By Padmaja Kandula, MD

Assistant Professor of Neurology and Neuroscience, Comprehensive Epilepsy Center, Weill Cornell Medical College

Dr. Kandula reports no financial relationships relevant to this field of study.

SYNOPSIS: Patients with LGI1 and CASPR2 IgG-associated autoimmune epilepsy were identified and randomized to treatment with intravenous immunoglobulin (IVIG) vs. placebo. The authors hypothesized that IVIG would show superiority over placebo, with a primary endpoint of 50% or greater seizure reduction.

SOURCE: Dubey D, Britton J, McKeon A, et al. Randomized placebo-controlled trial of intravenous immunoglobulin in autoimmune LGI1/CASPR2 epilepsy. Ann Neurol 2020;87:313-323.

The last decade has brought increasing attention to autoimmune etiologies for fulminant epilepsy. As the number autoantibodies discovered continues to increase, the quest for the most optimal treatment regimen becomes more challenging, particularly in an aging population. Autoantibodies against the extracellular domain of leucine-rich, glioma-inactivated 1 (LGI1) and conactin-associated protein-like 2 (CASPR2) can be associated with seizures. Patients with autoimmune disorders often are nonresponsive to traditional anticonvulsant agents, and practitioners have resorted to treating patients empirically with immune therapies, based on case series or expert opinion.

In this study, the investigators designed a randomized, placebo-controlled trial to evaluate the efficacy of intravenous immunoglobulin (IVIG) vs. placebo in LGI1 and CASPR2 IgG-associated autoimmune epilepsies.

Between 2016-2018, patients were identified through the Mayo Clinic Neuroimmunology Laboratory and recruited to either the placebo or treatment (IVIG) arm following patient and treating-physician consent. The enrollment goal was 30 patients, but because of slow enrollment only 17 patients (eight IVIG and nine placebo) were randomized over 34 months. The treatment group received IVIG (0.5 g/kg) on day 1, week 1, and IVIG (1 g/kg) on day 2, week 1. Once every two weeks, patients received 0.6 g/kg IVIG for weeks 3 and 5. In a similar fashion, patients in the placebo group also received four volume-matched infusions with the same infusion schedule. All patients were evaluated at the end of the five-week course, and blinding was removed. Nonresponders in the placebo group then were treated with IVIG. All patients remained on a stable dose of anticonvulsants during the blinded five-week course.

Complete neurologic examinations and cognitive assessment (Repeatable Battery for the Assessment of Neuropsychological Status, or RBANS) were performed at baseline and at five weeks. RBANS is a standardized battery assessing five major cognitive domains in 12 subsets. Electroencephalographic data and seizure diaries were reviewed. Primary clinical outcome was 50% or greater seizure reduction from baseline. Secondary outcome measures included RBANS scoring.

Three-quarters of the IVIG treatment group met the primary endpoint for 50% or greater seizure reduction at baseline vs. 22% in the placebo arm. Two LGI1-IgG seropositive patients receiving IVIG, but none in the placebo group, were seizure-free at five weeks. The three CASPR2-IgG patients received placebo, with one patient reporting 50% or greater seizure reduction and another patient reporting seizure freedom at the five-week mark. The median change in RBANS score among the IVIG treated LGI1-IgG patients showed a group trend toward cognitive improvement vs. the placebo group. In the open-label arm, seven of the nine patients receiving placebo subsequently received open-label IVIG. One of the seven patients (CASPR2-IgG) received IVIG for treatment of ataxia, and not for persistent seizures. Of the six patients with persistent seizures after placebo, four had 50% or greater seizure reduction over the 11 weeks. However, there were no seizure-free patients. All seven patients showed improvement or stabilization of RBANS scores.

Overall, treatment was well-tolerated. One patient developed headaches during open-label IVIG treatment and another patient developed generalized body rash, initially attributed to IVIG and later attributed to concurrent anticonvulsant treatment with levetiracetam. In total, 15 patients (eight during the blinded phase and seven during open label) eventually completed IVIG treatment, and three patients became seizure-free. The remaining 12 patients received either concomitant high-dose intravenous steroids, mycophenolate mofetil, plasmapheresis, oral prednisone, or recurrent IVIG, with seizure freedom of about 56%.

COMMENTARY

In this study, the investigators provided objective evidence to support extensive clinical experience. Although the study numbers were small, IVIG was statistically superior to placebo and achieved a favorable seizure response rate with either stable or improved cognitive profile and no persistent adverse effects in either the blinded or the open-label arms of the trial.

However, few patients achieved complete seizure freedom with initial IVIG monotherapy. With additional adjunctive intravenous steroids (after the blinded or open-label phase), the majority of patients achieved seizure freedom, begging the question of whether concurrent treatment with IVIG and intravenous steroids may lead to earlier and sustained seizure remission.