Background Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by the abrupt onset of obsessive–compulsive symptoms and/or restrictive eating accompanied by disturbances in sleep, affect regulation, behavior, motor function, and sensory processing. Increasing evidence implicates systemic immune activation and circulating autoantibodies in basal ganglia dysfunction. Blood–brain barrier (BBB) impairment has been proposed as a mechanism by which peripheral inflammatory mediators access the central nervous system; however, the molecular pathways linking systemic inflammation to BBB disruption in PANS remain incompletely defined. Methods To determine whether circulating factors contribute to BBB dysfunction, human brain endothelial cell (BEC) monolayers were exposed to plasma from PANS patients during symptomatic flare and recovery, as well as from matched healthy controls. Barrier integrity was assessed by paracellular permeability assays; transcriptomic changes were analyzed using bulk RNA sequencing. Junctional organization and cytoskeletal architecture were examined by immunofluorescence microscopy. Circulating and endothelial-derived mediators associated with barrier disruption were quantified using multiplex bead–based immunoassays and enzyme-linked immunosorbent assays. Results Plasma from PANS flare (n = 15 samples) significantly increased BEC monolayer permeability compared to plasma from matched controls (~ 50% change in permeability; p < 0.001), corresponding with increased concentration of S100B, an in vivo biomarker of BBB permeability (~ 2 fold increase vs controls; p < 0.01). Transcriptomic profiling of flare samples demonstrated downregulation of genes essential for endothelial stability, including those encoding tight junction, adherens junction, and extracellular matrix components. Immunofluorescence of flare samples confirmed disruption of zonula occludens-1 (ZO-1) and vascular endothelial cadherin (VE-Cadherin), accompanied by increased actin stress fiber formation, consistent with enhanced cytoskeletal tension and junctional disassembly. Matrix metalloproteinase-9 (MMP-9) concentration was elevated in flare plasma vs controls (> 2.5 fold increase; p < 0.001) and was highly correlated with BEC monolayer permeability (r = 0.84; p < 0.001). Inhibition of MMP-9 in flare samples (n = 6) resulted in significant decrease in BEC monolayer permeability ( p < 0.01), approaching that of matched controls. Conclusions Circulating factors present during PANS flares induce brain endothelial dysfunction in vitro , correlating with in vivo biomarker findings. Elevated MMP-9 functions as a key downstream effector linking systemic inflammation to endothelial barrier disruption, providing mechanistic insight into how peripheral immune activation may facilitate neuroinflammation in PANS.

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by sudden onset obsessive-compulsive disorder (OCD) symptoms in conjunction with other neuropsychiatric manifestations including disturbances in sleep, cognition, and behavior. Studies have revealed high rates of autoimmune and inflammatory markers—as well as comorbid rheumatologic disease—in patients with PANS. While published studies have suggested autoantibodies are common in PANS patients, the molecular targets of these autoantibodies (AAbs) remain poorly characterized. Here, we profile the AAbs in 224 plasma samples taken from 166 PANS patients during periods of active disease, or flares, compared to 83 pediatric healthy controls using custom Luminex microbead panels conjugated with highly curated antigens from common autoimmune diseases as well as cytokines and chemokines. We find that PANS patients exhibit increased prevalence of AAbs against autoantigens known to be targeted in scleroderma and GI/endocrine autoimmune conditions. Furthermore, a subset of PANS patients exhibited AAbs against IFN-λ, an important line of defense against infections at anatomic barriers. Among the 11 tested PANS plasma samples with IFN-λ-binding AAbs, 9 showed detectable inhibition of IFN-λ signaling, and 4 met our predefined stringent threshold for IFN-λ-neutralizing activity, while no tested HC samples met this neutralization threshold. These findings support a link between autoimmunity and PANS, and may provide insight into a potential disease mechanism mediated by immune deficits at barrier surfaces in a subset of patients.

