Pediatric Acute-onset Neuropsychiatric Syndrome (PANS): new insights

Introduction - Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a clinically heterogeneous disorder presenting with: unusually abrupt onset of obsessive-compulsive disorder (OCD) or severe eating restrictions, with at least two concomitant cognitive, behavioral, or affective symptoms such as anxiety, obsessive-compulsive behavior, and irritability/depression. PANS consists of the expression of various serological alterations sustained by a supposed autoimmune/inflammatory disease. Sleep disorders represent one of the most frequent manifestations of PANS (around 80%). Objectives - The Study N.1 describes the clinical and laboratory variables of 39 PANS children. The Study N.2 describes the clinical and polysomnographic features of 23 PANS children identifying the relationships between sleep disorders and other PANS symptoms. The Study N.3 explores potential serum biomarkers in 34 PANS patients and 25 neurotypical subjects through the metabolomics approach. Study N.1 - Methods: Using the Artificial Neural Networks (ANNs) analysis, the putative associations between PANS working criteria were explored by the Auto Contractive Map (Auto-CM) system, a mapping method able to compute the multidimensional association of strength of each variable with all other variables. Results: The PANS symptoms were strictly linked to one another on the semantic connectivity map, shaping a central ‘‘diamond’’ encompassing anxiety, irritability/oppositional defiant disorder symptoms, OCD, behavioral regression, sensory motor abnormalities, school performance deterioration, sleep disturbances, and emotional lability/depression. The map also showed that the emotional lability/depression resulted as a highly connected hub linked to autoimmune disease in pregnancy, allergic and atopic disorders, and low Natural Killer percentage. Also anxiety symptoms were shown to be strongly related with recurrent infectious disease. Conclusion: It was shown a very specific constellation of symptoms having strong links to laboratory and clinical variables consistent with PANS feature. Study N.2 - Methods: It describes both clinical and polysomnographic variables and studies the relationships between them using a data mining approach with ANNs analysis. Results: Polysomnography showed abnormality in 17 out 23 subjects. In particular, 8/17 children had ineffective sleep, 10/17 fragmented sleep, 47.1% Periodic Limb Movement Disorder (PLMD) and 64.7% REM-Sleep Without Atonia (RSWA). Most patients had more than one sleep disorder. Among the 19/23 patients with Tic/Tourette Disorder, 8/19 showed PLMD and 10/19 RSWA. ANNs analysis and the Auto-CM exploited the links among the spectrum of variables revealing the simultaneous connections among them. Conclusion: Sleep disorders represent, for prevalence and impact on quality of life, a cardinal symptom in patients with PANS with a potential impact on the prognosis of this condition. Study N.3 - Methods: Serum samples were obtained from each patient/subject and were analyzed through the Nuclear Magnetic Resonance Spectroscopy. Subsequently, multivariate and univariate statistical analyses, as well as Receiving Operator Curves (ROC) were performed. Results: Significant differences in the concentrations of several metabolites were observed, suggesting the involvement of specific patterns of neurotransmission (tryptophan, glycine, histamine/histidine) as well as a more general state of neuroinflammation and oxidative stress (glutamine, 2-Hydroxybutyrate and tryptophan-kynurenine pathway) in the disorder. Conclusions: It was found a unique plasma metabolic profile in PANS patients, significantly different from healthy children. This metabolomics study offers new insights into biological mechanisms implicated in PANS.