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OBJECTIVE: Drug-resistant seizures are common in patients with Leucine-rich, glioma-inactivated-1 (LGI1) and contactin-associated-protein-like-2 (CASPR2)-IgG associated encephalitis. We performed the first randomized double-blind placebo-controlled trial to evaluate efficacy of intravenous immunoglobulin (IVIG) in reducing seizure frequency. METHODS: Our enrollment goal was 30 LGI1/CASPR2-IgG-seropositive adult patients with ≥2 seizures per-week. Patients were randomized to receive IVIG (0.5g/kg day-1, 1g/kg day-2, 0.6g/kg week 3 and 5) or volume-matched intravenous normal saline. Following the blinded-phase, the non-responders in the placebo group received IVIG. The primary clinical outcome was 50% reduction in seizure frequency from baseline to 5 weeks. RESULTS: After enrollment of 17 patients (LGI1-IgG, 14; CASPR2-IgG, 3) over 34 months the study was terminated due to slow enrollment. Six of eight patients in the IVIG group were responders compared to two of nine in the placebo group (p=0.044, OR 10.5, 95% CI 1.1 to 98.9). For the LGI1-IgG seropositive subgroup: 6 of 8 patients in the IVIG group were responders, compared to zero of 6 in the placebo group. Two LGI1-IgG seropositive patients receiving IVIG, but none receiving placebo, were seizure free at the end of the blinded-phase. Four of the six patients entering the open-label IVIG arm reported ≥50% reduction in seizure frequency. There were no correlations with LGI1/CASPR2-IgG1-4 subclasses. INTERPREATION: Superiority of IVIG to placebo reached statistical significance for the primary end-point for all patients and the subset with LGI1-IgG. These results have to be interpreted with the caveat that the study did not reach its originally selected sample size. This article is protected by copyright. All rights reserved.

Original publication




Journal article


Ann Neurol

Publication Date



Autoimmune encephalitis, Autoimmune limbic encephalitis, Epilepsy, Immunotherapy