ICNTN-FLICNA Clinical Case Club
By ICNApedia
April 18, 2022
0:00 / 56:09
Shermila Pia00:11

Okay, can everybody see the screen? Okay. So thank you so much for the introductions. I'm Shermila Pia. I'm one of the third year residents at University of Rochester. Thank you for introducing all of my colleagues who are listed here. Dr. Stone, Dr. Ellica. Dr. Korones may join if he's able to.

So I gonna kind of jump right into our case here? This is the story of an 11 month old boy who presented to us after his parents had noted some right-hand preference starting at about four months old, he would only reach for objects with his right hand and he would prefer to keep that left hand in a fist.

He seems to be pretty unsteady when he's sitting and will only catch himself if he leans towards the left. In terms of his development for his motor skills, he will briefly sit up. He can't yet crawl. He is able to pull to stand, but won't take any steps. In terms of fine motor, he keeps his left hand with the thumb tightly adopted into the Palm, and then he can extend the fingers.

He has a normal pincer grip on the right side. In terms of his speech and social development. Really no concerns. He's saying his first words already and he's playing peek-a-boo and smiling. Some more history about his birth. So the pregnancy itself was complicated by maternal nicotine use and some mild anemia.

But he was born at 39 weeks and two days via an unscheduled C-section due to failure to progress. His initial APGARS were nine and nine and there was no complications with his neonatal course in terms of social history. He is watched full-time by his parents. He has a three-year-old sister at home.

He doesn't have any medical issues. He's up-to-date on his immunizations and his family history is pretty unremarkable. Mom has migraines. Dad has a question of some ADHD and his three-year-old sister is healthy. Any questions on this brief history before we move to his physical exam?

Okay. Here's his exam at 11 months old, as you can see, he's on the smaller side, but he's playful and interactive the most notable part of his exam this time. His motor exam. So he had some hypertonia of the left arm and left leg. He holds that left hand in a fist and won't reach with that side or catch himself when unsteady.

He also couldn't really sit up for more than a minute at a time. His reflexes on that left side were also increased both in the arm and the leg.

So I wanted to open it up for thoughts on differential diagnosis at this point, and maybe what the next steps and work up would be.

Robert Stone03:18

We can have people just enter their thoughts in the chat.

Do you have the chat open terminal? Or do you want me to read that?

Shermila Pia03:30

Yeah, so it looks like a couple people are commenting about concern for CP perinatal stroke. Also from several people and then antenatal vascular events, other suggestions of malformations or scizhencephaly. hemiplegic CP and stroke.

Yeah. So we felt that at this time he would meet clinical criteria for a spastic hemiplegic CP. He had a fixed motor deficit, which was present since birth. We thought that at this point we would get an MRI to look for any signs of an in utero vascular event. And also to rule out any masses or structural abnormalities, which may be present.

So here's his MRI, which was done at 12 months old. You can see the T1 images on the left and the T2 on the right. I don't know if you can see my cursor here, but there is an area of what looks like encephalomalacia and then maybe some gliosis. So some T1 hyperintensity towards the center here on the T2 images, you can see more clearly the thinning of the cerebral white matter, posterior and lateral to that occipital horn of the right lateral ventricle.

And then here is a coronal view of the same T2 sequence. So again, really prominent white matter injury here noted on that right side. And we will go through these images in more detail with Dr. Ellika in a bit

Robert Stone05:04

I'm just going to interrupt for a second. There's a couple of questions that popped up. One was any seizures during the neonatal time period, but another one asking about any abnormal movements.

Shermila Pia05:15

Thank you. So no, there was no seizures or abnormal movements at this time.

So what are we left with in terms of diagnosis at this point?

I see another question about abnormal movements or dystonia. So he did have some increased tone in terms of the left arm and leg, but no other movements or dystonia specifically.

And no family history of cerebral palsy.

So we felt at this time comfortable diagnosing him with a hemiplegic CP. We felt that the birth history was not particularly convincing for a perinatal event and suspected maybe it was more likely due to an in utero event. Some kind of infection or stroke causing that encephalomalacia in that area.

