Rethink Imaging Podcast Transcript

Guest: Claudia F.E Kirsch MD, FACR, FASFNR

Host: Chris St. John

CHRIS ST. JOHN 00:00:55 Welcome back to Rethink Imaging. Today’s guest is Dr. Claudia Kirsch. She is a professor of neuroradiology at Yale School of Medicine, and she’s currently finishing a PhD focused on how viruses affect the nerves and structures at the base of the brain. After experiencing a severe case of COVID herself, she began asking new questions about how infections like COVID, HPV, and Epstein-Barr virus interact with the head and the neck. Her work uses advanced imaging to look at the pathways most of us never hear about. Welcome to the show, Dr. Kirsch. Claudia, what would you like me to call you today?

CLAUDIA F.E. KIRSCH 00:01:27 Call me Claudia. I have three older brothers, so I’ve heard every name in the book. Claudia works fine.

CHRIS ST. JOHN 00:01:33 Well, Claudia, I am so thrilled to have you here today. Let’s just dive in. When we spoke before this recording today, you told me COVID changed your life and pushed you back into deep research. Can you just tell our listeners what happened and what it unlocked for you?

CLAUDIA F.E. KIRSCH 00:01:50 Oh yeah, so I was invited to speak in Australia at the Australian and New Zealand Skull Base Society meeting, so I was very excited. I went out there and my husband and daughter were supposed to come join me. That was back in March when the COVID epidemic was starting. I was there actually lecturing on EBV and HPV, and I started reading about it in the newspaper. I was out in Australia, having an amazing time, and told my husband and daughter they need to come join us. My husband was like, “You don’t understand what’s happening here in New York. We’re not going to come join you. They’re shutting things down.” He was in panic mode and he said, “We’ll get trapped there.”

I was having a great time in Brisbane, Australia. Then I started reading about this stuff and they literally started shutting things down. They put the clamp down on flying back into England, they were shutting that down, and the meeting ended. The organizers said, “We need to get you back to the States because everything is closing down.” So I went to the airport and they were hauling people off that were supposed to go to the UK on the flight. They had air marshals there; a whole new world was starting.

I remember getting on that flight. It flew from Brisbane directly to LA. When I got to LA at the Delta Lounge, you couldn’t touch anything. People had gloves. I’m like, “Okay, this is interesting.” Then I flew into New York City and I arrived at JFK. I was the only one going through customs. It was eerie. It was very, very strange. I remember saying, “This is the strangest thing I’ve ever seen.”

Then I was home for a couple of weeks, and I was working, doing whatever. Then I started having a tightness in my chest, my eyes [unclear: missing phrase], and I couldn’t breathe. I went to the doctor and I remember she said, “You’ve got COVID.” I was like, “What do you mean I have COVID?” She says, “It doesn’t discriminate. You’ve got COVID, you need to go home, quarantine.” It was the beginning of March.

So I went home, told my family, and it went from initially feeling a little bit to the point where it was like someone was taking a hatchet to my back; I couldn’t breathe or move. I was spiking temperatures, 110, I was quarantining, my family was rolling the food into me, and I got very sick and couldn’t breathe or function.

I remember reading about two patients in China. One was a doctor who got COVID, went into the hospital, got intubated and died. One was a nurse who quarantined herself in a hospital room, got pretty sick for about 10 days, proned and survived. And I said, “I’m proning. I’m not going on a ventilator. I’m not doing that.” They had a ventilator teed up for me. My O2 sat—I had an O2 sat monitor—my sats dropped, I just proned. It was miserable for about 10 days of hell. It was that initial infection, it was brutal. I mean, if you saw pictures of me, I just looked like death warmed over. I could barely breathe or move.

Then I recovered. After about 10 days, my fever came down, I was functioning, I was okay. They set me up with a home workstation for what I do in radiology. I started feeling better, and I contacted my job and said, “I’m feeling fine. You can put me on call.” That was the first week in April, and I started taking cases. Every case I had was somebody who had either a brain bleed from a venous infarct from COVID, somebody with massive infarctions, massive inflammation—people were dying. It was horrifying. I had a little bit of survivor’s guilt, like, I’m fine, I’m working, I’m reading cases, what the fuck is going on here? It was a wake-up call, a shocker.

It was the very beginning of everyone trying to figure out what was happening, and it was pretty bad here in New York. My hospital in particular was overrun. They had to peel out beds and put ICUs in there. We had people who were radiologists trying to run the ventilators. It was crazy. I was like, “I want to understand this disease. I want to go back and truly understand what’s happening and why are things happening to patients. These don’t make sense to me.”

So I decided to go back and do a PhD. I got recruited to Yale and my thesis is in, and I have my defense coming up, and there you have it. I feel like one of the lucky ones, but I also realize there’s a lot we still don’t know about what is happening in COVID. We’re still trying to piece together what will happen to those who’ve had COVID, who are at risk for long COVID and long COVID brain sequelae, which is going to be impacting all of us in the next 10 to 20 years.

CHRIS ST. JOHN 00:06:16 I’m not familiar with that term, the brain sequelae. Would you mind explaining that a little bit to me?

