Pediatric Acute-Onset Neuropsychiatric Syndrome: Current Perspectives.

Pediatric acute-onset neuropsychiatric syndrome (PANS) features a heterogeneous constellation of acute obsessive-compulsive disorder (OCD), eating restriction, cognitive, behavioral and/or affective symptoms, often followed by a chronic course with cognitive deterioration. An immune-mediated etiology is advocated in which the CNS is hit by different pathogen-driven (auto)immune responses. This narrative review focused on recent clinical (ie, diagnostic criteria, pre-existing neurodevelopmental disorders, neuroimaging) and pathophysiological (ie, CSF, serum, genetic and autoimmune findings) aspects of PANS. We also summarized recent points to facilitate practitioners with the disease management. Relevant literature was obtained from PubMed database which included only English-written, full-text clinical studies, case reports, and reviews. Among a total of 1005 articles, 205 were pertinent to study inclusion. Expert opinions are converging on PANS as the effect of post-infectious events or stressors leading to "brain inflammation", as it is well-established for anti-neuronal psychosis. Interestingly, differentiating PANS from either autoimmune encephalitides and Sydenham's chorea or from alleged "pure" psychiatric disorders (OCD, tics, Tourette's syndrome), reveals several overlaps and more analogies than differences. Our review highlights the need for a comprehensive algorithm to help both patients during their acute distressing phase and physicians during their treatment decision. A full agreement on the hierarchy of each therapeutical intervention is missing owing to the limited number of randomized controlled trials. The current approach to PANS treatment emphasizes immunomodulation/anti-inflammatory treatments in association with both psychotropic and cognitive-behavioral therapies, while antibiotics are suggested when an active bacterial infection is established. A dimensional view, taking into account the multifactorial origin of psychiatric disorders, should suggest neuro-inflammation as a possible shared substrate of different psychiatric phenotypes. Hence, PANS and PANS-related disorders should be considered as a conceptual framework describing the etiological and phenotypical complexity of many psychiatric disorders.

Metabolomic Characterization of Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS).

INTRODUCTION: PANS is a controversial clinical entity, consisting of a complex constellation of psychiatric symptoms, adventitious changes, and expression of various serological alterations, likely sustained by an autoimmune/inflammatory disease. Detection of novel biomarkers of PANS is highly desirable for both diagnostic and therapeutic management of affected patients. Analysis of metabolites has proven useful in detecting biomarkers for other neuroimmune-psychiatric diseases. Here, we utilize the metabolomics approach to determine whether it is possible to define a specific metabolic pattern in patients affected by PANS compared to healthy subjects. DESIGN: This observational case-control study tested consecutive patients referred for PANS between June 2019 to May 2020. A PANS diagnosis was confirmed according to the PANS working criteria (National Institute of Mental Health [NIMH], 2010). Healthy age and sex-matched subjects were recruited as controls. METHODS: Thirty-four outpatients referred for PANS (mean age 9.5 years; SD 2.9, 71% male) and 25 neurotypical subjects matched for age and gender, were subjected to metabolite analysis. Serum samples were obtained from each participant and were analyzed using Nuclear Magnetic Resonance (NMR) spectroscopy. Subsequently, multivariate and univariate statistical analyses and Receiver Operator Curves (ROC) were performed. RESULTS: Separation of the samples, in line with the presence of PANS diagnosis, was observed by applying a supervised model (R2X = 0.44, R2Y = 0.54, Q2 = 0.44, p-value < 0.0001). The significantly altered variables were 2-Hydroxybutyrate, glycine, glutamine, histidine, tryptophan. Pathway analysis indicated that phenylalanine, tyrosine, and tryptophan metabolism, as well as glutamine and glutamate metabolism, exhibited the largest deviations from neurotypical controls. CONCLUSION: We found a unique plasma metabolic profile in PANS patients, significantly differing from that of healthy children, that suggests 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. This metabolomics study offers new insights into biological mechanisms underpinning the disorder and supports research of other potential biomarkers implicated in PANS.

Pediatric Acute-Onset Neuropsychiatric Syndrome: A Data Mining Approach to a Very Specific Constellation of Clinical Variables.

Objectives: 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. This study describes the clinical and laboratory variables of 39 children (13 female and 26 male) with a mean age at recruitment of 8.6 years (standard deviation 3.1). Methods: Using a mathematical approach based on Artificial Neural Networks, the putative associations between PANS working criteria, as defined at the NIH in July 2010 (Swedo et al. 2012), 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 in predefined dataset. 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, obsessive-compulsive symptoms, behavioral regression, sensory motor abnormalities, school performance deterioration, sleep disturbances, and emotional lability/depression. The semantic connectivity map also showed the aggregation between PANS symptoms and laboratory and clinical variables. In particular, 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 remarking the possible role of infections as a risk factor for PANS. Conclusion: Our data mining approach shows a very specific constellation of symptoms having strong links to laboratory and clinical variables consistent with PANS feature.