Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections Research Articles

Case report: Early use of whole exome sequencing unveils HNRNPU-related neurodevelopmental disorder and answers additional clinical questions through reanalysis

This case report chronicles the diagnostic odyssey and resolution of a 27-year-old female with a complex neurodevelopmental disorder (NDD) using Whole Exome Sequencing (WES). The patient presented to a precision medicine clinic with multiple diagnoses including intellectual disability, autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), tics, seizures, and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Although this patient previously had chromosomal microarray and several single-gene tests, the underlying cause of this patient’s symptoms remained elusive. WES revealed a pathogenic missense mutation in the HNRNPU gene, associated with HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD) and developmental and epileptic encephalopathy-54 (DEE54, OMIM: # 617391). Following this diagnoses, other treating clinicians identified additional indications for genetic testing, however, as the WES data was readily available, the clinical team was able to re-analyze the WES data to address their inquiries without requiring additional tests. This emphasizes the pivotal role of WES in expediting diagnoses, reducing costs, and providing ongoing clinical utility throughout a patient’s life. Accessible WES data in primary care settings can enhance patient care by informing future genetic inquiries, enhancing coordination of care, and facilitating precision medicine interventions, thereby mitigating the burden on families and the healthcare system.

Microglia as a Target of Immunomodulation in Pediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal Infections (PANDAS)

PANDAS, or Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections, is a neuropsychiatric condition characterized by the abrupt onset of diverse neuropsychiatric manifestations following streptococcal infections in children. It's believed to involve immune dysregulation and autoimmune targeting of the brain basal ganglia. However, the precise mechanisms remain unclear. Hypothesis: considering the role of microglia in neuroinflammation, evidence for their activation in PET imaging of PANDAS patients, and increased number of CD68+/Iba1+ activated microglia in mice inoculated with group A Streptococcus (GAS), we hypothesized that as a consequence of disrupted blood-brain barrier (BBB), circulating factors modulate microglial functions towards a pro-inflammatory phenotype. Methods: Untargeted metabolomics was performed with sera from 10 children with PANDAS and 12 healthy controls. Human iPSC-derived microglia were generated and exposed to 5% serum from PANDAS patients or healthy controls in the presence or absence of Polymyxin B (PMB; endotoxin scavenger) and assessed for nitric oxide (NOx) production, immunophenotyped with flow cytometry (TMEM119, TREM2, CD68, and Iba-1) and bulk RNA-seq analysis. Results: Significant differences in serum metabolomic profile of PANDAS cases were observed, particularly in pathways associated with amino acid, fatty acid, lipid, steroid, and oxidative stress-related pathways. Treatment of iPSC-derived or primary human microglia with PANDAS serum led to a significant increase in NOx production, which was blunted by approx. 30% by PMB. Immunophenotyping revealed a significant reduction in homeostatic markers TMEM119 and TREM2, and expansion of CD68+ and Iba-1+ microglia associated with inflammatory response. Regulation of TMEM119 and TREM2 was endotoxin-independent, while PMB partially blunted the increase in CD68 and Iba-1. RNAseq revealed dramatic effects of PANDAS sera on microglial gene expression pattern, with upregulated genes associated with C-type lectin receptor, TLR, TNF, and NFk-B signaling pathways among others. Conclusion: The results suggest that as a result of BBB disruption in PANDAS, associated systemic inflammatory mediators modulate the phenotype and function of the brain microglia, a mechanism that likely contributes to neuroinflammation and the observed symptoms. The observed contribution of endotoxin may also suggest a dysfunction of intestinal barrier which may compound the systemic immune responses in PANDAS. Arizona Department of Health Services RFGA2022-010-23 (PK) & ADHS17-00007403 (SR, MD); The Alex Manfull Fund (PK). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

PANDAS: Twenty-Five Years Later

Background:: It has been 25 years since the definition of the concept of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). The abrupt onset of neuropsychiatric symptoms requires a comprehensive differential diagnosis involving complementary tests and optimal treatment selection. Methods:: This paper describes aspects related to the diagnosis and clinical management of PANDAS. A clinical perspective is developed starting from an example that meets the Swedo's criteria. Discussion:: A comprehensive approach, including interdisciplinary management and urgent evaluation of potential organic causes, is crucial for effective treatment. Treatment decisions should consider severity, symptoms, and available evidence. Collaboration with neuropediatric or neurological services is needed. ASLO/anti-DNase B and 25-OH-Vitamin D tests are valuable for atypical OCD/Tic presentations, always maintaining a broader organic screening.