CLAUDIA F.E. KIRSCH 00:06:25 They call that neuro-PASC or the long neurologic sequelae post-COVID, because what happens with some patients is they have memory loss or brain fog. They just don’t feel like they’re functioning; they can’t function back at the level they used to function at. One of the papers—I was not the primary author on that, but I helped work on that paper with my colleagues—was from Dr. Preeti Balchandani’s lab at [unclear: sounds like “17”] at Mount Sinai, where I’m an adjunct associate as well. We were working on one where we were using AI looking at what are called the perivascular spaces in the brain. We saw that these were significantly enlarged in patients who had a larger body mass index and had long COVID neurologic symptoms, meaning brain fog. They couldn’t remember things, their memories weren’t good, and they couldn’t function as well. We are still seeing that in some patients who have difficulty; they’re just not back to themselves. We saw the changes in the brain and we published on that.

CHRIS ST. JOHN 00:07:20 I feel like that’s me, by the way. I neatly fall into that bucket, or I believe I fall into that bucket. I was vaccinated and throwing weddings all the time by the time I got COVID in late 2022, I think. My only symptom was a runny nose for about 24 hours. I was vaxed, I was boosted. But since then, my vocabulary recall is astonishingly below what it used to be. There are even times where I’ll have trouble coming up with a word like “bicycle.” I’m like, “You know, it’s that thing, it’s got wheels and gears and you ride it to work.”

CLAUDIA F.E. KIRSCH 00:07:58 There are many others, and many people are embarrassed to talk about it. Many people know something’s not quite right, but they don’t know what’s going on. Even more fascinating to me was we had a series of patients with smell loss, but there was nothing going on in the sinuses. I’m like, “How’s the virus getting in there causing that? How is it causing smell loss when there’s not—” The virus can only enter your body if it has a receptor, like an ACE2 receptor, to allow it to get in there. But there are not a lot of ACE2 receptors in the olfactory bulb and tracts. How is it affecting the smell? How is that happening? How is it getting in?

We are still trying to understand how it gets into the brain and then causes these changes. Is it going through the bloodstream? Is it getting through there? How is it doing these changes we see? How is it causing that loss of smell?

Then we had some fascinating cases when the vaccines came out where people got vaccinated with a specific type of vaccine and would have a very distinct type of smell loss or abnormal smell that smelled like burnt rubber. We published it. Another patient wrote to me and sent me their scans, and they have the same exact areas, so we think it’s probably an inflammatory response that caused that. Specifically, though, to small little neurofibers that have been known about since the 1900s in pathology. They’ve been published in beautiful pathology diagrams since 1914, 1917. Nobody had ever published them in imaging. I was like, “Why? We can see these, let’s go back and look, can we identify them?” We also just recently published on the changes in that as well. So lots still that we’re learning, but we’re excited to find the stuff that we are seeing.

CHRIS ST. JOHN 00:09:41 I want to come back to the nerve thing, but before we get there, your PhD work is about viral-mediated disease in the skull base. Would you mind just breaking that down a little bit so we can lay that foundation?

CLAUDIA F.E. KIRSCH 00:10:00 When we think about the world around us, there are more viruses than there are stars in the sky. Just let that fact sink into your brain for a second. There are more viruses—that’s the most abundant microbe on the planet. There are more viruses than anything; it’s like trillions. They’re all around us all the time, they are everywhere, whether we like it or not. In fact, our own DNA is about one-twelfth retroviruses that have incorporated into your DNA over time. Whether we like it or not, they’re part of who we are as well. I think we need to understand that in order to better help treat and understand diseases.

For example, HPV, human papillomavirus, is a very stable virus. It has these little shells. That virus has been around for a very long time. That virus is the number one cause of oropharyngeal cancer in the head and neck. It’s the number one sexually transmitted disease—I’m going to just put that right out there—worldwide, the number one sexually transmitted disease. We know it causes cancer in the orogenital region, but it is now the number one cause for cancer in the head, neck, and the tonsillar region. It likes to go deep into the reticular tissues of the tonsil. Why it only causes cancer in one tonsil we don’t know, but we know it’s a leading cause of cancer.

We have also seen this in kids where it was sometimes in the oral cavity, and it may be because when they lose their tooth—maybe they were exposed in the birth canal—that virus gets into the deep reticular tissue when that tooth is lost, and then it likes to replicate in the deep basal layers. That is a virus which is a leading cause for head and neck cancer that we are still determining different subtypes of, and we know that it can behave and often has a better prognosis than smoking and drinking cancers, which are in more superficial layers. But we are still trying to understand why some people are getting this cancer and others aren’t, how the immune system regulates that, and why people have a better prognosis often. It’s more radiosensitive and it often presents radiographically slightly differently. I just finished editing a paper looking at that. There’s a lot more, I think, with AI that we can analyze regarding how this tumor behaves to kind of determine that. So that is a virus which causes cancer.

