Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): Autoimmune Mechanisms, Diagnostic Controversies, and Therapeutic Implications.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is a proposed postinfectious neuroimmune syndrome characterized by the abrupt onset of obsessive-compulsive disorder, tic disorders, and associated neuropsychiatric symptoms temporally associated with Group A beta-hemolytic Streptococcus infection. Since its initial description by Swedo and colleagues in 1998, PANDAS has generated notable scientific interest and controversy. Increasing evidence from immunology, neuroimaging, epidemiology, and translational neuroscience suggests that infection-triggered autoimmune processes may contribute to neuropsychiatric symptom development in a subset of pediatric patients. However, significant uncertainty remains regarding diagnostic validity, biomarker reproducibility, pathophysiologic mechanisms, and optimal treatment strategies. This review carefully evaluates current evidence regarding the epidemiology, immunopathogenesis, clinical manifestations, diagnosis, treatment, prognosis, and controversies surrounding PANDAS and related Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Relevant literature published from 1998 through May 2026 was critically reviewed. Recent publications from 2021-2026 were incorporated to update evidence on clinical guidance, neuroimaging, immune biomarkers, autoimmune comorbidity, and IVIG outcomes. Evidence supporting the PANDAS construct includes epidemiologic associations with streptococcal infection, parallels with Sydenham chorea, identification of antineuronal antibodies, neuroimaging abnormalities involving basal ganglia structures, translational animal models, and selective responsiveness to immunomodulatory therapies. Conversely, substantial concerns remain regarding inconsistent biomarker replication, methodological heterogeneity, diagnostic overlap with primary psychiatric disorders, and the absence of universally accepted diagnostic tests. Current evidence supports the biologic plausibility of infection-triggered neuroimmune neuropsychiatric syndromes in a subset of pediatric patients. However, the specificity of the PANDAS construct, the boundaries between PANDAS and Pediatric Acute-Onset Neuropsychiatric Syndrome, and the identification of immune-responsive subgroups remain incompletely defined. Future multicenter prospective studies incorporating standardized diagnostic criteria, advanced immunophenotyping, neuroimaging, genomics, and longitudinal outcome measures are required to clarify disease mechanisms and optimize patient management.