normal gestational age. The development of congenital heart brain because of fetal prenatal factors is actually that of about a 34 week old infant. And it's thought that it's these, um, post-delivery, post-birth neuronal micro migration that it is really important for some of the more significant kinds of problems that we see both in PBL and in these children with congenital heart disease that have a very similar profile. So, um, you know, the subventricular zone is the sort of the, the, the, the cradle, the bed, the niche of where the neural stem cells and progenitor cells sort of migrate from, and they go up along these radial glial lines to the cortex, as we all know, get sort of laid down from layer 6 to layer 1. And then there's a debate as to whether the actual Radial glial cells persist as the attached axon, whether they die off and then the AI neuron actually generates a new axon. But regardless, we now also know that in addition to these descending axonal fibers, there's a lot of interneuronal communication between the two neurons. And these so-called interneurons are really what develops around birth and then the early postnatal phase. Um, And these uh interneurons have very, very high, um, when they're present have cortical inhibitory inhibition. Um, and so it's thought now that damage in these perioventricular, the slate zones to this population of cells that are still there, that are undergoing migration around term in the first few months of life, is also a significant reason why we see some of the classic problems that we see from prematurity. And this includes a lot of executive dysfunction because it's in the forebrain. Uh, region. So things like ADHD, things like, um, uh, processing kind of, uh, problems, the more complex kind of, uh, issues, uh, to do with, uh, developmental problems in the premature babies. Um, and, uh, it's, it's, it's an important structure that's still present. A slightly complex picture, but what we have on the right here, this is a coronal section. This is a sagittal section here with the ventricle, the frontal lobe, and then this is sort of a, um, again, almost a lateral coronal section. But the important thing to realize is these interneurons start to migrate out as an arc, and they're going to go through two streams. There's a medial migratory stream to the forebrain, and there's also this uh smaller ostral migratory stream. But it's this area that we know is hit by PVL. And so it's thought that these migrating neurons, which are going to become inter neurons, or what, uh, what gets injured and what gets damaged. And it's a result of these interneurons that give rise to a significant portion of what we now call the encephalopathy of prematurity, uh, of the higher executive cortical functions that are repaired in PVL in about 25 to 50% of babies born under 1500 g under 34 weeks gestation. So, I've gone through this a little quickly, but hopefully it will give a little bit of time uh for questions. But basically, um, if we look at PBL, it's still the typical lesion of the premature infant. Uh, it is a symmetric white matter injury for the most part, and it's due to these three unique components that we see in the premature brain. The first is this vascular anatomy, which gives rise to the watershed zone being in the deep white matter rather than in the parasatittal cortical region because of these penetrators, both from the cortex and these basal penetrators coming up through the, uh, the deep greater basal ganglia region. The second is in premature babies, term sick babies, uh, the pressure passive circulation is sort of the default of what's occurring in these brains. And so blood pressure control becomes absolutely critical, and we know that the fluctuation of blood pressure post delivery in these premature infants is a really significant problem, and management has changed quite considerably, and all of this is acting on a population of cells made up of preoligodendrocytes, which, as I showed earlier, are exquisitively sensitive to hypoxemia. Once they mature and become mature oligodendrocytes, it's actually the neurons. That become much more sensitive. And that's why when we look at HIE in a term baby, um, we see the classic pattern of HIE in a term baby involving cortical injury in parameter distributed cells in the deep gray structures, uh, in the cerebellum and the seeing one of the, um, Of the temporal lobe. So it's a cortical lesion as it is in an adult. Now, the longer that hypoxia goes on, not only are you going to lose those sort of highly selective areas, but you're going to disinfect the entire brain. So in a term baby, we talk about selective neuronal necrosis, and there's certain areas that are more vulnerable, certain neurons that are more vulnerable, um, whereas in the premature brain, it's the oligodendrocytes that are much more sensitive and more vulnerable. And on top of this, we've now gone back 40, 50 years to realize that actually it's the cortical gray matter that is responsible for a significant amount of this injury. It's probably the result of both dying back of the axon because of the preoligodendrocyte injury. You don't get that axonal formation, therefore you get damage to the To the cerebral cortex. Very, very hard to see on 2D imaging. You really need, um, advanced neuroimaging to be able to really appreciate that. Um, and then finally, what's become a little more apparent in the last decade or so are the so-called late migrating into neurons that are very important. Um, and so when we think about PBL and we think about prematurity now, we need to remember that it's really more than just a white matter injury. So, um, I will stop there, um. I went through that just a little quickly, but, uh, uh, uh, happy to take uh take any questions. Neil, this is Michael Brewer. Uh, wonderful talk as usual. Um, was had a question for you. It's interesting to see how concepts have evolved over time and, uh, you know, as you were mentioning that, uh, the focus has shifted over time, uh, to pre-alligos and then back to back to neurons. What about the spinal cord? Um, is, is there thought to be much of a role um for spinal cord related injury in um PBL, um, and, and some of these processes? Yeah, so that's a great question. There's nothing, I, I haven't looked more recently, to be 100% honest. But there hasn't, there wasn't anything in the literature that has really focused a whole lot, uh, on that. You do get, um, you know, sort of thinning of, so sometimes you'll see the brain stem is a little thinner because of the descending fibers, the loss of general loss of the, uh, parameal tracts, uh, the thinning of the parameter tracts. Um, and so sometimes the spinal cords have been a little bit narrower, a little bit thinner like you see in the brain stem. But I'm not aware that the same issue has applied to the development of sort of either the secondary neuron and the secondary axons from the spinal cord from the anterior horns, or that the anterior horns themselves have been affected with PVR. I haven't really seen literature on that. But it's it's sort of an interesting, uh, it's an interesting thought, yeah. All right. Well, I guess if nobody else has