Richard Frye, MD, PhD
Chief of the Division of Neurodevelopmental Disorders
Phoenix Children’s Hospital
Dr. Frye is a Child Neurologist with expertise in neurodevelopmental and neurometabolic disorders. He received an MD and PhD in Physiology and Biophysics from Georgetown University. He completed a residency in Pediatrics at the University of Miami, Residency in Child Neurology and Fellowship in Behavioral Neurology and Learning Disabilities at Harvard University/Children’s Hospital Boston and Fellowship in Psychology at Boston University. He also received a Masters in Biomedical Science and Biostatistics from Drexel University. He holds board certifications in Pediatrics, and in Neurology with Special Competence in Child Neurology. He has authored over 300 publications and book chapters and serves on several editorial boards and is currently the Editor-in-Chief for the Section on Mechanisms of Diseases of the Journal of Personalized Medicine.
Video Interview with Dr. Frye – June 2019
Dr. Frye is a national leader in autism spectrum disorder (ASD) research. He has led several clinical studies on children with ASD, including studies focusing on defining the clinical, behavioral, cognitive, genetic and metabolic characteristics of children with ASD and mitochondrial disease. Dr. Frye has also led several clinical trials demonstrating the efficacy of safe and novel treatments that target underlying physiological abnormalities in children with ASD, including open-label studies on tetrahydrobiopterin, cobalamin and leucovorin, and a recent double-blind placebo controlled trial on leucovorin. His ongoing research efforts focus on defining metabolic endophenotypes of children with ASD and developing targeted treatments.
PANS, Autism, and the Immune System: An Interview with Dr. Richard Frye – September 2018
Dr. Richard Frye is a pediatric neurologist and Chief of The Division of Neurodevelopmental Disorders at Phoenix Children’s Hospital. He’s recognized as an expert on the treatment of autism. Thank you to Dr. Frye for allowing Anna Conkey to interview him.
Could you summarize the results of your recent study, “Intravenous Immunoglobulin For The Treatment Of Autoimmune Encephalopathy In Children With Autism”?
Our study recently published in Translational Psychiatry showed that a subset of children with autism spectrum disorder (ASD) who did not respond to standard interventions had autoantibodies in their blood targeting brain tissue which might qualify them for the diagnosis of autoimmune encephalopathy (AIE). The majority of children with ASD had elevated levels of autoantibodies measured by the Cunningham Panel™ (Moleculera Labs, Oklahoma City, OK) along with an elevation in the activation of calcium calmodulin dependent protein kinase II (CaMKII). A few patients had other brain targeted autoantibodies associated with AIE, such as voltage-gated calcium channels autoantibodies.
Some of the patient qualifying for the diagnosis of AIE were treated with intravenous immunoglobulin (IVIG) and their symptoms were monitored with two widely-used validated behavioral questionnaires, the Aberrant Behavior Checklist (ABC) and the Social Responsiveness Scale (SRS). Overall, IVIG was found to improve scores on both the ABC and SRS questionnaires and the great majority of parents reported improvements in additional symptoms related to ASD. The majority of patient experienced side effects from the IVIG treatment but most of the time these were mild and limited to the time around the infusion period. We were also able to divide the patients who received IVIG into those that demonstrate a positive response on the behavioral questionnaires and those that did not. This allowed us to determine if autoantibody titers of the Cunningham Panel™ collected prior to IVIG treatment could predict which individuals would response to IVIG. We found that, overall, the Cunningham Panel™ could predict which individuals would response to IVIG treatment with over an 80% accuracy rate and that the anti-dopamine receptor D2L and anti-tubulin antibodies were particularly sensitive to predicting response to IVIG treatment.
What initially led to your interest in considering immune-mediated factors in autism?
I have built my clinical practice with a vision of discovering new treatments for children with ASD. Some children with ASD do not respond to standard treatments or even new novel treatments and many times a standard medical workup does not reveal any additional obvious treatment targets. Such patients need to be investigated further to determine if there are other factors preventing them from developing skills or causing disruptive behaviors. For me, integrating an investigation of immune factors into my practice was the next step for further determining treatable factors for children with autism.
Do you have a sense for the percentage of children with autism who also have AIE?
The study describes 82 patients that were screened for AIE. This was about 8% of the patients seen in my autism clinic during the study period. 60% of these children were believed to probably have AIE, or about 5% of the children seen in my autism clinic. The percentage of the other 92% of patients seen in my autism clinic that might also have AIE is not known but it is very likely that a significant percentage of these children may have AIE. Many of these children were not investigated further because of various reasons including insurance coverage of testing, parental preference and/or difficultly in drawing blood. Further studies that systematically evaluate the general ASD population for AIE so we have a better understanding of the number of children with ASD that may benefit from treatment for AIE.