Folate Receptor Alpha Autoantibodies in the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Population.

The folate receptor alpha autoantibodies (FRAAs) are associated with cerebral folate deficiency (CFD) and autism spectrum disorder (ASD). Both of these syndromes have overlapping characteristics with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Thus, we propose that the FRAAs may contribute to the symptomatology of PANS/PANDAS. To test this hypothesis, 1 mL of serum from 47 patients (age range = 6-18 years old) clinically diagnosed with PANS/PANDAS was sent to Vascular Strategies (Plymouth Meeting, PA, USA) for analysis of FRAAs. Moreover, 63.8% of PANS/PANDAS patients (male = 15; female = 15) were found to have either the blocking and/or blinding FRAAs, with 25 (83.3%; male = 14; female = 11) having binding FRAAs, two (6.7%; all female = 2) having blocking FRAAs, and 3 (10%; male = 1; female = 2) having both binding and blocking. Furthermore, surprisingly, ASD was associated with a 0.76 lower binding titer (p = 0.02), and severe tics were associated with a 0.90 higher binding titer (p = 0.01). A case of a FRAA-positive patient is provided to illustrate that a treatment plan including leucovorin can result in symptom improvement in patients with PANS/PANDAS who are FRAA-positive. These data, for the first time, demonstrate that PANS/PANDAS is associated with FRAAs and suggest folate metabolism abnormalities may contribute to PANS/PANDAS symptomatology. Further studies investigating the therapeutic nature of leucovorin in the treatment of PANS/PANDAS are needed. Such studies may open up an alternative, safe, and well-tolerated treatment for those with the PANS/PANDAS diagnosis.

Immunological characterization of an Italian PANDAS cohort.

This cross-sectional study aimed to contribute to the definition of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) pathophysiology. An extensive immunological assessment has been conducted to investigate both immune defects, potentially leading to recurrent Group A β-hemolytic Streptococcus (GABHS) infections, and immune dysregulation responsible for a systemic inflammatory state. Twenty-six PANDAS patients with relapsing-remitting course of disease and 11 controls with recurrent pharyngotonsillitis were enrolled. Each subject underwent a detailed phenotypic and immunological assessment including cytokine profile. A possible correlation of immunological parameters with clinical-anamnestic data was analyzed. No inborn errors of immunity were detected in either group, using first level immunological assessments. However, a trend toward higher TNF-alpha and IL-17 levels, and lower C3 levels, was detected in the PANDAS patients compared to the control group. Maternal autoimmune diseases were described in 53.3% of PANDAS patients and neuropsychiatric symptoms other than OCD and tics were detected in 76.9% patients. ASO titer did not differ significantly between the two groups. A possible correlation between enduring inflammation (elevated serum TNF-α and IL-17) and the persistence of neuropsychiatric symptoms in PANDAS patients beyond infectious episodes needs to be addressed. Further studies with larger cohorts would be pivotal to better define the role of TNF-α and IL-17 in PANDAS pathophysiology.

Ocular tics in Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)