So we set him up with therapy services and he was seen by orthopedics.

Okay. So our story continues at 21 months of age. He presented with continuous left hand and arm clonic jerking in the setting of a GI illness. So by the time he came to the emergency room, he had a continuous chronic jerking for about two hours. Given the history of his known brain lesion, there was a concern for focal status epilepticus, and he was started.

A couple of rounds of Ativan (Lorazepam) and a load of Fosphenytoin before the movement stopped. At this point, he was started on standing Trileptal or oxcarbazepine and was discharged. However and the next five months he started having breakthrough seizures about once a month. And his dose was slowly increased of the Trileptal.

Initially we attributed this to sub-therapeutic dosing of the Trileptal because he had rapid weight gain. Some of his breakthrough seizures were associated with illness. And none of the seizures ended up generalizing. They all stayed focal. But it should be noted that all of these events were quite prolonged.

So on the order of 15 to 20 minutes, even with the administration of rescue Diastat (Diazepam),

Our story continues. Six months later, when at 27 months old. He had an unwitnessed fall down 10 stairs. Mom was in the room over and came around the corner and found him to be immediately alert, crying, but responsive. He didn't have any signs of an obvious head injury and it was really unclear.

Or if he fell due to tripping and clumsiness associated with his hemiplegia, or if he could have fallen by loss of consciousness or another mechanism after this fall, he had one of his typical focal motor seizures, which lasted about 20 minutes and had resolved by the time mom took him to the emergency room.

So at this outside hospital, he seemed to be at his neurologic baseline. And we'll go into his neuro exam at this point, unless you have more questions on the fall,

Robert Stone08:38

just

catching up. There was a couple of questions and we can go back to the fall. So one was about the upper and lower left. Was it equal or was it upper more than lower or vice versa?

Shermila Pia08:52

Yeah, so his weakness and hypertonia were more in the leg, but both the arm and leg were pretty effected.

Again, he had that left hand fisted and a lot of hypertonia and spasticity in the leg as well.

Robert Stone09:08

There's some comments.

Shermila Pia09:10

Oh, cognitively. There weren't a lot of concerns early on. I think at the time of 27 months, he was noted to be very busy, so concerns for some attention problems. But that was the only thing at that time.

Okay. So we'll I see the question about the imaging. I'm going to hold off on that until Dr. Ellika does the imaging discussion. Oh, so they also did a head CT, but before I show you that, we'll just talk through his exam at that point. So here's his exam at 27 months. As you can see he's caught up with his growth a little bit.

He still shows that same left sided hypertonia and hyperreflexia and a right-hand preference. However, now he is able to walk and run. He is walking with quite a spastic gait. So his left leg is internally rotated and the foot is inverted. He walks up on the ball of that left foot and sometimes he actually is rolling over the toes and walking on the dorsal aspect of his toes on that foot.

Mom notices at this time that maybe his falls and clumsiness, might've been a little bit worse in the last week. And she wonders if that left side is tighter than it typically is.

So we'll go

into his CT next. So this is the CT done at the outside hospital. And as you can see, there's an area of really heterogeneous appearing hemorrhage in that same area, which corresponds to his known encephalomalacia seen on his MRI. At 11 months old. So it was notable because of the circumscribed appearance of that CT lesions.

And also again, the heterogeneous nature. So based on this any thoughts on the differential diagnosis now?

Yeah. So I see some thoughts about, could this potentially be a tumor, such as a DNET or an aneurysm,

also questions of some kind of arterial venous malformation.

All right. So I think given the CT our initial thoughts were that this might be something like an AVM, which perhaps existed at the time of his original MRI, and then maybe the fault caused it to bleed or maybe the bleed caused him to fall. The other thought was, could this be some kind of. At this point we went ahead and got the MRI and I'd like to turn it over to Dr.

Ellika to walk us through the MRI findings.

Shehanaz Ellika12:21

Can you hear

me? Okay. I'm just going to share my screen now. Can you see my screen? Okay. Perfect.