Now let’s talk about EBV. Epstein-Barr virus is ubiquitous; we all have it whether we like it or not. We’ve probably been exposed to a little episode of EBV hanging out in our cells right now. It’s there whether we like it or not. It is incredibly infectious, and we know from the Harvard study where they looked at military recruits that if you were obese in childhood or if you had a lack of sun exposure and you had Epstein-Barr, you’re more likely to develop multiple sclerosis or a brain demyelinating disease.

Why is that? What is going on? It’s probably because that virus is very clever. The virus hangs out in your immune system, and then it stays there until your T cells and B cells can’t regulate it enough. Then when it activates, it can do a couple of things. It can activate the MYC oncogene, and you get these Burkitt’s lymphomas, but in other patients, they’re getting demyelinating disease. It may be that when it’s replicating, it’s exposing to the immune system your own fat or proteins that are associated with myelin, leading the body to attack itself. To me, it’s really important to understand the mechanism of how these things are doing that so we can then figure out how to treat patients, how we can better evaluate them, and how we can improve things. We use the tools that we have, especially higher-resolution imaging and artificial intelligence, to understand how that disease is caused, and then we can improve treatments and outcomes for patients, which to me is the bottom line so everyone can thrive and do better.

CHRIS ST. JOHN 00:13:42 Is it safe to say we just don’t have an entirely clear picture of how viruses impact the head and the neck and the ways in which they cause harm? Like, we don’t know if it’s direct infection and/or an immune reaction, or what it is exactly that is triggering these cancers.

CLAUDIA F.E. KIRSCH 00:13:58 How is SARS-CoV-2 getting in and causing smell loss? How are these cells being affected? If you don’t have ACE2 receptors, how is it then damaging the olfactory bulb and tracts? It has to have an ACE2 receptor. We know that for any virus—like when you go to a hotel, you can’t just enter any room; you have a key that allows you to enter your room because it fits that lock. Same thing with a virus: it has to have a receptor for it to bind to that allows it to enter, then get to the cells, then affect them.

We know that for SARS-CoV-2, the spike protein specifically binds to the ACE2 receptor, so I have to look for areas that have ACE2 receptors. If there are no ACE2 receptors, then it’s not getting into that tissue. But if it’s damaging that tissue, then it’s affecting something that is involved with that tissue.

I was very keen to look for where there could be ACE2 receptors. How is it getting in from the olfactory tracts and bulbs? That’s why when we saw these little nerve fibers—this nervus terminalis—it was key for me. When we look at animal models, they’re loaded with ACE2 receptors. So I’m like, okay, now we know there’s a pathway, but they’re tiny, small little neurofibers, very delicate and unmyelinated, so if you break them—like when you do an autopsy, you could easily damage that tissue if you take the brain out. They’re often not taught to students in medical school, so a lot of people are unaware of them.

CHRIS ST. JOHN 00:15:16 Right, I had never heard of the nervus terminalis. Where exactly is it, and where is that pathway?

CLAUDIA F.E. KIRSCH 00:15:20 You’re not alone. Not a lot of people, even in medicine, are taught about them or their importance. They are very tiny little unmyelinated fibers that run next to your olfactory bulbs and tracts, and these little unmyelinated fibers actually go all the way back into the hypothalamus region, which is literally the lecture I just gave to our incoming fellows because we are doing some work trying to sub-segment out this very critical area. These unmyelinated fibers are preserved in all vertebrate species, these little nerve fibers. They run next to the olfactory bulbs and nerves along the olfactory tracts. They’re really important because all species, all vertebrates—even whales and dolphins that don’t have an olfactory system—have these little key fibers.

These little fibers are associated with nitrous oxide and with the immune response. They control nitrous oxide, and nitrous oxide controls vessel dilation, so blood supply. We know they’re right next to the olfactory bulb and tracts. We say there are 12 cranial nerves, but really the first two, the optic and the olfactory, are tracts; they’re different myelin from the brain, from the oligodendrocyte. So the olfactory bulbs have next to them these really important little fibers controlling the blood supply that goes to those tissues. It could be that when you have a virus that affects them, they get activated, releasing the nitrous oxide, controlling the blood supply or damaging the blood supply getting to the olfactory bulbs and tracts, and that’s where we saw the response.

Over time, usually about three months, that tissue can regenerate, so most people do regain their sense of smell back in about three months. Some people don’t; 15 to 20 percent have difficulty with that. There are smell training and tests, and people are working on that, but we’re still trying to uncover what happens. In addition to noting that patients had this olfactory tract volume loss and abnormal high T2 signal that was published by others, we also noticed that as well on high resolution. We are now looking at trying to trace these striae from the olfactory bulbs and tracts to the temporal lobe region, which is where your memory—your hippocampus—is. That’s where you store memory and how you function, to see how it’s relating to those tissues, and we’re seeing that there are alterations in those patients that may be associated with depression and behavior.

We know that when people lose their sense of smell, it can be associated with depression. Importantly, loss of smell, which is a really critical sense if you think about it, is one of the first things that goes in Alzheimer’s disease and in Parkinson’s. Many people are unaware of that, and it can be associated with depression, so it’s a really important thing. More importantly, when you think about how a smell works, we don’t know how it works, so it’s a phenomenal area for research. I have my own theories—I think it’s probably frequency-mediated, but there are arguments about that, and that’s a whole other discussion topic for another day.