any questions, we'll give you back a little bit of your morning. Um, I think Doctor Hopman has a question. Oh, OK. Uh, sorry, I apologize. Uh, yeah. Sorry. Yeah, hi, can you hear me? Yeah. Yeah, you know, that was, that was a terrific talk for a dilettante like myself who knows next to nothing about PVL. The one thing that struck me though is that some of the concepts seem awfully similar to traumatic brain injury, particularly with regards to loss of er auto regulation. And so I sort of wonder out loud, I mean, is that the direction that this field is going? Is it going in the direction of more intensive physiologic manipulations in preterm children? Like, where do we go from here and then how do we study it methodologically? Yeah, so I think you're exactly right. Certainly it's a pressure passive circulation, which is very, very akin to what we see in traumatic brain injury that we see in birth not birth asphyxia, but HIV, perinatal depression, and the term baby. The only real key difference in that scenario, as I mentioned, because of certain Certain areas is that it's affecting the cortex, you know, neurons, selective neuronal necrosis rather than the deep white, but principally it's the same concept. It's just which selection of cells that you're talking about and addressing. Um, the change in management since I first started doing this work in, uh, neonatal neurology, uh, you know, I remember sort of in the 80s, uh, everything was hands-on. When we saw these premature babies, you had to examine them and you had to go through all sorts of different maneuvers and do things with them to try and get a sense of, uh, how they were doing. Uh, nowadays, you know, you walk into the NICU and the whole concept is, don't touch, don't talk, and don't see. Uh, it's kept in a very quiet, dark environment, as you know. The concept is to really not touch as much as possible because of this fluctuation of blood pressure. It's really, really hard because of this narrow window of water regulation to try and manage these babies. And so the best thing is to try to avoid fluctuations. And as I alluded to, one of the biggest changes and one of the most successful changes of all became really heavy deep sedation when they do, uh, so-called interventional procedures. And by that I mean just things like deep suctioning, which we never used to think of as a big deal. But now, you know, procedures of any sort, they're doing with quite significant sedation in these newborns. Uh, and it, I think, has been shown to be much more effective. It's certainly effective in controlling their blood pressure. Um, but yes, I mean, you know, obviously supporting volumes and the traditional stuff we would do, um, within a TBI sort of case or an older child case, they do do in the NICU. It's just your armamentarium is much, much more limited compared to what, what we can do obviously in an older child. But that's where we have to be very careful with some of our treatments and some of our medications that we actually don't exacerbate the situation. Um, so seizures, for example, in the premature brain, the whole brain is excitatory, and so the natural state is for an excitator to brain. The GABA receptors only become inhibitory at around 3 months. And so there's at least a theoretical consideration that the use of benzodiazepines, especially in a premature baby, can actually be counterproductive. And there's a very classic midazolam-induced myoclonus that you'll see at the bedside if you do this long enough, where the nurses will push midazolam and these babies go into incredible myoclonus. It's non-epileptic, but it does start to affect the hemodynamic state. So we just have to be very, very cautious in how we treat these babies. The premature baby. Hey, uh, fabulous presentation. Um, I was just gonna ask before you mentioned about the occurrence of seizures, is there um a differential impact on long term neurodevelopmental outcome if you have seizures um with a term injury versus a premium injury given the selective uh variability or differential response of depolarization or hyperpolarization with GABA receptors. Yeah, that's another great question. And I, I'll probably answer by saying is the truth is we probably don't know, um, the answer to that. We now know in term babies, and even there, quite honestly, it's a little bit controversial and how aggressively you should be treating neonatal seizures. If you look at the work, some of the early work by Mary Johnson around some of the medications, but mostly the work by Greg Holmes, uh, decades ago showing that it's not clear that neonatal seizures, which are often symptomatic, are always detrimental to the baby. I think in a term baby, it's now generally accepted, generally considered that the treatment of those seizures is probably beneficial. The problem with premature babies is defining what a seizure is, and these premature babies can be exceedingly hard. And I would almost suggest that if you show 10 epileptologists a pre-term baby EEG, you'd probably get 10 different readings on it because they can be incredibly difficult to interpret just because of the hyper excitability state. But personal philosophy is if it's a clear clutch seizure pattern. I would probably go ahead and treat it to a moderate degree, but not to a point of where you're going to start dropping blood pressures or leading to other, uh, complications on it, because there is really no good evidence in the pre-term brain that it really does much as far as long-term outcome. The other thing is, so I'm a lot more tolerant than the premature babies. The other thing that I've learned over time and I sort of have almost resorted to is because of the difficulty of interpreting these premy EEGs, uh, and B, because of the fact that again, applying these electrodes, fixing these electrodes, messing with these kids on a day to day basis to try and make, to get the EEG readings, uh, you know, as best you can. That in itself can be as detrimental as trying to treat the seizures. So I have a very low tolerance of just treating because again, at least the preterm infant, there's some evidence, not strong, to suggest something like phenobarbital is actually neuroprotective in these babies. Um, so I would often just have a much lower threshold to empirically treating if on clinical grounds you think these are seizures, not necessarily waiting for an EG uh confirmation. And we know from term babies that the electrocortical signature of neonatal seizures, especially the so-called subtle seizures, is, uh, is the correlation is very poor. Um, and so in particular in the neonatal seizures, eye deviations, Iversive eye movements have been the strongest correlated with neonatal seizures. The same is probably true, but there's not good evidence yet for that in the preterm baby. So, um, I tend to be a little more just clinically treating when the babies reach term you do EEGs, you can see if you still need to be on medication or not. But, but they're very tough to treat the preterm babies when you're worried about seizures. All right. Well, thanks everybody. I appreciate you joining this morning. Uh, have a good day and be careful in the heat of the.
