Prevalence of Neurological Soft Signs at Presentation in Pediatric Acute-Onset Neuropsychiatric Syndrome.

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. Key Points: Question: Do patients with pediatric acute-onset neuropsychiatric syndrome present with neurological soft signs reflective of basal ganglia dysfunction, and are these examination findings associated with disease severity?Findings: In this cohort study of 119 patients with pediatric acute-onset neuropsychiatric syndrome, most patients presented with at least one neurological soft sign pertaining to the basal ganglia. The number of signs was associated with global impairment and the number of PANS symptoms. These findings are consistent with basal ganglia pathology in pediatric acute-onset neuropsychiatric syndrome.Meaning: Targeted neurological exams may help support the diagnosis of pediatric acute-onset neuropsychiatric syndrome.

Psychometric Properties of the PANS 31-Item Symptom Rating Scale.

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.

Postinfectious Inflammation, Autoimmunity, and Obsessive-Compulsive Disorder: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection, and Pediatric Acute-Onset Neuropsychiatric Disorder.

Postinfectious neuroinflammation has been implicated in multiple models of acute-onset obsessive-compulsive disorder including Sydenham chorea (SC), pediatric acute-onset neuropsychiatric syndrome (PANS), and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). These conditions are associated with a range of autoantibodies which are thought to be triggered by infections, most notably group A streptococci (GAS). Based on animal models using huma sera, these autoantibodies are thought to cross-react with neural antigens in the basal ganglia and modulate neuronal activity and behavior. As is true for many childhood neuroinflammatory diseases and rheumatological diseases, SC, PANS, and PANDAS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. In this review article, we outline the accumulating evidence supporting the role neuroinflammation plays in these disorders. We describe work with animal models including patient-derived anti-neuronal autoantibodies, and we outline imaging studies that show alterations in the basal ganglia. In addition, we present research on metabolites, which are helpful in deciphering functional phenotypes, and on the implication of sleep in these disorders. Finally, we encourage future researchers to collaborate across medical specialties (e.g., pediatrics, psychiatry, rheumatology, immunology, and infectious disease) in order to further research on clinical syndromes presenting with neuropsychiatric manifestations.

Evaluation of C4 Gene Copy Number in Pediatric Acute Neuropsychiatric Syndrome.

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.

Arthritis in Children with Psychiatric Deteriorations: A Case Series.

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.

Validation of the 2019 European League Against Rheumatism/American College of Rheumatology Criteria Compared to the 1997 American College of Rheumatology Criteria and the 2012 Systemic Lupus International Collaborating Clinics Criteria in Pediatric Systemic Lupus Erythematosus.

OBJECTIVE: Different classification criteria for systemic lupus erythematosus (SLE) have been proposed for many years. The most widely used and accepted criteria has been the 1997 American College of Rheumatology (ACR) criteria. In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) criteria were published in an attempt to improve the clinical relevance of SLE criteria. In 2017, weighted criteria were proposed that included entry criteria, something the 1997 ACR and the 2012 SLICC criteria did not identify. The aim of the present study was to validate the 2017 weighted criteria, the 1997 ACR criteria, and the 2012 SLICC criteria and compare the sensitivities and specificities in pediatric SLE. METHODS: For the past 15 years, retrospective chart review of patients diagnosed with SLE before age 19 years was conducted. The controls were patients referred for serologies positive for antinuclear antibodies but did not fulfill criteria for diagnosis of SLE at the initial visit or were diagnosed with another autoimmune disease. The 3 classification criteria sets were applied to these patients and compared against a gold standard of physician diagnosis. RESULTS: A total of 156 patients were diagnosed with SLE. The sensitivity for the 2017 weighted criteria was 0.974 (95% confidence interval [95% CI] 0.936-0.993) and the specificity was 0.984 (95% CI 0.966-0.994). The sensitivity for the 1997 ACR criteria was 0.872 (95% CI 0.809-0.920) and the specificity was 1.00 (95% CI 0.990-1.000). The sensitivity for the 2012 SLICC criteria was 0.974 (95% CI 0.936-0.993) and the specificity was 0.997 (95% CI 0.985-1.000). CONCLUSION: The 2017 weighted criteria and the 2012 SLICC criteria were more sensitive than the 1997 ACR criteria. There were no significant differences in sensitivity and specificity between the 2012 SLICC and the 2017 weighted criteria.