Aims/Purpose: Little is known about ocular tics in Paediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal infections (PANDAS). The purpose of this retrospective study was to assess ocular symptoms in 40 children with PANDAS.Methods: The clinical records of children with PANDAS referred to the Ophthalmology Unit, Azienda Ospedaliero‐Universitaria di Sassari, Sassari, Italy, between 2010 and 2019 were examined. The detection of ocular tics was investigated. Data about plasma antistreptolysin O (ASO) and anti‐DNAse b titres, erythrocyte sedimentation rate (ESR), plasma C‐reactive protein (CRP), and antibiotic use were recorded and statistically analysed.Results: 40 children (34 boys, 6 girls; mean age: 7.6 ± 2.5 years) with PANDAS were identified; 33 (82.5%) showed ocular tics, whereas the remaining 7 (17.5%) had extraocular tics. Children with ocular tics had significantly higher plasma values of anti‐DNAse b antibodies (p = 0.04) and CRP (p = 0.016) than those with extraocular tics. A course of oral antibiotics was given to 25 (76%) out of 33 children with ocular tics. All the treated patients showed marked improvement/complete resolution of symptoms; conversely, no improvement was observed in those untreated. A post‐antibiotic recurrence occurred in 8 (32%) children.Conclusions: Results suggest that higher plasma values of anti‐DNAse b antibodies and CRP may play a role in the pathophysiological mechanisms underlying ocular tics in PANDAS. Oral antibiotics may be beneficial in improving ocular symptoms. Further research is necessary to confirm our findings.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Syndrome: A 10-Year Retrospective Cohort Study in an Italian Centre of Pediatric Rheumatology.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) syndrome is a rare pediatric disorder consisting of a sudden onset of obsessive-compulsive disorder (OCD) and/or tics after a group A Streptococcus (GAS) infection. In the period between 2013 and 2023, 61 children presented to our Pediatric Rheumatology unit with a suspicion of PANDAS syndrome. Among these, a retrospective analysis was conducted, and 19 fulfilled the current classification criteria and were included in this study. The male-to-female ratio was 14:5, the median age at onset was 7.0 (2.0-9.5) years, and the median age at diagnosis was 8.0 (3.0-10.4) years. The median follow-up period was 16.0 (6.0-72.0) months. Family and personal history were relevant in 7/19 and 6/19 patients. Tics were present in all patients. Details for motor tics were retrospectively available in 18/19 patients, with the eyes (11/18) and neck/head (10/18) being most often involved. Vocal tics were documented in 8/19, behavioral changes in 10/19, and OCD in 2/19. Regarding the therapeutic response, all patients responded to amoxicillin, 12/13 to benzathine benzylpenicillin, and 7/9 to azithromycin. Our findings partially overlap with previous reports. Larger prospective studies are needed to improve treatment strategies and classification criteria.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): Myth or Reality? The State of the Art on a Controversial Disease.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) syndrome is one of the most controversial diseases in pediatric rheumatology. Despite first being described more than 25 years ago as the sudden and rapid onset of obsessive-compulsive disorder (OCD) and/or tic disorder symptoms as complications of a Group A beta-hemolytic Streptococcus (GAS) infection, precise epidemiological data are still lacking, and there are no strong recommendations for its treatment. Recent advances in the comprehension of PANDAS pathophysiology are largely attributable to animal model studies and the understanding of the roles of Ca++/calmodulin-dependent protein kinase (CaM kinase) II, disrupted dopamine release in the basal ganglia, and striatal cholinergic interneurons. The diagnosis of PANDAS should be made after an exclusion process and should include prepubescent children with a sudden onset of OCD and/or a tic disorder, with a relapsing/remitting disease course, a clear temporal association between GAS infection and onset or exacerbation of symptoms, and the association with other neurological abnormalities such as motoric hyperactivity and choreiform movements. Antibiotic medications are the primary therapeutic modality. Nonetheless, there is a paucity of randomized studies and validated data, resulting in a scarcity of solid recommendations.

Cerebrospinal fluid findings in patients with obsessive–compulsive disorder, Tourette syndrome, and PANDAS: A systematic literature review

BackgroundObsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are related mental disorders that share genetic, neurobiological, and phenomenological features. Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) is a neuropsychiatric autoimmune disorder with symptoms of OCD and/or TS associated with streptococcal infections. Therefore, PANDAS represents a strong link between OCD, TS, and autoimmunity. Notably, cerebrospinal fluid (CSF) analyses can provide insight into the central nervous processes in OCD, TS, and PANDAS. MethodsA systematic literature search according to the PRISMA criteria was conducted to collect all CSF studies in patients with OCD, TS, and PANDAS. The total number of cases and the heterogeneity of the low number of studies were not sufficient for a meta-analysis to provide a high level of evidence. Nevertheless, meta-analytical statistics could be performed for glutamate, 5-hydroxyindoleacetic acid (degradation product of serotonin), homovanillic acid (degradation product of dopamine), 3-methoxy-4-hydroxyphenylglycol (major metabolite of noradrenaline), and corticotropin-releasing hormone (CRH) in OCD. A risk-of-bias assessment was implemented using the Cochrane ROBINS-E tool. ResultsMeta-analytical testing identified elevated glutamate levels in the CSF of OCD patients compared with healthy controls, while no significant differences were found in other neurotransmitters or CRH. Single studies detected novel neuronal antibodies in OCD patients and elevated oligoclonal bands in TS patients. For TS and PANDAS groups, there was a dearth of data. Risk of bias assessment indicated a substantial risk of bias in most of the included studies. ConclusionsThis systematic review of available CSF data shows that too few studies are currently available for conclusions with good evidence. The existing data indicates glutamate alterations in OCD and possible immunological abnormalities in OCD and TS. More CSF studies avoiding sources of bias are needed.

