Autoantibodies and cell-mediated autoimmunity to NMDA-type GluRepsilon2 in patients with Rasmussen's encephalitis and chronic progressive epilepsia partialis continua

Abstract

Purpose: To evaluate antibody-mediated and cytotoxic T cell-mediated pathogenicity that has been implicated as the autoimmune pathophysiological mechanism in Rasmussen's encephalitis.

Methods: We examined autoantibodies against the N-methyl-d-aspartate glutamate receptor (NMDA-type GluR) epsilon2 subunit and its epitopes in serum and CSF samples from 20 patients [five histologically proven (definitive) Rasmussen's encephalitis with epilepsia partialis continua (EPC), four definitive Rasmussen's encephalitis without EPC, and 11 clinical Rasmussen's encephalitis with EPC]. We examined 3H-thymidine uptake into lymphocytes after stimulation by GluRs.

Results: All nine definitive patients (five patients with EPC and four without EPC), and 10 of 11 clinical Rasmussen's encephalitis patients had the autoantibodies. In four patients, the autoantibodies were absent in early stage when epileptic seizures had already become frequent, and appeared subsequently. In two patients, the autoantibodies persisted in the serum after frontal lobe resection or functional hemispherectomy, although epileptic seizures were completely controlled. Autoantibodies to the C2 epitope predominated, while autoantibodies to the extracellular N epitope were rare. The mean 3H-thymidine uptake ratios (stimulation by GluRepsilon2-containing homogenates/stimulation by PHA) were significantly higher in definitive and clinical Rasmussen encephalitis patients than in controls. The mean 3H-thymidine uptake ratios (relative to PHA) were significantly higher for GluRepsilon2-containing homogenate than for control homogenate or GluRdelta2-containing homogenate.

Conclusions: Autoantibodies against GluRepsilon2 may be one of the diagnostic markers for Rasmussen's encephalitis with and without EPC. Patients have activated T cells stimulated by GluRepsilon2 in peripheral blood circulation. We speculate that cellular autoimmunity and the subsequent humoral autoimmunity against GluRepsilon2 may contribute to the pathophysiological processes in Rasmussen's encephalitis.