Background: Multiple lines of evidence suggest that some cases of OCD are underlain by autoimmune and/or inflammatory processes that act on the brain to create neuropsychiatric symptomatology. However, studies of immunomodulatory treatments for such cases are sparse. Here we present consecutive cases of presumed-neuroimmune OCD in youth that have been treated with rituximab +/- adjunctive immunomodulatory treatments. Methods: Of the 458 cases evaluated by our clinic between September 15, 2012 and January 6, 2023, 23 patients were treated with rituximab +/- adjunctive immunomodulation orchestrated by our team (based on evidence of autoimmunity) and were followed routinely by the outpatient clinic team. Patients who presented for a second opinion and were not diagnosed, treated, and/or followed by our outpatient clinic (n=5) or did not have OCD (n=1) are not included. We present the immunological and psychiatric profiles (prior to treatment), selection criteria for use of rituximab, rituximab treatment protocol, recovery status, and reasons for discontinuation (if applicable). Data was obtained from chart review of clinical records. Determination of recovery status was confirmed by the clinical team caring for the patients; patients were classified as: did not recover, partial recovery (PR), or full recovery (FR). Since multiple treatments (psychotherapy, psychiatric medication, and immunomodulation) together contributed to recovery, the team additionally assessed attribution of response to rituximab and details are documented. Results: Patients were between ages of 4 and 20 at initiation of rituximab treatment. All suffered from severe, debilitating neuropsychiatric symptoms prior to rituximab initiation in the context of evidence for systemic autoimmunity. Approximately 70% had an unequivocal recovery following treatment with rituximab (+/- induction and adjunctive immunomodulation) which in most cases allowed the patients to achieve normal levels of function and cease psychotropic medications. Interpretation of attribution in many cases is complicated by the use of induction and adjunct immunomodulation. Most patients experienced transient increases in symptoms before improving; 11 experienced mild self-limited infusion-related reactions, and 14 experienced hypogammaglobulinemia. No patient had an organ or life-threatening reaction or infection following rituximab. One patient developed recurrent sinusitis following rituximab and thus rituximab was stopped despite neuropsychiatric improvements, then rituximab was restarted later due to recrudescence of psychiatric symptoms; the approval to use rituximab with IVIG permitted its use. Patients who received adjunctive immunomodulation (IVIG, methotrexate, leflunomide, etc.) had a higher likelihood of achieving recovery (FR or PR) after rituximab (Fisher’s Exact Test, one-sided, p<0.0001). Discussion and Conclusions: For a small fraction of our patients, systemic autoimmunity and severe, debilitating psychiatric symptoms (including but not limited to OCD) led to a trial of rituximab. A randomized placebo-controlled trial will be necessary to objectively determine efficacy with regards to OCD/complex neuropsychiatric disease in the setting of systemic autoimmunity. Patients may have better responses to rituximab when given with adjunctive immunomodulation (IVIG, methotrexate, etc.). Reasons for the benefit of adjunctive immunomodulation is likely multifactorial: controlling infections, addressing inflammation driven by immune pathways beyond T& B cells (i.e. proinflammatory monocytes which have been linked to OCD), and preventing anti-rituximab antibodies.

INTRODUCTION:Establishing clear and standardized terminology regarding disease state and course is crucial for enhancing communication, research, and treatment decisions, particularly when there are no clearly identified biological markers, as in the case of pediatric acute-onset neuropsychiatric syndrome (PANS). We aim to propose terminology for assessing disease state and classifying long-term clinical courses in individuals evaluated for PANS, advancing standardization in clinical care and research. METHODS:We drew upon clinical expertise, insights from similar conditions, and a decade of longitudinal clinical data from the Stanford University Immune Behavioral Health (IBH) Clinic to devise terminology for characterizing patient status and clinical progression among patients evaluated for PANS. Utilizing parent- and clinician-reported data spanning from 2012 to 2023, we constructed a comprehensive dataset documenting patients' disease trajectory from initial flare to latest clinical encounter, encompassing intervening recovery periods. This allowed us to apply the proposed terminology to the IBH Clinic patient cohort, offering a detailed phenotypic analysis of PANS flares and clinical courses. RESULTS:We analyzed 264 patients evaluated for PANS at the IBH Clinic and stratified them based on whether they met PANS criteria at initial flare (51%), after initial flare (24%), or had not met criteria at the time of analysis (25%). The average age at the initial flare ranged from 6.1 to 8.3 years across these patient subgroups. Among patients with PANS, the average isolated flare lasted 3.7-4.1 months and 95% of flares resolved within 1 year. Five years after initial flare, most (77%) patients with PANS had had multiple flares, and nearly half (43%) had experienced a flare that lasted >12 months, approximately half of which occurred at the initial flare. CONCLUSIONS:Patients evaluated for PANS at the IBH Clinic showed diverse clinical presentations and illness courses over the long term, with most experiencing a relapsing-remitting clinical course but some exhibiting persistent symptoms. Many experienced neuropsychiatric flares before meeting PANS classification criteria. This underscores the importance of clinicians being vigilant for new neuropsychiatric symptoms in pediatric patients, even if they do not immediately meet PANS criteria. Based on these data, we propose terms and definitions for characterizing patient status, flares, and clinical course, which we hope the clinical and research communities will build on and refine.