So I'll start with I'll go, I'm going to show it the the opposite way of what Shermila showed you. I'm going to show you the most recent scan and then we'll go back to the older scan and we'll compare them.

So this is the most recent .This is the recent. And MR I'm going to show, so you can see that on the MR, this area of there's encephalomalacia and there is gliosis. So it's involving the thalamus it's involving the posterial limb of internal capsule. And as we go down, you can see there's involvement of this white matter surrounding the.

Temporal horn as we come up, you can see there's all this white matter around the occipital horn, as well as the atrium of the lateral ventricle. All of of those regions show gliotic changes and you can see those gliotic changes extend up into the parietal Centrum Semi Ovale. And as we go up, you can also see that these gyri, especially near the.

Central gyrus in the parietal lobe .They look very dysmorphic. It's probably very gliotic and ulegyria you can see the, almost like this mushrooming of the gyri there. So it was hard to say if it was ulegyria or polymicrogyria , but I think it is probably more likely to ulegyria there mushrooming because of gliosis.

In addition to that, you can also see some volume loss. You can see that the posterior right lateral ventricle is dilated. And then when you look at the sagittal, you can see that there is paucity of white matter. Then, you can see there's thinning of the, almost imperceptible, very severe thinning of the posterior body, as well as splenium of the corpus callosum, the splenium is small, but the posterior body looks really thin and almost non-existent on the T2.

In addition to those findings, you can also see that is this lesion that Shermila showed you the CT. And you can see this lesion has got mixed signal intensity on the T2. It's got areas of T2 hyperintensity. Most of it is isointense .There are areas of T2 hyperintensity like over there. And then when you look at it on the T1, also, this is the T1 pre contrast.

Again, you can see very heterogeneous appearing, master areas of mixed isointense, as well as hyperintense signal. We did the susceptibility weighted sequences, and as you can see this lesion shows internal hemorrhage. You can see that over there corresponding to what we saw on CT and then there was this, when we give contrast, you can see that this lesion enhanced and more interestingly, there was differential enhancements.

So as you can see here along the anterosuperior aspect of this lesion, there is more increased. There is more the, enhancement is much more than the rest of the mass and that area actually shows slightly more T2 hyperintensity when compared to the rest of the solid enhancing components of the mass.

If you see the rest of the enhancing components that are iso intense, but when you come to this more intensely enhancing component, that is more hyperintense. Similarly on the diffusion, you can see that the lesion shows heterogenous diffusion, but that area which showed a differential enhancement show slightly more restricted diffusion when compared to the rest of the.

Also on the, we did this we, do ASL perfusion on all our cases and on the ASL perfusion, you can see that area which showed increased enhancement, also showed increased cerebral blood flow on these maps. So let's suggest that there was probably so you, for sure, we know that it's not a hematoma because of its enhancement characteristics and probably this area of.

More differential enhancement and as well as increased cerebral blood flow likely to represent, an area of more like de- differentiation. When you look at the we also did a spectroscopy through the, through this mass. And then I just want to run you through the spectroscopy just to show you the normal spectroscopy.

So you have, this is a normal Hunter's angle, so you can see the NAA is the largest peak and you have the creatinine and the choline and this is on the contralateral side and you can see the voxels moving. And as we come into the to the mass, I'm just going to scroll there so you can see the Hunter's angle is reversed here.

You can see the NAA is low and the choline is high. So that also is typical for tumoural signature pattern. So at this point obviously and to just tell you that a lot of people actually put in the chat box that they were suspecting an AVM. And just to let you know, even on the CT, there were no prominent flow voids or any in the sense, normally you see, let me pull up the CT just to show you all.

What we see normally when we, big prominent vessels on the surface, this was a contrast enhanced scan. So none of which we saw, so AVM was definitely low on the possibility on the CT. So the thing that was confirmed. On the initial non-contrast CT was basically, is it a hematoma or is it a tumor?

And I think it's easy to say that it is a tumor because it's so well, circumscribed, there was not much edema around. It's all of those kinds of favor the tumor. And obviously the MR is very characteristic for it. And I will just now go back to the initial MR. Let me just change show you my other screen here.