Smell is one of the most important things. We wake up in the morning, we shower to smell nice, we want to smell good. You recognize your partner innately by the sense of smell, and babies can smell their mother. Your tea or your coffee that you drink has a smell that you like, makes you feel good, helps you taste your food—all related to that and very important. Smell and memory, like from Proust, the madeleine, are absolutely related. When you enjoy something, when you smell something, it reminds you of something positive. It’s what we call hedonic; it’s things that give you joy. When people lose that, they can be very depressed. We know the INXS drummer who had brain trauma damaged his olfactory system and he committed suicide. So it’s a serious thing when people lose their sense of smell, losing the sense of enjoyment to recognize things. That’s why it’s a forgotten area that many people don’t look at in depth, and it’s something we’re really trying to study in detail using high-field MRI.

CHRIS ST. JOHN 00:19:14 So it was the loss of smell and that association that led you to identify the nervus terminalis as one of the potential pathways?

CLAUDIA F.E. KIRSCH 00:19:25 Exactly. The first thing was, can we see it? Is it on MRI? There was a picture on a Twitter feed where someone was like, “I’ve heard about these fibers, has anyone seen them?” There was nothing in the imaging literature. There was some beautiful pathology literature that showed pictures of them on path specimens, but nobody had published an imaging picture until we published our paper. Now I hope more people publish and look and find them. You can see them not just on 7 Tesla; you can see them on 3 Tesla, and if you look carefully, you can see them on 1.5 Tesla along the olfactory bulbs and tracts, which are really low down. You have to look down and see the area, and they’re tiny structures, so you have to look very carefully on a heavily T2-weighted MR.

CHRIS ST. JOHN 00:20:04 Just for my own edification, a 7 Tesla MRI is just way more powerful imaging, right?

CLAUDIA F.E. KIRSCH 00:20:12 Exactly, field strength. We name it after Nikola Tesla, who developed alternating current—he was brilliant, kind of a polymath. It was officially given his name by the scientific naming society, and that’s just a measure of magnetic field strength, how strong that external magnet is that we put you in. The stronger the magnet, the improved signal-to-noise ratio, the better resolution we get. We can see structures that might be very small with more detail that we might not appreciate at lower field strength. Exactly right.

CHRIS ST. JOHN 00:20:40 When you’re looking at the nervus terminalis on the 7 Tesla MRIs, are you seeing their presentation as different?

CLAUDIA F.E. KIRSCH 00:20:48 Yes, that’s a great question. The first question was, could we see them? Could we actually see these fibers? Yes, we could. We did a paper presentation at Mount Sinai on seeing it to the end, the nervus terminalis. You could see them on 3 Tesla, you could see them on 7 Tesla—they were there. We just didn’t pay attention to them. They’d always been there, we hadn’t caught them. There are these little tiny neuro linear fibers along the olfactory bulb and tract. You can see them; they’re there. I can see them now whenever I do my imaging, I point them out, and they’re not vessels, which have little flow voids. It’s these little tiny neuro linear fibers that can be beautifully seen.

When you do high-resolution imaging—and we share our protocols with whoever would like, we can’t share the patient information because of HIPAA, but we share the protocols so other people can image them—I’m sure more people will say, “Wow, in retrospect, here they are, we just didn’t comment on them or we didn’t notice them or we didn’t pay attention to them.” There’s been some beautiful additional research in animal studies and I hope there’s more work. We also have one of our colleagues, Dr. Alice [unclear: sounds like “Heaver”] who looks at the brain pathology specimens, so we’re imaging that as well.

But remember, unfortunately, these can be broken if they’re not taken out carefully. I have pictures of path specimens where you see them, these little tiny fibers. In a patient who’s alive, I can look at them and see them if I do dedicated imaging and look in that area. To me, that’s a really fascinating area because now we want to try to trace these little unmyelinated fibers. Unlike the olfactory bulb and tract, they’re unmyelinated, so if a virus does infect them, it can go more rapidly into the brain, which is what we saw with COVID, versus the olfactory bulb and tract, which are myelinated tissues where it’s a little slower transmission. We think they’re probably the putative entry site for SARS-CoV-2. Of course, we’d like to look at that in human specimens, look for these little SARS-CoV-2 receptors on these tiny little nerves, and measure that. We’re doing ongoing work; much more work needs to be done.

But it would be key because if we know that’s where it’s entering, where the area is going into and affecting, and we also know it’s probably coming in through the bloodstream and through other mechanisms like the blood-brain barrier, those are all key questions. We know we saw these enlarged perivascular spaces, and to me, those are important because that relates to something called glymphatic clearance or glymphatics, which is basically your brain clearing out waste material when you sleep at night. Sleep is absolute critical. When you sleep at night, your brain is washing away all this stuff and clearing it out. If it’s disrupted, like with Alzheimer’s proteins, and it can’t clear it out, we see changes. If it’s got inflammation, which probably affects it as well, we may not be clearing that out. Those little important perivascular spaces, which we saw enlarged in long COVID, maybe a secondary effect of infection or inflammation blocking those spaces. Much work needs to be done in that area to better understand those mechanisms.