OBJECTIVE:Abrupt onset restrictive food intake can be a cardinal symptom of pediatric acute-onset neuropsychiatric syndrome (PANS). However, few reports detail eating restriction patterns and baseline eating behaviors in patients with PANS, which we aim to address. Additionally, we aim to compare PANS eating restriction with ARFID. METHODS:Retrospective chart review of 130 patients with PANS, aged 4-18 years, presenting for initial assessment at Stanford's PANS/Immune Behavioral Health (IBH) Clinic. Data were abstracted from electronic medical records (EMR) and parent/child questionnaires which included symptom ratings and psychometric scores. Baseline eating restriction and abrupt onset changes in eating associated with PANS flares were studied. RESULTS:Over half (56%) of the PANS patients developed abrupt-onset restricted food intake during flare prompting clinic entry. Of youth with restricted intake, 48% had selective eating, 41% had low appetite/interest in food, 37% feared aversive consequences (26% swallowing/choking/vomiting concerns, 16% feared contamination), and 4% overweight concerns. Youth with restricted intake had high levels of emotional lability and/or depression (96%), irritability, aggression, or oppositional behaviors (89%), behavioral/developmental regression (60%), cognitive impairment (69%), and sensory amplification (64%). Baseline eating restriction was noted in 16 (12%), with 9 altering eating behaviors during flare. CONCLUSIONS:Eating restriction is common during PANS flares, reasons align with 3 main presentations of ARFID: Selective eating, low appetite/interest, and fear of aversive consequences. High levels of other neuropsychiatric symptoms are noted in youth with PANS and eating restriction during flares. Twelve percent of PANS patients have baseline eating restriction; over half of whom alter eating behaviors during the flare.

Introduction: Pediatric acute-onset neuropsychiatric syndrome (PANS) is an immune-mediated disease characterized by abrupt onset neurobehavioral changes. Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn's disease (CD), chronic conditions characterized by gastrointestinal inflammation. We describe eight individuals with both PANS and IBD. Methods: All individuals with both IBD and PANS were identified from Stanford Immune Behavioral Health Clinic, Cedars-Sinai Medical Center Pediatric Inflammatory Bowel Disease Program, and Dartmouth Neuroimmune Psychiatric Disorders (NIPD) Clinic. Data were collected by chart review. Results: Eight cases of PANS with IBD were identified. Five were male. The mean age of onset was 9.3 years for PANS and 15.6 years for IBD. PANS preceded development of IBD in 7 of 8 cases by a mean of 8.4 years. Seven patients (88%) had a first-degree relative with an immune-mediated disease, including 5 with psoriasis or psoriatic arthritis. Five patients themselves had arthralgias or arthritis (63%). All 5 cases where PANS preceded IBD treatment sufficiently for analysis were free of major behavioral relapses after IBD was managed. Conclusion: The triad of PANS, joint complaints, and family history of autoimmunity, including psoriasis, may represent a subset of PANS at heightened risk for IBD and additional immune-mediated disorders. For children with this triad, clinicians should have a low threshold to evaluate for gastrointestinal inflammation with biomarkers like hemoglobin, CRP, fecal calprotectin, and diagnostic endoscopy when indicated. PANS symptoms may improve with effective treatment of IBD. The high prevalence of joint complaints in our cohort and psoriasis in first-degree family members suggests this subset of PANS may share immune mechanisms with psoriasis and arthritis. Treatment strategies used in IBD and arthritis should be studied for potential application in PANS.