A Bibliometric Analysis of Global Research on Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are a clinical syndrome characterized by the abrupt onset of major personality, movement, and behavioral changes in a patient with a history of streptococcal infection. We aimed to do a bibliometric analysis of the published research on PANDAS. All the published articles available on the PubMed database from the time of inception till August 2022 were included in the study. All the PubMed IDs (PMID) of the articles were entered in Harvard Catalyst, a free online software, for bibliometric analysis, and data were extracted and verified. A total of 289 relevant published articles were identified. The average number of authors per article was 4.89 and the average number of times an article was cited was 11.19 (excluding self-citation). The H-index of the published articles was 31. The Journal of Child and Adolescent Psychopharmacology published the maximum number of articles ( n = 36). The highest number of average citations (39.50 citations/articles) was for the articles published in the American Journal of Psychiatry. The most common type of articles were journal articles ( n = 259) and of which 27 were original research articles. Most of the original research discusses the effectiveness of various interventions (penicillin and other antibiotic prophylaxis, role of immunoglobulin), neuropsychiatric symptoms, and outcomes in the longitudinal course. Though PANDAS is a well-researched entity, more clinical trials, and large-scale studies will help provide better insight on this subject.

Abnormal mTOR Signaling Pathway Activity in Autism Spectrum Disorders: Prospects of Mechanism-Based Therapy

Autism spectrum disorder (ASD) is a developmental disorder characterized by the early onset of problems with communication, learning, and behavior. The syndromic form of ASD is caused by monogenic mutations. When it is not possible to find genetic or other known mechanisms, the term "idiopathic autism" is used. A significant part of both syndromic and idiopathic autism is associated with translational deregulation dependent on the mechanistic target of rapamycin (mTOR). In this review, we present both bioinformatic and experimental data that link the mTOR signaling pathway to maternal autoantibody related autism and childhood autoimmune neuropsychiatric disorders such as Sydenham's chorea and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). The need for ASD subtyping and the prospects of mechanism-based therapy with inhibitors of the mTOR signaling pathway are also discussed.

Infections and obsessive-compulsive disorder - results from a systematic review and meta-analysis

IntroductionObsessive-compulsive disorder (OCD) is a psychiatric disorder affecting 1.3% of the population worldwide where both genetic and environmental factors, such as perinatal events and neuroinflammation, are thought to contribute to the etiology of the disorder. In the past, the description of clinical entities such as Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS), in which an acute neuropsychiatric syndrome with prominent obsessive-compulsive features emerges in children infected with group-A beta-hemolytic streptococcus (GABHS), sparked the hypothesis that infections may be a risk-modifying factor for the development of OCD. Along with streptococcal infections, other pathogens such as Toxoplasma gondii have been implicated in the pathophysiological models of the disorder, although causal associations have not been established for any of beforementioned pathogens.ObjectivesTo perform a systematic review and meta-analysis about the presence of biological evidence of infection in patients diagnosed with OCD.MethodsWe conducted a systematic review and a meta-analysis (PROSPERO registration CRD42021223415) by performing a standardized electronic database search in MEDLINE/PubMed, Web of Science, Embase and Scopus. Search was conducted on 17/10/2022. Eligible papers included case-control and cohort studies using a comparator group, that tested for specific biomarkers providing evidence of infection in patients diagnosed with OCD; exclusion criteria included studies without quantitative or qualitative measures of infection, case reports, systematic or scope reviews, and animal studies. Selection process was conducted according to PRISMA 2020 statement guidelines. Study quality was assessed through Newcastle-Ottawa Quality Assessment Scale.ResultsWe identified 8911 records through the search after duplicate removal. A total of 22 studies met inclusion criteria after selection process, and 15 were eligible for meta-analysis. Most evidence concerned Toxoplasma gondii (10 studies), and patients with OCD appear to have higher odds of being infected compared to controls, with a meta-analytic odds ratio of 2.39 (95% IC 1.60-3.58), when comparing 467 patients with 5411 controls. However, most studies were methodologically heterogeneous, which compromises the interpretation of meta-analytic results. Information regarding other agents, including GABHS, Borna disease virus and Toxocara canis was gathered but due to an insufficient number of papers it was not possible to perform a meta-analysis for each of them.ConclusionsOur work suggests that albeit exhaustively reported in the literature, there is no strong evidence of the over-representation of biomarkers of infection in patients with OCD compared to control volunteers. Methodologically robust studies are needed to further test this hypothesis.Disclosure of InterestNone Declared

