Psychiatry & Psychotherapy Podcast - PANS & PANDAS

Episode Date: May 10, 2022

PANS/PANDAS is the hypothesis that there are certain types of obsessive compulsive symptoms, tic symptoms or restrictive eating symptoms that are caused by an infection and the immune response to an infection. Kyle Williams, MD, PHD and Sarah O'Dor, PhD join the podcast to discuss their research and diagnoses of PANS/PANDAS.  By listening to this episode, you can earn 1.5 Psychiatry CME Credits. Link to blog. Link to YouTube video.

Hello and welcome to the Psychiatry and Psychotherapy Podcast. I'm here to talk about getting rid of burnout, increasing job satisfaction, and feeling like an expert in what you do. One thing that created a lot of burnout and angst for me was trying to get continued medical education right at the last minute. So why not join the CME membership and do CMEE while listening to this podcast? Go to Psychiatrypodcast.com, sign up, sign in, take the test, and the certification is emailed to you in seconds. All right, welcome back to the podcast. I am joined today with two world-class experts, Kyle Williams, MD PhD, and Sarah O'Connell, PhD. They work together to help people with pandas.

Pandas is an onset of OCD and ticks after a streptococcal infection strep throat. This is a very important child and adolescent psychiatry episode. They're going to talk about how OCD presents in young kids, what they do to diagnose pandas or just OCD, how they treat it, what the research says, what the research doesn't say. Anyone who has any curiosity about child and adolescent psychiatry, I think we'll find this a deep dive into a topic that we do not receive enough education on. Just to go over the conflicts of interest, Kyle Williams has several conflicts of interest for research support, Octafarmavaphym of pharmaceutical, Pandas Network, Pandas Physician

Network, International OCD Foundation, F Prime Bioscience Research Initiative. Sarah O'Connell, get some support from Octofarma. I have no conflicts of interest. And before we begin, I'd like to thank people for signing up for the continued medical education that goes with this podcast. This is something that I'm very grateful for. And if you are a subscriber, I thank you. If you're considering it, you could go to Psychiatrypodcast.com and check out how easy it is to get CME continued medical education for this podcast. All right, let's begin. All right, welcome back to the podcast.

I am joined today by Dr. Sarah Adore, Ph.D., and she's the director of research of the pediatric neuropsychiatry and immunology program at Mass General Hospital and an instructor at Harvard Medical School. And also with Kyle Williams, MD, Ph.D., and founder and director of the pediatric neuropsychiatry and immunology program at Mass General Hospital. And a practicing child psychiatrist, it's great to have you guys on and talk about pandas, pans and pandas.

Why don't you just kind of jump in and say like what that is? And then I'd kind of like to hear about your stories how you got interested in this. Sure. I can jump in and just kind of give an overview of pans and pandas. It is, Panza and Pandas is the idea, kind of the hypothesis that there are certain types of obsessive-compulsive symptoms or tick symptoms or restrictive eating symptoms that are actually, they're caused by an infection and the immune response to an infection. So Panda stands for pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections. And the idea with Pandus is that it is a strep infection that then after the strep infection clears, typically someone develops new onset, rapid, obsessive, compulsive, or movement disorder symptoms.

And so Pandus is specifically tied to a strep infection like strep throat. And Pans, which stands for pediatric acute onset neurop psychiatric syndrome, is similar to Pandas in that it's rapid onset obsessive compulsive. Pulsafe symptoms or tick symptoms, that it can be due to any infection. So it can be COVID. It can be, you know, pneumonia, things like that. And it also includes restrictive eating. So new onset, acute, avoidant, restrictive food, and take disorder symptoms. Okay.

And is this only in children or also in adults? Yeah. So by definition for the clinical criteria, now it's only in kids. Okay. And it's a good question because it's something that comes up a lot about is this something that is possible in adults? And I wouldn't say it's impossible. It's just, I think it's all of the focus has been on kids for this.

So we've had kind of isolated reports of people 18, 19, 20, having something like this, too. But is it a typical cause of, let's say, obsessive-compulsive disorder starting someone in their 30s and 40s? We haven't heard those kind of reports. Okay. And maybe Kyle, maybe you could start and then I'll have Sarah jump in and tell me how you were telling me this story before he started recording on how you got interested in this topic and how far it dates back for you. So can you walk me through that a little bit? Yeah, yeah, sure. I'll try to give you the condensed version. But so I was in college and a long time ago and I was really interested in neuroscience and I was really interested in neuroscience. And I was really interested in. obsessive commulsive disorder. And this was back when there was a kind of a seminal paper that came out from Lewis Baxter that was looking at, it was a pet study looking at the metabolism of certain brain regions if you took an SSRI compared to if you had cognitive behavioral therapy in people

who had OCD and showing that both cognitive behavioral therapy or SSRIs could change the brain metabolism in those that had OCD. And I thought it was so just fascinating that this kind of concept of neuroscience and OCD and Tourette syndrome and Tick's was just kind of building that it really made me want to go into neuroscience and psychiatry. And then I met somebody and it was a tennis coach for someone who had Tourette syndrome. And the family was able to talk to me a little bit about how they thought that, you know, this child's symptoms were due potentially to a strep infection and that they noticed that this child's symptoms got much worse every time, you know, this kid had a strep infection.

And so I switched kind of my, my, I switched my major to neuroscience, and I started researching strep infections and obsessive compulsive disorder. And the first paper describing this phenomena, one of the first papers had just come out from the National Institute of Mental Health, from someone named Susan Sweeto, who is really Sue Sweeto and Judy Rapoport, but, but mainly Sue Su Su Suido are really credited for the concept of coming up with. PANDAS and later PANs. So that kind of set me on this path to be interested in this. And after college, then I went to the National Student Mental Health to work on

obsessive-compulsive disorder for a couple of years. And I didn't work for Sue Sweedo, but I worked kind of down the hall and I was doing research on OCD and still interested in PANDAS. And then I left the National Student Mental Health to go to medical school back in Minnesota where I'm from. And in Minnesota, there was a researcher who was looking at obsessive. of compulsive disorder in a genetic family tree that was in Salt Lake City in Utah. And so I went to Salt Lake City to do research on this family, and they had an amazing

amount of strep infections in their family. You know, so, I mean, there were five generations of family that we looked at, and the oldest generations of family had really high rates of Sydenham's Korea. And Sidenham Korea is a post-streptococcal movement disorder. So it's a strap infection that results in abnormal movement. And those folks who have Sidd and Hemskorea have a really high rate of new onset, obsessive compulsive symptoms. And so Sidenham's Korea was actually kind of the model disorder for what PANDAS was, if that makes

sense. It was kind of, PANDIS didn't completely come out of, you know, thin air. It came out of looking at this disorder, which had been around for decades, hundreds of years, and noticing that certain children who had a strep infection, they developed a brain disorder, a movement disorder, and they also had a high rate of obsessive compulsive symptoms too. And so Pandas really was characterized then as an infection that developed into obsessive compulsive symptoms,

but didn't have the characteristic movement disorder of Sydenham's Korea. So akin to Sydenham's Korea, but doesn't kind of meet all the same criteria there. So when I went to Sult, City to look at kind of do research with my preceptor and with this family, there was a high rate of Sydenham's Korea, a high rate of strep infections. And we left there thinking, maybe this is, you know, we thought this was a pedigree of obsessive compulsive disorder and maybe it's something kind of similar to pandas and not necessarily OCD. And we really were kind of convinced that

it must be something with the family. Like it must be a gene with the family that is causing pandas or OCD or something like that. And I remember thinking like, all right, that's probably 99% what it is. But what if it's something, and this is nothing yet Salt Lake City, but I thought, what if it was something about the place that was also kind of generating something with strep infections or something else? And it turned out that there was a, there is an outbreak of rheumatic fever in Salt Lake City every 10 to 15 years.