Studies of brain imaging and movements during rapid eye movement sleep indicate basal ganglia involvement in pediatric acute-onset neuropsychiatric syndrome (PANS). Characterizing neurological findings that commonly present among patients with PANS could improve diagnostic accuracy. To evaluate the prevalence of neurological soft signs (NSSs) that may be associated with basal ganglia dysfunction among youths presenting with PANS and assess whether clinical characteristics of PANS correlate with NSSs that may be associated with basal ganglia dysfunction. This cohort study included 135 new patients who met strict PANS criteria and were evaluated at the Stanford Children's Immune Behavioral Health Clinic between November 1, 2014, and March 1, 2020. Data on these patients were retrospectively reviewed between December 13, 2020, and September 25, 2023. Sixteen patients were excluded because they had no neurological examination within the first 3 visits and within 3 months of clinical presentation. Statistical analysis was conducted between September 26, 2023, and November 22, 2024. The following NSSs that may be associated with basal ganglia dysfunction were recorded from medical record review: (1) glabellar tap reflex, (2) tongue movements, (3) milkmaid's grip, (4) choreiform movements, (5) spooning, and (6) overflow movements. Data from prospectively collected symptoms and impairment scales (Global Impairment Score [GIS; score range, 1-100, with higher scores indicating greater impairment] and Caregiver Burden Inventory [score range, 0-96, with higher scores indicating greater caregiver burden]) were included. The study included 119 patients; the mean (SD) age at PANS onset was 8.2 (3.6) years, the mean (SD) age at initial presentation was 10.4 (3.6) years, and 66 (55.5%) were boys. At least 1 NSS that may be associated with basal ganglia dysfunction was observed in 95 patients (79.8%); the mean (SD) number of NSSs was 2.1 (1.6). Patients with 4 or more NSSs had higher GISs (mean [SD] score, 56.0 [22.6] vs 40.6 [26.7]; P = .05) and more symptoms (mean [SD] number, 15.1 [4.9] vs 11.5 [4.2]; P = .008) than patients with 0 NSSs. There was no significant difference in age at visit or in Caregiver Burden Inventory score. On Poisson and linear regression, the number of NSSs was associated with global impairment, with 1 more sign increasing the GIS by 2.86 (95% CI, 0.09-5.62; P = .04), and with the number of symptoms, with 1 more sign increasing the number of symptoms by 5% (1.05; 95% CI, 1.02-1.08; P = .002), but not with age or duration of PANS at presentation. This cohort study of patients with PANS found a high prevalence of NSSs that may be associated with basal ganglia dysfunction and an association between these NSSs and disease severity that was not associated with younger age. PANS may have a unique profile, suggesting that targeted neurological examinations may support PANS diagnosis.

Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by the sudden onset of obsessive-compulsive symptoms alongside a constellation of neuropsychiatric and somatic features. Disease progression typically includes flare and recovery states, with some patients exhibiting a persistent disease course (> 12 months of flare). We characterized circulating monocyte subsets during flare and recovery in pediatric patients with PANS, uncovering disease-state–dependent shifts in polarization and trafficking phenotypes. Inflammatory M1-like monocytes and monocyte-derived dendritic cells were elevated during flare, while anti-inflammatory M2-like monocytes were enriched in recovery. We also identified a circulating subset with a surface phenotype consistent with central nervous system (CNS) homing, which was reduced during flare and restored in recovery. These cells were detectable in the cerebrospinal fluid (CSF) of new-onset patients but not in persistent cases, suggesting differential compartmentalization during disease progression. Notably, monocyte phenotypes, including M2 polarization (monocytosis) and circulating CNS-homing profiles, exhibited striking sex-associated differences, particularly during recovery, with several subsets enriched in males but not females. Plasma from flare-phase patients modestly induced CNS-homing markers in monocytes from healthy donors, indicating the presence of circulating modulators. Together, these findings support a model in which distinct myeloid phenotypes—including sex-biased patterns—may contribute to both the pathogenesis and resolution of neuroinflammation in PANS.