Diagnosis and treatment options for pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS): literature review

Marta Šaulytė¹, Julija Rugelytė¹, Alvydas Navickas¹, Kęstutis Kuzmickas¹, Rūta Praninskienė² ¹Vilnius University, Faculty of Medicine, Vilnius, Lithuania ²Vilnius University, Faculty of Medicine, Institute of Clinical Medicine, Clinic of Children’s Diseases, Vilnius, Lithuania Abstract Background. Recently, more and more information has become available on the association of neurological and psychiatric conditions with immune activation and inflammation of brain structures, such as pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). The exact prevalence and etiology of PANDAS are not known, but the development has been linked to a history of streptococcal infection and immune activation. Aim: to present the clinical presentation, diagnostic and therapeutic options for PANDAS based on the available scientific literature. Material and methods. A search of scientific articles was performed in PubMed database for the term ,,PANDAS“, in combination with ,,pathogenesis“, ,,symptoms“, ,,diagnosis“ and ,,treatment“ from 2004 to 2022. Inclusion criteria was represented by articles relevant to these searches. Exclusion criteria was represented by studies written in other languages than English and articles without free access. Results. The diagnostic criteria for PANDAS include (1) the presence of OCD symptoms or tics; (2) onset of symptoms in childhood before puberty; (3) sudden onset or exacerbation with an episodic (relapsing – remitting) course; (4) the association of onset/exacerbation of symptoms with a group A streptococcal infection; and (5) the association with other neuropsychiatric disorders. Significant symptom improvement was observed after specific treatment with antibiotics, intravenous immunoglobulin and plasmapheresis. The beneficial effect of NSAIDs and corticosteroids on the reduction of exacerbations is unquestionable. Conclusions. Diagnosis and treatment of PANDAS are challenging. Further large-scale controlled trials are needed to assess the effectiveness of treatment. Keywords. PANDAS, OCD, tic disorder. Full article https://doi.org/10.53453/ms.2023.2.3

Abnormal mTOR Signaling Pathway Activity in Autism Spectrum Disorders: Prospects of Mechanism-Based Therapy

Autism spectrum disorder (ASD) is a developmental disorder characterized by the early onset of problems with communication, learning, and behavior. The syndromic form of ASD is caused by monogenic mutations. When it is not possible to find genetic or other known mechanisms, the term "idiopathic autism" is used. A significant part of both syndromic and idiopathic autism is associated with translational deregulation dependent on the mechanistic target of rapamycin (mTOR). In this review, we present both bioinformatic and experimental data that link the mTOR signaling pathway to maternal autoantibody related autism and childhood autoimmune neuropsychiatric disorders such as Sydenham's chorea and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). The need for ASD subtyping and the prospects of mechanism-based therapy with inhibitors of the mTOR signaling pathway are also discussed.

Untimely care: How the modern logics of coverage and medicine compromise children's health and development.

How do families manage when health care systems do not "cover" and clinicians do not acknowledge their children's condition? This article presents an ethnographic study in the Northeastern region of the United States with 20 families with children diagnosed with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS)/Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). Two of the 20 families had moved to the U.S. seeking care. The for-profit structure of the U.S. health care system resulted in costly and lengthy therapeutic journeys to access a diagnosis and adequate treatments. In the U.S., PANS/PANDAS coverage depends on legislation, advocacy, clinical characteristics of each child, and how for-profit insurance companies react to an increased demand for a given service. Many medical professionals, both in the U.S. and in other countries, refuse to acknowledge the condition or offer effective treatments that lack "acceptable" evidence. We argue that the financial logic behind coverage exists across modern health care systems and imposes restrictions and exclusions that impede access to care. Thus, untimely care, the time gap from PANS/PANDAS symptoms to diagnosis and treatment is the result of the modern logics that structure medicine and coverage. The results of this study illustrate how modern medicine and coverage fail to protect families with children with PANS/PANDAS against catastrophic expenses and often block care that would prevent developmental disruptions and losses, avoid much suffering, and even save costs to health care systems. New and controversial conditions like PANS/PANDAS highlight the importance of separating the financial logics behind proposals such as "universal health coverage" from the provision of comprehensive forms of care that acknowledge uncertainty and prioritize action and flexibility.

