Relapsing CNS-restricted Autoinflammatory Demyelination Due to Complement Factor I Deficiency: A Diagnostic Odyssey in Seronegative Neuroinflammation

Objective To characterize a novel CNS-restricted autoinflammatory phenotype of complement factor I ( CFI ) deficiency and highlight diagnostic challenge. Background Relapsing CNS inflammation is typically evaluated within the frameworks of demyelination disease, or antibody-mediated autoimmune encephalitis. However, autoinflammatory and complement-mediated disorders are underrecognized mimics. While CFI deficiency classically presents with recurrent severe systemic infections, CNS-restricted inflammatory presentations without fulminant infection are rare. Design/Methods We analyzed longitudinal clinical, radiologic, lab and genetic data from a 31-year-old woman with recurrent encephalitic episodes and seizures. A focused literature review of CFI deficiency with isolated or CNS-predominant inflammation was performed. Results The patient initially presented in late pregnancy with aphasia, encephalopathy, seizures, multifocal T2/FLAIR abnormalities, and neutrophilic CSF pleocytosis. Over three years, she experienced recurrent flares with evolving enhancing brain lesions, refractory seizures and neurocognitive decline. Extensive infectious, autoimmune, and demyelinating evaluations were repeatedly negative. During a major exacerbation, CSF demonstrated a marked CNS-restricted cytokine storm (elevated IL-6, IL-8, IL-10), which normalized during remission. Serum studies showed persistently low C3, normal-to-high C4, and suppressed CH50. Whole-genome sequencing identified a homozygous pathogenic CFI frameshift variant (c.111dup; p.Tyr38IlefsTer8). She stabilized following targeted therapy with corticosteroids and anakinra. The literature review identified 19 reported cases of CFI deficiency featuring isolated or CNS-predominant inflammation. Spectrum diagnosis consideration included ADEM-like cerebral inflammation, acute hemorrhagic leukoencephalitis, relapsing CNS vasculitis-like disease and aseptic meningoencephalitis. Common hallmarks included atypical MRI abnormalities, neutrophilic or mixed CSF pleocytosis, elevated protein, absent oligoclonal bands, and—crucially—low C3 with preserved C4, reflecting alternative pathway complement dysregulation. Conclusions CFI deficiency can present as a relapsing, CNS-restricted autoinflammatory encephalopathy, mimicking seronegative autoimmune or atypical CNS demyelination. Unexplained recurrent neutrophilic CSF pleocytosis, atypical MRI findings, absent oligoclonal bands, and a low C3/normal C4 serum profile should prompt immediate complement and genetic testing. Early recognition enables mechanism-directed therapy and prevents prolonged reliance on empiric or nonspecific treatments.