Importance: Studies of brain imaging and movements during REM sleep indicate basal ganglia involvement in pediatric acute-onset neuropsychiatric syndrome (PANS). Characterizing neurological findings commonly present in patients with PANS could improve diagnostic accuracy. Objective: To determine the prevalence of neurological soft signs which may reflect basal ganglia dysfunction (NSS-BG) in youth presenting with PANS and whether clinical characteristics of PANS correlate with NSS-BG. Design, Setting, and Participants: 135 new patients who were evaluated at the Stanford Children's Immune Behavioral Health Clinic between November 1, 2014 and March 1, 2020 and met strict PANS criteria were retrospectively reviewed for study inclusion. 16 patients were excluded because they had no neurological exam within the first three visits and within three months of clinical presentation. Main Outcomes and Measures: The following NSS-BG were recorded from medical record review: 1) glabellar tap reflex, 2) tongue movements, 3) milkmaid's grip, 4) choreiform movements, 5) spooning, and 6) overflow movements. We included data from prospectively collected symptoms and impairment scales. Results: The study included 119 patients: mean age at PANS onset was 8.2 years, mean age at initial presentation was 10.4 years, 55.5% were male, and 73.9% were non-Hispanic White. At least one NSS-BG was observed in 95/119 patients (79.8%). Patients had 2.1 NSS-BG on average. Patients with 4 or more NSS-BG had higher scores of global impairment (p=0.052) and more symptoms (p=0.008) than patients with 0 NSS-BG. There was no significant difference in age at visit or reported caregiver burden. On Poisson and linear regression, the number of NSS-BG was associated with global impairment (2.857, 95% CI: 0.092-5.622, p=0.045) and the number of symptoms (1.049, 95% CI: 1.018-1.082, p=0.002), but not age or duration of PANS at presentation. Conclusions and Relevance: We found a high prevalence of NSS-BG in patients with PANS and an association between NSS-BG and disease severity that is not attributable to younger age. PANS may have a unique NSS-BG profile, suggesting that targeted neurological exams may support PANS diagnosis.

ObjectivesThis study characterizes cerebral spinal fluid (CSF) indices including total protein, the albumin quotient, IgG index and oligoclonal bands in patients followed at a single center for pediatric acute-neuropsychiatric syndrome (PANS) and other psychiatric/behavioral deteriorations.MethodsIn a retrospective chart review of 471 consecutive subjects evaluated for PANS at a single center, navigational keyword search of the electronic medical record was used to identify patients who underwent lumbar puncture (LP) as part of the evaluation of a severe or atypical psychiatric deterioration. Psychiatric symptom data was ascertained from parent questionnaires and clinical psychiatric evaluations. Inclusion criteria required that subjects presented with psychiatric deterioration at the time of first clinical visit and had a lumbar puncture completed as part of their evaluation. Subjects were categorized into three subgroups based on diagnosis: PANS (acute-onset of severe obsessive compulsive disorder (OCD) and/or eating restriction plus two other neuropsychiatric symptoms), autoimmune encephalitis (AE), and “other neuropsychiatric deterioration” (subacute onset of severe OCD, eating restriction, behavioral regression, psychosis, etc; not meeting criteria for PANS or AE).Results71/471 (15.0 %) of patients underwent LP. At least one CSF abnormality was seen in 29% of patients with PANS, 45% of patients with “other neuropsychiatric deterioration”, and 40% of patients who met criteria for autoimmune encephalitis. The most common findings included elevated CSF protein and/or albumin quotient. Elevated IgG index and IgG oligoclonal bands were rare in all three groups.ConclusionElevation of CSF protein and albumin quotient were found in pediatric patients undergoing LP for evaluation of severe psychiatric deteriorations (PANS, AE, and other neuropsychiatric deteriorations). Further studies are warranted to investigate blood brain barrier integrity at the onset of the neuropsychiatric deterioration and explore inflammatory mechanisms.