So it's different from almost any other city in the U.S., this intermountain region in Salt Lake and around Utah, had a really high rate of strep disease and rheumatic fever, and then Sydenham's Korea as well. So there was an outbreak of Sydenham's Korea in this same region. And so what we found out was that there was actually a clone of group A strep that was unique to this region that was driving a lot of sort of unique streptoccal disease. And so I took two years off then from medical school, actually study kind of that clone of strep in an infectious disease laboratory to see if there's anything about that that could cause Pans or PANDAS, and then came back, finished medical school, went to residency and fellowship, and still kept this interest in Pants and

Pandas and throughout residency and fellowship. And then that's still what I do now at Mass General a number of years later with the clinic and with Dr. Ador and with a growing team of folks. Okay, let's, long story. I don't want to, I want to know, like, what did you find from those two years of studying that clone? Did you find something that was interesting? That's, I think, the most, the saddest part is that I, so what I was looking for in that clone was, is there something from, so that clone was more associated with Sydenham Korea than other clones previously had been. or so we thought. Because it turns out that group A strep is not a monolithic thing. It is a zillion different strains and substrains and things like that, just like we see these different strands from COVID. We see different strains from the flu.

Group A strep has that same variance. And that's also why you never build global immunity to strep. So you can get strep year after year after year, not like the chicken pox where you get, you know, you build a sort of protective immunity after you, had it once and then you can't get it again. Strep, you can get year after year because it's varying these different genes. And so that clone had picked up some toxin genes from other strains of strep and strains

of other bacterial, like, staff and other bacterial species. So it had more toxins in it, and it had novel toxins, we thought, compared to other strains. And so we were looking to see, do those toxins make it more likely? to cause an immune reaction. And ultimately, I really couldn't find any evidence of that, unfortunately. And, you know, I think a lot of that had to do with my kind of inexperience, most likely. It was the first time I was doing anything like that. But also, too, it was, you know, the immune system in mice is really different than the immune system in humans.

And Strep itself only infects humans. it doesn't naturally infect mice. So we were using this model system kind of to see in mice, you know, can this strain, you know, tweak the immune system in a way that pushes it towards autoimmunity? And maybe there was a better way to study it. I'm sure there is now. But back then it was hard to really get a definitive answer to that.

I never, I finished those two years there still with an interest to go on to continue to research this field, but not with any clear answer about sort of the strain or what happened there. Okay. Well, sometimes, you know, first of all, your tenacity as a medical student to do this kind of work is like, I don't, I don't, I think medical school I was just trying to survive, you know, I was just trying to like pass the classes and, you know, learn the basics. You're like trying to solve this like new, amazing hidden issue. Yeah, I got, I got interested in it, I think. And that that also carries. me through medical school because I think medical school is like you said I mean I was trying to to get through it and and I needed sort of I needed something to motivate me through it as well and this really helped me to sort of like okay you know this is this is more of a path for me and and this is

what I'm interested in and so it kind of organized sort of all the the work and the everything else okay so Sarah how did you guys connect or tell me your story how you got interested in this I know you're utilizing neuroimaging and randomized control trials and neurocognitive assessments. So are you more of the sci-di neuroscientist Ph.D.? Yeah. So my, yeah, my background is a PhD in clinical psychology. And so I had heard about Pans PANDAS coming up through training. But then when I was an intern at Massachusetts General Hospital, I saw one of Kyle's patients who had pandas. I was seeing them for kind of behavioral therapy. And that's what I really saw this piece of where it's for these kids, it's amazing to be able to have this interdisciplinary approach where this kid was

seeing Kyle for medication, but also being tracked by his PCP. And everyone was very aware of what was going on in terms of his medical status in tracking his symptoms. And so it was amazing to see those fluctuations based on where he was at in terms of whether or not he was in what they call a flare when he would have strep again. And you'd see the symptoms come back in a very dramatic way such that he could barely even go to school. And then, you know, after effective treatment with something like antibiotics, keeping on his regimens of SSRIs, you know, then he could return back almost to kind of normal functioning in between. And so my role in that case as a psychologist was to help support him to learn the tools of how to manage those times

kind of between flares where he had lingering symptoms and to help the family kind of understand what was going on. And it was amazing for me because it was one of the first times that, you know, I could possibly answer the question of what is going on with my child. Because as a therapist, we get that all the time and especially in diagnosing kids. Like, why is this happening to my kid? And this is the first time that I was seeing a kid that I felt like I had somewhat of answer to that question. And what an amazing opportunity to then understand what's going on in pediatric, psychiatric conditions. And so I have always been really interested in neuroscience as well. And now my specialty is more in neuropsychology. And these kids also sometimes have these

sudden degradations of their fine motor control where all of a sudden, it's like, it's like their kindergartners again and they can barely write their name. And so it's amazing as a neuropsychologist as well to be able to see what are the different ways that are impacted in this and then to loop back to say, okay, neurologically, what is going on? How can these multiple things be happening at once? And how can we kind of track all of those together to figure out the best treatments for these kids? So we're looking at that in a number of different ways. So we're trying to understand really what's going on neurologically with these kids. And so right now there's no really good way to detect neuroinflammation in kids that's not invasive, like with something like

pet. And so we've spent a lot of time and energy trying to figure out how we can detect whether or not this is related to neuroinflation in a non-invasive way. And so we're trying a lot of different mechanisms to do that. And actually colleagues in Stanford have found that it does seem like there are disruptions in white matter for these kids compared to healthy kids that are starting to potentially show some of that sequela of having some level of neuroinflammation. And then we're also looking at, like you said, randomized controls trials to look and see if we give kids things that treat inflammation, does that make their symptoms better? Right. If the hypothesis is that this is inflammatory related can giving an anti-inflammatory actually help these kids. So we're trying things

like that to better understand both how to treat them, but to actually understand what is going on with this disorder. Yeah, I think I'm still like, and maybe you guys can educate me what's known and what's not known here. Is it the antigens like from this, you know, bacterial infection? Or is it the, you know, antibody response against something on the bacteria that's, and the sort of, you know, kind of like an auto or not an autoimmune issue, but like it's like the, it's like the inflammation that's secondary, or is it the actual antigen? Or is it all the same? I don't think it is all the same. And it's a, I think it's a really key question to the mechanism and then to validate this as, you know, as a hypothesis. Because, you know, we still don't understand for kids or adults,

why anyone gets obsessive compulsive disorder, right? There is not, uh, there hasn't been a single gene that's been identified that is now sort of widely accepted as a major risk factor for OCD. It sounds like I think some, uh, folks are close to identifying something, but, uh, compared to, you know, autism, schizophrenia, you know, a lot of those different disorders have found a gene, you know, multiple risk genes, uh, that are kind of, exactly, that are sort of accepted. And, and, And obsessive compulsive disorder is is anywhere from one to three percent of the adult and the pediatric population around the world. And there's not a single gene that's been identified for it, which is, you know, still I think is just, it's wild to me. You know, it's got to be there.

There's like, it seems like if the parents have it, there's a higher risk or if the monosygodic twin has it, there's a higher risk of OCD. So it seems like there is some strong heritability. Definitely true. Okay. Yeah. Definitely true. But you're saying, okay, so we don't really know the specific gene. There's probably many, many genes that are influencing this.

