Dr. Edward R. Smith - Craniophaygi-what? (Why do I care about this?)

At Mass General and during that time did a postdoctoral research fellowship in neuro-oncology. After residency, he did his pediatric neurosurgery fellowship uh here at Boston Children's and was a clinical research fellow in biomarker development. Uh, He, he is currently an associate professor of surgery at Harvard Medical School and an assistant in surgery in the neurosurgery departments at Brigham Children's and Dana-Farber. Uh, he's a faculty member in the vascular biology program at Children's and a, uh, a member of the consulting staff, consulting surgical staff at Beth Israel. He is the co-director of the Center, uh, for Head, Neck and Skull-based Stroke Program. A director of the Pediatric Cerebrovascular Surgery, a co-director of the Cerebrovascular Surgery and Interventional Center, and the R. Michael Scott Chair in Neurosurgery. He's won numerous awards, has over 100 peer-reviewed publications, and has funding from multiple sources including the NIH. Um, his research program focuses on mechanisms of vascular regulation shared by both brain tumors and cerebrovascular disease. Uh, he's interested in developing tests to better screen for the presence, recurrence, and progression of brain tumors and cerebrovascular disease using non-invasive biomarkers. Uh, his lab published the first report describing the successful use of urinary biomarkers to identify brain tumors, and this work has now expanded to use biomarkers to predict the therapeutic efficacy of various treatments for cerebrovascular disease. Uh, many of you remember his excellent grand rounds, uh, that he gave to us a few years ago on Moya Moya and he's fortunate enough to, uh, return today to speak to us on craniopharyngioma. Please, uh, join me in welcoming Doctor Smith. Oh, thank you very much. I, uh, long, longer introduction. Whew, um, I, I know I only got 5 hours to fire through this, so, uh, you know, and I know all of you probably see 1012 cranialphringioma a day, so I'm gonna really hit the, the rare points as best I can. Um, you know, in looking at this, you know, a lot of people say a cranialpharynia, what, you know, why, why do people care about this, especially non-neurosurgeons, you know, admittedly, it's a pretty rare disorder. Um, however, we do see an awful lot of them, relatively speaking here at Boston Children's, and, and I hope today sort of to highlight the fact that there are some systemic issues that are particularly important for those in the intensive care unit. In anesthesia and in nursing and hopefully make it a little less boring. I think that's Dr. Scott in his younger years. So to start off, because it is kind of a rare thing, I thought it'd be worthwhile sort of going over, you know, what is craniopharioma, and I went to the definitive source as best I could. We're here at Harvard Medical School. We have a bunch of very smart people around, so I, I went to the source and I hit Wikipedia up for their best possible answer. And they said that craniopharyngioma is a brain tumor of embryonic tissue. So, you know, they're not wrong, I suppose. Uh, and I thought I would start off with a little bit of background here. Um. So first of all, the term craniophringioma was a phrase first coined by Harvey Cushing. Harvey Cushing was sort of the first sort of bona fide American neurosurgeon. He actually was in part over at the Brigham right across the street and here at Children's, and it was used to describe this sort of tumor in the cellar region, and I'm not talking down in the basement. I'll go over the anatomy in a couple of minutes. And these are congenital tumors arriving from remnants of Arrake's pouch, which is not sort of a fancy, you know, pocketbook you can buy in Macy's, and a craniopharyngeal duct. And there are what's important here is there's two types. There's adamatomatous, which I'm going to say wrong. It is not a special metal that Wolverine has in his claws, and papillary, which Tends to be more for adults. And these are a very important difference because only recently have we really starting to get smart enough to understand that there are molecular and genetic differences that lead to new therapies. Uh, this is sort of concordant with the fact that there are two age groups. There are basically kids, which is what all of us together see here, and the adults, uh, 50 to 74 years. Um, the reason it's so rare, and, and, uh, you know, we're lucky to, and lucky is probably not the right word, but to see a number of them here, there's only about 340 cases per year, all told in the US, about 100 of which are in kids. They make up about 5% of pediatric brain tumors. So you don't see a whole heck of a lot of these. And, and although I think all of us have probably seen one or two in the ICU or the unit at different times, um, they are pretty rare tumors, and, and we do see sort of the zebras here at Boston Children's. So with that, I, I mentioned, you know, we're talking about the cellar region, you know, where are we? This is sort of a nice little Grey's Anatomy picture, and what we're talking about, you know, there's the pituitary gland here, and then there's this craniopharyngeal duct, this sort of remnant of a, of an old tube between where the, you know, the head bones and the neck bones smash together. That's a fancy Harvard medical term. I don't like to show off or anything like that. But, but this is the part. The brain that we're interested in and to try not to bore you before 6 or 7 cups of coffee in the morning, a little relevant embryology. But essentially what happens is I'm told on good good accounts that this foldy thing is supposedly what a baby looks like early on. I really, I slept through that part of embryology, but as the head part is folding over, there's this little part near where the nascent mouth bends in. And where that happens and sort of described to me is you have the epithelial stuff of the mouth and you have the brain bits up top, and they kind of mash together. I, I think that's exactly how it's described in the biochemistry handbooks. And the, it creates the pituitary gland where the front part called the adenohypothesis is made up of Sort of rudimentary mouth bits and the back part, the neuro hypothesis, is a little piece of the brain that sort of drops down made of neurons. And in between there is this space called Rathke's cleft and Rathke was a heck of a guy, really very exciting, a lot of fun, really enjoyed playing cards, but he was known most for this cleft, and there is a place where a lot of bad stuff can happen. And that embryonic tract between the two where these became together and got pinched off is the pharyngeal hypothesis of the craniopharyngeal duct. If you look at the sphenoid bone, sort of looking from the side here, this is where the mouth and the nose is, where you folks do all that exciting and important anesthesia stuff, and just behind there is where we hide up in the brain, and this duct is where little bits of tumor, for lack of a better phrase, can kind of get pinched off as the brain is closed off. And it sits up here and this is the cella right here. So behind the sphenoid, this little bit of bone, and then the cella there, and this is a picture, same anatomy. This is all the air bits of the sphenoid sinus. This is the pituitary gland and along that axis all the way from sort of essentially the top of the nasopharynx all the way up into the third ventricle of the brain is where these little bits of embryonic tissue can be left behind and you get these sort of very large tumors. So. I mentioned earlier there are two types of these tumors, and, and it actually is kind of important despite just sort of getting quizzed in tests. The pathology really is an important aspect