While acceptance of post-infectious autoimmune encephalopathy and pediatric acute-onset neuropsychiatric syndrome (PANS) continues to grow, there seems to be a bias within the medical community against considering PANS in children with autism. Would you agree or disagree with this statement and do you have a sense for why this might be?
I believe that the idea that there are physiological abnormalities underling ASD which can be treated is novel concept that is faced by significant skepticism. Also many are skeptical that children with ASD can recover from their disorder at all. This skepticism, I believe, it based on an old concept of children with neurodevelopmental disorders having a “static encephalopathy” in which it is believed the brain is damaged and cannot improve. As new research connects neurodevelopmental and neurobehavioral disorders such as ASD with abnormal physiology and treatments that target these physiological abnormalities, evidence will become more compelling. As treatments are shown to improve function in disorders which previously had few effective treatments, I believe more people in the medical community will embrace treatments that help children with neurodevelopmental disorders.
Some physicians have questioned the validity of the Cunningham Panel due to the fact that many children with autism have positive results. The conclusion by some is that this means the test is producing false positive results. How would you respond to this?
In our study 57% of the children we tested were positive for the Cunningham panel as we defined a positive test. We set a more stringent criteria as compared to others. For our clinical practice, the Cunningham panel is considered positive when one or more autoantibodies are elevated AND CaMKII is elevated. One of the reasons we examined the predictability of the Cunningham panel is too validate and refine the accuracy of the Cunningham panel. Our study points to two particular autoantibodies which appear to predict response. Since the components of the Cunningham panel have been developed based on converging animal and human basic research, it is very clear that these components are very likely to be very meaningful. It is likely that different components (or combination of components) will identify different subgroups of neurobehavioral, neuropsychiatric and/or neurodevelopmental disorders. Further studies are needed to further refine the most accurate use of interpreting the components of the Cunningham panel.
Do you ever treat children who did not have an abrupt or acute onset of neuropsychiatric symptoms, and if so, do they respond similarly to children who did have an abrupt onset?
Abrupt onset of neurological, behavioral or psychiatric systems as well as abrupt loss of previously acquired skills are red flags for an underlying metabolic or immunological disorder. All three cases described in our recent paper had abrupt onset of symptoms and approximately one-third of children with ASD are estimated to have neurodevelopmental regression. However, there are children without a history of an abrupt onset of systems who also respond to immune and metabolic treatments that target medical abnormalities usually associated with an acute onset of disease. Thus, I do not usually use the history of abrupt symptoms onset to guide my workup. Treatments I prescribed are guided by biomarkers.
What is your approach to managing children with autism who develop neuropsychiatric symptoms? How does this differ from your approach to those without autism?
I have found that many children with neuropsychiatric symptoms without ASD have similar metabolic and immune abnormalities as those with ASD. I use the same approach for such children and have had successes in improving their symptoms and ability to function.
Is there any research you’re working on currently that you’d be willing to tell us about?
At this time I am working with several collaborators on the interaction between metabolism and the immune system. Emerging research demonstrates connections between the immune system and metabolism, both mitochondrial disorders and oxidative stress. We have recently published a review article on mitochondrial dysfunction in autism which discussed this and previously Dr Rossignol and I published a review article outlining the evidence for connection between these abnormalities in the brain of children with ASD. I think this is a promising area of research which may pave the way for new treatment targets.
You’ve published “Autism Spectrum Disorder in The Emergency Department: Looking Beyond Behavior.” What should ER physicians, primary care clinicians, and specialists be considering when a patient with autism presents with acute behavioral or neuropsychiatric symptoms?
It is very important to consider that there may be medical issues that can be driving behavioral decompensation. These medical abnormalities do not have to be complicated immune and/or metabolic abnormalities but may be more basic problems such as sleep disruption, gastrointestinal disorders and/or anxiety which may need to be evaluated and addressed. There may also be other underlying more complicated metabolic and/or immune disorders, so it is important to consider referring the child to a practitioner experienced in looking into these treatable abnormalities. Most importantly, it is important to have a vision of try to treat the underlying biological cause of the symptoms rather than just treating the behavior with medications to suppress it. Indeed, disruptive behavior may be signaling that something that is not obvious needs to be addressed and suppressing this signal may simple make a untreated medical problem worse by allowing it continue and progress without appropriate treatment.
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