Right. And so then pandus is another hypothesis as to why someone's OCD is happening, right? It's not in doubt, you know, if you look at the obsessive-compulsive symptoms that these kids have, they look similar, if not identical to what someone with non-Pandis OCD would have. So, you know, it's still a lot of hand washing, but then a lot of intrusive thoughts about harm, you know, a lot of checking rituals, sometimes hoarding rituals. They look, it runs the kind of gamut of typical symptoms. And I guess the reason I'm going into this is that Pandus is still the hypothesis is really kind of what it has caused, I think, some controversy, right? Because, again, we don't know why anyone has developed OCD.

and now we're saying, here's another reason potentially why someone develops obsessive compulsive disorder. It's due to this infection. And then when we are asked, what is the mechanism of how that works? Then it comes down to kind of the nitty gritty about what you're talking about is, is it an antigen on strep? Then that looks so much like a neuron or something in the brain that you generates an antibody to strep, to fight off the strep. and then it cross-reacts with your own brain proteins, your own neurons or glia or something else that causes these symptoms. And that's, I don't know if you, I mean, remembering back to medical school, the molecular

mimicry hypothesis is essentially the term for that, where you've got mimicry between a bacterial or viral protein that in either amino acid sequence or in three-dimensional structure is so similar to your own proteins, that your antibodies and your immune cells essentially can't differentiate between the two. So you get an infection that then triggers an autoimmune process. And that, you know, that happens in, there's a, there are a lot of, there are a lot of examples for something like that for, I think, campelobacter, you know, and ankylosing spondylitis. But strep has always been thought rheumatic fever to be something that is kind of molecular mimicry related.

And there's some evidence for that for pandas. And then there is some evidence that maybe it's something different to you. That maybe instead of molecular mimicry, it's that strep is uniquely sort of disregulating the human immune system such that you have a propensity to have this autoimmune condition that strep just sort of unlocks and that it doesn't necessarily have to be that there's a cross-reactive antibody on one to the other. It's just sort of that you had this propensity to begin with. and this infection sort of brought that out.

Okay. And so I think this goes into like getting a clear diagnosis. Like what, I've heard from you a couple times. It's sudden onset some time period after a strep infection or a throat infection, right? Maybe it's not diagnosed with strep. Maybe it is. Maybe they didn't go to an ER. Maybe they just thought it was something viral, right?

Mm-hmm. How soon after the strep infection, do we normally start to see the symptoms? It's so variable. And sorry, I know you can speak to this too. I mean, we in clinic, there are some folks. So let me just say the diagnosis is the hardest part of this, right? Because we have these clinical criteria that we're using. And sometimes they're really hard to actually apply to a patient to the situation.

We'll know that they have obsessive compulsive symptoms, and the family will tell us they started rapidly, but the strep infection happened three months prior to the OCD onset. And then we think, well, are those two things related if it's three months? You know, we tend to look for, I guess the short answer to the question is sometimes we see a six-week kind of interval because it's typically when the strep infection has cleared. So someone has usually been given antibiotics and the strep is no longer there. And that's why we think it's actually the immune response to strep and not the actual. It's not like a toxin from the bacteria. It's not, you know, a disseminated bacterial strep infection. But then there are the kind of cases where we'll see someone in clinic and they'll be strep positive without knowing it.

Or, you know, they will have the onset of their symptoms and then the PCP or the pediatrician will check them for strep. And they'll be positive at the kind of the time of the symptom onset too. So it can go in a lot of different directions. I wish there was, you know, it's just, it seems really variable from kid to kid. Okay. So it's very variable, the onset, but it's how, I mean, I'm thinking as like in child psychiatry, it's like, how often do you get a kid that's like it's the first time they're having OCD, it's rapid onset.

Like, in my mind, it's like, you don't usually get those referrals, right? Like, it's usually like it's gone on for a long time and the parents have gotten like, what the heck is going on and they start reading online, right? So are those more of the clients that you're seeing when the parents kind of like are like, oh, wow, I need to see, you know, this guy who's got this organization and he's like got this clinic and he specializes in this. And it sounds like my kid has this. Is that the kind of kids that you're seeing?

So we still get a lot of kids like that or people who have had OCD for for six years. You know, I think I can't quote the paper, the researcher who looked at this, but I think someone, and I could be getting this wrong, but someone looked at sort of the average length, the delay and getting to treatment between when the OCD symptoms start in childhood. And I think the average was like four years, you know, between when the symptoms starts to when they get to see sort of like an OCD specialist. So we certainly get kids who have had OCD for six, eight, ten years. And the parents or the kid is saying, this started when I had a strep infection. Do I actually have pandas as opposed to OCD? And this is just my, you know, opinion and

bias here. And Sarah can jump in too. But I think it's almost impossible to tell at that point. It's so hard to tell if someone has had symptoms for six or eight years, whether they have Pandus or OCD because it's just so hard to kind of wind back the clock and see if these criteria fit, you know, the clinical criteria fit. But those kids who have been sick for a long time, those are primarily when we started this program nine years ago, that was kind of the primarily of the referrals that we were getting. And now that we're sort of known in the area and known by the pediatricians and things like that, we're getting kids six weeks after the onset of their receiving symptoms, sometimes within a month, you know. And, and so it's changed over time. It's

actually allowed us to, you know, and Dr. Doris doing the imaging research on this now, but we are scanning now kids who, you know, doing an MRI on kids who are one month into their symptoms and, you know, are like six to seven to eight years old. So I think we have, we haven't published it yet, but we probably have a collection of the sort of youngest age of onset of neuroimaging for OCD as well. Okay, I'm trying to get my mind into like what a six-year-old with OCD looks like. And so, you know, I have a six-year-old. I don't know how well he would be able to communicate this with me. So what are the parents saying that they're observing of a six-year-old with OCD? I guess, I guess, Sarah, you can answer this one. Sure. Yeah, I have a six-year-old, too.

So I know exactly what you mean. Oh, yeah. Yeah. Okay. And so it's interesting that you bring this up because I feel like as you were talking about, too, how long it takes people to get to a specialist. I feel like that's, this is one of the big difficulties with diagnosis, not just about diagnosing OCD or not pandas, but also recognizing panda. I mean, OCD just in general in such a young population. And, you know, for a lot of these kids, it might start as some. something that seems reasonable, right? It might be very fixated around their bedtime routine,

where all of us with six-year-olds, like our six-year-olds have something that they need to do in a specific order at bedtime. But for these kids, it will very suddenly get to a level where bedtime is taking hours or the kid, you know, won't be able to go to bed without things being done a certain way, where it's influencing things at school, like to the level of, you know, not not being able to go to school because they're so worried that certain things might either happen at school or they won't be able to do, maybe potentially concerns that they're going to be exposed to other kids who are sick if they have the germ phobia is related to OCD,

worries about sometimes certain areas of perfectionism and their performance. And so they're unable to go to school. Dr. Williams probably has some really good examples of this too. But it's sometimes, again, not that they can necessarily convey it as a six-year-old, but that the parents can recognize these behaviors are not typical for them. Maybe it's something that sure, any six-year-old will be worried about, but it's to the level that's so severe and so extreme. Or even things like worrying that they're going to end up harming other people

by doing something just by having a thought, right, that they are suddenly going to stab someone. Of course, you know, the six-year-old is not in any, mindset where they would actually have homicidal ideation, but they're so suddenly their thoughts are real enough that they could actually happen. And so they're so worried about having these thoughts that they start doing things to try and keep from having those thoughts or be put in situations where those thoughts might come up again. And when you mean by like, when they do things that keep them from having those thoughts, what are the things that you're seeing them doing?

