TY - JOUR
T1 - Randomized Placebo-Controlled Trial of Intravenous Immunoglobulin in Autoimmune LGI1/CASPR2 Epilepsy
AU - Dubey, Divyanshu
AU - Britton, Jeffrey
AU - McKeon, Andrew
AU - Gadoth, Avi
AU - Zekeridou, Anastasia
AU - Lopez Chiriboga, Sebastian A.
AU - Devine, Michelle
AU - Cerhan, Jane H.
AU - Dunlay, Katie
AU - Sagen, Jessica
AU - Ramberger, Melanie
AU - Waters, Patrick
AU - Irani, Sarosh R.
AU - Pittock, Sean J.
N1 - Funding Information:
This study was supported by Grifols Shared Services North America, Option Care, and the Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology. Patient travel and accommodation expenses were supported by a grant from the Autoimmune Encephalitis Alliance. M.R. is supported by the Austrian Science Fund (FWF J4157‐B30). S.R.I. is supported by the Wellcome Trust (104079/Z/14/Z), the British Medical Association research grants Vera Down grant (2013) and Margaret Temple grant (2017), Epilepsy Research UK (P1201), and the Encephalitis Society. The research was funded/supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (the views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. We thank G. Ayer for methodological guidance and continued support for the study; E. Polley, S. Bryant, and M. Masoud for statistical support; all the physicians who kindly referred their patients for inclusion in the study; and the patients and their families for participation in this study.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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. ANN NEUROL 2020;87:313–323.
AB - 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. ANN NEUROL 2020;87:313–323.
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U2 - 10.1002/ana.25655
DO - 10.1002/ana.25655
M3 - Article
C2 - 31782181
AN - SCOPUS:85076764098
VL - 87
SP - 313
EP - 323
JO - Annals of Neurology
JF - Annals of Neurology
SN - 0364-5134
IS - 2
ER -