Research

Danieli, M.G.; Buti, E.; Longhi, E.; et al. Advancing Our Understanding of IVIg in Pediatric Acute-Onset Neuropsychiatric Syndrome. Journal of Mosaic of Autoimmunity 2025, 1 (2), 5. doi.org/10.53941/jmai.2025.100012

• Reviews intravenous immunoglobulin (IVIg) as a pooled IgG product with broad immunomodulatory and anti-inflammatory effects.

• Describes mechanisms including modulation of Fcγ receptors, inhibition of complement activation, cytokine regulation, and control of pro-inflammatory immune cells.

• Explains that IVIg can influence both innate and adaptive immune systems, including via epigenetic mechanisms.

• Summarizes evidence indicating IVIg can attenuate neuropsychiatric symptoms and restore immune balance in children with PANS.

• Notes variability in randomized trial outcomes but highlights converging clinical and mechanistic support for IVIg in selected patients.

• Emphasizes the need for biomarker-guided studies to identify responders and optimize treatment strategies.

Matera M, Biagioli V, Illiceto MT, Palazzi CM, Cavecchia I, Manzi A, Lugli S, Pennazzi L, Meocci M, Pedaci FA, Bertuccioli A. Pediatric acute-onset neuropsychiatric syndromes and the gut-oral-brain axis: a narrative review of emerging microbiome-immune interactions and therapeutic perspectives. Frontiers in Immunology. 2025;16. doi:10.3389/fimmu.2025.1726630

• Narrative review examining evidence linking gut and oral microbiota to immune dysregulation in PANS/PANDAS.Summarizes literature describing microbiome-related mechanisms including immune activation, increased intestinal permeability, and blood–brain barrier disruption.

• Discusses how microbial metabolites and inflammatory signaling may influence neuroinflammation and neuropsychiatric symptoms.

Thomas T, Eyre M, Ferrarin E, Newlove-Delgado T, Sie A, Armangue T, Ben-Pazi H, Benrhouma H, Clavenna A, Cardoso F, Dure LS, Jones HF, Gilbert DL, Gulati S, Jiang Y, Krajnc N, Mohammad SS, Orsini A, Sharma S, Swedo SE, Webb R, Wilmshurst JM, Yaramis A, Yilmaz S, Zuberi SM, Morton M, Dale RC, Nosadini M, Lim M. Evaluation, diagnosis, and treatment of Sydenham chorea: consensus guidelines. Pediatrics. 2025;156(6):e2025072466. doi:10.1542/peds.2025-072466

• Developed through a Delphi consensus process involving 27 international experts across neurology, psychiatry, and patient representation. Generated 88 consensus recommendations for evaluation, diagnosis, and management of children with Sydenham chorea.

• Emphasizes identification of core clinical features, including chorea and hypotonia, and screening for neuropsychiatric, cognitive, speech, swallowing, and mobility impairments.

• Recommends assessment for acute rheumatic fever features, including carditis, with etiologic evaluation tailored to regional risk.

• Supports antibiotic treatment at first presentation and long-term secondary prophylaxis per guidelines.

• Recommends corticosteroids for moderate to severe disease and IVIG or plasma exchange for inadequate recovery.

• Stresses the importance of patient, family, and school support to reduce academic and social impact.

PANDAS and PANS: Pathophysiology, Diagnostics and Therapeutic Approaches in Pediatric Autoimmune Neuropsychiatric Disorders – a literature review. March 2025. Journal of Education Health and Sport 79:57830. DOI:10.12775/JEHS.2025.79.57830

• Identifies a subgroup of children with PANS characterized by the triad of PANS symptoms, joint complaints, and family history of autoimmunity (including psoriasis).

• Suggests this subgroup may be at increased risk for inflammatory bowel disease and other immune-mediated disorders. Recommends a low threshold for evaluation of gastrointestinal inflammation using biomarkers such as hemoglobin, CRP, fecal calprotectin, and endoscopy when indicated.

• Reports that PANS symptoms may improve with effective treatment of inflammatory bowel disease.

• Notes high prevalence of joint complaints and autoimmune family history, suggesting shared immune mechanisms with psoriasis and arthritis.