of this, and the Aetna, and again I'm going to butcher this, I was practicing the other day and I can't get it wrong, we'll call it adamant, you know, great group, derived from this neoplastic transformation of remnants, these epithelial remnants of the craniopharyngeal duct. So So this is epithelial tissue basically they got pinched off in there and it's about 90% of the pediatric cases are this adenomatous type of tumor. So this is, this is basically all what we're seeing here at Children's is gonna be this first type of tumor. Um, and in fact, it makes up about 2/3 of the adult cranioppharyngioma as well. So this is really the bulk of what we see, uh, for tumors. Um. It's interesting if you want to call tumors interesting because it comes from the mouth area and it mimics a lot of the embryonic tissues that are there. It makes teeth, and that's why it's so hard surgically sometimes. This is a CAT scan. I'll talk about radiology in a second. This is essentially a tooth in the brain. There was a nice photograph in the New England Journal a couple of years ago by one of our former fellows, Ed On, that showed a tooth in the brain, and I don't think he put it there just for the photo op. This is, you know, what these grow. Um, the other problem other than the calcification is that because it's skin stuff, it makes dandruff. It makes skin bits that fill off and it makes skin oil, and that oil and that dandruff, if you will, as it melts away, unlike when it's on our skin and we wash it off in the shower every week or two if you shower, uh, it builds up inside of these cysts, and that's 11 of the real problems that we face as, as surgeons and as docs that treat these because those big bubbles keep filling up and They smoosh unimportant brain parts. So, those, uh, that fluid, that crank case like oil fluid, those of you who've been in the OR and seen them, uh, those two characteristics, the hard tooth enamel, the, the, the bony aspects, and the cysts really characterize this tumor and make it a problem. The other type of tumor is papillary. This is sort of metaplasia of the adenohypothesal cells, so more of a pituitary type tissue. It's about 1/3 of adult tumors almost never seen in kids. It's stratified squamous epithelium. It's a lot more flat and smooth, and it's rare for this calcium formation. What you see grow. Mostly is not only this hard calcium, but this is a cross section. Here's sort of the gland down here, pituitary gland sort of looking from the side in a sagittal view, and you get these big cystic things with these little flecks of calcium floating around and this nasty black crank case stuff that they're really lousy things to operate on. But hopefully it's going to put us out of business, and I'm gonna talk about this at the end, is the exciting discoveries that have gone with the genetics of these tumors. So, essentially, almost all of the adenomatous tumors have this CTN and B1 mutation. This is a protein that encodes beta. And, and that sort of drives the WIND pathway. So the hope is that as these new drugs that are being developed that specifically target the WIND pathway, we may have a new class of chemotherapy agents that hopefully will help us to treat these really stubborn tumors a lot better. One of the real home runs, and I'll talk about this at the very end of the case talk, is the papillary tumors. About 95% have this BRAF mutation, V600E, and I'll talk a little bit about the end, but essentially this is another druggable target, and there's been some nice reports, one in Nature Genetics a couple of years ago from the group over at Mass General that showed that you can actually treat these successfully with medication. So I hope that this will be one of the last talks over the next few years because they'll have better cures for these, and this is not something we need to deal with as much, but, but still a little ways away, but some exciting stuff on the horizon. In terms of epidemiology, um, as I mentioned, about 340 cases a year. There's no difference in sex or race. About 1/3 of the cases are pediatric, but that's really because, you know, about 1/5 of the population are kids, so it's actually more common per kid than it is per adult, if that makes sense. It's about 5 to 10% of all pediatric brain tumors. And if you look at a tumor in the cellar region, this sort of area down in the bottom of the brain here, it's the cellar of the brain. Nothing. OK, good. It's about, yeah, I'm OK. I'm just checking you're all with me. It's, it's still early in the talk. Bear with me, we're moving along, but it's about 50% of all cellar tumors in kids. Um, how do they present, and this is something where it really, you know, they, they have a wide range of presentations. The sick ones, the ones that we see kind of emergently, are almost due to the fluid being built up in the brain. They have brain constipation, if you will. So this is a, a sagittal image of the brain. The nose is down here. This is the regular brain here. This black stuff is all fluid. Normally your brain makes fluid up. The top of your head, the spinal fluid, every day it makes about half a liter, you know, 30-400 milliliters of spinal fluid. It's supposed to drain down to the bottom of the brain. Joe Madsen, Ben Wharf, super smart hydrocephalus guys, they probably have a bunch of equations. I'm just a dumb surgeon. The faucet built in the top comes out to the bottom, and if you've got a big old tumor in the way, it backs it up. Brain gets constipated, kids get sick. So those kids will show up. They have, you know, bad. Nausea, bad headaches. Sometimes they can be very acutely sick, uh, and, and those are the kids that are kind of emergent. Um, you can have a bitemporal field cut. I'll go over the anatomy of that in a minute cause probably other than the neurosurgeons in the room, neuroanatomy is not razor sharp for everybody here. And, uh, a really important one is this idea of endocrine dysfunction. These are the sort of You know, crazed, panicked pediatricians that call with this huge guilt complex because little Timmy or little Susie's about this high and they're, you know, 13 years old, and they've had this growth arrest for a long time because their pituitary gland is damaged by this growth. They don't make growth hormone and up to, you know, over half, sometimes. in some reports 90%, which I think is a little high, but a large number of these kids, and it's funny because you're saying a large number in small kids, have growth arrests, and it's very subtle, and they also tend to have problems with their hypothyroid, and this is relevant for anesthesia along with some other things I'll talk about in a minute, but this I find is a very common presentation. Another one, which is almost the opposite of that is this hypothalamic dysfunction. The hypothalamus sits at the bottom of the brain as well. It controls a lot of the auto-regulatory functions of the brain. When do you eat? What's your temperature like? And if it's getting smooshed by this big tumor in the third ventricle. You're gonna have problems like uncontrollable weight gain. I thought I had a craniopharioma for a little while in residency when I wasn't exercising, but it turns out just because I was lazy, uh, and temperature dysregulation. So these are some common presentations, and, and I would, uh, emphasize that. For folks in the ICU, it is relevant to know, uh, the sort of anatomy of, um, uh, this field cut, this bitemporal field cut. So just a quick review on your anatomy, bear with me, we'll, we'll get right out of it in just a second. But you've, you've got your eyeballs here and light comes in, and as light comes into your eye, it hits the opposite side of your retina. So things that are over here on this right side for me are gonna hit the