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Melanie Cole (Host): From new diagnostic tools and technology to advances in rare disease research, this is Pediatrica, pediatric research and innovation podcast presented by clinicians and researchers at Children's Health of Orange County.

Host: I'm Melanie Cole. And joining me today is Dr. Tom Megerian. He's board-certified in Child Neurology and Pediatrics, the Division Chief of Neurodevelopmental Medicine at CHOC, and he's the Clinical Director of the Thompson Autism and Neurodevelopmental Center with Children's Health of Orange County. He's here to tell us about research and innovation in autism.

Dr. Megerian, it's a pleasure to have you join us today. As we get started with this topic, which is of interest to so many providers, tell us a little bit about the autism spectrum disorders and what you see in your clinic. Are we seeing a rise in prevalence? And if so, do you have any theories on what you might attribute this to? Are we looking at better diagnostic tools, awareness? Is it something else? Tell us a little bit about it.

Dr Tom Megerian: Thanks and thanks for having me. I really appreciate the opportunity to be on and talk about these topics that's near and dear to my heart, obviously. And a great question, it's probably the million dollar question. Everyone's been asking, what's behind the rise in the prevalence of autism and what's behind the rise in the prevalence of autism and what can we do about it?

So fortuitous for the timing, we just came out with the new statistics, the CDC, on prevalence of autism and it's now down to one in 36 from one in 44 just a year ago. And so, the prevalence is still increasing. The latest statistics, looking at 2020 prevalence, indicating that it is continuing to rise. And I think the reasons, these include all the things that you said actually. It is greater awareness. The people are screening for it. Physicians, especially pediatricians, are really being encouraged by the American Academy of Pediatrics and by practice standard committees to really start doing routine screening at all of the routine well-child visits in the first five years of life. So, screening for any developmental delays has really become standardized and part of all practice. And so, we're recognizing more of these neurodevelopmental disabilities, especially autism as a result. If you don't look for something, obviously you don't find it. In our own area, screening has gone up from about 40% to the vast majority of pediatricians are now routinely screening. So obviously, that is definitely one of the factors.

There's also been changes in the criteria for what constitutes autism. And the DSM-III, which is when autism was officially first put out as a diagnosis in the DSM, the Diagnostic and Statistics Manual. American Psychiatric Association puts out the DSM and first put autism in there in the DSM-III. We're now at the DSM-V. And if you look at the criteria for diagnosing autism, it's changed pretty dramatically. There used to be multiple subtypes of what were called pervasive developmental disorders, which included autism, included Asperger's syndrome, included diseases like childhood disintegrative disorder, all of those disorders now are subsumed under one category of autism spectrum disorders, and the criteria for making that diagnosis has changed. And one example of that is some of the criteria used for diagnosing autism such as social communication impairments and impairments in repetitive restrictive behaviors have gone from being required to be actively present to now being required to have either active presence or a history of. So even if a child that we see, say, today doesn't have repetitive and restrictive behaviors present, if they had a history of them, they still would be considered to be in the autism spectrum.

So, criteria has definitely changed. Recognition has changed because of people looking more for it. There's also more of an acceptance. When I first started practicing in the late '90s, parents didn't want to hear that their child had autism. They were very, very upset. And really oftentimes denied it or really did not want to accept it. It was, I think, at that point, thought to be a terrible diagnosis to have. It was stigmatizing. And now, there's much more acceptance of autism. And oftentimes families are seeking a diagnosis because they think their child has autism. And so, there definitely is a component of some of what we call autism is not always truly autism. I don't know how much of that is prevalent in the population, but it definitely happens.

There's also differences in identifying autism from the school's point-of-view versus the clinician's point-of-view. And so, there are studies that show that not all autism is necessarily diagnosed medically. Some of it is labeled as a disability by the school. School systems can't diagnose anything, but they can list a child as being eligible for special education services because of a specific set of symptoms or impairments, and autism is one of them. So, sometimes we see kids who have autism listed, on their record because the school has said they're receiving services for autism. And that also contributes to some of the changes we see in the prevalence.

Host: Interesting points, all of them that you made, Dr. Megerian. And also, thank you for telling us about how that criteria has changed and that is so interesting about the schools and their criteria for identification and special education services. Why is it difficult to do research in autism and neurodevelopmental disorders? As you've just pointed out, some of the things and the stigma changing and that sort of thing. What are some of the other barriers that you haven't quite touched on yet that would make this type of research a little bit more challenging?