Group Psychotherapy for Parents of Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome.

Parents of children with diagnoses of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS) may experience significant psychological distress related to their child's severe and relapsing illness and challenges with the traumatic nature of its treatment. No manualized or studied psychological interventions specifically for parents of youth with PANS have existed prior to this study. In this pilot study, we assessed the feasibility, satisfaction, and treatment fidelity of a brief 9-session group therapy intervention for parents based on principles of trauma-focused cognitive behavior therapy (CBT). We hypothesized that, if initially elevated, symptoms of depression, anxiety, and trauma would decrease and participants' utilization of positive coping mechanisms would increase post-intervention. We adapted an existing evidence-based group intervention developed for parents of children with premature infants to target sources of stress and coping in parents of children with PANS. Ten parents participated in the study. The 9-session intervention used a combination of techniques that included cognitive restructuring, coping skills, self-care, and a trauma narrative to address psychological stress, trust, grief, and unwanted emotions. Outcome measures included parental symptoms of anxiety, depression, and posttraumatic stress disorder (PTSD), as well as rating of parental satisfaction with the intervention. The treatment was feasible and deliverable with high fidelity. The intervention was rated as useful and satisfactory by parents (overall average usefulness of 4.54 and satisfaction of 4.71 out of 5.0). Elevated symptoms of PTSD and depression decreased with large effect sizes (Cohen's d = 1.42 and Cohen's d = 1.38, respectively). Participating parents demonstrated significantly more active coping and acceptance behaviors and stances. A brief 9-session group therapy intervention based on principles of trauma-focused CBT was found to be effective in reducing symptoms of psychological distress in parents of children with PANS.

A Survey of Demographics, Symptom Course, Family History, and Barriers to Treatment in Children with Pediatric Acute-Onset Neuropsychiatric Disorders and Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections.

Objective: Few large-scale studies of pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) have been conducted, and thus demographic data on these conditions are limited. The current study describes comorbid medical and psychiatric conditions in a self-referred cohort of children with PANS/PANDAS, along with treatment history, barriers to treatment, family medical and psychiatric history, and perceived caregiver burden in these conditions. Methods: A total of 441 primary caregivers of patients with infection-triggered PANS/PANDAS under the age of 18 were included in this online anonymous survey, reporting on a total of 490 children (due to some caregivers reporting multiple children in the family with PANS/PANDAS). Data were collected between July 2018 and May 2019. Primary caregivers completed questions pertaining to patient demographics, symptom presentation, disease course, family medical and psychiatric history, and severity of patients' obsessive-compulsive disorder (OCD) symptoms. Results: OCD was the most common psychiatric symptom reported in children at the onset of PANS/PANDAS (83.06%), along with a high percentage of medical and psychiatric comorbidities. Most psychiatric comorbidities began or worsened at the onset of PANS/PANDAS symptoms, while major depressive disorder was the most frequently reported psychiatric disorder to develop after PANS/PANDAS onset (10%). A high frequency of autoimmune and inflammatory conditions was reported in family members, with nearly 30% of mothers endorsing one or more autoimmune conditions (29.95%). Mean caregiver burden (Caregiver Burden Inventory; M = 44.0) fell above the "burnout" level, and standardized measures showed mildly elevated levels of depression, anxiety, and stress in caregivers (Depression, Anxiety, and Stress Scale-21; M = 11.85, 7.16, and 15.56, respectively). Conclusions: Primary caregivers of children with PANS/PANDAS reported a multitude of medical and psychiatric comorbidities in their children, along with a high frequency of autoimmune and psychiatric conditions in family members. Obsessive-compulsive symptoms were the most frequently reported psychiatric symptom. Caregivers of these patients experience elevated levels of burden, stress, anxiety, and depression. Further research is needed to better understand the varied disease course in PANS/PANDAS and to develop interventions to reduce caregiver burden in these disorders.