So some different compulsions that they might be doing. So one of the things that often gets overlooked by parents is kids seeking frequent reassurance or confessing because their child is telling them frequently about these thoughts that they're having, right, without realizing that part of the child's compulsion is telling the parent, right, that the child is so distressed by the thought that that the distress of the, that doesn't get alleviated until they've told the parents and confessed to them. So even if they're not doing it at school, when they come home, they're immediately telling their parent about all these thoughts that they had that day. And they've been so distressed until they were able to convey these to the

parents. So that's one of those that will often get missed by parents because they're glad that the child is vocalizing what's going on in their head so they can understand those intrusive thoughts to help understand that it might be OCD without realizing that the child describing these things and then the parents giving reassurance just sometimes propagates these loops that they have. And then there's also the very, I don't want to say, more typical, but things that people might more often associate with OCD, which would be things like, you know, washing their hands over and over again until they get raw and might even be bleeding or being unwilling to get out of the shower until they've been in there, an hour, hour and a half doing their specific rituals that they have to do. So certainly the more

kind of characteristic things are things that people are more used to hearing about can also be symptoms of OCD that could be related to pandas. Yeah, I think one of the fascinating things about OCD symptoms in a six-year-old actually shockingly don't look that different from OCD symptoms in a 30-year-old and a 40-year-old. Depending on what the kind of the construct of the symptom is, right? So hoarding behaviors you can see in five and six-year-olds who they get, you know, you'll hear them talk about, you know, I'm just, I feel so bad for this rapper, you know, like to a hamburger or something, or I feel so bad for this rock or this trash is going to get thrown

out and nobody cares about it that I need to keep it, you know, so they sort of create some some meaning and some emotion irrationally about an object and it allows. them to or prevents them from throwing it out. Or, you know, a lot, I think of OCD comes down to core beliefs about kind of poorly assessing risk about something and then and then overly attributing kind of your control of that situation. So I had a, you know, I had to worry about something bad was going to happen to mom or dad and I couldn't get that worry out of my head. And so I had to tap 15 times, you know, uninterrupted to make sure that something bad doesn't happen. And then it turns and then they feel better in those few minutes and then they have to tap again.

So those kind of, we see those exact same symptoms in kids with pans of pandas in five or six years old. And it's shocking to when you talk to parents, usually what's coming out is just how rapidly and how significantly the kid has changed. That these behaviors were never there before and now they are absolutely reeling the roast. you know, family life cannot proceed or take place without dealing with these symptoms in some, you know, some way, shape, or form. And yeah, and I guess the last couple ones that are, frequent ones that we see are, our fear of vomiting is incredibly, you know, can be incredibly strong in kids. And we see kids who stop eating as much or they stop eating certain foods or they will avoid certain family members because they think they're more likely to sort of get ill from

certain family members. So you can see these really deep-seated and complicated symptoms come out, even at young ages, where they may not be able to sort of express into words why they're doing it, but you will absolutely see them dig their heels in and, you know, really throw a tantrum if their symptoms are not accommodated or, you know, allowed to take place. Yeah, that's good. So you're seeing a pattern of all these different things, that perfection issues around bedtime, going to school. And then, you know, there's that confessing, frequent reassurance that they're looking for, worries about harming other people, maybe some hoarding, behaviors like washing that may be extended,

raw hands, prolonged bath time, shower events. Yeah. Yeah. Yeah. I think we see that. It's more hand-wash. is the easier one. We see some kids tons of wiping. They feel like they didn't, you know, get totally clean after they use the bathroom. And so they are using just roll after roll of toilet paper, things like

that. It's usually not, you know, I think one of the things that you kind of do with five and six years old, you know, year olds or that age is you think about what do they actually have power to control in an environment and usually sort of like extending bath time or shower time isn't something that they have a lot of control over. But if they're in the bathroom, like, how how much toilet paper they're using, or if they are, you know, like usually, you know, they're washing their hands independently. So how much soap they're using or if they're going to wash your hands? Those are things that they can sort of do without kind of a parent being involved. And then it's sort of like, wait, okay, if that behavior is now taking three hours, now a parent's

going to get involved because it's like, we just washed our hands or why are, you know, why is all the soap gone from the house, things like that. Okay. Okay. So you have this kid, you get that history. They have some recent history of a infection, upper respiratory throat infection. What are the types of questions that you're asking day by day to sort of see if those people had those infections that are linked to this rapid onset or onset of OCD-like symptoms? Well, why don't I talk about the infection stuff?

And then Sarah, if you want to talk about the ancillor symptoms stuff that we, because I think that Dr. Dord has a lot of experience and also in the neuropical changes that accompany this too. But so my interview, basically, what I'm looking for are first and foremost, you know, did you have a verified group base drop infection, right? Did you have a throat swab that said, yes, I had group A strep? Because that is a relatively easy one that we can test for, right? There's a lot of infections that can be associated with this that we can't test for. So viral infections, sometimes we can't test for, or mycoplasma pneumonia is another type of

bacterial infection that we think is associated with this. And there are immune tests to look at antibody titers to mycoplasma, but many times they're not very accurate. And so the first thing I want to know is, you know, was there an illness? Was it tested? And what did the test come back as? And so that's kind of, that's the initial set. And then we're usually very interested in, is this the first time it happened?

You know, has this ever, have you ever seen any anxiety symptoms, movement disorder, tick symptoms, things like that previously prior to this? And sometimes there are some mini symptoms, you know, kind of some, but most of the time there is not. And it's kind of the, in the criteria for the clinical criteria for Pans and Pantison should be really the first onset. And then I think the other things that are striking about this, aside from some of the other symptoms that we think that are associated with pans and pandas, it's how quickly things go from not being there to it's like full tilt. Everything is just terrible. And the family is absolutely at its end. That process, I think, in pans and pandas, most of the time when we see it really happens, you know, within a week. sometimes, right? Where, and it's almost hard to believe, I think, from psychiatry perspective at times,

that things can happen that rapidly. But we see that quite a bit and really put faith into it when we hear from it from parents that it actually did sort of escalate that quickly. And I think that that is one of the things that separates this from non-Pandus and pans OCD, you know, which, again, I think we still have a pretty poor understanding of how those things develop over time. But it usually isn't sort of like, while this week is completely different from the week prior, because now we're doing rituals six hours a day and last week we hadn't done any of them. That's usually not kind of the, I think the quote unquote, typical onset for OCD that we see. Dr. Adore, you were going to.

Yeah, I was going to just add to the, you know, you've been talking a lot about the core symptoms like OCD. But earlier I'd have mentioned that some other things can happen as well because we hypothesize that what might be going on for these kids in the brain is related to the cortical striatal loops, which have impacts on executive functioning, motor circuitry, motivation. And so what you will often hear from parents as well is the kid that's had some other new symptoms. So like I mentioned earlier, that their handwriting might suddenly look terrible. they might be in third grade and suddenly they can barely write their name. Difficulties with sleep, more mood lability.

And actually when we surveyed parents of kids with pans and pandas, this is one of their major complaints or what was most consistent is this mood liability where the child's mood swing suddenly becomes so great and they become much more dysregulated than you would expect for a child their age. it's like they're throwing temper tantrums again, or they might be more aggressive towards their family members when they're typically not an aggressive child. You might see things related to executive functioning.

So they might have a lot more difficulties concentrating, and that might be the pieces that the child presents in school, that the teacher notices that there might be much more suspect that the child has attention deficit hyperactivity disorder or something like that. The kids also might present, with urinary changes where they feel like they need to go to the bathroom more difficult. Or they might even start having accidents again during the daytime or at night,

even though they've been body trained for years. So it's also important for both parents and practitioners to be looking out for these other symptoms too to help also give you a little bit of a heads up that there might be something else involved. Because earlier when Dr. Williams was talking about the related disorder of pans, pediatric acute onset neuropsychiatric syndrome, those kids don't need a documented infection to get that diagnosis, but they do have to have at least two of these other symptoms that I mentioned along with the restricted eating or the OCD or the ticks.

And so even if a kid doesn't have a documented strep infection, either because it wasn't done or it was negative, it still should be on people's radar to be looking out for these other pieces. In case, you know, there's something going on with some of these other symptoms where they might benefit from something even beyond what we would typically do for a kid with OCD or ticks. When I hear a lot of those symptoms, I'm thinking like, it's almost like a sensorium, like a light delirium, you know, kind of like a total brain function decreased due to like

an acute infection. I've seen that in my own kids. I've seen like kind of like a regression when they're having. you know, vomiting, GI issues. Maybe it happens for the next couple days. Or, you know, if we have like a big, like, event, like Christmas, the couple days after Christmas, it's like they are more irritable, more upset. So are we talking about that kind of stuff or is it more chronic, like you're seeing this day in and day out for like weeks and weeks and weeks, the mood swings, the poor focus, the restricted eating, the irritability, urinary accidents.

