Aims of this study were 1) to evaluate which autoimmune encephalitis autoantibodies can co-exist in patients with aquaporin-4-IgG (AQP4-IgG) and 2) what is the clinical phenotype of patients with AQP4-IgG+ and autoimmune encephalitis autoantibodies.

Neuromyelitis optica spectrum disorder (NMOSD) typically presents with optic neuritis, myelitis, or brainstem attacks. Rarely, patients can experience encephalopathy. NMOSD patients often have co-existent systemic autoimmunity.

To ensure homogeneity in tests, the frequency of AQP4-IgG and autoimmune encephalitis antibodies association was evaluated on patients with AQP4-IgG+ tested for autoimmune encephalitis antibodies (2018- 2022). Then, we interrogated the Neuroimmunology laboratory database for AQP4-IgG+ patients (2007 to 2022, n=6,645) and identified patients with coexistent NMDA-R-IgG or GFAP-IgG. Clinical and radiological features of these patients were then compared to those of a control group of AQP4-IgG+ NMOSD from the clinical database.

Coexistent neuronal/glial-IgGs were found in 1/128 (0.7%) sera and 21/126 (17%) cerebrospinal fluid tested. NMDA-R-IgG was the most frequent antibody detected in children (6/8 [80%], GFAP-IgG was the most common in adults (9/13 [69%]).

We identified 21 AQP4-IgG+ with coexistent neuronal or glial antibodies and clinico-radiological data (9 isolated NMDA-R-IgG, 9 NMDA-R-IgG/GFAP-IgG, 2 isolated GFAP-IgG, and 1 NMDA-R-IgG/MOG-IgG). Compared to 311 AQP4-IgG+NMOSD in the clinical database, those with coexistent neuronal/glial antibodies had a higher frequency of encephalopathy, ovarian tumors, temporal lobe, basal ganglia and diencephalic involvement (all p<0.001).

AQP4-IgG can rarely coexist with autoimmune encephalitis autoantibodies, especially with NMDA-R-IgG and GFAP-IgG. These patients usually have features of autoimmune encephalitis, and several had ovarian teratoma.