During childhood and adolescence, some children experience sudden-onset neuropsychiatric deteriorations. Known as “Pediatric Acute-onset Neuropsychiatric Syndrome (PANS),” symptoms of this illness include abrupt-onset obsessions, compulsions, eating restrictions, anxiety, cognitive impairment, memory problems, academic decline, movement disorders, severe sleep disruptions, and behavioral changes. Currently, PANS has not been widely recognized as an illness; therefore, no epidemiologic studies have occurred to understand this condition. Dr. Jennifer Frankovich, Associate Professor of Pediatric Rheumatology and Co-Director of the PANS Clinic and Research Program at Stanford University, is exploring PANS and the key role infections play in its development. When children are not diagnosed early, infection-triggered inflammation injures brain tissue causing severe psychiatric disability. Dr. Frankovich wants to treat and prevent deteriorations, which will lead to overall improved well-being and prevent expensive, lifelong institutionalization.

The standard approach to treat children suffering from this growing epidemic uses psychotherapy and psychiatric medications alone, which have proven largely ineffective. By identifying which infections and inflammatory processes tip a child into a deterioration, Dr. Frankovich’s novel approach enables the discovery of treatments that restores the brain-immune and vascular health and allows the mind to heal  after the inflammatory process stops. When patients come into their clinic, the patient undergoes a systematic assessment for infections, inflammation, and autoimmune disease. By targeting the source of neuronal and vascular inflammation in the brain, including systemic and sinonasal infections, Dr. Frankovich and her team are able to resolve their psychiatric symptoms within a few weeks (if diagnosed early) to months.  Sometimes a child has a simple (or complicated) infection in the sinuses, and after treatment by their collaborating ENT surgeon and infectious disease doctor, the psychiatric symptoms quickly remit.  Sometimes, the brain-inflammatory process is autoimmune, and thus therapy may span a few years. After diagnosis and treatment, they closely follow their patients. They collect blood work at each visit, and disease-state blood samples to remission blood samples in order to find biomarkers which can predict neuropsychiatric deteriorations and predict which antibiotics and anti-inflammatory treatments will work for each particular patient.  Together, with their collaborating basic scientists (Mark Davis, Larry Steinman, Dave Lewis, Betsy Mellins, Ron Davis, Bill Robinson, etc) they are working to understand the immunologic triggers for neuropsychiatric deteriorations.

Currently, Dr. Frankovich’s clinic is one of few academic centers with a comprehensive and interdisciplinary team tackling this illness. Her interdisciplinary team is highly collaborative and includes experts, clinicians, and therapists in pediatric and adult psychiatry, neurology, allergy and immunology, rheumatology, otorhinolaryngology, infectious disease, pain medicine, sleep medicine, and genetics. Her program innovatively translates decades of data on infections and inflammation, and their connection with the brain. They’re using this information to guide evaluations and therapies in children with these sudden-onset neuropsychiatric deteriorations, giving every child and young adult coming to their clinic the  opportunity to have a complete medical work-up. The overarching goal of her research program is to fundamentally understand the drivers of this illness and the underlying modifiable inflammatory factors that drive mental health in children. She aims to identify the the most effective treatments in her patient population so as to develop clinical trials that will enable her team to disseminate the knowledge so that children everywhere can have access to brain-saving therapies. Their research focuses on what their patients have taught them, so that they can learn and eventually scale their program, enabling all children with mental health deteriorations to receive an evidence-based clinical evaluation and treatment plans that includes standard-of-care psychiatric support, as well as addressing their often overlooked infections and inflammatory processes.

Current Research Includes:

 Understanding PANS Through Genetics – Dr. Frankovich and her team are investigating the infections that trigger PANS. They believe children suffering from this neurological condition have an immune propensity to develop this illness. Dr. Frankovich and her team are performing genetic evaluations on all of their PANS patients. Using HLA data, Genome-wide Association Data (GWAS), and whole exome sequencing, they are looking at underlying genetic factors and patterns that make children predisposed to this deterioration. Together with collaborating geneticists, they are working to understand this data and how PANS overlaps with other autoimmune diseases. Based on what they learn, they aim to understand which treatments best treat and prevent future deterioration. By doing so, they will help clinicians hone in on better treatments more quickly, as treatments used for the other autoimmune diseases can be borrowed.