Yeah, I think it's the latter. We usually hear a pretty dense, you know, change that most days are like that, particularly with irritability aggression. It's less of a kind of when people find us, basically, because, you know, we're a specialty clinic, right? It's sort of like a few levels of kind of getting to us. It's almost always it hasn't been a couple days and then got better sort of thing. It's usually the last six weeks, the last three months have been like this day after day.

I would say the OCD symptoms are usually the most consistent, you know, like severe and consistent. Some of the bedwetting, urinary frequency, kind of handwriting stuff, that stuff can fluctuate a bit during the kind of the, I think, initial onset. But yeah, I agree. I think that it does seem like, I don't know, if we want to call it in Sepul an encephalopathy or, you know, like we haven't seen EG changes, although we haven't systematically looked at that in kids with this because we're usually not getting them right at the moment of their onset. And so EG usually is not, you know, it's almost like we're doing it a few months later. But, you know, I think when, you know, just I think going back to

medical school as well, right, when we see someone who, you know, someone who is elderly who comes in with altered mental status, we always think of infection, right? is kind of commonplace for us. It's just we don't think about that in kids or in, you know, but we have these kind of models already in medicine that we apply and we understand that this is something we need to think about. It's just we think that it doesn't or can't happen in this population in the same way. And I think that we actually see evidence that it can and it does. Okay. So that's helpful. So it is, there is something a little bit more chronic to a lot of these things. That makes me, I think it's not like waxing and waning. It's not like there's an acute

infection and then the sensorium drops and cephalopathy. You're seeing something a little bit more chronic. It makes me also wonder, like, how do you distinguish this from like autism in a young kid? Yeah, any thoughts on that? Just to, yeah, I can give that a shot. I think it just looks very different from autism. I think most of these kids that we're seeing are, I would say the average onset that we are seeing in our clinic is seven or eight. And so most of these kids have not had any kind of developmental flags along the way. Some of them have, you know, like some of them, there have been some delays. So I don't want to say that it's, you know, 100 percent. There has never been any issue. But most of them have sort of are out of the realm where we would be,

they've had periods of either, you know, adequate or high kind of social function, academic function, motor function that, and then we see a drop off after the infection in conjunction with new onset, obsessive-compulsive symptoms. And to go back to, I think, with your previous point about sort of, is it waxing and waning or is it chronic, it's sort of dense in the, I think, the initial episode of post-influenced. infection. And for some kids that can last a year, it can last six months. With treatment, we actually see that a lot of kids go back to baseline. So we do actually see a waxing and waning in this where we've seen some kids with absolutely terrible obsessive-compulsive symptoms for a few

weeks. I mean, six to seven hours a day. And then with treatment, we see them essentially go back to where they were, you know, within a couple of weeks. which is also totally abnormal for, you know, kind of typical onset OCD. And that is not the, I would say, that's not the majority of the kids that we see in clinic have that same response. But we do see a waxing and waning of these symptoms with infection and with kind of inflammatory conditions too. Okay. All right. So I want to make sure providers know what to do when this comes into their office. Like, is there antibiotics? Are you ever at a point where you're like, this kid needs antibiotics still?

Or is that something that's usually taken care of before they get to your office? No, we do advocate for antibiotics for kids. Not indefinitely and not sort of, I think that the majority of the children that we see don't require prophylactic antibiotics. But one of the things that we started doing early on was testing the immune function, testing the immunization. testing the immunoglobulin levels in all of the kids that we see in clinic. Because initially when our program started, it was a joint program between child psychiatry and infectious disease at Mass General with Mark Pasternak, who's the chair of pediatric infectious disease.

And then also Yolonne Walter, who is the chair of the pediatric immune deficiency program at Mass General. And sadly, Yolin Walter went to Greener Pasture. She runs now a really large immune deficiency program in St. Petersburg and Florida. But she, you know, when we started all seeing these patients together, she started testing IGG levels, IGG subclasses, IGA, IGM to see, are these kids getting more ill from strep than you would expect? Or are they getting strep or opportunistic infections at a higher rate because they actually have an immune deficiency? So that makes sense?

Yeah. And so we, because we started to see a lot of kids who we thought had immune deficiencies. And so we've seen now a number of kids who we have diagnosed with hypogamagallopulamia with low IgG levels from our workout, not from their pediatrician, but because we, you know, we're kind of the first ones to catch it. And those kids have repeated infections. And they may need sort of prophylactic antibiotics to cut down on the number of, of, um, But I think for our standard kind of PANIS patient who comes in, do we advocate antibiotics? So I think that the, and, you know, Dr. Dora is leading to our clinical trial on this right now. And we can talk about that in a minute, too.

But the most important thing that we do for kids is an anti-inflammatory initially. Okay. And because we see a pretty strong reaction, positive benefit from an anti-inflammatory. And then sometimes we will advocate for them starting an antibiotic. as well. And that primarily is because for reasons that we don't understand yet, we have seen a positive beneficial behavioral effect from antibiotics. Some of the antibiotics that, you know, are commonly used for strep have a glutamate modulating function. So if you look at them actually in cell culture, they modulate some of the glutamate transporter genes. They increase their expression.

Which antibiotics do that? So amoxysolin does it? But most of the seplosporants then. So cephylaxen, amoxicillin. And a few of the antibiotics have actually been looked at in IV form as acute antidepressant treatments. This is prior to ketamine. But I think I'd have to look it up. But I think septraaxone was looked at for its rapid kind of potential antidepressant effect. And it was, I think that trial was stopped because it caused so much venous inflammation

that they stopped the IV antibiotics for depressive effect. depression, but it was looked at for treatment for ALS as well because of this glutamaturgic effect from the antibiotics. So we are using kind of the antibiotics in short courses, you know, and again, not in a prophylactic and a sustained long-term way, but because we think that there may be a glutamate modulating effect from the antibiotics that is beneficial for OCD symptoms in the short term. So you're using amoxicillin. and what else do you what else do you tend to use uh so amoxicillin and um so the cephalosporin antibiotics so

keflex cephalyxin at times uh augmentin at times which is again a moxacosin plus uh plus another agent and then um if someone is is allergic to those then uh then you know our infectious disease folks have tried as ifamycin at times too and what's interesting about is if mycinin 2 is that it's got a known anti-inflammatory effect. So it, and it's used in, actually in COPD, I think frequently for that, for that effect as well. So it's not, it's sort of given prophylactically not to treat an infection, but to sort of reduce systemic inflammation. Wow. Yeah. Okay. So that's the antibiotic. And then what are you giving for the inflammation? You said you're giving, are you giving like steroids or are we talking inseds? What do you,

What do you guys send to use? Let me, yeah, I can speak to that and then maybe Dr. Ador, if you want to talk about the trial, too. So we have tried steroids previously, and I think that the behavioral activation and some of the side effects on the steroids is problematic for many, if not maybe half of the patients that we tried them. And that's kind of follows some of the data that's come up to Stanford, too, is that there are a lot of side effects from steroid treatments. for these kids. But we've still tried that in some and have had a great response. But our first, our first sort of foray into anti-inflammatory treatment with this population is non-steroidal anti-inflammatories. And usually neproxin sodium, so, which is a leave, is the, you know, the over-the-counter name for it. Because neproxin sodium only has to be dosed twice a day, as opposed to the ibuprofen, motron, things like that,

which usually have to be dosed three times a day, which I think is impossible for parents to up with three times a day dosing and two times a day is a little a little more realistic. And that's the, that is the clinical trial that we have going right now, essentially is, or one of the clinical trials we have is looking at neproxid sodium and the treatment of, of PANDA symptoms and kids. Wow. And how many patients have you enrolled and had go through this trial so far? Any preliminary data you want to share?