left side of my visual field and vice versa. Then as the wires come back in the brain, they crisscross in the back. As they crisscross, the central part is where the two outer parts of your retinas cross. So if you have a brain tumor right where this green arrow is, and it's pushing up from below, as I'll show you in a couple of minutes with some pictures, you're going to selectively injure the wires that are crossing. So you lose the fields on either side of your eye, on the temporal sides of your vision. So that's why these Kids are kind of like their horse with blinders on where they really can't see things on either sides. The reason I emphasize this a little bit is for those of you in the ICU that are seeing these kids after surgery, sometimes they have a pretty good field cut at the beginning and rarely if we've left some tumor behind, if there's a hemorrhage after surgery, if there's some swelling, and there's a blood clot from the operative site that then suddenly rises up in the middle of the night in the ICU, they'll develop a headache. And an acute bitemporal field loss. So they can see you, they're acting OK, but if you don't look to test for this bitemporal field loss, and if it's not, if it's different from before, that may be a reason you need to get an urgent scan. So that's why I'm kind of harping on this a little bit in terms of um the imaging. Um, so in, in terms of other things to look for uh for the physical exam, uh, growth arrest, the bitemporal hemiopathy we just went over, pap. Edema, swelling in the back of the eye. Um, lab studies are important and again this is something where the ICU team and the anesthesia team are really critical if we do decide to bring in the surgery. Um, electrolytes, uh, taking a look at, uh, their, uh, endocrine labs, and, uh, one of the things that's a mimicker of this is a germ cell tumor, and we can look for alpha fetoprotein or beta HCG, uh, which are embryonic markers for certain types of germ cell tumors, um. People always ask, you know, if you say an endocrine workup, what is that? Um, Essentially, it's this big laundry list of a bunch of tests here. Uh, but the key thing to think about, and I'll emphasize this again, especially for anesthesia, especially for surgery, if you folks in general surgery ever have a former cranioppharyngioma patient or any patient that has a pituitary history of where they've had tumor radiation, they, because they may have. Lost their pituitary function, they may need stress dose steroids, and they can frankly go into shock with the induction of anesthesia or with surgery and die from that. So it is important to remember that they may need supplementation with stress dose steroids if they're going to have surgery or if they're in the ICU, they have a fever, they have a cold. So this isn't just in the perioperative period, this is their whole life. So I do want to emphasize a little bit as a clinical point for the crowd here. In terms of what else we do for evaluation, kid comes in, uh, we are suspicious of this based on the history of physical. We, uh, get a CAT scan. Uh, here at Children's, you almost always get the CAT scan in addition to the MRI cause the CAT scan shows us whether there's calcium there or not. We look for the enlarged cella. These are usually slow-growing chronic tumors, so the bone will be remodeled, and I'll show you a picture of this in just a second. Um, and then MRI is immensely helpful. There's really no need for catheter angiography unless there's a specific question we're we're looking to ask for. There's a big long list for differential diagnosis, basically, what else lives down there. The take-home message is you're, for us, almost always, the other things are a tumor of the eye nerves and optic glioma, a tumor of the brain itself in that region, a hypothalamic glioma, uh, and then rarely these germ cell tumors, uh, and the one that's incredibly. Where I've only seen one or two, but you don't want to miss is an aneurysm, particularly a thrombosis aneurysm, because boy, it really stinks if you think you're taking out a tumor, you go to grab that big thing and then pau City. So you really want to make sure you're confident in your imaging before you proceed. What does imaging look like? Well, uh, I mentioned earlier, you know, this is an MRI, and you can see here there's often a solid component of the tumor, and then this is all that keratin keratin sort of secreting gunk. It's a big. a cyst here of this nasty, think about like all your teenage kids when they come down with the Clearasil and everything else on that's this trapped inside there. And if this stuff leaks into the brain, it can stick and wrap around a lot of the blood vessels and the nerves. So this can be a real problem. This is the other big problem as I showed before, these just rock solid lumps of calcium. Imagine having a tooth stuck in the middle of your brain. It's not very convenient and it sometimes lends itself to having a drill and really. Awkward spots, uh, you know, and you got to have the Mr. Sucky in there and try to make conversation with him like you're after the dentist. Other things in terms of imaging, uh, this is looking, for example, with a CAT scan. These are some of the characteristic findings, uh, not the yellow arrows, but you can see how they have this little rind of calcium sometimes along the edge of these, and that can change a really fun case into a really lousy case if you have this rock hard eggshell uh stuck up along some important things, um. This is an example of a widened cella. Uh, I'm sure that not folks see this every day, but the point is that this space down here where the pituitary gland normally lives is about 1/3 of the size. And the fact that it's enlarged gives us a clue as surgeons and as radiologists that this thing has been growing for a while and, and gives us a little chance to suggest that maybe this isn't, for example, a germ cell tumor which tends to grow more quickly, but rather it's something that's grown sort of a very fast, rather, very slowly. Um, we also look on MRI where these things are relative to things like blood vessels, other parts of the brain, and I'll talk about that with regards to surgical and treatment, uh, things. So, now you've got a diagnosis, you've taken the pictures, you say, all right, Ed, what the heck are we gonna do? How do we treat these kids? So, really, the question, you know, parents ask all the time is, so I got a cranial pharyngioma, you know, now what? What are we gonna do? It's in there. Um, for All patients, we start with an endocrine evaluation, as I mentioned with those labs. Uh, we like to, if we can, if they're not acutely sick, to get an ophthalmology examination to get them, uh, taken care of and get a sense of their baseline visual fields, uh, neurosurgery, uh, and then we have neuroradiology go over the pictures to make sure that we're happy with what we got. There are some kids, as I mentioned, they come in, they, they're, they're very sick. The fluid spaces are enlarged. Um, they're not actually blue, although they may seem like that. And these kids may be acutely sick. It's almost always because of hydrocephalus or high intracranial pressure. Those kids will have headache. Uh, they may have vomiting, um, they may be somnolent, um, and they may have hydrocephalus or a big cyst. The two things to think about with those. Those are one, they may need a drain fairly quickly. Putting in an external ventricular drain, it's not going to take the tumor out, but it's going to drain the hydrocephalus. It's going to let the water out so there's more room in there and the child can function better. The other thing, as I mentioned, if you folks are in the middle of the night and some crazy neurosurgeon like me calls us, we've