Robert Stone17:16

Actually. Alika,

before you do that, there was a question about cerebral cavernous malformation, and it's a good question. As opposed to AVM.

Shehanaz Ellika17:27

Yeah. The cavernous malformations, they don't look like this. They don't have solid enhancing components like that. They will, they have a very popcorn like appearance.

There will be a complete hemosiderin rim surrounding it. Here if you see there's no hemosiderin around the lesion, it's actually the bleed is within the lesion. So all of this is very uncharacteristic. Similarly , cavernous malformations, don't enhance like this. There will be some enhancement of the septations, but they don't have this kind of solid enhancement.

Similarly, you will not see increased cerebral blood flow in a cavernous malformation. So all of these findings go against cerebral cavernous malformation. So this like and then similarly, if it was a cerebral cavernous malformation, when you do the spectroscopy, you will not see much signal because it's all blood in there.

So you will get a very, like a very shaggy baseline. You'll not see any internal signal from that because it's all, there's so much of blood products. All of the, advanced imaging as well as also the enhancement, the T2 characteristics of the mass point in favor of a mass, not a hematoma, not an AVM or a TA or cerebral cavernous malformation.

And now going back to the, I'm just going to share my the older scan just to discuss it. So I had all these slides arranged here. So this was the scan that was done in September, I think at initial presentation. Shermila so this is 12 months old. So that scan shows you that again, we're seeing all these areas of encephalomalacia, and gliosis similar to what we saw in the most current scan.

And then there was this small area which Shermila pointed to, which is T1 hyperintense. When we look at it on the T2 weighted images, it is T2 hypointense .This is the SWI sequence. There is no susceptibility signal loss. There was not much diffusion change there. And then on the post contrast scan, I don't know if someone called this enhancement, but if you look at the pre contrast, it is bright on pre contrast.

So you can't really comment on the enhancement because it was bright too. I don't know if it was hemorrhage or not, but I think at the time they thought it was hemorrhage, but it was very unusual for hemorrhage because it didn't show susceptibility signal loss, but this is the same lesion that Sharmila is talking about that has grown in size over the last one and a half year.

And it has become this big. So in retrospect, when you go back and look, it was probably the beginning of the lesion on that initial scan and it has slowly grown.

Shermila Pia19:52

So Dr. Ellica, I just wanted to ask a couple follow-up questions. So based on this initial image, can we tell at what point this encephalomalacia and gliosis occurred? Can we tell if it's secondary to a stroke or the tumor?

Shehanaz Ellika20:10

They must have been I don't know if it is because of the tumor or not, Shermila, but definitely there was some kind of insult to the brain.

It's probably perinatal because you can see a lot of gliotic response. So normally the gliotic response, you don't see where the early trimesters it's more commonly seen either late trimester or perinatal. So I'm assuming that it was there. And then, like you said I don't think the tumor caused it.

Probably the tumor was there or the beginnings of the tumor was there when we had the initial scan, but probably this was there. The, injury was there predated that the tumor I feel, but it's hard to say we don't have that timepoint where we don't see the tumor. So it's hard to say.

Shermila Pia20:53

Sorry, Dr. Stone, go ahead,

Robert Stone20:54

I was just going to say one thing. That's a really good question. A major question we had, and some people are echoing that in the chat as well, is was this a perinatal or, antenatal ischemic insult with a secondary tumor or was there something about a congenital tumor that was impacting the growth of the normal tissues late in the pregnancy?

And it was, it's a really difficult question. There's one comment in the chat about different areas appearing smaller on the right. So I don't know if you want to point that out again Dr. Ellika it's absolutely true. And could that be accounted for by some destruction or from the tumor or.

Did that predate the tumor?

Shehanaz Ellika21:43

I thought to say Rob, but all of that is probably volume loss from all this gliotic change that we're seeing in the right cerebral hemisphere. And you can also see the, like they rightfully pointed out. I pointed out the corpus callosum. And the other thing that I didn't show you is if you look at the thalamus, so you can see this thalamus is also small in size, when you compare it to the other side.