Rahman SS, Hussein N, Galfrè SG, et al. Sex-associated and disease state-dependent monocyte polarization and CNS-trafficking phenotypes in pediatric acute-onset neuropsychiatric syndrome (PANS). Journal of Neuroinflammation. 2025;22:273.doi:10.1186/s12974-025-03549-6

• Characterized circulating monocyte subsets in pediatric PANS during flare and recovery states.

• Identified increased inflammatory M1-like monocytes and monocyte-derived dendritic cells during flare, with anti-inflammatory M2-like monocytes enriched during recovery.

• Described a monocyte subset with CNS-homing phenotype that was reduced during flare and restored during recovery; this subset was present in CSF in new-onset cases but absent in persistent disease.

• Authors suggest monocyte polarization and trafficking patterns vary with disease state and may relate to CNS involvement in PANS.

• Study Overview: Large population-based analysis of >56,000 Finnish adolescents in mental health services who received antibiotics.
• Key Finding: Doxycycline use linked to 30–35% lower risk of developing schizophrenia in adulthood vs. other antibiotics.
• Mechanism: May reduce brain inflammation and moderate excessive synaptic pruning, a process tied to schizophrenia.
• Implications: Suggests repurposing doxycycline as potential early preventive intervention for high-risk youth; needs clinical trials to confirm.

Sonbol, H.M., Abdelmawgoud, A.S., El-kady, N.M. et al. Serum zonulin level in autistic children and its relation to severity of symptoms a case-control study. Sci Rep 15, 27802 (2025). https://doi.org/10.1038/s41598-025-11420-0

• Findings: Children with autism had significantly higher serum zonulin levels (avg. 73 ng/ml) vs. neurotypical controls (avg. 22 ng/ml).
• Correlation: Higher zonulin levels were strongly associated with greater symptom severity (r = 0.9).
• Mechanism: Zonulin regulates tight junctions in the intestinal and blood–brain barriers; elevated levels increase permeability (“leaky gut”), promoting systemic and neuroinflammation.
• Relevance to PANS/PANDAS: Similar barrier dysfunction and inflammation may contribute to symptom flares following infections or immune triggers.

Han VX, Alshammery S, Keating BA, Gloss BS, Hofer MJ, Graham ME, Aryamanesh N, Marshall LL, Yuan S, Maple-Brown E, Yan J, Bandodkar S, Kothur K, Nishida H, Jones H, Tsang E, Lau X, Dissanayake R, Perkes I, Mohammad SS, Brilot F, Gold W, Patel S, Dale RC, et al. Epigenetic, ribosomal, and immune dysregulation in paediatric acute-onset neuropsychiatric syndrome. Molecular Psychiatry. 2025;30:5389–5404. doi:10.1038/s41380-025-03127-5

• Compared children with PANS and other neurodevelopmental disorders to neurotypical controls; PANS/non-PANS groups reported more early childhood infections and loss of previously acquired developmental skills than controls.

• Found routine immune testing largely normal, but RNA sequencing showed upregulated ribosomal biogenesis/RNA methyltransferase pathways and downregulated mitochondrial, signaling, endocytosis, and immune pathways.

• Toll-like receptor stimulation showed reduced TNF and IL-6 responses in PANS; post-IVIG RNA sequencing demonstrated partial normalization of dysregulated pathways.

• Authors conclude findings support immune and epigenetic dysregulation in PANS and provide rationale for immune-modulating therapies.

Fekete, R., Simats, A., Bíró, E., Pósfai, B., Cserép, C., Schwarcz, A., Szabadits, E., Környei, Z., Tóth, K., Fichó, E., Szalma, J., Vida, S., Kellermayer, A., Dávid, C., Acsády, L., Kontra, L., Silvestre-Roig, C., Moldvay, J., … Dénes, Á. (2025). Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19. Nature Neuroscience, 28(3), 558–576. DOI: 10.1038/s41593-025-01871-z

• Neuropathological study examining brains of individuals with COVID-19.

• Identifies microglial dysfunction, astrocyte involvement, and neurovascular inflammation linked to systemic IL-1 and IL-6 signaling.

• Demonstrates blood–brain barrier disruption and gliovascular pathology even in the absence of direct viral invasion of brain tissue.

• Provides strong evidence for self-sustaining inflammatory loops between peripheral immune signals and CNS cells.