ImportanceEpidemiologic studies indicate a high rate of autoimmune conditions among patients with obsessive-complusive disorder and other psychiatric conditions. Furthering the understanding of the inflammatory diatheses of psychiatric conditions may open doors to new treatment paradigms for psychiatric disorders.ObjectivesTo evaluate whether pediatric acute-onset neuropsychiatric syndrome (PANS) is associated with an inflammatory diathesis by assessing signs of immune activation and vasculopathy during a psychiatric symptom exacerbation (flare), estimating the risk of developing arthritis and other autoimmune diseases, and characterizing subtypes of arthritis.Design, Setting, and ParticipantsThis retrospective cohort study used longitudinal clinical data on 193 consecutive patients with PANS followed up within the Stanford Immune Behavioral Health Clinic from September 1, 2012, to December 31, 2021.Main Outcomes and MeasuresMedical records were reviewed, and a predefined set of immune markers that were measured during a flare and the features and imaging findings of arthritis and other autoimmune diseases were collected. Immune activation markers included (1) autoimmunity signs (antinuclear antibody, antihistone antibody, antithyroglobulin antibody, C1q binding assay, and complement levels [C3 and C4]); (2) immune dysregulation or inflammation signs (leukopenia, thrombocytosis, C-reactive protein, and erythrocyte sedimentation rate); and (3) vasculopathy signs (livedo reticularis, periungual redness and swelling, abnormally prominent onychodermal band, palatal petechiae, high von Willebrand factor antigen, and high d-dimer). Last, the cumulative risk of developing arthritis and autoimmune diseases was estimated using product limit (Kaplan-Meier) survival probability.ResultsThe study included data from 193 children (112 boys [58.0%]) who had PANS at a mean (SD) age of 7.5 (3.5) years. They were followed up for a mean (SD) of 4.0 (2.1) years. Among those tested for immune activation markers, 54.2% (97 of 179) had nonspecific markers of autoimmunity, 12.0% (22 of 184) had nonspecific signs of immune dysregulation or inflammation, and 35.8% (69 of 193) had signs of vasculopathy. By 14 years of age, the estimated cumulative incidence of arthritis was 28.3% (95% CI, 20.8%-36.3%), and the estimated cumulative incidence of another autoimmune disease was 7.5% (95% CI, 4.0%-12.4%). Novel findings in the subgroup with arthritis include joint capsule thickening (55.0% [22 of 40]), distal interphalangeal joint tenderness (81.8% [45 of 55]), and spinous process tenderness (80.0% [44 of 55]). Among the 55 patients with arthritis, the most common subtypes of arthritis included enthesitis-related arthritis (37 [67.3%]), spondyloarthritis (27 [49.1%]), and psoriatic arthritis (10 [18.2%]).Conclusions and RelevanceThis study found that patients with PANS show signs of immune activation and vasculopathy during psychiatric symptom flares and have an increased risk of developing arthritis and other autoimmune diseases compared with the general pediatric population. The most common arthritis subtype was enthesitis-related arthritis. These findings suggest that PANS may be part of a multisystem inflammatory condition rather than an isolated psychiatric or neuroinflammatory disorder.

Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by sudden onset of obsessive-compulsive disorder and/or eating restriction with associated neuropsychiatric symptoms from at least two of seven categories. The PANS 31-Item Symptom Rating Scale (PANS Rating Scale) was developed to identify and measure the severity of PANS symptoms. The objective of this study was to define the psychometric properties of the PANS Rating Scale.Methods: Children with PANS (N = 135) and their parents participated. Parents completed the PANS Rating Scale and other scales on Research Electronic Data Capture. The PANS Rating Scale includes 31 items that are rated on a Likert scale from 0 = none to 4 = extreme. Pearson's correlations were run between the PANS Total score and scores on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), Yale Global Tic Severity Scale (YGTSS), Modified Overt Aggression Scale (MOAS), Columbia Impairment Scale (CIS), PANS Global Impairment Score (GIS), and Children's Global Assessment Scale (CGAS).Results: Convergent validity was supported by significant correlations between the PANS Total and scores on the CY-BOCS, YGTSS, MOAS, CIS, GIS, and CGAS. The largest correlations were with measures of functional impairment: PANS Total and CIS (r = 0.81) and PANS Total and GIS (r = 0.74). Cronbach's alpha was 0.89 which demonstrates strong internal consistency of the 31 items. PANS Total score was significantly higher in children in a flare of their neuropsychiatric symptoms compared to children who were not in a flare.Conclusions: This study provides preliminary support for the PANS Rating Scale as a valid research instrument with good internal consistency. The PANS Rating Scale appears to be a useful measure for assessing children with PANS.

