Seizures and memory impairment induced by patient‐derived anti‐N‐methyl‐D‐aspartate receptor antibodies in mice are attenuated by anakinra, an interleukin‐1 receptor antagonist

Abstract Objective Neuroinflammation associated with anti‐N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis may facilitate seizures. We previously showed that intraventricular administration of cerebrospinal fluid from patients with anti‐NMDAR encephalitis to mice precipitates seizures, thereby confirming that antibodies are directly pathogenic. To determine whether interleukin (IL)‐1‐mediated inflammation exacerbates autoimmune seizures, we asked whether blocking the effects of IL‐1 by anakinra, a selective IL‐1 receptor antagonist, blunts antibody‐induced seizures. Methods We infused C57BL/6 mice intraventricularly with purified serum IgG from patients with anti‐NMDAR encephalitis or monoclonal anti‐NMDAR IgG; subdural electroencephalogram was continuously recorded. After a 6‐day interval, mice received anakinra (25 mg/kg sc, twice daily) or vehicle for 5 days. Following a 4‐day washout period, we performed behavioral tests to assess motor function, anxiety, and memory, followed by hippocampus tissue analysis to assess astrocytic (glial fibrillary acidic protein [GFAP]) and microglial (ionized calcium‐binding adapter molecule [Iba]‐1) activation. Results Of 31 mice infused with purified patient NMDAR‐IgG ( n = 17) or monoclonal NMDAR‐IgG ( n = 14), 81% developed seizures. Median baseline daily seizure count during exposure to antibodies was 3.9; most seizures were electrographic. Median duration of seizures during the baseline was 82.5 s. Anakinra administration attenuated daily seizure frequency by 60% ( p = .02). Anakinra reduced seizure duration; however, the effect was delayed and became apparent only after the cessation of treatment ( p = .04). Anakinra improved novel object recognition in mice with antibody‐induced seizures ( p = .03) but did not alter other behaviors. Anakinra reduced the expression of GFAP and Iba‐1 in the hippocampus of mice with seizures, indicating decreased astrocytic and microglial activation. Significance Our evidence supports a role for IL‐1 in the pathogenesis of seizures in anti‐NMDAR encephalitis. These data are consistent with therapeutic effects of anakinra in other severe autoimmune and inflammatory seizure syndromes. Targeting inflammation via blocking IL‐1 receptor‐mediated signaling may be promising for developing novel treatments for refractory autoimmune seizures.