BALTIMORE –
Although the numbers of enrolled subjects was small, it was the first double-blind, placebo-controlled randomized trial in autoimmune epilepsy, the start of a level 1 evidence base. Until now, treatment has been based mostly on case reports and expert opinion. “We’ve clearly shown that immunotherapy works and that treating early makes a difference, much more so than antiseizure medications,” said lead author Divyanshu Dubey, MBBS, from the Mayo Clinic.
The lack of data has meant that “we couldn’t get insurance approval for IVIG, so people have generally leaned towards” high-dose intravenous steroids, which are problematic because LGI-1 antibody epilepsy is a disease of older people, in whom osteoporosis, underlying infections, and other problems complicate steroid use, Dr. Dubey said.
The trial also included three people with contactin-associated-protein-like-2 (CASPR2) antibody epilepsy, but they all wound up in the placebo arm, “so it’s hard to say anything about them,” Dr. Dubey said at the American Epilepsy Society annual meeting. The work was published shortly before the meeting (Ann Neurol. 2019 Nov 28. doi: 10.1002/ana.25655).
CASPR2 and LGI-1 are proteins found in brain cells; attack by antibodies triggers encephalitis and tens to hundreds of seizures per day. The seizures tend to diminish with time, but the cognitive damage caused by the encephalitis does not. “We’ve seen patients end up in nursing homes diagnosed with Alzheimer’s disease” because the conditions weren’t recognized and treated, Dr. Dubey said.
He and his team chose LGI-1 and CASPR2 epilepsy because of the potentially devastating consequences and because they are among the most common autoimmune epilepsies for which antibodies have been identified. There was also a hope that positive results might open up insurance coverage.
The trial randomized eight people to IVIG 0.5 g/kg on day 1; 1 g/kg on day 2; and 0.6 g/kg once at 3 and 5 weeks. Nine others were randomized to volume-matched IV saline placebo on the same schedule. After enrollment of 17 patients (LGI1-IgG, 14; CASPR2-IgG, 3) over 34 months, the study was terminated because of slow enrollment.
Although none of the LGI-1 subjects in the placebo group responded, two CASPR2 patients did, yielding an IVIG response rate of 75% versus 22% (2/9) in the placebo arm after week 5 (odds ratio, 10.5; 95% confidence interval, 1.1-98.9; P = .044).
Two of the LGI-1 subjects in the IVIG arm were completely seizure free after treatment. Results in both arms, meanwhile, did not correlate with concomitant antiseizure medications among those who were on them.
All eight IVIG patients showed stabilization or improvement in cognitive function, compared with two of five in the placebo arm, as gauged by Repeatable Battery for the Assessment of Neuropsychological Status scores. Patients in the IVIG arm gained a median of 3 points, while patients in the placebo arm lost a median of 1 point (P = .077).
At week 5, six patients with persistent seizures who were in the placebo group were switched to the IVIG regimen after unblinding; four (67%) reported more than a 50% reduction in seizures.
Responses did not correlate with LGI-1/CASPR2-IgG1-4 subclass, and there were no IVIG-associated adverse events. One IVIG patients fell because of a faciobrachial dystonic seizure, a classic sign of LGI-1 disease. Antibodies were not measured in the trial because they “do not correlate with severity of autoimmune epilepsy,” Dr. Dubey said.
The original plan was to enroll 30 subjects, but the investigators terminated the study after 18 because of slow enrollment. With knowledge of autoimmune epilepsy growing at Mayo, it was increasingly difficult to find immunotherapy-naive patients, he said.
All the subjects were between 60 and 70 years old, and the majority in both arms were men, which was not surprising because the conditions skew male, Dr. Dubey said. None of the patients had underlying tumors, which are known triggers of autoimmune epilepsy.
This work was funded by Grifols Shared Services, a maker of IVIG, and Option Care, a provider of home infusion equipment. Dr. Dubey said the company had no active role in the trial, but that the lack of insurance coverage for IVIG in autoimmune epilepsy was one of the drivers of the study. He disclosed research support from Grifols; another investigator is a consultant.
SOURCE: Dubey D et al. AES 2019, Abstract 1.292.