CHRIS ST. JOHN 00:23:39 Here I am trying to catch up, but you said that the brain doesn’t have a lot of ACE2 receptors. Are we talking about the virus physically getting into the brain, or is it more about inflammation or the reaction?

CLAUDIA F.E. KIRSCH 00:23:54 Exactly, both. First off, we know we can see changes. We know in patients with olfactory volume loss, I could see volume loss along the olfactory bulb and tract, and I could see a high T2 signal, so it was inflamed; it was having a problem. But why? It doesn’t have ACE2 receptors. So it’s probably something that’s involved with providing blood supply or innervation to those tissues—that’s really critical. We know that the nervus terminalis has ACE2 receptors. Looking at that now in humans to see if they have ACE2 receptors is key because if they do, it might be how that virus is getting in there. That’s important.

Your nose is filtering things out all the time; your immune system in this area is vitally active, working overtime to keep you safe and cleaning and clearing things out. But if something can get into the brain, how is it getting in there and then affecting it? It has to have a receptor, and it’s got to have some tissue that allows it to get in there. It’s also going through the bloodstream at the same time. How is it getting from that if you’ve got this blood-brain barrier designed to protect you? And then at night when you sleep, it’s designed to clear things out. We’re still working on how exactly it’s coming into the brain, which I think requires a little more work on the ACE2 receptors, looking at path specimens on patients and tracking those out with the biobank specimens, and seeing which regions of the brain were affected. We know from the biobank a lot of those areas are involved with smell and that hedonic agitation; those areas were very much involved in patients who passed away.

CHRIS ST. JOHN 00:25:28 So these nose-to-brain pathways, it’s real, it’s happening. What are the practical implications of this? What does it change about how we think about prevention and treatment?

CLAUDIA F.E. KIRSCH 00:23:34 Huge. Absolutely, if you can create some sort of nasal barrier that prevents that going into there, like a mask? That’s why people were masking; it was effective. We know that we touch our face all the time without even realizing we’re doing it. It’s a leading cause of spreading infection. They did a very interesting study where they just told people to keep their hands below a certain point, like a beeper, and they couldn’t raise their hands, versus using antibiotics. Keeping the hands below was very effective at preventing infection. Not touching your face when you want to touch your face—hands, coins, things we touch are very effective vectors.

We also know that when we look at the SARS-CoV-2 virus itself, it was coated with sugar. It’s a very sticky viral particle coated with glucose, so it sticks to things. That’s why you have to wipe things down with bleach. And it can mutate; these viruses mutate over time, that’s just what they do. They’re like anything else, trying to survive and mutate and get into our system.

Patients who were diabetic and patients who were obese had a much worse prognosis with COVID—that is hands down. We then also published on seizures because we know the temporal lobes were being affected, and we saw that whether inpatient or outpatient, there was a higher risk of seizures that we published on as well. There’s still a lot of work. I personally think that there may be some interplay between how it’s coming into the temporal lobe region and maybe interacting with the ARC gene and ARC protein, which is part of your temporal lobe, your hippocampi, that ferries information for you and how you form your memories. That’s still ongoing research that needs to be done in that area—a lot of questions that we still need to answer.

We’re still working this out, and we’re literally now doing some of the tractography, tracing the olfactory bulb tracts to the hippocampal regions, to the temporal lobes, to your amygdala, and to these key areas that control your emotions and behavior, and seeing what the effects are in patients who may be depressed with anosmia versus patients who had COVID but didn’t get depressed or anosmia. We see changes. To me, that’s really important because for somebody who’s suffering from it, you want to know why. Is there something going on, first off? Then if you identify it, can we treat it or prevent it, or what can we do to help them? That’s important, because for patients who are told they’ve got something wrong and then they don’t find anything, they’re just told, “Well, it’s all in your head.” That’s not helping them. You need to know what it is, and if we can see that change and then measure it and look at progress and then treat it, that’s huge. It gives patients a sense of how we can go forward and improve things.

I think we’re still trying to understand why we have smell loss in Parkinson’s, why we have smell loss in Alzheimer’s—it’s one of the first things that happens and yet is kind of ignored in these patients, and it obviously affects them. To me, that’s important. If we understand that, then we can work on how we treat it, prevent it, improve it, and help patients out.

CHRIS ST. JOHN 00:28:37 This is one of those moments where I’m going to pause for a second. I love talking to you, you’re just extremely engaging. I’m literally on the edge of my seat, physically and metaphorically. We have about 28 minutes left. I was thinking about pivoting a tiny bit. I feel like we have a really nice foundation for all the COVID stuff and the nervus terminalis. I want to change gears a little bit and talk about cancers. You have highlighted HPV and Epstein-Barr as viruses tied to head and neck cancers. I’ve been hearing about HPV causing cancers my whole life, but how does the viral infection actually lead to these cancers?