got to do a drain. Let's go. You need to think, I wouldn't say in that voice usually, but you'd want to think about the fact that they would need stress dose steroids in terms of How you can treat them once you've stabilized them or if they're not sick and it's a, you know, growth or rest child that is perfectly well otherwise, how can you get rid of these? Basically, there's sort of four ways. The most common is surgery, and that's what we see a lot of here. Um, you can do that with a craniotomy where you come from above, or you can do that with a transtenoidal where you come from below. And in a moment I'll show you how we do that to try to demystify what the heck I'm doing on the other side of the screen. Or what I've done before they come up to the ICU and you see them upstairs on 7th South. Radiation is another option that works pretty well. Uh, and then a little less common, but sort of things we hold in our back pocket are things like intraraccystic therapy where we inject medicines into those cysts that I showed you, or there's some new approaches with chemotherapy, which, uh, I'll sort of wrap up with. Uh, this is a picture of myself and Craig McLean in the OR and, uh, you know, we're just trying to figure out what to do. Um. How do you choose, right? You have all these options, and I'll tell you that a lot of really boring neurosurgeons will stand up for hours on end and argue about Picayune points, uh, but it is a really controversial discussion. Um, in general, there is an imperative to treat these because the tumors will grow as the child grows. So, it's very unlikely that if you had one of these, you'd say, yeah, give us a call, let's see how things go. Um, surgery is typically first-line therapy, especially here at children's. Assuming the anatomy is appropriate, but there's a lot of debate given how about the aggressiveness of the surgery. Should you try to take it all out? Should you try to just debulk it and then radiate it, given the risk of side effects like endocrine dysfunction, injury to the hypothalamus, or injury to the blood vessels around there. So this is, I mean, you know, let's think about some really nerdy neurosurgeons with nasal voices arguing back and forth over their pocket protectors, but it is a very valid point and it's one to which I I think there's very little hard data other than if you have an experienced team that handles them routinely. In general, if the anatomy is favorable, trying to get a gross total surgical resection is usually the right way to go. Radiation is kind of hard to do if you have a big lesion. The radiation field is too large, and you'll injure the surrounding brain. So there is a role either for tiny lesions or for lesions that we can debulk with surgery to subsequently be treated with radiation thereafter. Um, with surgery, like I mentioned, the question is, do you want to get it all out, or do you want to get some of it out and then, uh, treat it with radiation or medical therapy afterwards. And then with radiation, the big question is, you do that upfront or do you debulk it or only save radiation for later on. You really can't do it in very young kids because radiation is not tolerated in the developing brain, particularly under age 3. It's something we try to shy away from. So at the end of the day, at least here at Children's, the policy regarding cranioppharyngioma and treatment choice usually is surgery. Doctor Scott has codified this in our guidelines which come out something like this, uh, which is try to be aggressive and treat these if you can. Um, So let's talk a little bit about surgery since most of in this room are involved in the surgical care of patients, either from anesthesia, nursing, or in the intensive care unit. What are the types of surgery and how do we do them? And I know the first thing you're saying is, but wait, Ed, what about me for anesthesia, pre-op, in the ICU? How can you make my life better? Well, one big thing is this, uh, concern about diabetes insipiditus, and I have a little slide about this in just a second, but this is a critical part of the management of this patient, especially. In the intraoperative and perioperative period. And then if you've had a patient who has a cranial phyndrome that's been treated in the past, they may have the eye forever. And for any other surgical procedure, for any other stay in the ICU, you need to be cognizant of the fact that they have this endocrine dysfunction that affects their fluid balance and their sodium balance. Um, Stress steroids, I've stressed many times already. Nothing, OK. Uh, uh, for transynoidal patients, managing the airway will be important. I'll talk a little bit about that in just a moment. For the cranial. om ies these can be very long cases. These are the cases that can go 18 hours, 20 hours. We're just picking away for a long time. And from an anesthetic standpoint, from a nursing standpoint, being aware that these are kids that are at risk of DVT, these are at risk of, you know, having sores on the bed from not moving around a lot. I think having a good conversation about prepping them for being on the table for a long time is important, along with blood loss, not necessarily from dramatic bleeding, but from slow ooze with this big craniotomy over time and a little kid. That can add up. Uh, and then, uh, again, as a general note, one thing that uh we recognize a lot because we see it here, uh, but, uh, there is this known association of moya moya after radiation therapy for these kids. So if you have a kid who had cranioppharyngioma, you're treating them for some other reason. You, you're seeing them for an appendix or for pneumonia. Um, you need to think about the fact that they've gotten radiation in addition to the endocrine concerns, they, they may have a risk for moya moi, especially having odd TIA-like spells. I mentioned DI, diabetes insipiditus. Just a quick review on the pituitary gland. I, I, you know, if you remember, this is the front, this is the back. The front part is all made of mouth bits. They make the thyroid hormone, uh, cortisol secreting stuff. All the sex hormones and those types of things come from the front of the pituitary gland. The back is basically a little bit of brain that kind of dangles down. So these Big long nerves, the, the nerve bodies live way up in the hypothalamus. They're kind of hiding up there going, what's going on down there? Everything cool? OK. But the, the axons come all the way down along the stalk, this pituitary stalk that comes down, and they end down here where they squirt out vasopressin, this short peptide, and, and basically what the peptide does is it stops you from peeing. Um. And so the problem is if you take the pituitary gland out or if you cut the stalk, let's say that there is a tumor up here and I take the tumor out up above, I leave the gland behind. I think I'm a hotshot surgeon, but as part of that, I cut the gland. I cut the stalk. What can happen is this, what's called a triphasic response. So the triphasic response is normally this gland is squirting out vasopressin. Here. If I cut this spot right here because there's a tumor there, the first thing that will happen is that the, the uh gland is kind of shocked and goes, Whoa, uh, it's not getting any more commands from up above. It stops squirting out the vasopressin. So if there's no more vasopressin, your body can't hang on to the pee. Uh, it starts dumping water out and essentially you lose volume. The water's going away, so you're concentrating your blood and your sodium level shoots up. The second thing that happens is over the next couple of days, those axons, the little things sitting down at the bottom that are full of neurotransmitter, they die. And as they die, the cell membranes lose their integrity. They