And as I scroll down, you're also going to see that the right cerebral peduncle is smaller when compared to the contralateral side. So there is some amount of volume and degeneration on that side. So that was there initially, even on this scan, actually, if you scroll back, you can see the low, let me just pull up the.

Let me I have to stop the screen share and share the other screen. Sorry, let me do this on the go to screen six. Okay. Sorry. I'm showing you on the older scan. So just to show you the thalamus on this side, it's small, you can see that the cerebral peduncle on this side is small. So there was wallerian degeneration.

When I pull up the, initial scan let me pull that up here, just to show you that it was all these findings were there, even on the initial scan. So you can see all of this gliotic change, the volume loss and then the cleaning of the Corpus callosum, as well as the wallerian . You can also see that the thalamus on this scan was small.

Again, you can see the wallerian degeneration involving the brainstem, so all of those changes were there. So is that what you were asking about?

Robert Stone23:05

Yeah we could see that those changes are there. That's helpful. The question that I had, and I think is important question is, was the tumor some kind of secondary event, or could it have been growing in some way?

During the pregnancy and that's the disruption of the normal development of those pathways. It

Shehanaz Ellika23:25

could have been very small to begin with. It was almost imperceptible on the first scan to think that kind of small lesion could disrupt this amount of, it seems a little implausible, but like, you said I can't explain.

Shermila Pia23:42

And I will say that I did do a lot of looking in the literature for other cases of ischemic stroke being followed up by the development of a glioma. I, found a handful of case reports. Five or six total all in the adult literature. And when you think about the frequency of ischemic strokes and adults these case reports are exceedingly rare.

So I think it's pretty unlikely that there's a causal relationship between. Post infarct brain tissue gliosis and the development of a glioma.

Shehanaz Ellika24:21

Generally. I just thought I just, stopped my screen share so you can share. Are there any other questions for me? I don't think, right?

Shermila Pia24:34

We didn't do a vessel wall imaging. There was a question about that. I guess they can,

Shehanaz Ellika24:38

No, we didn't do vessel wall imaging . This the, T1 imaging that we did, it's almost like a surrogate for that. And there was no abnormality of vessel wall. If you want, I could show those images too.

So it's almost like a technique within the T1 space . So that looks almost like a vessel wall imaging. So there were one millimeter sections. There was no abnormality of the vessel wall. Do you want me to share the screen and show that Shermila sure I can share my screen and show it

so this post contrast scan is like a vessel wall imaging.

You can see the vessels are black and you can see there is no abnormal vessel wall enhancement in any of these vessels. So that would be arteries over here, nothing. So I don't think you need a dedicated vessel wall imaging separately. This is almost similar to what we do in vessel wall imaging,

Shermila Pia25:34

Thank you very much, Dr. Ellika for that discussion of the imaging.

Let me just share my screen again.

Biju Hameed25:46

So there was significant gliosis even quite early when the 11 month scan. Isn't it. With a significant difference between the two hemispheres if, it was secondary volume loss what was the what, is the pathophysiology for that? If the tumor was so small at that time?

Shermila Pia26:05

So I think the shorter answer is we don't know for sure, but we suspect that the most likely thing is that this tumor, whatever it was, likely present in utero.

And could it have had a small bleed or in some other way, disrupted the development of the normal cerebral parenchyma in that area.

Ebru Arhan26:26

Sharmila.

How about

thalamic involvement in the

previous first images is there any moments? Was there any abnormalities, in the thalamus

interna?

Shermila Pia26:46

Yes, there was

Ebru Arhan26:49

doesn't that show a term

hypoxia. Unilateral.

Shermila Pia26:54

Its unilateral.

Ebru Arhan26:57

Yeah, it's unilateral. Yeah.

Biju Hameed27:00

And also the reason for the bleed is the trauma causing the bleed or was it a spontaneous hemorrhage causing the fall?