Dr Tom Megerian: I'd just add one more thing about the previous question. I am not of the opinion that the things that I listed for why the prevalence is changing account for all of the change. There definitely is likely also something else going on that we are still struggling to understand. So when I say the increase prevalence is due to many of those other factors, those probably don't count for everything. There probably really is a true increase in prevalence. I just don't know how much is attributed to maybe something in the environment or some increasing sensitivity to autism. Whether that's true or not, we still don't know.

And going on to the question about research is a really great question. And research has really, I think, been difficult in the areas of autism and neurodevelopmental disorders. In the case of autism, I think it's probably best explained by the fact that, and I'm semi-quoting something that was put out by Dan Geschwind and Matthew State from UCLA, which is that autism really needs to be thought of as not one disorder, but a hundred or more rare disorders, meaning that the causes for what symptoms appear to be autism are manifold. In the diagnostic realm of autism, there are probably many, many, many disorders. We just call them one disorder because of commonality of symptoms and presentation. But the causes. for autism have many different origins sometimes, in many cases, in fact, in most cases I would say it's genetic susceptibility. And in some cases ,it's a single gene that is involved. In some cases, other cases, it's multiple genes that are involved. And in other cases, it's a gene or multiple genes in combination with an environmental exposure such as an autoimmune problem or a problem with inflammation or an exposure in utero or an exposure outside of the birth period that leads to the autism because of a genetic susceptibility. And in other cases, it's really a genetic disorder or a metabolic disorder that leads to autism that we haven't identified yet.

And that's what makes research difficult. Because if you think about the fact that, I like to use cancer as an example, 40 years ago when someone talked about cancer, people often thought we were talking about one disorder. And we now know of course that lung cancer is very different than colon cancer. And the treatments are very different. And the treatments for colon cancer are very different than the treatments for brain cancer because they are different disorders and there are different genes and different causes. So if we tried to use one drug to treat all cancers and we tried to do a study on that, we would fail miserably.

And that's one of the problems I think when we approach research in autism, is the need to think about this as multiple different disorders and the need to tailor the treatments that we come up with that we're going to study in research studies and make sure that they're designed for the particular type of autism an individual has. That's not to say that we can't come up with treatments that will treat multiple subtypes of autism, in other words, autism due to multiple different causes, we can. And we see ABA, for instance, applied behavioral analysis, as being a behavioral treatment that works across autism regardless of the etiology or the cause of it. And similarly, there may be drugs that attack a final common pathway that is involved in the different causes for autism. So if I have gene A causing autism and gene B causing autism and gene C causing autism, those genes may produce autism in an individual by some pathway that has a final commonality. And if I have a treatment that can attack or address that final common pathway that treatment might work across a few different types or causes of autism. But it does present difficulty with research because you need to be careful when you do studies to make sure you understand that you're studying similar types of autism. We know that autism presents with high functioning, medium functioning, low functioning, and clearly those are probably different causes behind autism in those cases. And so if we do a study and we use, say, say a new drug and we try to treat those individuals across the spectrum, we might not see efficacy in one or two of those groups. And so, we would consider the study failed. When if we had only customized the study to study one of the groups, we might have had a successful study.

Host: This is such an interesting topic. So many avenues as you say. And tell us some of the current innovative trends in diagnosing autism and other neurodevelopmental disorders. Tell us a little bit about what you're seeing, any research you feel is important to share with other providers.

Dr Tom Megerian: I think what we're trying to do is push autism diagnosis back into the hands of the primary care physician when possible. There are many types of autism which are obvious or more obvious, and we want our pediatricians at the primary care level to be empowered to make those diagnoses. So, there are tools being discovered or being produced or being developed that are geared toward allowing the pediatrician to incorporate those tools in their routine care so that they can make the diagnosis. There are salivary tests to look at markers for autism including protein markers or RNA markers or DNA markers. There are artificial intelligence tools that are being utilized. I should mention, just by disclosure, that I consult for one of the companies that's helping to produce those tools. But there are several of those that are on the market now that have received 510(k) clearance from the FDA to be used by primary care physicians at the point of care to allow them to feel more comfortable in making the diagnosis. Most of those tools, it's really important to understand, in fact, all of those tools do not make the diagnosis. They're just tools that the clinician can use to discover whether or not the child has the symptoms that would allow them to state with high levels of confidence that their suspicion that the child has autism is in fact true and supported by data.

