Randomized Placebo‐Controlled Trial of Intravenous Immunoglobulin in Autoimmune LGI1/CASPR2 Epilepsy

Abstract

Objective: Drug-resistant seizures are common in patients with leucine-rich, glioma-inactivated 1 (LGI1)-IgG associated 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 weeks 3 and 5) or volume-matched intravenous normal saline. Following the blinded phase, the nonresponders 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 8 patients in the IVIG group were responders, compared to 2 of 9 in the placebo group (p = 0.044, odds ratio = 10.5, 95% confidence interval = 1.1-98.9). 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 6 patients entering the open-label IVIG arm reported ≥50% reduction in seizure frequency. There were no correlations with LGI1/ CASPR2-IgG1-4 subclasses. Interpretation: Superiority of IVIG to placebo reached statistical significance for the primary endpoint 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.

Combining clinical and molecular heterogeneity within CASPR2-antibody mediated diseases: towards the underlying disease biology

“…Hence, with a frequency akin to HLA-DRB1*07:01 in patients with LGI1-antibodies, 6 a single allelic HLA association of CASPR2-antibodies in CNS diseases may almost be the rule. 7 This finding now awaits confirmation: analysis of our published cases showed a less striking bias given 13/22 (59%) with exclusive CNS features carried HLA-DRB1*11:01, compared with 2/5 (40%) with PNH +/-. Despite incomplete data sets for some patients, Muñiz-Castrillo et al illustrate a simple yet elegant method to use the fundamental biology to (re)define the clinical syndrome.…”

Long-term Outcomes of Patients with Anti–Leucine-Rich Glioma-Inactivated 1 Encephalitis

“…A total of 19 (16%) patients experienced a relapse in our cohort, indicating that the overall prognosis of anti-LGI1 encephalitis is good, and this nding is consistent with previous studies. 1,8,11 A report from the United States on clinical syndrome and long-term follow-up of anti-LGI1 encephalitis stated that 67% of 21 patients who were followed up for more than 2 years had a favorable outcomes. 4 These data are consistent with a good prognosis for anti-LGI1 encephalitis, although some differences may be related to race, region, and number of cases.…”

“…A total of 117 patients, who were diagnosed with anti-LGI1 encephalitis according to the diagnostic criteria suggested by previous studies 6,8 , were retrospectively selected from the database of 5 , and γ-aminobutyric acid receptor-B (GABABR) from 49 patients were assessed by indirect immuno uorescence tests in serum or CSF. The protocol for indirect immuno uorescence was followed according to the instructions provided by the manufacturer (Euroimmun, Germany).…”

“…According to previous reports, there are differences between countries in clinical features and treatment strategies of anti-LGI1 encephalitis. 4,5,8,9 China proposed a consensus for the management of AE in 2017 to better identify and manage this disease in Chinese patients. 10 Due to the lack of reports with relatively large sample sizes and since an AE-related antibody analysis is not routinely performed, the data of clinical characteristics and long-term prognoses of Chinese patients with anti-LGI1 encephalitis is limited.…”

Immunologic Treatments of Seizures and Status Epilepticus

“…Despite the small sample size for the LGI1-IgG seropositive subgroup, 6 of 8 patients in the IVIG group were responders compared with 0 of 6 in the placebo group, demonstrating superiority of IVIG to placebo. 44 Recent validated models have been created to predict seropositivity of neural-specific antibodies and immunotherapy trial response in epilepsy (►Table 1). These models include clinical variables (e.g., inflammatory CSF, refractory seizures) that were retrospectively identified to be significantly associated with neural autoantibody positivity or favorable immunotherapy outcomes.…”