I wish we had preliminary data. We don't have preliminary data yet. This was really based on anecdotal evidence that we had seen, where we had just seen a lot of kids respond to this very positively. And it seemed as though the kids who responding very well to it were the kids who were closer to the onset of this. And so we've tried to be really restrictive with the kids that were getting in this trial to be kids that are, our new onset. But what's interesting is we found that the word about this has gotten out, where we're seeing more and more kids presenting to clinic who have been put on aproxen by

their PCP and have started to see some benefits from it. So, so, you know, obviously you can't use those kids. Yeah. You can't use those kids. In your study, it's so hard. Right. And it's one of mixed blessing sort of things is that, you know, part of part of us doing things, you know, part of us doing things like this podcast or different kind of educational initiatives we're trying to do is because we've seen that kids do better when they get the treatment closer to when this starts. And so as much as we can kind of educate people so that they don't need to come to specialty clinics like ours, you know, that's great. We want this to be part of kind of common knowledge so that people know how to treat this. And it makes it a little bit harder to research, right?

Because it's cut out of the bag. But I must emphasize that it's still very important that we do you know, the randomized controlled trials and get some of the kind of gold standard treatments for this disorder because we don't have those yet. I mean, Dr. Williams has to talk about, you know, what we've seen be efficacious. And there's a lot more research that needs to be done in terms of actually doing placebo-controlled trials to understand what are the most effective medications for these kids? Are the most effective treatments more generally? And so providers have confidence using those and families have confidence using those. Because, we've had a lot of experience with families where they get told a number of different things to try,

and it can be really confusing for patients and families. Okay, what definitely doesn't work? Let's start. Just rattle it off. Come on. What doesn't work? Let's go. What doesn't work, and I'll punt this a little bit, but what doesn't work is feeling like this is only it has happened to your child and getting kind of a sense of isolation and defeat from it. Because sometimes that's what the, you know, you know, I think an important thing for people who listen to this to hear is that even though this is somewhat rare, it's happened to a lot of families. And it can be really confusing to hear about different types of treatments, both medical and non-medical. And I don't know if there's any

that I could personally say, you know, Dr. Williams, you might be able to speak to this more generally. It's not like I would ever know that something wouldn't work for anyone, right? But there are certainly things that we can have more confidence in because of what we've seen and that the types of scientific rigor that they've already had to, or that they've been under investigation for versus some things haven't had that level of rigor yet. So there's not much that we can really say about those. Yeah. But Dr. Williams, I don't know if there's anything in particular that you want to give people warning about. Yeah. So I haven't seen like restriction or elimination diets work. You know, there's sort of, we have a lot of, so there is a lot of discussion

about inflammation and OCD and pans and pandas and also even just kind of beyond pants and pandas too. And we can talk about that a little bit as well. And so I think we have seen folks take that and run with it in the sense of like, oh, I read that gluten is inflammatory. And so we cut gluten out in order to see if their OCD symptoms would be better, or we cut dairy out. And unless someone has celiac, and if they have celiac disease, then cutting gluten out, certainly, you know, like leads to an improvement in across multiple domains. Same with, you know, dairy allergies, things like that. Outside of those symptoms, I have not seen elimination diets. I've seen them make kids miserable, right? Like, kid can't go and have birthday cake next door. I haven't seen

does work. And I'm sure, you know, there are people listening that that would disagree. So I think that that's one thing that doesn't work is elimination diet. I don't think that CBD oil or CBD treatments have worked. I've had people talk about those. And I think that that is still something that's to me just too kind of unknown and scary to use in kids. So I don't advocate that. And I haven't seen supplements work, sort of non. We have some folks who have looked at like turmeric or curcumin, which have, which are, you know, food supplements that do seem to have some anti-inflammatory properties as well, but using sort of like hypodosis of curcumin or turmeric, things like that, I have not seen that work either.

So that's, I'm sure there's a more kind of exhaustive list. And this is, again, nothing against the parents who are trying those. I think one of the things, too, that we'd be, we're miss not to kind of mention here is that parents are a lot of times trying these things because they've not gotten an inviting or welcoming response from medical personnel about this, you know, this disorder. So I think a lot of times parents are finding their own, they're sort of finding their own way through this. And they're trusting other parents, which a lot of times can be great and sometimes, you know, is not great. But I think that we, in some ways, we've kind of left families to find their own way through

this because of the controversy about whether or not this is actually a disorder or not a disorder. Like, this is something that is treatable or not treatable. And a lot of parents that we talk to have had pretty bad experiences with medical providers where they brought this condition up. Yeah. Yeah. Yeah. So, okay. Okay. So what about IVIG? Is there a place for that? Is this? So IVIG, maybe explain what that is and what any, if any data exists, that that would help at all for this sort of issue. Yeah. Yep. So there is data. So IVIG stands for intravenous. That's the first part, IV. And then immunoglobulin is the second part of the IVIG. And essentially, you are getting IgG and, that's the first part of. And

You're getting an infusion of those into, you know, intravenously. And you are getting the antibodies that have been given by donor populations, who are, you know, the donors are highly screened. And, you know, they're actually, I think, on like a list where they can't, you know, their travels restricted and things like that. But there are certain people just like people that are giving blood donate immunoglobulin. And then that is condensed down. So you actually are getting sort of the combined, I think,

is how it works. You're getting kind of the combined IGG from multiple people, not just a single person. And then you get this sort of hyperbolis of IGG. And for reasons, I think, that are still being completely worked out, it is, the high-dose IVIG is an effective treatment for autoimmune conditions, for some autoimmune conditions. So Kawasaki syndrome, idiopathic thrompsetic purpura, you know, there was some, I think the data is not there yet, but there was a interest if IVIG was going to treat long-haul COVID or post-COVID symptoms. But there are certain conditions where treating with IVIG is, you know, it's a bit counterintuitive, right? Like we think that these are antibody mediated autoimmune disorders, and yet we're infusing antibodies from other people into, you know, we're actually increasing the amount of IGG in someone's body. and it seems to have an anti-inflammatory effect.

So that mentality is sort of using IBIG, and it's been used for a long time. It's relatively safe. Again, it's not without side effects, but it can be used in safe ways, and it's been effective for these other autoimmune conditions. And so that was the rationale for using it in pans and pandas, initially was the idea that, you know,

if this is an autoimmune or inflammatory condition, can this autoimmune treatment be beneficial? for kids with Pants of Pandas. And so there have been two blinded trials. And the first one was with Su-Suiteau. And I forget her first name, but Peromutter, P-E-R-L-M-U-T-E-R is her first name, or I'm sorry, her last name, who did this trial at the National Institute of Health. And they compared IVIG to plasma exchange.

And plasma exchange, just briefly, is a different type of autoimmune therapy where you actually remove antibodies from someone's bloodstream. So they're almost kind of polar opposites, but they have the end benefit of doing the same thing, where in one, you're infusing antibodies with IVIG and with plasma exchange, you're actually removing them. They compared those two treatments, and they tried to do it as best they could in a blinded way,

but it's tough to do kind of blinded, you know, blinded therapy with these two very invasive treatments. So they compared IVIG to a sham IVIG. And this was, I think there were probably 10 kids per group, so it was not. And this was really the first sort of randomized trial, treatment trial on Pandas. And it showed that IVIG and Plasma Exchange had a very significant benefit on the OCD and tick symptoms. And kids who got that, either treatment, either IVIG or Plasma Exchange. And the kids who got the sham IVIG did not get any better.

They did not improve from that. And this was looking six weeks after their infusion or treatment, you know, is their OCD or ticks better. And then they treated the kids who had the sham treatment with active IVIG, and those kids did improve. So this was kind of the first evidence that, you know, you can treat this this way, and maybe it's a good idea to do so. And that really, I think, partly because we're psychiatrists and, you know, and psychologists and we're not, you know, like, we're not writing for these medications and usually we don't necessarily work so closely with neurologists or other people who are going to do this. it just didn't catch on, right? Like nobody who comes in with OCD, most child psychiatrists and psychiatrists weren't thinking,

we should think about IVIG for you, sort of like, well, you know, maybe this, you know, one paper's out there, but we don't even know how to go about getting that. And IVIG is very expensive too, right? It's like, you know, it can be up to $10,000 plus dollars per treatment. So it's a significant cost that was not being covered by a lot of insurance companies because they felt like it was experimental.