pop open, and as they pop open and degrade, they release all this vasopressin all of a sudden. So then the body's like, Whoa, we got a whole lot of vasopressin. And what will happen then is that the kidneys clamp down. You're saving all your water, and then basically, You've got an extra water in your body. Your volume status may go up, but your salt level goes down. You become hyponatremic, a low salt, because you're diluting yourself. That's a big problem. That's a lot harder to manage. And then lastly, when those cells are finally completely dead and they're completely destroyed and all the vasopressin has been washed out or used, you're left with nothing. And the third part of the triphasic response is there's nothing there and you go back to having DI usually permanently because there's no. More vasopressin around and you can't hold on to water anymore, so you pee like crazy and your salt level rises unless you take exogenous DDAVP. You take the medicine either by mouth or with a nose spray. So I just want to go over that a little bit because I think that's really very relevant physiology for what you folks see upstairs. And again, while you may not see the tumor in the first case, when we see them for the rest of their lives, if you see them for other procedures or other interventions, this is something you're gonna have to manage. So, um, surgical approach, what do we do? We're curious about the size of it. We're curious about whether it's solid or cystic that's going to affect whether we can take it out. Is there calcium in it? Is it built like a rock? And then if we do think of coming in through the nose, the sphenoid, the air sinus, is it pneumatized, meaning is it full of air and I can just ease on in there, or is it like a solid rock in little kids, it hasn't pneumatized yet. And sometimes you have to drill through that. We did that last week ago Wednesday where we had a non-pneumatized sinus. Uh, lastly is the inter carotid distance. That's the width between the two carotid arteries as you're coming up through the nose. If you are a little off target, usually the distance is about 1 centimeter. So if you kind of put your drill in the wrong direction, all of a sudden there's a lot more for you guys to manage with physiology or maybe nothing at all in a very short window. Uh, so that's, those are sort of the anatomic things that we reference. Like all of surgery, like much of medicine, the key. The thing with these tumors is real estate, right? So it's the location, location, location. What are the things that dictate whether this can be removed or whether we have to try some other therapy? This is a little look again from the front right here, uh, same view as the tumor here. This is the sphenoid bone at the base of the skull. This pink area is your sphenoid sinus, the sort of air thing that gets all stuffy when you're going up and down on an airplane or you have a. Cold. This is the optic nerves. I mentioned those earlier. They're kind of laying over the top of the, uh, pituitary gland. Pituitary gland is here where this little star is, and then these red things apparently are important, and they carry some stuff around through the head, which I've heard of Circle of Willis is not on the cape where you're getting a rotary. So there's some really important real estate here pituitary gland, optic nerves, uh, the blood vessels, and just above it, the hypothalamus, um. That means this whole region really, it makes these tumors particularly difficult to manage surgically. Uh, one big thing, and you may hear the surgeons talking about this just to demystify it is, is it pre-chismatic? Is it post-cosmatic? It's a lot of fun. You're out at night at a bar, you know, with your wife or your husband, you're trying to show off, oh honey, is this a pre-cosmatic tumor or not? Um, what this means is if you look at the optic nerves here and the eyeballs are right here in the front, is the tumor behind the optic chiasm and pushing it forward? And the reason that's relevant is, as I, if I come in as a surgeon, the first thing I'm gonna see is normal optic nerves, and apparently, you're not supposed to cut through those. And that makes it very hard to think about resecting the tumor if the optic nerves are your boundary for getting in and out. On the other hand, If the tumor is sort of in front of the chiasm, so here's the chiasm back here, and the tumor is pushing the optic nerves forward, you have all these little windows where the nerves have been stretched and pulled, where there's a normal corridor that I can get in with my little fancy tools and take this tumor out. So a pre-chiasmatic tumor, this one that's in the front that you've got a lot of room, is, is good for me, and that helps me as a surgeon, whereas a post-chismatic tumor is bad news. To show that a little more graphically, this is sort of the lay of the land where right here you're looking from the front. Here are the carotid arteries, the anterior cerebrals. This is your little window, your optic nerves are here, and then there's the kia and the tumor in the third ventricle with the hypothalamus is back there. So you got a lot of, sort of, you gotta really picture where you can go and what you can do safely. Below all that is the pituitary gland and the stalk. So let's talk about a craniotomy. You know, what the heck is Ed doing under the scope? We usually position the kids with their head up and slightly turned to the side. Um, we make an incision, as you see marked out here from the scalp across. Sometimes if it's a very large tumor, we'll do a bicoronal incision because we'll take the 4, the whole bandeau off, the whole. Front of the forehead, we may move one of the eyes to the side. This is the orbit here where we've taken the orbital roof off and you can see the top of the eye in the periorbita here. Uh, we remarkably found an asterisk here which we've never really found before. We reported that in the Journal of Neurosurgery, a bunch of grammar and neurosurgery, rare thing. That this is the dura right here, relevant to anesthesia, tugging on the periorbita when we're doing our dissection can induce bradycardia, and uh that induces tachycardia in the anesthesiologist, but bradycardia in the neurosurgeon and the patient. Uh, so that's a very common finding in this region. Once we have this exposed and we've got a good view, um, uh, sometimes as we come across the midline, the superior sagittal sinus is exposed, and that runs a risk of air embolus. Um, we then take the bone off. One of the big things that eats up a little bit of time, this is the sphenoid wing. This is the sort of, uh, bony ridge that separates the frontal lobe up top from the temporal lobe down below. We want to go so usually in the space in between these two. So we may spend some time drilling down the sphenoid wing, and you may be wondering what the heck we're doing. This is where you can get some blood loss just from ooze over time and it may eat up a little time, but it gives us a corridor to get in there. Once we've got that exposed and we can see where we need to go, we bring in the microscope. And again, just to orient you here, um, this was a transparent woman we operated on a little while ago, and you can see the optic nerves here on either side, the carotid, the middle cerebral artery, the anterior cerebral artery, and that's the normal anatomy, and you can see how that would be distorted with a tumor inside. Side there, so what does it look like actually under the microscope? Well, this is one of my cases from a little while ago. This is again, we're looking in sort of from the side here on the right. We'll typically go on the right side because it's the non-dominant hemisphere, assuming the tumor anatomy is favorable, all things being