Sex and Aggression Characteristics in a Cohort of Patients with Pediatric Acute-Onset Neuropsychiatric Syndrome.

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.

Children With PANS May Manifest POTS.

Objectives: Pediatric 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 Design: We 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. Results: Our 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). Conclusions: Our 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.

Hypoferritinemia and iron deficiency in youth with pediatric acute-onset neuropsychiatric syndrome.

BACKGROUND: Pediatric acute-onset neuropsychiatric syndrome (PANS) is an abrupt debilitating psychiatric illness. We anecdotally observed hypoferritinemia and iron deficiency in a subset of patients with PANS, prompting this study. METHODS: In this IRB-approved prospective cohort study, we included patients seen at the Stanford PANS Clinic who met study criteria. The prevalence of hypoferritinemia (using cut-offs of 7 ng/ml in children ≤ 15 years and 18 ng/ml in adolescents > 15 years) and iron deficiency was estimated. Differences in patients with and without hypoferritinemia during PANS flare were explored. RESULTS: Seventy-nine subjects (mean age of PANS onset of 8.7 years) met study criteria. Hypoferritinemia was observed in 27% and three quarters occurred during a PANS flare. Compared to patients without hypoferritinemia during PANS flare, patients with hypoferritinemia had worse global impairment, more comorbid inflammatory diseases, and exhibited a chronic course of PANS illness. The estimated prevalence of iron deficiency was 3-8% in the PANS cohort, 1.4-2.0-fold higher than in the age- and sex-matched U.S. POPULATION: More stringent ferritin level cut-offs than the comparison CDC dataset were used. CONCLUSION: Hypoferritinemia and iron deficiency appear to be more common in PANS patients. More research is needed to confirm and understand this association. IMPACT: Our study suggests hypoferritinemia and iron deficiency are more common in patients with pediatric acute-onset neuropsychiatric syndrome (PANS) than in the sex- and age-matched US population. Hypoferritinemia was commonly observed during a disease flare but not associated with dietary or demographic factors. In patients with PANS and iron deficiency, clinicians should consider possibility of inflammation as the cause especially if iron deficiency cannot be explained by diet and blood loss. Future research should include larger cohorts to corroborate our study findings and consider examining the iron dynamics on MRI brain imaging in order to better understand the pathophysiology of PANS.

Psychometric Properties of the Pediatric Acute-Onset Neuropsychiatric Syndrome Global Impairment Score in Children and Adolescents with Pediatric Acute-Onset Neuropsychiatric Syndrome.

OBJECTIVES: This study validates the caregiver-rated Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) Global Impairment Score (GIS), a single-item, 0-100 scale, for use in PANS. METHODS: We collected longitudinal data from community patients meeting PANS criteria. We included 128 patients with 1926 GISs, each from a unique clinic visit. To assess discriminant validity, we compared GISs from patients with PANS with scores from a population of healthy controls. To evaluate external validity, we compared global impairment with a clinician-reported global measure-the Child Global Assessment Scale (CGAS)-using the Bland-Altman plots and correlation coefficients. Then, we evaluated associations between the PANS GIS and symptom-specific disease severity variables by fitting mixed models with repeated measures. RESULTS: The GIS shows excellent discriminant validity, distinguishing patients with PANS from healthy controls. The scores on the GIS show an acceptable level of agreement with the clinician-reported CGAS. The regression line in the Bland-Altman plot had a positive slope, indicating that parents tend to report higher disease severity than clinicians at higher levels of disease severity. Correlation was higher during disease remissions than during disease flares (r = -0.69 vs. r = -0.48). All disease severity scales predicted GIS in the expected direction. CONCLUSION: The GIS has excellent discriminant validity and acceptable construct validity.

The Burden of Caring for a Child or Adolescent With Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): An Observational Longitudinal Study.

OBJECTIVE: To describe the longitudinal association between disease severity, time established in clinical treatment, and caregiver burden in a community-based patient population diagnosed with pediatric acute-onset neuropsychiatric syndrome (PANS). METHODS: The study included an observational longitudinal cohort design, with Caregiver Burden Inventories (CBIs) collected between April 2013 and November 2016 at the Stanford PANS multidisciplinary clinic. Inclusion criteria for this study were as follows: pediatric patients meeting strict PANS/pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) diagnostic criteria (n = 187), having a caregiver fill out at least 1 complete CBI during a disease flare (n = 114); and having family who lives locally (n = 97). For longitudinal analyses, only patients whose caregiver had filled out 2 or more CBIs (n = 94 with 892 CBIs) were included. In the study sample, most primary caregivers were mothers (69 [71.1%] of 97), the majority of PANS patients were male (58 [59.8%] of 97), and mean age at PANS onset was 8.8 years. RESULTS: In a patient's first flare tracked by the clinic, 50% of caregivers exceeded the caregiver burden score threshold used to determine respite need in care receiver adult populations. Longitudinally, flares, compared with quiescence, predicted increases in mean CBI score (6.6 points; 95% CI, 5.1 to 8.0). Each year established in clinic predicted decreased CBI score (-3.5 points per year; 95% CI, -2.3 to -4.6). Also, shorter time between PANS onset and entry into the multidisciplinary clinic predicted greater improvement in mean CBI score over time (0.7 points per year squared; 95% CI, 0.1 to 1.3). Time between PANS onset and treatment with antibiotics or immunomodulation did not moderate the relationship between CBI score and time in clinic. CONCLUSIONS: PANS caregivers suffer high caregiver burden. Neuropsychiatric disease severity predicts increased caregiver burden. Caregiver burden tends to decrease over time in a group of patients undergoing clinical treatment at a specialty PANS clinic. This decrease could be independent of clinical treatment.

Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part II-Use of Immunomodulatory Therapies.

Introduction: Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a clinically heterogeneous disorder with a number of different etiologies and disease mechanisms. Inflammatory and postinfectious autoimmune presentations of PANS occur frequently, with some clinical series documenting immune abnormalities in 75%-80% of patients. Thus, comprehensive treatment protocols must include immunological interventions, but their use should be reserved only for PANS cases in which the symptoms represent underlying neuroinflammation or postinfectious autoimmunity, as seen in the PANDAS subgroup (Pediatric Autoimmune Neuropsychiatric Disorders associated with Streptococcal infections). Methods: The PANS Research Consortium (PRC) immunomodulatory task force is comprised of immunologists, rheumatologists, neurologists, infectious disease experts, general pediatricians, psychiatrists, nurse practitioners, and basic scientists with expertise in neuroimmunology and PANS-related animal models. Preliminary treatment guidelines were created in the Spring of 2014 at the National Institute of Health and refined over the ensuing 2 years over conference calls and a shared web-based document. Seven pediatric mental health practitioners, with expertise in diagnosing and monitoring patients with PANS, were consulted to create categories in disease severity and critically review final recommendations. All authors played a role in creating these guidelines. The views of all authors were incorporated and all authors gave final approval of these guidelines. Results: Separate guidelines were created for the use of immunomodulatory therapies in PANS patients with (1) mild, (2) moderate-to-severe, and (3) extreme/life-threatening severity. For mildly impairing PANS, the most appropriate therapy may be "tincture of time" combined with cognitive behavioral therapy and other supportive therapies. If symptoms persist, nonsteroidal anti-inflammatory drugs and/or short oral corticosteroid bursts are recommended. For moderate-to-severe PANS, oral or intravenous corticosteroids may be sufficient. However, intravenous immunoglobulin (IVIG) is often the preferred treatment for these patients by most PRC members. For more severe or chronic presentations, prolonged corticosteroid courses (with taper) or repeated high-dose corticosteroids may be indicated. For PANS with extreme and life-threatening impairment, therapeutic plasma exchange is the first-line therapy given either alone or in combination with IVIG, high-dose intravenous corticosteroids, and/or rituximab. Conclusions: These recommendations will help guide the use of anti-inflammatory and immunomodulatory therapy in the treatment of PANS.

An effective second-generation outer surface protein A-derived Lyme vaccine that eliminates a potentially autoreactive T cell epitope.

The antigenic component of a common Lyme disease vaccine is recombinant outer surface protein A (rOspA) of Borrelia burgdorferi (Bb), the causative agent of Lyme disease. Coincidentally, patients with chronic, treatment-resistant Lyme arthritis develop an immune response against OspA, whereas those with acute Lyme disease usually do not. Treatment-resistant Lyme arthritis occurs in a subset of Lyme arthritis patients and is linked to HLA.DRB1*0401 (DR4) and related alleles. Recent work from our laboratory identified T cell crossreactivity between epitopes of OspA and lymphocyte function-associated antigen 1alpha(L) chain (LFA-1alpha(L)) in these patients. We generated a form of rOspA, FTK-OspA, in which the LFA-1alpha(L)/rOspA crossreactive T cell epitope was mutated to reduce the possible risk of autoimmunity in genetically susceptible individuals. FTK-OspA did not stimulate human or mouse DR4-restricted, WT-OspA-specific T cells, whereas it did stimulate antibody responses specific for WT-OspA that were similar to mice vaccinated WT-OspA. We show here that the protective efficacy of FTK-OspA is indistinguishable from that of WT-OspA in vaccination trials, as both C3H/HeJ and BALB/c FTK-OspA-vaccinated mice were protected from Bb infection. These data demonstrate that this rOspA-derived vaccine lacking the predicted cross-reactive T cell epitope, but retaining the capacity to elicit antibodies against infection, is effective in generating protective immunity.