Shehanaz Ellika27:08

It could, I think it's more likely that there was hemorrhage within the, the hemorrhage probably caused the fall, I think because the bleed was within the tumor.

And if you look at it on the follow-up, if you compare the CT and MRI, the tumor kind of shrunk a little bit, because the, some of the bleed had occurred, what's got, was collapsed.

Biju Hameed27:29

True, and it in the repeat ones, there wasn't a significant edema around the around

the tumour.

Shehanaz Ellika27:38

Exactly. There was an all, that was around. It was the gliosis normally when you see tumour, you expect mass effect and structures being pushed away from it. But in this case, because there was so much surrounding gliosis, everything was pulled towards it.

Biju Hameed27:51

Sure.

Shermila Pia27:58

So we can keep going through his hospital course if there's no more questions right now.

So he was admitted to the hospital for resection of the mass after this MRI. In terms of his function, he actually returned to his baseline postoperatively, maybe even with a little bit of improvement with some spasticity and walking flatter on the ball of his foot. He had not had a seizure since his operation and at the time that I made these slides, that was true.

And unfortunately, yesterday he just had a seizure in the setting of three different viral illnesses in high fevers. But he's continuing on his trileptal (oxcarbazepine)

at home.

Biju Hameed28:42

So Shermila when he

Initially he presented with just the left side motor symptoms. And then when he developed the seizures, did he not have an MRI at that time?

Shermila Pia28:52

So he had the MRI at 12 months old and didn't develop seizures until around 21 months. And so he did not have a repeat MRI because it was felt that the initial MRI showed the CP lesion, which was likely causing his seizures

Biju Hameed29:11

but the seizures were particularly difficult to treat isn't it, didn't respond initially to the oxcarbazepine and he then went into status even before the fall, didn't he?.

Shermila Pia29:21

Yeah. So every time he went into a seizure, it was prolonged. We, again had attributed at the time to sub therapeutic dosing because each time he had a seizure, he had grown before or had an illness before. But in hindsight, we wonder if could that have just been the progression of seizures due to the mass

Biju Hameed29:42

and an MRI then might have, could have picked up the growth it's difficult, isn't it?

Shermila Pia29:49

... So going on to the pathology this the WHO integrated diagnosis came back as an infant type hemispheric glioma. The pathologists are, the grade is pending, but if you take a look at the histopathology, so high cellularity, this elevated ki 67 is a marker of proliferation there. There's also atypical pairing cells, a lot of mitoses.

So all these are typical morphology for higher grade tumors. Which kind of contrasts with the fact that based on his clinical history, we think this is a mass that's been present likely since in utero. But definitely at least since one year of age. And so to not have a clinical progression over two years of the tumor being present would argue for a lower grade tumour.

The molecular analysis so far has been pretty unrevealing. The reason that I have a question mark, after this infant type hemispheric glioma at the top is because those types of tumors usually have a receptor tyrosine kinase or RTK mutation associated. And so far, all of the RTK is we've tested for have been negative.

So at the end of our list here, ROS, ALK and then the NTRK are the three receptor tyrosine kinase mutations, which we're testing for.

So I wanted to just jump into a brief discussion about congenital brain tumors. So these are very, rare. They represent less than 2% of all pediatric brain tumors. And you'll see them called either congenital brain tumors or fetal brain tumors. And in terms of terminology, there is also the category of infantile brain tumors, which include both fetal neonatal.

and also into the first couple of years of life. And those represent under 10% of all brain tumors. Some of the older literature, those infantile tumors would actually include children as old, as five years old at the time of diagnosis. The typical presentation of these congenital tumors is usually delayed because of the flexibility of the skull and infancy.

So they often might present with macrocephaly hydrocephalus on bulging fontanelle, and later on, they might have headache, vomiting ,ataxia, visual problems, or seizures, when the ICP is actually increased. But these focal neurologic deficits are rarely the presenting feature. And then it's also important to know in terms of the clinical presentation of these tumors is that it's rarely subtle.

They're usually very large tumors. They present with a lot of edema at the time of diagnosis.