CLAUDIA F.E. KIRSCH 00:29:36 Great question, and I love talking about this. I used to be at Ohio State University when Maura Gillison was there; they noticed that association with HPV. HPV is a very clever little virus. When it goes in, it goes into the deep basal layers of the tissue—I always find this fascinating. It goes into the cell in the deep basal layers and it tells it to produce these two key proteins that then block your body’s own proteins that help clear things up. If you have certain proteins designed to clean up garbage DNA, like the retinoblastoma protein, it produces proteins that block that. We call it p16—it’s not because HPV16 is the number one cause, the 16 is for a different reason. People get that confused all the time.

When you block those normal host mechanisms that control the ability of the cell to reproduce—it’s like a football or basketball analogy, blocking—it’s preventing that person from making the shot, preventing the other proteins from doing their job. Because of that, those cell replication mechanisms get turned on and it tells the cell, “Keep going, keep producing more cells.” It is hijacking that mechanism so it starts replicating and producing more viral particles, and keeps ramping it up, because it’s effectively blocking your own host mechanisms. That’s very clever. The virus is producing two key proteins, blocking the host mechanisms, preventing other proteins from doing their jobs. So the body gets switched on, its cell cycle is set to replicate, and in doing so, it produces more viral particles and spreads it to the next and spreads it to the next.

Now, why it only likes the deep reticulated tissues of the tonsil, we know that. It’s along the epithelial, it likes those kinds of skin tissues, so orogenital, but deep tissues, especially the reticulated tissues of the tonsil. But why is one tonsil developing a cancer and not the other? What are the other interplays of the immune system? Maybe we need to think about cancer a little bit differently: maybe some of us are exposed but our immune system is functioning effectively, gets rid of it, you’re immune, and you’re fine.

I cannot emphasize this enough: we do know that when people are vaccinated now with Gardasil or Cervarix—for the young patients to prevent anogenital cancers—it uses a denatured protein, a part of the shell, it doesn’t have anything to do with live virus, and it’s incredibly effective. It’s reducing these cancers. So you have a vaccine that can prevent this. We’re looking to see over time if there’s going to be data showing it actually reduces oropharyngeal cancers. We don’t know that data yet, it’s still pretty new coming out, but it’s likely protective. You have a preventable way of preventing an orogenital cancer with these vaccines, which is absolutely essential. I get horrified when I see what’s happening in the country right now because I know that if you prevent these vaccines, there’ll be a secondary effect where these are going to increase in resurgence. We just know it’s happening, and we see it happen around the world.

I will tell you, it used to be reportable to see it in a young pediatric patient to have these oral head and neck cancers. If you look in the literature before the ’70s or ’60s, it had to be a kid who had some bizarre genetic abnormality like a telomere deficiency or Fanconi anemia or something that would really affect the immune system for them to get these cancers. Now we’re seeing them in kids who don’t have that, so we know the exposure is likely from HPV. The HPV is getting into those tissues somehow and then replicating, and they’re not immunocompromised. These children have other things, but we’re seeing them. There’s often a delay because nobody can imagine a young kid with an oral cavity cancer, but we are seeing it reported worldwide, and that’s exposure.

You have a preventable way of preventing these cancers with a vaccine. Same thing with the other viruses that we see going around in the world. People are too young right now to think about the polio scares and things that happened where people were on iron lungs—it was horrifying. You should be vaccinating for this, and I’m a firm believer that vaccines save lives. I cannot emphasize this enough. As a physician who is now seeing the numbers increasing in my hospitals of people with encephalitis and other things: vaccinate against these things, it saves lives. There’s just no question about it; it prevents cancer and the long-term effects of these infections. If you reverse that, we will see those effects, and we will see them 5 or 10 years from now—these long-term effects from these viruses.

We know that these viruses are involved in both head and neck cancers. Epstein-Barr virus is a leading cause of nasopharyngeal carcinoma in middle-aged people; that should sink in. These are things that we can now treat for HPV and prevent using vaccination, which could have long-term effects preventing these other cancers in the future. For EBV, they’re working on hopefully coming up with some sort of vaccine.

I want you to think about the fact that your immune system is really designed to protect you, but things can destroy it. For example, astronauts: we know that they are some of the healthiest people on the planet, right? Then they leave the planet, and they get exposed to the cosmic radiation of the sun when they’re out in space. That cosmic radiation is very damaging to the immune system, and they often get a reactivation of the Epstein-Barr virus because you’re destroying that immune system. We normally have the Earth’s magnetic field protecting us, kind of shielding us. You leave that protective effect of the Earth, and then exposure will affect the immune system.

I think we are really now at an edge of relearning how to understand the immune system, especially how the immune system can be used for cancer treatments and improving outcomes in patients with cancer. The future in this is tremendously bright, but there’s still a lot we need to understand, and we’re using AI. Part of the work in our lab is using computer analysis of the DICOM images to take it to another degree level that I might not appreciate with the naked eye, and then tell me there are different things in that tissue that make it a more aggressive tumor versus a less aggressive tumor, and I can use that to help predict outcomes.