equal, we choose the right side because we wouldn't affect language as likely. Um, the tumor here, you can see this is the left optic nerve, this is the right optic nerve. This is the carotid artery right here, anterior cerebral, middle cerebral, and then you've got these little tiny windows, the optical carotid triangle. Uh, down here is the third nerve that can blow the pupil if you tug on it at all. Uh, but this is sort of, these are where we're working to take this sort of, you know, acorn or golf ball sized tumor out of, and that's why it takes a long time for us. We're just kind of picking away under the scope. Um, this is what it looks like after it's decompressed. You can see here the optic nerves and the chiasm is tented up. This is a kid who had a bitemporal hemianopsia, and you can see how the chiasm right here is sort of stretched. And then as we take it out, you see it's nice and deflated like a little trampoline, uh, and things are, are good. Another thing to be worried about from an anesthetic standpoint is vasospasm, right? Here is, uh, the same patient. This is from Mike Scott's patient. Where you see the cyst is tumor here, it's all gone. But what I'd draw your attention to is this is a normal anterior cerebral artery right here, big, fat, chubby, happy artery, lots of blood cooking along, and then at the end of the case, by touching and manipulating it, it clamps down. And uh while that in a peripheral limb might cause a little bit of sort of a cold arm or leg, this can cause strokes in the anterior cerebral territory. So this is where he may ask for Paparin or other medicines to fix that up. For anesthesia. Long case, blood loss, air embolus over the sinus. DI can happen during the case, so you need to be cognizant of that, watch your urine output, check your electrolytes. Uh, we really move the table a lot for these cases. So from a nursing perspective, strapping them in pretty well, uh, and then redosing the steroids and antibiotics during the case can be important. Uh, the other kind of big surgery we do here is transhenoidal. You can pick your friends, you can pick your nose, you can't pick your friend's nose. Uh, the reason for doing this sort of approach is that, uh, sometimes if the tumor is under the chiasm and we can't get at it from the front, we have a great route from below. To start off with this, again, looking at what's relevant to you folks from anesthesia, positioning these patients, we really wanna uh make sure that the ET tube is off to the left side so that it Runs down if we're coming in from the right into the nose, which is our preferred approach. We'll often prep out some of the belly for a fat graft because we like to close a little piece of fat. I like to donate mine, but apparently there's rules against doing that. Um, and we'll give these kids nasal cocaine and Afrin. Um, they go to Club 54 after, but beforehand, uh, that can affect their heart rate and their blood pressure. So we really wanna make sure from anesthesia you're aware of that. Um, bleeding is very rare in these cases. Unlike the craniotomies, but if we do have bleeding, it's usually because there's an injury to the carotid, and that can be extremely dramatic. So those are the things to be cognizant of surgically. What we're trying to do basically is come up through the nose here. We come along the vomer, um, and we get into this air sinus, which is our natural pocket, and that brings us right to the cella, the bottom of the pituitary gland, and we can get in where we need to go. Uh, this is an older picture, but really highlights the steps of the operation, um. You come in through the nose, we'll often cut the mucosa and strip it off the bone. We go submucosally along this midline septum. Many times we'll take a lot of the septum out, and what you're looking at straight up down the barrel is the cella. I'll show you another picture in a second. And as you drill the cella away, as you take this bone away at the bottom of the skull, you see the dura, just like the lining of the brain anywhere else. There can be a circular sinus, a big vein that's around there that can bleed a lot. And we just have to be cognizant of how to control that. We cut open the dura, and then there's our tumor. At the end of the case, we'll pack in some fat or gel foam, and then we'll put in these little uh Marisel, I mean, I'm sorry, uh, medpore grafts, which are these little artificial plastic grafts that reconstitute the bone and prevent spinal fluid from falling out or nose booger germs getting in. I think that's what the ID team calls it, is nose booger germs. Um, if we have to get access. The nose and kids, sometimes it could be hard. And for the plastic surgery folks, we had a case when John Mulligan had treated the other in the past, but I operated on last week who had a cleft palate. These kids sometimes they have to come sublabial. So instead of going through the nose, you lift up the lip here and then you can just disconnect the top of the lip over the hard palate, and then you can come in over the hard palate and get up into the nose that way. The advantage of that is you're not limited by nostrils. Uh, you can imagine. If you tried to pick your nose, you can maybe get your pinky in, but not your thumb. Uh, and that's sort of the same problem with the instruments for transformidal surgery is that you can be limited. And so by going sublabial, even though there's additional morbidity, it's a little harder to heal, you can get the entire range of access of getting up in there and it gives us a good view of the pituitary gland. There's a little 215 year old, I think that we operated on with a pituitary tumor. When you get in there. When we're looking up the nose, this way you folks will see on the TV screen, uh, this is the floor of the cellar right here. So we're looking straight up. This little bony ridge here on the bottom is what we're seeing here. The carotids are here on either side. The optic nerves are here under a little bony sheath on either side, and this is the clius, the base of the skull. So those are all the things you're trying to not hurt. What is it? look like, well, one of our former fellows did this nice little video of a tumor, uh, uh, and, and so just to credit him, uh, you're gonna see here a tumor here. This is sort of a more atypical uh tumor type, but, um, we come up through the nose. So this is the cella right here. We've taken it out. Carotids are on either side. We have the endoscope looking up inside. So unlike a microscope. And get the endoscope right in there. You see the tumor right there, and what we're doing is just sort of a piecemeal removal of this tumor at the base of the brain. Up above there is the optic nerve, the pituitary gland, and as you keep removing the tumor, it's just sort of a slow piecemeal remover. This is great with coffee in the morning, get your bagels. It's really, you didn't see this coming, did you? It's kind of a left curve, but The goal is to move along carefully and you're really operating through the nose. There's no visible scar. Um, you've got a very nice view. You see the optic nerve right there as we're pulling this down from below, which gives us a much better approach for this without injuring the nerve. It lets us, if we have that prefixed chiasm, uh, a transhenoidal approach is wonderful for that because you never touch the nerves till you're done. You can leave the nerves alone and basically you're pulling it out from beneath it to decompress the nerves. As opposed to coming from either side of it above, ultimately, when you get all the tumor out at the end, you're gonna know that it's out by either sticking up the endoscope with an angle tip so you can actually look around and see the inside of the cella and in the under surface of