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by the abrupt onset of significant obsessive-compulsive symptoms (OCS) and/or severe food restriction, together with other neuropsychiatric manifestations. An autoimmune pathogenesis triggered by infection has been proposed for at least a subset of PANS. The older diagnosis of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS) describes rapid onset of OCD and/or tics associated with infection with Group A Streptococcus. The pathophysiology of PANS and PANDAS remains incompletely understood. We recently found serum antibodies from children with rigorously defined PANDAS to selectively bind to cholinergic interneurons (CINs) in the striatum. Here we examine this binding in children with relapsing and remitting PANS, a more heterogeneous condition, collected in a distinct clinical context from those examined in our previous work, from children with a clinical history of Streptococcus infection. IgG from PANS cases showed elevated binding to striatal CINs in both mouse and human brain. Patient plasma collected during symptom flare decreased a molecular marker of CIN activity, phospho-riboprotein S6, in ex vivo brain slices; control plasma did not. Neither elevated antibody binding to CINs nor diminished CIN activity was seen with plasma collected from the same children during remission. These findings replicate what we have seen previously in PANDAS and support the hypothesis that at least a subset of PANS cases have a neuroimmune pathogenesis. Given the critical role of CINs in modulating basal ganglia function, these findings confirm striatal CINs as a locus of interest in the pathophysiology of both PANS and PANDAS.

Pediatric acute-onset neuropsychiatric syndrome (PANS), pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections, Sydenham chorea, and other postinfectious psychiatric deteriorations are thought to be caused by inflammatory/autoimmune mechanisms, likely involving the basal ganglia based on imaging studies. Patients have a relapsing-remitting course and some develop severe refractory psychiatric disease. We found that 55/193 (28%) of consecutive patients meeting PANS criteria developed chronic arthritis and 25/121 (21%) of those with related psychiatric deteriorations developed chronic arthritis. Here we describe 7 of these patients in detail and one sibling. Many of our patients often have "dry" arthritis (no effusions found on physical exam) but subtle effusions detected by imaging and features of spondyloarthritis, enthesitis, and synovitis. Joint capsule thickening, not previously reported in children, is a common finding in the presented cases and in psoriatic arthritis in adults. Due to the severity of psychiatric symptoms in some cases, which often overshadow joint symptoms, and concomitant sensory dysregulation (making the physical exam unreliable in the absence of effusions), we rely on imaging to improve sensitivity and specificity of the arthritis classification. We also report the immunomodulatory treatments of these 7 patients (initially nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs with escalation to biologic medications) and note any coincidental changes to their arthritis and psychiatric symptoms while on immunomodulation. Patients with overlapping psychiatric syndromes and arthritis may have a unifying cause and pose unique challenges; a multi-disciplinary team can utilize imaging to tailor and coordinate treatment for this patient population.