For example, I think about the tumor adenoid cystic carcinoma all the time. This is a tumor that loves to go perineural; it’s designed to grow along your nerves, which is also, if you think about it, a little science fiction. Things aren’t designed to grow along your nerves, but this tumor loves to grow perineural, to track along nerves. We know in pathology it tells me how it’s going to behave. I know if a patient has a cribriform pattern, they’re going to have a much better prognosis. They’re probably going to have maybe lung mets or some other metastasis, but they’re going to live a long time. Versus a solid form—those tumors behave very aggressively, and those patients have a much worse outcome. I know that in pathology. So we’re now taking that data and we’re using AI to predict, when I see an adenoid cystic, can it tell me if it’s a solid versus a tubular or cribriform pattern? And those predictions are really key because it’s a big difference in how you treat those patients, even though it’s the same tumor, if I can help predict the type of pathology they have. That is huge. That is changing outcomes for patients and strategizing in a way that they can get the best treatments possible for them at the earliest stage. Absolutely critical.

CHRIS ST. JOHN 00:36:58 I’m so curious about that perineural cancer spreading.

CLAUDIA F.E. KIRSCH 00:37:02 Oh my God, it is huge. I’m going to tell you some stuff and it’s just true: in our literature, it’s considered acceptable to miss that finding up to 50 percent of the time. That is horrible; that’s like flipping a coin. That just gives me [unclear: sounds like “spulkes”] or anxiety—I don’t like that. It’s like me and your mother saying, “Oh, it’s okay, we’re going to miss it.” No, it’s not okay. We know skin cancers have much higher genetic alterations in deep tissue, especially cancer of the skin with squamous cell carcinoma that is going to have perineural involvement. But the key question is, why is the tumor growing along the nerves, and is there a mechanism of the tumor that’s encouraging the nerves to grow to it so that it can say, “I can hitch a ride and then track back into the brain and spread”? If you figure out that mechanism, those receptors, and how that tumor behaves to encourage that perineural spread, that’s huge because you can block that mechanism. Patients live a lot longer; patients don’t die from that primary tumor.

I want you to think about this: you’re not going to die because you got that little tumor there; you die because the tumor spreads and grows. You die because the tumor gets to places it shouldn’t be getting and then causes a lot of damage. If you can block that spread, you can prevent that and just keep removing that primary tumor, and that patient can live a long time. You change the outcomes for those patients, and that’s’ really key. The fact that certain tumors, especially squamous cell carcinoma in this region of the skin, love to get on those nerves—the fifth and seventh cranial nerves—and retract back into the brain and cause problems, we can see that on imaging way before they’re clinically symptomatic. To me, that’s absolutely critical to make the diagnosis as soon as possible for the patients’ outcomes.

I have a TED talk on this called “Hitchhikers for Perineural Spread” because the tumor is basically hitchhiking and growing along there. As part of that talk, people say, “Well, the outcome and you’re making a difference…” There’s a great parable of the story of that little girl throwing starfish in the water when they’ve all washed up on shore. The guy says, “There are thousands of starfish,” and she throws one and says, “I made a difference to that one.” If I can make a difference in any patient and improve their outcome, that’s your goal; that’s what we’re taught in medicine to do. How can we improve those outcomes? It doesn’t matter how many people are affected; if we figure that mechanism out, improve it even for one, and then apply it to another, we can improve outcomes for a lot of patients over time. I think that is one of the key goals in medicine: understand the mechanism, understand why it’s doing that, and then if you can prevent it or figure out treatments for it, the outcomes change. That’s truly a remarkable thing. If you change the outcome for someone, that’s life-changing for that person, and that is our goal.

CHRIS ST. JOHN 00:39:48 Before we start wrapping up, we have a few minutes left, but I have to ask: you’re talking about perineural spread both with squamous cell carcinoma, like a skin cancer, and also with these viral-initiated cancers. Do you think that the viral biology affects this hitchhiking behavior?

CLAUDIA F.E. KIRSCH 00:40:15 That’s a great question, absolutely. We know that when patients have an HPV-related cancer, it’s often a teeny-tiny primary tumor, but they often present with a big cystic lymph node in the neck. Why is that? Why is it going more into the lymphatics? It’s cleared out maybe by the viral system, leading to this larger reaction in the node from just a tiny primary, versus people who smoke and drink where it’s damaging that cellular DNA tissue in the superficial layers and involves those layers. But what happens if you’ve got somebody who has both the virus and a history of smoking and drinking? What’s happening in that interplay?

We know that there’s EBV, which can cause nasopharyngeal carcinoma, and if you’re doing things that may expose you to certain carcinogens in your diet or whatever, maybe it’s affecting that as well. There’s a lot. To me, there’s no question that the virus is triggering and altering the DNA, and how it does that is key, leading to the replication of certain oncogenes forming behavior that says, “Hey, let’s replicate and cause a tumor.” But then how do we prevent that? I think we’re still figuring out and learning many of those mechanisms, and the more we understand it, the better we can basically treat and have improved outcomes for patients. We know if we find someone with demyelinating disease and we get them on treatments earlier, they’re going to have a better outcome. Risk factors—why you have those, what can we do, how can we improve it? To me, those are all essential, and using all the information and tools in the toolkit—and AI has a lot of tools in the toolkit—is incredibly helpful and useful in that regard.