the brain. Uh, you're also gonna know by reaching in there and feeling with your transhenoidal instruments, these sort of long skinny instruments are poking around. We may get a dental mirror and get in there. Uh, this is sort of the speeded up hyperkinetic. I wonder if you had. Nasal cocaine when he was doing this case beforehand, but you know, typically the prep for this case is many times as long, if not longer. You can see up into the brain inside there. We're looking up into the hypothalamus here. This is the optic chiasm right there, spinal fluid down there at the bottom, and on either side you can see the carotids right above here is the anterior cerebral artery, and you can really get, it's the visualization is amazing if you have a good view, even if they're tiny kids. Uh, you can get a great view and you can really sort of clean out the bottom of the cellar right here. Uh, usually it's just suction and grabbing. Sometimes you have these little, um, uh, uh, the cauterizing devices that lets us get in there, but you can see how you can really get on the undersurface of the chiasm right here and um it's a very safe way to do that, uh, in terms of time here. Let's see if we can sort of, uh, get to the end where it shows the relevant anatomy, um. But there's the optic chiasm. You see the undersurface of the brain right there. This is the frontal lobe, the anterior cerebral arteries, uh, spinal fluid back here, carotids on either side, and you really have a great view of everything the pituitary stalk is preserved in this case. So it's a, it's a nice way to get this done if you need to. Um, last thing, you know, how do you treat these kids? Um, radiation is good, it's particularly in small lesions. Uh, rates are all over the map from 30 to 95% cure rates for 5 years. You really can't do it in young kids, and you do have a risk of vascular injury, uh, from radiation injury, cavernous malformations and moya moya. Uh, intra-cystic therapy, I mentioned earlier, the idea there is you put a tube into the biggest cysts, uh, and you try to kill the, uh, growing, uh, skin cells in there, either with radiation, with P32, chemotherapeutic agents like bleomycin, or immune modulating agents like interferon. There's a wide range of success rates. It's sort of a second tier therapy, and the big side effect is if this stuff spills out into the surrounding brain, it's bad news. Um. This is essentially what you do. If you see the cyst right here, uh, you drop the tube inside there with stereotactic placement, and then you essentially instill medicine and flush it around. There was a nice study by this that was done in Italy, and they use 60 patients and they showed that basically, while it has no Effect really on the solid tumor. So this does not cure. The tumor does not make the tumor go away. It can shrink the cyst down, which can reduce mass effect on the brain and can help visual function or function of the hypothalamus. So it is something that seems to be helpful. Um, I did mention at the beginning that there are some new treatments on the line. Uh, Interferon has been used not just by injecting it here, but systemically, and the really exciting things are these gene-directed targeted therapies. So for adenomatous tumors, this overactivation of WIN pathways, there's a number of different in vitro trials and in animal models that have been looked at. The really exciting one is the use. Of BRAF inhibitors. This is over the counter, Telfinar, which I'm probably saying wrong as well. Whoever makes these drug names up, I think they probably have had a little bit to drink and they make up names. But essentially what it does is it blocks the effects of this mutation, this BRAF, it's a BRAF inhibitor, and it's remarkable. They've had a number of reports where tumors have essentially just vanished after this oral medication. So it really is an extraordinary example of how the genetics of these tumors can lead to drug directed therapies that completely change the outcome that we failed at at surgery for decades, and with a couple of pills with almost no side effects, these kids can have incredible cures. The result of all this work though is still, other than the drugs, pretty depressing. About 80% of the kids will have transient DI. About a third of them will have permanent DI. Almost all of them will need. Growth hormone replacement. If you take the tumor completely out, they'll need stress steroids for any procedures they have in the future or bad infections. Obesity occurs. This is one of Doctor Scott's patients that put on 45 kg, so 90 pounds, um, just after surgery. These are kids that may be candidates for, um, uh, uh, obesity surgery. Um, they, they're just, they're very sad kids, um, and it can be very difficult to manage, um. Cognitive dysfunction can be very severe in these children. Uh, vision loss occurs in over half the kids. Uh, about 1/5 I'm sorry, about 5% will get moya moi if they get radiation therapy. They get these sort of dystrophic, uh, interned carotids. Uh, recurrence rate, uh, is fairly high. Most of them, if they do recur, will occur in the first few years. Uh, if they get past 5 years, about 50% will remain disease-free. But these are tumors that come back. They come back like a bad penny, and you will see. Now that I've been here long enough, they come back 5, 1015 years later. You need to monitor these tumors. If there's no recurrence and you've completely gotten them out, there's a 90% 10 year survival. But if there is recurrence at any time, there's a 30% mortality 10 years from recurrence. So one third of these kids will die from their tumor associated problems. These are lousy, lousy tumors. They're a depressing disease. You need lifetime monitoring. And despite being some so-called fancy crappy table this did this. Best impossible things are terrible. We're not doing a great job of taking care of these kids, and the question is how can we do better, um, you know, we try to work hard, all of us in, in different ways. One of the first papers that we were able to publish with Dr. Moses' help over in the vascular biology group was looking for biomarkers, and the first one was looking at urinary biomarkers in a cranioppharyngioma patient. And people say, Well, wait, Ed, urine, what the heck are you doing with urine? This is Joe Madson, uh, before he had a good shave in the morning. You know, why are we using urinary biomarkers? They're non-invasive. There's no needles. It's cheap. It's easy. You can ship them. You put the P in UPS, uh, and they're sensitive and specific. You can quantify them unlike an MRI where you kind of look at them and go, uh, is it bigger? Is it smaller? This is from the original paper. You can see that, uh, you know, tumor is taken out, tumor comes back, and with the tumor coming back, this is a very primitive, almost. A decade ago, but essentially we can see the recurrence. This is a control patient. This is pre-op and then post-op when the tumor goes away, the markers go away. We're able to show with the pathology that the same things we're identifying in the urine were actually histochemically present in the tumor. So we sort of linked the disease to the scene of the crime like the game Clue, and this. It is sort of a real uh cool thing for us in terms of what we're doing next. Uh, well, for urinary biomarkers, uh, one of our former fellows who's now coming on staff here next year, Katie Fennell, uh, did a beautiful bit of work in, uh, Doctor Moses's lab and, and with us, uh, showing that there are unique fingerprints for different types of tumors. So not just you got something, but what kind of tumor do you have? Do you have a medulloblastoma? Do you have a pilocytic? And with these fingerprints we. Identify tumor type. She also was able to show that