Pediatric acute-onset neuropsychiatric syndrome (PANS) is an abrupt-onset neuropsychiatric disorder. PANS patients have an increased prevalence of comorbid autoimmune illness, most commonly arthritis. In addition, an estimated one-third of PANS patients present with low serum C4 protein, suggesting decreased production or increased consumption of C4 protein. To test the possibility that copy number (CN) variation contributes to risk of PANS illness, we compared mean total C4A and total C4B CN in ethnically matched subjects from PANS DNA samples and controls (192 cases and 182 controls). Longitudinal data from the Stanford PANS cohort (n = 121) were used to assess whether the time to juvenile idiopathic arthritis (JIA) or autoimmune disease (AI) onset was a function of total C4A or C4B CN. Lastly, we performed several hypothesis-generating analyses to explore the correlation between individual C4 gene variants, sex, specific genotypes, and age of PANS onset. Although the mean total C4A or C4B CN did not differ in PANS compared to controls, PANS patients with low C4B CN were at increased risk for subsequent JIA diagnosis (hazard ratio = 2.7, p value = 0.004). We also observed a possible increase in risk for AI in PANS patients and a possible correlation between lower C4B and PANS age of onset. An association between rheumatoid arthritis and low C4B CN has been reported previously. However, patients with PANS develop different types of JIA: enthesitis-related arthritis, spondyloarthritis, and psoriatic arthritis. This suggests that C4B plays a role that spans these arthritis types.

Objective: This study describes for the first time the characteristics by sex of patients with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), including clinical phenotype, treatment, and psychosocial aspects of disease. Methods: This cross-sectional study included 205 consecutive community patients evaluated between January 1, 2012 and March 30, 2019 and compared 87 females with 118 males. Our primary hypothesis was that males would display more aggression, as measured by the Modified Overt Aggression Scale (MOAS) and would be treated with immunotherapy earlier than females. The MOAS began to be administered 5 years into the study period, and 57 of the 205 families completed the MOAS for this study. Results: Our analysis revealed that males had a higher median MOAS score in the first year of clinic when compared with females (median 11, interquartile range [IQR] [4-24] vs. median 3, IQR [1-9]; p = 0.03) and a higher median subscore for physical aggression (median 4, IQR [0-12] vs. median 0, IQR [0-8]; p = 0.05). The median time from PANS symptom onset to first administration of immunotherapy, which did not include nonsteroidal anti-inflammatory drugs or short bursts of oral steroids, was 6.9 years for females and 3.7 years for males (p = 0.20). The two groups did not differ significantly in age of PANS onset, time from onset to clinic entry, other psychiatric symptom measures, or laboratory markers of inflammation. Conclusion: Among patients with PANS, males exhibit more aggressive behavior when compared with females, which may advance the decision to treat with immunotherapy. Scores that capture a more global level of functioning show that despite there being a higher level of aggression in males, female patients with PANS have similar levels of overall impairment.

ObjectivesPediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by an abrupt-onset of severe psychiatric symptoms including OCD, anxiety, cognitive difficulties, and sleep issues which is thought to be a post-infection brain inflammatory disorder. We observed postural orthostatic tachycardia syndrome (POTS) which resolved with immunomodulation in a patient with Pediatric acute-onset neuropsychiatric syndrome (PANS). Here, we aim to present a case of POTS and to examine the prevalence of (POTS) in our PANS cohort, and compare the clinical characteristics of patients with and without POTS.Study DesignWe conducted this cohort study of patients meeting PANS criteria who had at least three clinic visits during the study period. We included data from prospectively collected questionnaires and medical record review. We present a case followed by statistical comparisons within our cohort and a Kaplan-Meier analysis to determine the time-dependent risk of a POTS diagnosis.ResultsOur study included 204 patients: mean age of PANS onset was 8.6 years, male sex (60%), non-Hispanic White (78%). Evidence of POTS was observed in 19/204 patients (9%) with 5/19 having persistent POTS defined as persistent abnormal orthostatic vitals, persistent POTS symptoms, and/or continued need for pharmacotherapy for POTS symptoms for at least 6 months). In this PANS cohort, patients with POTS were more likely to have comorbid joint hypermobility (63 vs 37%, p = 0.04), chronic fatigue (42 vs 18%, p = 0.03), and a family history of chronic fatigue, POTS, palpitations and syncope. An unadjusted logistic regression model showed that a PANS flare (abrupt neuropsychiatric deterioration) was significantly associated with an exacerbation of POTS symptoms (OR 3.3, 95% CI 1.4–7.6, p < 0.01).ConclusionsOur study describes a high prevalence of POTS in patients with PANS (compared to the general population) and supports an association between POTS presentation and PANS flare within our cohort.