Sarcoidosis and obsessive-compulsive symptoms

IntroductionAutoimmune obsessive-compulsive disorder (OCD) in the context of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) has been observed for decades. The first cases of autoimmune OCD in adulthood were recently described. An association between obsessive-compulsive symptoms (OCS) and systemic autoimmune diseases in the form of connective tissue disease has also been reported. However, whether an association exists between OCD and sarcoidosis is unknown. Case studyHere, the authors present an end 20-year-old female patient with symptoms of OCD in whom an advanced diagnostic work-up revealed inflammatory cerebrospinal fluid (CSF) changes (elevated IgG index, CSF-specific oligoclonal bands, intrathecal IgG synthesis, and a positive MRZ reaction). In tissue-based assays using unfixed mouse brain sections, both serum and CSF showed a distinct antinuclear antibody pattern with perinuclear staining. Electroencephalography identified frontocentral theta spindles. Upon endobronchial-guided lymph node biopsy demonstrating non-caseating lymph nodes in further work-up, sarcoidosis was diagnosed. Levels of the sarcoidosis parameters IL-2-R and neopterin were increased. Under immunotherapy for sarcoidosis, the OCS seemed to improve. DiscussionThis case study is paradigmatic, as an association between sarcoidosis and OCD has not been previously reported. After exclusion of alternative causes, the inflammatory CSF changes would be compatible with an inflammatory brain involvement of sarcoidosis. Autoimmune OCD may occur more frequently than is thought, probably also in the context of neurosarcoidosis. This could open up new opportunities through immunotherapies in rare cases with OCD.

S3353 Improvement in Paediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections (PANDAS) Syndrome Following Treatment With a Combination of Antibiotics and Fecal Microbiome Transplantation (FMT)

Introduction: Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) syndrome is a condition that impairs normal neurological brain function and is triggered by a streptococcal infection. It is characterised by an obsessive-compulsive disorder (OCD) tic disorder, or both and usually occurs suddenly between the age of 3-12 years. Other symptoms include mood changes, anxiety, attention deficit/hyperactivity disorder, trouble sleeping, and joint pain. Metagenomic profiles of those with PANDAS syndrome show an altered gut bacterial community. Commonly treatment involves antibiotics for streptococcal infection. Here, we report on the effects of fecal microbiota transplantation (FMT) on a set of identical twins with concomitant PANDAS syndrome. Case Description/Methods: Case 1: A male (16yrs) presented with slow transit type constipation with a colonic transit half clearance time of 70minutes. His medical history also showed he had PANDAS syndrome and later tested positive for Clostridium Difficile (C. difficile). The patient was treated with metronidazole before receiving a single dose of FMT which was transfused colonoscopically. At 1-month the patient tested negative for C. difficile. Post treatment he reported significant improvement in abdominal pain, bloating and constipation that lasted 2 years. Simultaneously he reported symptom improvement in anxiety, depression, and Rheumatoid Arthritis which are associated with PANDAS syndrome. Case 2: A male (16yrs) presented with severe constipation with a normal colonic transit half clearance time of 50minutes. Constipation prompted a worsening of symptoms of concomitant PANDAS syndrome which had previously been treated with steroids. After further testing he was found to have C. difficile for which he was prescribed metronidazole and vancomycin before receiving a single dose of FMT by colonoscopic infusion. At 1-month post treatment eradication of C. difficile was confirmed. Post treatment he reported experiencing improvement in constipation, diarrhoea, flatulence, and vomiting which lasted for 2 years. He also reported symptom improvement in Autism, OCD, and Rheumatoid Arthritis which are linked to PANDAS syndrome. Discussion: To the best of our knowledge these are the first cases of improvement in PANDAS symptoms after FMT treatment. Further study is required into the effects of FMT on PANDAS syndrome before FMT can be confirmed as a potential treatment.

Interdisciplinary Collaboration to Care for Students Diagnosed with PANDAS: An Education and Referral Intervention.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is an autoimmune disorder associated with sudden onset of behavior changes. The prevalence of PANDAS is increasing in schools and interdisciplinary collaboration, knowledge, and the use of referrals to the school nurse are important for supporting students. This project sought to provide education on PANDAS to the interdisciplinary school team and implement a referral process for students exhibiting behavior changes. A self-directed online educational intervention was employed. A pretest-posttest design was utilized to assess knowledge before, immediately after, and six-weeks after the educational intervention. A referral log was implemented to track the number of referrals to the school nurse. The final sample size included 19 participants. Mean scores increased from pretest to posttest, and the implementation of a referral system produced 12 new school nurse referrals. Further strategies are needed to enhance interdisciplinary collaboration and support students experiencing health-related issues.