with time, if tumor is taken out, the size of the tumor sort of correlates with the amount of biomarker, and at least as a proof of principle, I don't want to oversell this. It gives you an idea that it's possible that we could use these urinary biopsies as a way to maybe cut down on MRIs, not to replace them, but maybe to save these kids a few trips for anesthesia, having to do MRIs in the afternoon. So what can I conclude here? It's a little picture of the Boston Pea Party, uh, urinary biomarkers, pee party, nothing, OK. Um, so, to wrap up, hopefully on time here, you know, what are the take-home messages for cranioppharyngioma? It's a rare tumor, but it's a complicated disease. It's a long-term disease for neurosurgeons to follow it. And for all of you in anesthesia, nursing, surgery, ICU, there are a lot of side effects. That you folks need to know about that can critically impact many other parts of these children's care. Um, surgery is a potentially helpful treatment, but it really requires super careful anesthetic management, ICU management. It's a team disease, um, diabetes, insipiditus, stress steroids, the long-term vascular disease. These are all things that we together have to manage. Um, long-term follow-up is. Super critical for these kids and there needs to be awareness on behalf of everybody that touches them in the medical field that there are other things beyond just the brain tumor. Uh, what's exciting, I think, is that through work done here and at other places there are new biologically driven diagnostics and therapeutics that are in the pipeline, and, and I hope it will change this from depressing to something a little more smiley face emoticon at the end. So I want to thank all my colleagues in neurosurgery. I want to thank all my colleagues in the vascular biology program, uh, and certainly all of you who helped me take care of these tough kids and uh really do a great service to the children we care for. So I think that's about it. And if we have time, I'd be happy to take any questions. And I would like to first thank you for a great presentation. This is obviously a very tough topic. It's interesting, in most tumor surgery, you talk about trying to get a margin to decrease the, the risk of recurrence. When you're bounded by the optic nerve, the chiasm, and the carotid arteries, you don't have, have too much margin. Quite frankly, I'm surprised you don't have a higher incidence of Recurrence than you actually have. Oh, I, I do. Just Dr. Scott and Lily don't. I'm the only one that does. I see. Um, and unfortunately, the, the Medical therapy is for the tumor that's most rare in children. Is that correct? In other words, it's for the papillary. Correct. Although the hope is that the WINDT inhibitors, of which there are some, are very shortly following in the pipeline. It's just that the only clinical reports that I'm aware of of actual response to treatment that at least have been openly published have been for the BRAF inhibitors. And the BRAF inhibitors are much more mature, as I understand them from the, and if there's any neuro-on folks here, correct me if I'm saying anything stupid, but that's, uh, that's the reason that started. Uh, the, the BRAF is more common and better evolved in terms of medical therapies. The WINDT inhibitors are a little further behind, but hopefully next in line. But they're for the, the papillary, not the adenomatto. The, the BRAF is for papillary, and the wint is for adenoma, adenomatous, not adenoma. And quite frankly, the fact that you can do this transhenoidal is, uh, is amazing. And any, any prospect for Ways of getting it more completely resected to decrease the chances of recurrence. Well, I mean, you know, there've been such great, even in the past few years, I mean, we've got better optics, we've got smaller machines, we've got better neuron navigation, but to be blunt, these are all incremental advances. This is a sharper pair of scissors, and, and that's not really the way to cure these. I don't think the cure for these is going to be biologic, you know, no matter how good we are with, with sharper scalpels and brighter microscopes. At the end of the day, I believe personally that this is a biologic disease and we're just crude hacks as surgeons. It can be a surgical disease if you get it all out, but I would love to have something that is biologically driven, that is much more elegant, and, and actually, you know, something from the lab is going to be a heck of a lot better at treating these than anything I'm going to do with, uh, you know, a sucker and a bipolar. Additional questions for Doctor Smith. Doctor Fellows Great talk. Uh, have some of these patients had imaging of the craniofacial area done years before for unrelated reasons? And if so, has anything been found that could be considered a harbinger of the, the tumor developing later? So, uh, it's an interesting question, you know, I, there, the short answer is I'm not exactly sure. There are a couple of reports of these sort of unusual thickened bones. Um, anecdotally, I'd have to look at my own series to see if there are sort of these antecedent warning signs. Um, we have certainly had a number of kids where they've gotten plain skull films, for example, and in the past there's been a widened. which is not appreciated as the tumor, but, you know, at that point they didn't have an MRI or a CT, so I can't say for sure if we got an MRI at that point that you wouldn't have just seen the tumor then. But I would say for those, for example, that get trauma X-rays, dental X-rays, that the harbinger of a widened cella, that area I showed you where the pituitary gland lives, those, I mean I've seen a number of those here where they had that in the past and it just wasn't picked up on. There's no questions. Ed, you mentioned how important location is with respect to uh management strategy, but it seems like no matter what you do, the morbidity in these patients is extremely high. I'm wondering about the, uh, tumor cell migration and the wind sig signaling and potential biomarkers that might sort of improve your management decision-making, uh, particularly in terms of biomarkers. Uh, any specifics on that moving forward? So you raised a great point, David. I mean, you know, the, the question is, can we figure out better ways to identify those that might be more resectable versus those that might migrate? I would say that in general, unlike other tumors, this is not like a glioblastoma where it sort of invades the surrounding brain parenchyma. Many times. You'll have nice cysts and capsules. The problem that exists is if they wrap over tiny blood vessels and stick to them. So I guess what I would say is it's less of an invasive or migratory disease like traditional primary brain tumors in the substance of the brain, and it's more a Uh, sort of a locally bulging type thing. I think biomarkers in particular would be helpful, maybe not so much for the surgical aspects, but I do wonder if there's going to be a way to look for these mutations either with circulation. I don't have any sense as to whether they'll be circulating tumor cells in these or not, or if there's ways to detect these mutations, because then you could target them for drug therapy without surgery where there are potential drug therapies. So I think that would probably be a better role for biomarkers, more so than surgical selection is drug selection. Generally, the biomarkers will be a way to follow the response to therapy if you have factors. Any final question for Doctor Smith. Right. Now, thank you so much. Great presentation. I have. Thanks man. Mhm. Thank you how are you? Uh, I was yeah, yeah, I think so, uh, uh. So the two operations we're gonna do are number 1 and number 2 it should be a patient that um so.