Understanding the Immunophenotypes and Genotypes of PANS Patients and their infections –  Dr. Frankovich and her team are developing novel ways to characterize immune profiles of their patients in order to understand the immunophenotypes (in the context of their genotypes) of children who develop deteriorations in mental health. They believe that certain genetic and immune profiles will help to predict treatment response, and therefore enable clinicians to choose the right medicine for the right patient. They believe these profiles will allow for improved, personalized treatments. It may also help predict who will relapse, and the triggers for the relapses, so clinicians can be better prevent and treat relapses. Dr. Frankovich and her team will also use the immune profiles and genotypes to inform them of which infections are most likely to trigger in their patients. They’re also comparing this data to healthy control patients to identify what happens to a child with neurological deterioration versus a child who becomes ill with those same infections, but doesn’t have a psychiatric deterioration.  

Using Novel Brain Imaging Technology – Dr. Frankovich and her team are using novel brain imaging techniques to looking at two particular attributes: blood flow and activated microglial cells. Through their research, they have found clues that patients with PANS may have inflammation and/or other disruptions of microvasculature of the brain, extremities (in some) and other body regions.  Patients who develop inflammation in the blood vessels have blood flow disruptions. They have seen that their patients with long standing disease develop areas of hypoperfusion and have symptoms and brain imaging patterns resemble elderly patients with dementia; Dr. Frankovich and her team are tracking brain blood flow to identify correlations with disease activity. They also plan to use PET imaging to see if activated microglial cells are playing a role in the condition.  The pediatric PET facility is currently being built to support this type of research at Stanford. If brain blood vessel inflammation and/or microglial cell activation in playing a role in PANS, this will lead to new treatment options patients with these issues, and they can eventually bridge these novel findings with dementia research.

Automated Neurocognitive Testing – Dr. Frankovich’s team is gearing up to do automated (computerized) neuropsychiatric testing to identify which brain circuits are most impacted by infection-triggered brain inflammation. They will track this brain circuit data over time in order to obtain more objective measures.  Because most children have difficulty articulating how they are doing on a cognitive level (especially when they are experiencing a mental-health deterioration), this automated (computerized) data on the child’s processing speed, memory, and other neurocognitive functions will enable clinicians to better assess and track response to both psychiatric and immunological therapies,  Additionally, this neurocognitive data will be the basis for developing tailored rehabilitation plans for these patients.

Microbiome and Infection Evaluations – From their research, Dr. Frankovich and her team believe that inflammation plays a major role in PANS, particularly from repeated infections. For example, if a child continues to get strep throat, their reaction to it increasingly grows stronger, which can eventually breach the blood-brain barrier and inflame the brain. Dr. Frankovich and her team are exploring whether or not there is vulnerability to infections and/or tissue inflammation based on a patient's’ microbiome. They have been collecting blood specimens on PANS patients, and their goal is to sequence the nonhuman genomes in the blood to identify certain strains of pathogens and/or lack of a healthy biome is playing a role in this illness. For instance, they believe that streptococcus, mycoplasma, influenza, and other infections (?tick-borne illnesses, ?vaccines) are playing a role in this condition.  However, they feel that the majority of children/humans do not have deteriorations after these triggers, and that not all strains of the organisms are problematic.  Thus, their team of scientists are trying to identify the interplay between specific strains of infections  (through genetic sequencing) and specific human genotypes as the trigger for PANS.

Sleep Architecture Information/Data – When people enter the REM stage of sleep (i.e. “dream” sleep), they’re essentially paralyzed. However, children with PANS have movements during REM sleep, which is highly abnormal and is a known predictor of Parkinson's disease and Multiple System Atrophy. They want to understand if children with PANS may go on to develop Parkinson’s disease, and other brain degenerative diseases.  Many of their patients are unable to come into their sleep center and stay overnight due to intense fears and other psychiatric factors. Dr. Frankovich and her team’s goal is to set up a home sleep monitoring program so they can capture the data before antibiotics and/or immunomodulatory therapies are administered, and then after, in order to see if the treatment is working.