Neuroimmunological overlap syndromes in optic neuritis, myelitis, and connective tissue diseases.

BACKGROUND: Neuroimmunological overlap syndromes encompassing optic neuritis, myelitis, and connective tissue disorders (CTDs) represent an emerging autoimmune spectrum at the intersection of neurology, immunology, and rheumatology. These conditions share convergent pathogenic mechanisms including blood-brain barrier dysfunction, cytokine dysregulation, complement activation, and adaptive immune imbalance, yet are often managed as discrete entities despite overlapping clinical features. METHOD: A narrative review was conducted across PubMed, Web of Science, and Google Scholar (January 2014-March 2026) using keywords related to NMOSD, MOGAD, MS, optic neuritis, myelitis, and CTDs. Preference was given to systematic reviews, meta-analyses, randomized controlled trials, and large observational cohort studies. OUTCOMES: Shared pathogenic mechanisms include BBB disruption, pro-inflammatory cytokines (IL-6, IL-17, TNF-α, IFN-γ), complement activation, and B-cell/Th17-mediated autoimmunity. Disease-defining antibodies (AQP4-IgG, MOG-IgG) have refined diagnostic accuracy. Clinically, optic neuritis and myelitis serve as principal overlapping manifestations complicating differentiation among NMOSD, MOGAD, MS, and CTD-associated neuroinflammation. Four biologics inebilizumab (B-cell depletion), satralizumab (IL-6 blockade), and eculizumab/ravulizumab (complement inhibition) are approved for AQP4-IgG-positive NMOSD. However, no targeted therapies exist for MOGAD, and CTD-associated neuroinflammation lacks trial data. Emerging biomarkers (GFAP, NfL) and precision medicine tools remain unvalidated for routine clinical use. CONCLUSION: Neuroimmunological overlap syndromes should be conceptualized as a unified neuroimmune continuum rather than discrete diseases. Priority research includes biomarker validation, head-to-head comparative cohorts, and randomized trials for MOGAD and CTD-associated neuroinflammation.