So, I think that's probably one of the biggest areas of innovation, is these new tools that are being produced, and being made available to primary care physicians. The reason that I say it's important is because the waitlist at the tertiary care centers are very long. And so, what we're trying to do is, say, for a pediatrician in practice who's fairly confident that a child has autism, we want to give them the tools to be able to make the diagnosis at the point of care and make the referrals for therapy because that's the most important thing. Early diagnosis means earlier referrals for therapy means better outcomes. And so, getting a child diagnosed as early as possible so that referrals can be made for therapy is of paramount importance.

Host: Well then, tell us about some of the current studies at Thompson Autism and Neurodevelopmental Center and some promising avenues of research in autism spectrum disorders. What are you doing there?

Dr Tom Megerian: We have a few studies that we're doing and that we're real excited about in cooperation with sponsors. One of them is a study from AbbVie that is looking at a new drug for treating irritability associated with autism. Right now, there are two drugs that are approved, risperidone and aripiprazole, for treating irritability that's associated with autism. Those don't treat the core symptoms of autism, but they do address a common co-occurring symptom, which is irritability and agitation. What's needed is some more options and the study that AbbVie is doing on cariprazine, that we're happy to be and proud to be a part of is of paramount importance because we need other drugs available to help families and children who are dealing with these co-occurring symptoms of agitation, irritability.

We're also working on a study with a couple of different companies. Yamo is a company I also consult for, has a study that is across the country at multiple sites looking at a novel treatment for treating the core social impairments in autism. And CHOC is participating in that and so are several other centers. Another study looking at another drug is going to be starting very soon here at the Thompson Autism Center that we're proud to be the primary site for, looking at another novel treatment for treating the core social symptoms. And that one will be available to males ages four to 14.

So, we're real excited about these opportunities. We have a number of studies in the Fragile X space. Many children with Fragile X will present with autistic symptoms as well, so it's one of the disorders has a subset of individuals with fragile X have a higher rate of autism than the general population. And so, we're proud participants with Zynerba and Tetra, companies that are developing novel drugs for treating symptoms of cognitive impairment as well as behavioral symptoms in Fragile X. And so, I encourage people to contact us if they're interested in those studies.

Host: You're doing such exciting work, Dr. Megerian. And I'd like you to wrap up by kind of reiterating how current research is underscoring the need for services and support for children with autism spectrum disorders, both now and as they grow into adolescents and adulthood. I'd like you to take us from bench to bedside and how you see all of this research improving the patient journey and outcomes. How do you envision your research translating to patient care?

Dr Tom Megerian: Right now, there are no drugs that treat the core symptoms of autism. It's a desperate need. We're talking even if we can develop therapies that work on subsets of autism. Remember at the beginning of our discussion, I talked about the fact that autism has many different causes. And so, it's unlikely that we'll have one treatment that will treat all of autism, but we will have treatments that can treat vast percentages of individuals with autism. If we come up, for instance, with a therapy that helps 20% or 30% of individuals with autism and another therapy that helps another 30% or 20% or another therapy that helps 10%, when we put those innovative therapies together, we can eventually get to a point where we can treat the vast majority of individuals with autism to help them with the impairments that they're dealing with. And I'm talking about the significant impairments. I'm not talking about individuals who obviously may have the diagnosis of autism and they're functioning very, very well. And in those cases, really they don't have a disorder because they are accessing and functioning in society so well. But there are many, many individuals who are not able to access society and they're not able to function at the level that they or their families want them to.

And so, allowing us to develop these therapies that will eventually address the needs of the wide spectrum of individuals who want and need therapy is really our goal. And there are exciting things at the bench, looking at the molecular levels and looking at trying to treat autism from the gene level. I think about disorders like Phelan-McDermid syndrome where there's some really interesting work going on looking at insulin-like growth factors as a potential treatment. And I think, for instance, if that therapy is proven to be effective, that would be, although a small percentage of individuals with autism, a big chip and a big step forward in the rock that is the autism spectrum disorders that we're currently trying to devote ourselves to helping in society.

Host: Thank you so much, Dr. Megerian, for such a fascinating and informative podcast, really. I'm sure other providers can get so much information from this. Thank you for sharing your expertise. And thank you for listening to Pediatrica, pediatric research and innovation podcast presented by clinicians and researchers at Children's Health of Orange County.

To learn more about Children's Health of Orange County and to refer your patient, please visit choc.org for more information and to get connected with one of our providers. I'm Melanie Cole. Thanks so much for joining us today.