And then in terms of the type of tumor, there is a strong predilection for supratentorial tumors in the infant age group. So this is contrasted with pediatric tumors. We think of infratentorial or posterior fossa tumors. The fetal tumors that are the most common, teratoma is by far the most common.

So 30 to 50% of infantile, sorry, fetal or congenital tumors are teratomas, but there are also gliomas as the second, most common in terms of infantile tumors, gliomas are among the most common in terms of pathology with low grade being more common than high grade.

So going into infantile gliomas specifically as pediatric gliomas have the highest tumor associated morbidity and mortality in pediatrics, this is likely just due to the incidents of there being the number one brain tumor and adults versus pediatrics, as we've learned in the last many years, as they differ in the driving mutations and the natural history.

For example, adult low grade gliomas will invariably progress to become high grade first. In pediatrics, they rarely have that kind of malignant transformation. In terms of infants, we don't really know as much about this demographic. So there's a lot of reasons why that we have less data here, but there's higher mortality early on after diagnosis, they're less likely to enroll in clinical trials.

And there's a less predictable outcome between, or sorry, association between the grade and outcome. And this is an important concept in infantile brain tumors, and it's called this paradoxical clinical course. And what that means is that if we look at the overall survival of low grade gliomas and infants versus pediatric population.

The infants actually do a lot worse. So only 71% surviving at 10 years compared to 91% of the pediatric population. And then if we look at the high. OMAS the infant health population is doing much, much better. So 54% overall survival at five years versus only 6% in the pediatric population.

And this is well-documented even with infants, undergoing subtotal resections, most won't undergo radiation treatment, and they're doing a lot better than would be expected based on this histopathologic grade. What does this mean? Could our treatment for infants with low grade gliomas not be very effective compared to the pediatric population.

And is it possible that our treatment for infants with high grade gliomas is actually excessive and that they're doing well with, or without our treatment, in which case are we giving them side effects? That they may not need. So this presents a clinical challenge. It's a very vulnerable population and the treatment options, which we'll talk about in the data are pretty limited.

So what do we have for treatment .Surgery is the, main option for many of these tumors. We aim for a gross total resection as was fortunately achieved in our patient. Radiation therapy, as is very rarely used. Not only do we have the side-effects of cognitive outcomes and secondary CNS tumors, but they've actually shown that in infants, the outcomes and overall survival are worse with radiation compared to those who do not have radiation.

And then chemotherapy, as carboplatin vincristine thiotepa and Temodal (Temozolamide) are all used but they do have a high associated morbidity and the efficacy as we've just seen is not always the best. Is there a light at the end of the tunnel here for us in terms of treating these tumors? The one thing that has been of interest in this population is that infant gliomas are often single driver tumors, meaning that one mutation.

Could cause the tumor and kind of carry it along through its growth. So this presents an opportunity for immunotherapy. So could we find which mutations are driving these tumors and therefore target them through an immunotherapy agent? So a lot of work is being done to answer these questions. Why do these infantile tumors have this paradoxical clinical behavior?

Can we do a better job of categorizing the tumors in terms of prognosis? And then how can we better target therapies to have less side effects and some more efficacy? So this, top study is from 2019 at University of Toronto, and it looked at 150 infants over three decades. They're working on classifying them by the histopathology into low and high grade, but then they also looked at them molecularly and they were able to identify this group of RTK receptor tyrosine kinase driven.

Infantile hemispheric gliomas. And to the left, you can see a list of the four RTK mutations. They took a look at so ALK, ROS, NTRK, and MET are all different driving mutations that they identified. This 2020 study below is actually out of London, but it was a multicenter international study, looked at 200 infants and this study focused more on high grade glioma.

This study was really focused on just classification. So looking at the histopathology and then the genetics, and it didn't focus as much on kind of the outcomes and treatment data.