So that was the first trial, and that was 1999. And then we ran a second trial. When I was at Yale, we ran it in conjunction with the National Institute of Health with Suezwego again. So it was this joint trial between NIH and Yale. And I'm the first author on the paper that came out of that, which was in 2016. And we basically, we didn't look at Plasma Exchange there. We looked only at IVIG, and we looked at sham IVIG and real IBIG in a blinded fashion.

and we did as much as possible to blind, you know, to remove any bias from the study, you know, as we could. And what we found there was that that IVIG did not beat placebo statistically. That there was some, there was more improvement in the IVIG group, and this is in the blinded phase of the trial. There was more improvement in the IBIG group compared to placebo, but it was not statistically significant. And there was a huge amount of variance between sort of huge. who responded to who responded to IVIG versus who didn't. There were some kids who had phenomenal response to IVIG and some kids in the IVIG group who didn't. And then there were some placebo kids who got radically better from a salient infusion.

So, and this is a little bit confusing here, but that was the initial part of the study, which was a blinded phase. And then there was a second phase, which was open label. And it basically said, if you did not improve, in the blinded phase, whether you know, whether you got IVIG or not, we're not even going to look at that. We're going to offer you an open label IVIG treatment if your symptoms did not improve. And so some kids who were in the placebo group then got their first dose of IVIG as an open label treatment, so they knew what they were getting. And then some kids who got a blinded dose of IVIG,

then got another dose of IVIG as an open label, you know what you're getting at that point. And in that arm, 80% of the kids who got 5BIG improved dramatically. Wow. Is that like, first of all, congratulations on publishing anything. And this sounds like a monumental, expensive study that needs grants and a lot of coordination. So just congratulations on publishing that. But wow, I mean, it must be frustrating to not see the, the separation statistically significant?

What was the P value? I'm curious, like, was it close? Was it like a point? No. No? It wasn't close. Okay. It wasn't.

And part of it, too, just as, you know, as you said, it's, the stuff is tough to do and it's super expensive. And so the trial was small, right? And I know that if, you know, what I'm doing here is making it sound like IVIG doesn't work. And that's not the impression that I want to give. because I think the answer is just more nuanced. And there's some new data that we have, too, that we can talk about.

And then Sarah and I can talk about the IVG trial that we're about to start in conjunction with other sites, too. But the open label response, meaning if you know what you're getting, you have a much better response to it versus if you don't, if you have the chance of getting placebo or IVIG, that phase didn't look like it sort of worked as well. then Open Label worked much better. I think the variance between the groups, like some kids getting much better and other kids not having any response. That was huge. And when you have a small trial, that amount of variance just kills any type of statistical significance you're looking for. You know, like if you are, and this goes back in a sense to how hard it is to make the diagnosis.

You know, we, so we enrolled 36 kids in that trial. We screened 1,200 to get those. 36, 1,200 or over a thousand, maybe it was. Oh my gosh. Painful. It was over a thousand. It was really rough. And it was, again, a testament to all the people that we had working on that at NIH and at Yale, who, you know, did this, these, you know, these, uh, examinations. But, but we did as best as we could to try to get kids who were early on in their symptoms. And we felt, you know, met all the criteria. They had to, we had to have agreement between, you know, Bob King and Jim Luckman, who are, you know, very, very experienced and kind of child psychiatrist and work in OCD. And then Sue Sweet O2, so everybody had to say yes.

And then even still we saw a huge difference in who responded to IVNG and who didn't. And so what we did. And so, you know, Dr. Oren and I are looking at now, even still years on, we're looking at the MRIs from that trial to see are there differences or things that we can understand there. we're looking at some of the inflammatory molecules, cytokines, and to see if that had some difference between them. But the other thing that we did from that trial, so we took serum from kids who were in that trial with pandas, and we infused it into mouse brain, into the brains of mice,

which I know it does not sound like a kind thing to do, but we were trying to essentially see, are there antibodies, are there autoimmune antibodies that those kids with Pantus have that could bind to mouse neurons, to mouse brains? Because the mouse brain, you know, strangely is not that dissimilar from the human brain for protein structure. And so we thought maybe we can get lucky. And even though it's human antibodies, you know, we'll find that they bind to something in the mouse brain. And it turns out they did. And so, yeah, I know.

It was very, and so this was actually, so I started this out as this was my PhD dissertation. They're very, very early part of it. And then when I left in the middle to go to Mass General to start the clinic, and then Luciana Frick and then Jean-Ju in Chris Pittenger's lab at Yale kept going with this work. So I exited kind of very early on in the process of the mouse work. And they took it on to both show that the antibodies bind. to a certain type of neuron in the basal ganglia of mice. And we're actually fortunate enough that that neuron has a really, like, distinct shape to it. And so when they looked at it in the microscope, essentially because we're using these

antibodies that essentially fluoresce, so they will glow when they, under microscope, when they find to something, then the neuron looked like this thing called a colonergic interneuron. It's got this very characteristic shape. And so then they could use an antibody that they already knew bound to the colonergic interneuron and then serum from the kids with pandas. And if they both bound to the same thing, then they have kind of identified that it's to the cholinergic ender neuron. So they went on to show that, so one, it binds specifically to this.

And it doesn't, then, and healthy control serum doesn't bind to this neuron. And that it also binds to human brain to the same neuron and human brain, which is critically important so that it's not just an artifact of binding to mouse, you know, that you're using human antibodies and a mouse brain, but that it also binds to human brain. And that after IVIG, it actually decreased in the, because we had blood from these kids at multiple time points. So we could actually look to see how much of this antibody in kind of a relative term is present in the bloodstream. And it decreased after IVIG, and that decreased correlated with their improvement in their OCD symptoms.

Nice. How strong of a correlation? It's in the American Journal of Psychiatry from 2021, June 21. I don't know, but it's enough that it was significant. And that, that's awesome. That's great. It was really interesting. And so, and again, the reason I bring this up is that, so it could be when we go back

to say, okay, IBIG failed in the blinded phase, you know, that part of what, if we actually enrolled or looked at people who. who, if we tested for that antibody at the outset and said, oh, if you have a really high level of this, then maybe you benefit from IBIG and maybe, you know, you meet all the PANIS criteria that we have because they're the best guess that we had at the time. But, you know what, for whatever reason, this person had a low level of these antibodies. And so IBIG didn't look that affected in them. That would kill a clinical trial, not being able to differentiate between those populations, which we couldn't do. And now we can. And so I think that the story about who it works

for and how it works, I think, is going to evolve. We've become more clear over time. And Dr. Dorr and I, and more Dr. Adora right now, has done just a phenomenal model work on setting up this IVIG trial, this multi-center trial that we're joining on to that started from the University of Arizona and funded by Octa Pharmaceutical company. But there's going to be a larger trial of IVIG, essentially for PANS and PANDA starting. It's already started. We're or we're hoping to to on board soon. Okay. Wow.