CHRIS ST. JOHN 00:41:50 Let’s zoom out a little bit. I know you’ve talked a lot and there are all these parallels and paths and intersections throughout everything that you’re working on—both literal paths and metaphorical paths. What is this unifying thread between your COVID work and the viral-related cancer work? What do those connections look like?

CLAUDIA F.E. KIRSCH 00:42:11 What I’ve really found is that big risk factors especially include—and this is something else we need to talk about because I’ve done AI work on this as well—obesity. Obesity is a disease, and we know that patients who have obesity had a worse prognosis with SARS-CoV-2. They have a worse prognosis and high risk for developing Epstein-Barr with other diseases. We also saw venous thrombosis and other changes, so it has a lot of interplay with that. We know that’s a key risk factor. Why? In demyelinating disease, you personally may be exposed to certain myelin fat-type proteins that then cause the immune system to attack. To me, it’s a unifying thread that both diabetes and obesity, which are diseases, are risk factors.

Now we also get into GLP-1 drugs. We now actually have a medical treatment for reducing obesity, which is game-changing for a lot of people. It’s a game-changer, and we’ll see obesity be reduced over time. That might have implications for what happens in cancer in patients over time, and we’ll see that. I think we’re always going to have viruses around us mutating; there are probably more that we don’t know or understand. But we do know that they are going to interplay in the body with inflammation, and we know that obesity leads to increased inflammation and elevated sugar levels and diabetes—all of those play a key role. We’re still understanding those exact mechanisms, but we do know if you can reduce your hemoglobin A1c and you can reduce your obesity risk factors, patients will do better. They do better in the long term, probably related to the immune system and inflammation, and we’re understanding those underpinnings of the immune system.

I am a firm believer that with imaging, we can identify things early. If we make the clinician aware of what to look for, you’re going to see what you know. If you find that perineural spread early, you’re going to change the treatment algorithms and hopefully the outcomes of the patient. Being aware of that anatomy and how that anatomy is interacting with the environment is absolutely essential and critical for what we do in our job.

CHRIS ST. JOHN 00:44:09 What would you say to potential patients or clinicians who may or may not be getting this level of imaging done?

CLAUDIA F.E. KIRSCH 00:44:20 Get your vaccines; vaccines are key. Vaccines are going to save your life. We looked at patients who were vaccinated versus unvaccinated with what are called venous thromboses in the brain, looking at the difference in that. In patients who were unvaccinated, it was a far worse prognosis—there was just no question about it. So vaccines are essential in the long term for helping save people’s outcomes; there was just no question. We know that it’s a protective effect if you get immunized against these HPV things—it’s protective, it’s huge.

Obviously you can do certain things. People got the message; people are smart. The people out there want to know; nobody’s out there saying, “I want to destroy myself.” People want to do the right things, essentially. People got the message on smoking and drinking, so a lot of people stopped smoking and drinking. But the awareness that viruses can be transmitted through other things needs to be there. Like, if you’re smoking a joint, you’re sharing your saliva with somebody else, and if they have HPV, you’re getting that HPV virus. When you share certain things, you’re going to expose yourself, so you need to be aware of that, right? Prevent that, be smart in your behaviors, but also wash your hands, which is just a basic thing. Don’t touch your face—it’s hard to do, right? But exactly, keep the hands down. I like to use mine for talking, so it’s really hard!

But also see your doctor regularly for a checkup because you can be screened for things early on, and catching it early makes a big difference compared to catching it late. It’s a big difference in outcome. Earlier detection and prevention are huge. Get your colonoscopy, get your mammogram—do these things that are expected, routine, because if you catch it early, it changes the outcome before you let it grow, before it’s allowed to spread and become a problem. To me, that’s a huge message. It’s common sense, and you get vaccinated. I don’t care what else anybody is saying out there; you’re smart enough to know. Look at the literature, read the literature, read the room, follow the people that know what’s best for you, and your physicians are in agreement on this—there’s no question about that.

CHRIS ST. JOHN 00:46:20 I feel like that’s a beautiful place to stop. Is there anything else you wanted to touch on?

CLAUDIA F.E. KIRSCH 00:46:33 Chris, honestly, I’m honored and it’s a pleasure to be here to get a chance to talk about doing stuff I love. My thesis is in, I have my defense coming up, and we have multiple publications on it, which has been exciting, but there is still a lot to learn. I want to do a shout-out: I’m really lucky to have worked with the people that I’ve gotten to work with as my advisors. I owe them a debt of gratitude. I feel incredibly grateful to be working with the people that I’ve been working with around the world and around the country. I’m very lucky.

CHRIS ST. JOHN 00:47:10 Beautiful. Well, thank you so much for joining us. Today’s guest was Dr. Claudia Kirsch, Professor of Neuroradiology at Yale School of Medicine and almost no longer a PhD candidate. Claudia, thank you so much for joining us today on Rethink Imaging. It’s been truly wonderful having you today.

CLAUDIA F.E. KIRSCH 00:47:28 Chris, thanks so much. It’s absolutely been a pleasure. I hope you have a great rest of the day.

CHRIS ST. JOHN 00:47:32 Thanks, you too.