Abstracts

Rationale: Drug-resistant seizures are common in patients with Leucine-rich, glioma-inactivated-1 (LGI1) and contactin-associated-protein-like-2 (CASPR2) IgG associated encephalitis. To date, studies are retrospective and observational. Here, we performed the first randomized double-blind placebo-controlled trial to evaluate the effect of intravenous immunoglobulins (IVIG) on 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 week 5) or volume matched placebo/intravenous normal saline (day 1, day 2, week 3 and week 5). The primary clinical outcome was change in (patient/spouse) reported seizure frequency from baseline to 5 weeks. Responder status was defined as 50% reduction in seizure frequency. Secondary outcome measures included Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scores. Following the blinded-phase, the non-responders in the placebo group received open-label IVIG. LGI1 and CASPR2 IgG subclass determination was performed by flow-cytometry assay on HEK293T cells transiently transfected with membrane-tethered LGI1 or CASPR2 C-terminally fused to EGFP. Comparisons of categorical variables were done with Fischer’s exact test and continuous variables with Mann-Whitney U test. One-sided statistical test was utilized to demonstrate improved efficacy of IVIG compared to placebo. 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 six in the placebo group (p=0.009). Two LGI1-IgG seropositive patients receiving IVIG, but none in the placebo arm, were seizure free at the end of the blinded phase. The median change in RBANS total-score among LGI1-IgG seropositive patients showed a trend towards improvement for the IVIG group compared to placebo (3 [0 to 13] vs -1 [-12 to 6], p=0.077). All eight LGI1-IgG seropositive patients in the IVIG group showed stabilization or improvement of RBANS total score percentiles, compared with 2 of 5 in the placebo group (p=0.035). Six patients with persistent seizures at week 5 on placebo during the blinded phase of the study entered the open label IVIG arm of the study. Among these, four patients reported more than 50% reduction in seizure frequency during the week 11 evaluation. There were no correlations with LGI1/CASPR2-IgG1-4 subclasses. One LGI1-IgG seropositive patient in the placebo arm was unblinded at 3 weeks due to progressive neurological decline. One fall was reported during the blinded phase of the study in a LGI1-IgG seropositive patient receiving IVIG likely secondary to faciobrachial dystonic seizure. There were no other adverse events reported in the IVIG arm during the blinded phase. Conclusions: Superiority of IVIG to placebo reached statistical significance for the primary end point for all patients and the LGI1-IgG seropositive subgroup. These results have to be interpreted with the caveat that the study did not reach its statistically based sample size. Funding: This study was supported by the Grifols Shared Services North America and Option Care. Patient travel and accommodation expenses were supported by a grant from the Autoimmune Encephalitis Alliance.