Dr. Adore, do you want to say anything else about that? I guess the only thing I would add is, is we talk about how much these things cost and how many people are needed to find these differences. Just, I mean, you know, Dr. Williams was talking about how when he first heard of this was when, you know, Suswego had published one of the first papers about this. I mean,

is still a lot of work to be done, and it's amazing how much has happened in the past 30 years or so. And part of it is just resources. Like we are now looking ahead to kind of some of these big data approaches for this disorder that we haven't had the capacity to do before. We've been limited by small sample sizes and imaging trials, which we know impact how reproducible the results are. And now we're working to build consortiums with other sites that see these kids and are doing their imaging trials for them. this IVIG study will be bigger than the one that's been done before, hopefully, and trying to do kind of some big data approaches, connecting different cohorts of kids across the United States and then some internationally too. So I would say for those who are interested in this, it's a really exciting time because more resources are going into it. And it's fun to see them the speed with which these sorts of things start to happen.

you know, where this used to be controversial, now we have a better sense of what's actually going on with the with the evolution of the ideology for this. And I think once we really are able to tackle this problem of heterogeneity that comes from such a kind of wide range of presentations, the way that the clinical symptoms are described right now, I just think it's a really exciting time. And I think that looping kind of COVID into it too in the pandemic, it's been interesting. to see how there's another, you know, disorder where a virus can lead to neuropsychiatric symptoms and how quickly things can move when people put the resources in to see what's going on with that. And we're starting to see some parallels between post-COVID neuropsychiatric sequelae and some of the

symptoms that we're looking at for pans and pandas as well that we've had people present to our clinic, who look like they have pans or pandas, but they didn't have strep first. They had COVID. And so we're trying to understand that link as well. So there's a lot of things to happen, and I think a lot of things to come. And so I think it's just an exciting thing

for people to listen in on or for families or physicians to be a part of if they're interested in as well. Wow. Okay, so we're kind of bringing this to a close. I want to get anything out, any other pearls that you would have to providers who are on the front lines,

what they should do at this point maybe or what they should consider, like should they consider trying to get their person to enroll in a study? Should they treat with antibiotics, not proxone? That's probably, you know, N-SED type of thing. That's kind of like, that makes sense as like something every provider could do potentially,

although it's early. It's like the risk of harm in my mind is like so low that it's like yeah so go ahead yeah it's so it's tough about sort of what the what the first step to take is if you're a pediatrician or if you're a child psychiatrist because so I think I think the thing that is most important is actually listening I know that sounds like a not a cop out but but but listening to what the parents are saying has gotten us so much farther in our research and in our clinic than anything else has. Because most of the symptoms that we're describing, most of the associations that we've made,

have all come from parents. And I'm not saying that everything that we as parents say about thinking what our kid has or what's happening is correct. I mean, we can be wrong about anything too. But when you start to hear sort of a collective, I think, you start to hear things multiple times, it starts to, it starts to be less due to chance. And so most of the families that we've talked to have felt like their initial questions about Panzer Pandas were dismissed.

And that's kind of across both, you know, again, not to pick on pediatricians or neurologists, but it happens there as well. But same with psychiatry and child psychiatry. I think people have said like, oh, yeah, I heard about that. It's really rare. I don't really know what to do about it. and then it kind of gets sort of punted down the road. So I think that,

I think providers should not do anything that they're not comfortable with. So if you are not comfortable, like if you're not writing for a proxen or antibiotics, I think you don't feel pressure to do that, you know. And try to find help in, you know, the Pandas Physicians Network is something that people can Google that have some resources for helping parents find find resources, and then some treatment guidance too is on there for the PANDAS

Physicians Network. PPN.org, I think, is the website. Parents usually there's a website and an organization that we have, our research has been funded through called the PANDIS network that people can Google to look for providers. And then there's the International Obsessive Compulsive Disorder Foundation, which also is a phenomenal nonprofit group, that there will. website can help people find a treatment for OCD2 and Dr. Adore has a grant through them and I do as well for funding our research.

So I would say if you feel like you think that it's, if you're seeing someone with nuance at OCD and you feel like this could be part of it and it's not something that usually is on your wheelhouse, just reach out to someone if you can, you know, try to find someone. I get a lot of emails, you know, from other providers or discussions. but I would say to be open-minded to whether it doesn't have to be pans and pandas, you know, like it doesn't have it. It can still be rare. I feel like we have no idea how common or rare. It actually our ability to diagnose it is still pretty poor.

But listening and then trying to find someone to that could help to further down the road with diagnosis or treatment is probably the most important steps that you could take as a provider. Okay. Sarah, what do you think? That makes a lot of sense. That listening piece was going to be the first thing that I was speaking of two, because, you know, we, from having talked to these families, we know that oftentimes they go to, the meeting is, I think, three providers that they talk to before they get a diagnosis, that they, there's a huge range of money that they've spent out of pocket, like Dr. Williams said earlier, of trying to find treatments when, you know, they're not necessarily getting them from their own provider. And so most spend around $6,000, but some will spend up to a million dollars for out-of-pocket costs. We know that these kids, like a third of them, tend to present to the ER because their symptoms are so severe. So we know that these kids and these families are under a lot of stress and duress. And so I think, like Dr. Williams said, taking the time to hear that story to understand what the symptoms are,

and then linking people with, you know, those who can help provide supports or guidance is crucial. And I, we know, like you had said towards the beginning, that we, we tend to get a lot of the patients where parents have or physicians know about us and where it has gotten around. But, you know, that, that tends to be the more privileged within our society. And so I think the more that we stop and listen to parents who maybe have not heard of this and can help to provide that insight of, oh, here's another thing to think about or consider. Or like for fellow psychologists like me who aren't used to asking questions about, you know, was there an infection around the time that these symptoms started?

You know, starting to add those questions to your repertoire can also help to widen, you know, what kids can get caught early, right? That it's, we can also help to kind of approach the underserved populations too, who don't necessarily have the resources to have heard about these things or have the money to pursue kind of their own treatments for them. the message, I think, for psychologists and psychiatrists, too, that's super important here is that if you, if you pick up any publication and look at inflammation, the microbiome, right? Like, it is everywhere right now that we are thinking about these aspects that potentially contribute to, to psychiatric behavioral conditions, you know, neurological conditions. And we are not being trained in that as psychiatrists and psychologists right now, right?

that is wholly outside of sort of our training repertoire in medical school and in residency. And so if those things are going to be actually beneficial to our patients and modulating those things from inflammatory, you know, anti-inflammatory treatments or who knows, some types of probiotics or prebiotics, we better get, we better change things to understand those to be able to help our patients with these things. Because right now we're sort of, and I think it's, yeah, it's still very early days. we want to make sure that we are kind of understanding the right aspects of how and when to intervene. But it's not just going to, I mean, we have to change the way that we're doing this in order to be responsive to the information that's coming in. Yeah.

Well, great. I hope this is the first of a conversation we can have in a continued basis as you guys get further along in your studies and research. And if new things come out, please let us know. I'm going to put on my website, Psychiatrypodcast.com, a full. sort of summary of this with all the links to the articles we discussed. And I'll also put in the show notes, the Pandas Physician Network. That's www.pandas. And then ppn.org. That's the link to that. So I'll put that in the show notes. And you guys have as well, your organization, I'll put that linked as well. And are you guys on Twitter or is there any other way of interacting with people

that you would like to. I've ignored that, I think. So I have a Twitter account now, and I think there's nothing on it. Sir, do you have? I don't. And we've tried, mentioned our website. We've tried to put a lot of that on our website, too. So when we have updates about things,

because a lot of our patients have participated in our research and want a way to know once those things have come out. And so we're pretty good at keeping our website up to date on research opportunities, how to get involved in those, and then what's the research that's come out already. And your website is the mass general.org children, pediatric, neuropsychiatry and immunology. Is that the? Yes, that's it. Okay.

I will link that one in everything. So if you go to the show notes, you can find that. And yeah, it's great to talk with you guys. I think we even went over because it was so interested in me. And we like, hopefully we'll have you guys back. Just for my records, do you guys have any conflicts of interest? to report? Yes.

Now, so I think that our conflicts, so my conflicts would be, and maybe I should just write these down and send them to you. So for a child, like, you know, ACAP stuff, they want us to list all of our, who our research funding is coming from. So we've received grants from Pandus Network, Pandus Physicians Network, IOCDF, those three nonprofit organizations.

And then we have now, we haven't received anything yet, but we will, hopefully, funding for the IBIG trial from a pharmaceutical company from Octafarva, which I can email all this stuff to you, though. That's okay. I think those things are probably similar for Sarah and I, the Octafarma and the ISCDF. And then I've got a couple more in there that I can put in there too. Cool. Yeah, thanks again, guys, and appreciate you coming on.

Yeah, thank you. Yeah, thanks for having us. This is fun.