So I took this figure from the first study from the University of Toronto. And I wanted you to just focus on this left column in purple. So this is the group of infants that have the RTK mutations. The other two groups on the right do not have RTK mutations. So if we take a look at the histology more of these tumors were found to be high grade by our current histopathologic.

definition there. These children also tended to present much earlier, so zero to three months at the time of diagnosis, there is a male predilection in terms of gender. And then if we look at the molecular alterations here, you can see the frequency of each one of those RTKs that were driving the tumor.

The interesting thing about this group is they suggested clinical treatment recommendations. So not only did they suggest that we do safe surgical resection, but they also thought that this would be a group uniquely suited to targeted immunotherapy specifically to those receptor tyrosine kinases.

One other interesting thing from the study was that two of these patients in the high grade group ended up needing a second resection due to tumor recurrence. And both of those patients ended up with lower grade histology on the second biopsy. So it's odd, huh? We don't really see that in other groups, pediatric and adults.

So the question is, could there be some kind of continuum of high and low grade, could these tumors differentiate over time and mature from high to low grade? And I think the take home point here is that the histopathologic high and low grade does not really work in infancy to define the prognosis and outcome as it does in pediatrics and adult populations.

So some more work has yet to be done.

This is a very busy slide. I just wanted to briefly touch on the who 2021 central nervous system tumor classification. So you guys have seen it. So similarly to the 2016 classification, there's more of an incorporation of molecular biomarkers in classifying the types of tumors. In addition to the histology and pathology for pediatrics, kind of two groups of diffuse gliomas.

So here's the low grade diffuse gliomas. And then the high grade diffuse gliomas, these are separated out from the well circumscribed gliomas such as pilocytic astrocytoma and our infant type hemispheric glioma fits into this high grade glioma bucket. The other thing worth noting is that the term glioblastoma no longer is used in pediatric tumors.

Okay. So I wanted to wrap up our oncology discussion, talking about what therapies there are out there. This figure on the right was taken from a 2021, sorry, 2020 diagnostics review on infantile high grade glioma treatments. These are all different immunotherapies, which could target potential driving mutations.

So Vemurafenib being the oldest targets, this V600E BRAF there's two ALK inhibitors, which interestingly were developed for adult non-small cell lung cancer, and can actually be used in a completely different population in different tumor with pediatric infantile gliomas and then lastly, this Larotrectinib is a TRK inhibitor.

So this is a tropomyosin receptor kinase, which is again, just a type of RTK. This one has proven to be highly selective and is undergoing current studies in both infant and pediatric populations and has shown a really encouraging efficacy and safety. So this is a 2018 medication. So I just wanted to show you one case report with Larotrectinib

So again, this is a single patient case report out of Saudi Arabia. This was an 18 month old patient who presented with a pretty significant tumor. As you can see here, they were able to get a gross total resection. However, in only three months, the tumor had already shown signs of recurrence. This family elected not to undergo chemotherapy or radiation.

And so they were granted the use of Larotrectinib for compassionate use. And the reason this is important is because this case report is showing that Larotrectinib or immunotherapy could be used as a first-line treatment for these tumors with pretty impressive results. And also low side effects.

This patient six months after their treatment with was actually had no progression of symptoms.

And so clinical trials are ongoing and both the pediatric adolescent and adult literature, but Larotrectinib specifically has shown really encouraging results with over 90% of patients having tumor regression. So this is all that I want to talk about with oncology. I wanted to jump back into our patient case, but does anyone have questions or comments on the oncologic side of things?

Robert Stone43:29

I've answered a few in the chat. So I think that's up to date.

Shermila Pia43:36

All right. So bringing it back to our patients. So we had a patient who was diagnosed with cerebral palsy early on, and didn't present with a tumor for over a year. And so the question here is are there any studies on cerebral palsy being caused by infantile or fetal tumors and perhaps unsurprisingly, I couldn't find anything on the subject, even other case reports of this occurring.

So what we do know is that you can have CP due to a developmental malformation. So we know that proliferation migration, differentiation schizencephaly, all these things can cause a CP type picture. We also know that you can have CP due to stroke. So you can have a hemiparesis if you have a focal vascular injury versus like a para or quadriparesis and other types of CP.

So the consensus seems to be