Introduction The West syndrome or epilepsy with epileptic sp
The West syndrome or epilepsy with epileptic spasms (ES) is an epileptic encephalopathy in early infancy with probable seizure-related developmental regression. According to the United Kingdom Infantile Spams Study (UKISS), common causes of infantile spasms include hypoxic-ischemic encephalopathy (10%), chromosomal anomalies (8%), malformation (8%), perinatal stroke (8%), tuberous sclerosis complex (7%), and periventricular leukomalacia, hemorrhage (5%). Recent genetic studies revealed infantile spasms caused by abnormalities of genes such as cyclin-dependent kinase-like 5 (CDKL5), Aristaless-related homeobox, X-linked (ARX), syntaxin binding protein 1 (STXBP1), and spectrin alpha non-erythrocytic 1 (SPTAN1). Although advances in imaging and genetic screening technologies have reduced the proportion of patients with unknown cause, there remain many patients whose causative diseases are not identified. Furthermore, in spite of many enthusiastic studies, the epileptic mechanisms and the mechanisms of developmental impairment in patients with West syndrome or ES remain unknown. Although ES is refractory to various antiepileptic drugs, MK 886 therapy is effective for seizure inhibition in 47–93%,3, 4 and resolution of hypsarrhythmia in 50–89% of the patients, and ES occasionally remit spontaneously after a viral infection. These findings suggest that immunological mechanisms may affect the pathophysiology of ES.
The characteristics of immunological factors including cytokines and lymphocyte subsets in cerebrospinal fluid (CSF) and peripheral blood in patients with ES have been studied, but there are few studies that focus on autoantibodies against neural molecules in these patients. Recently, neural autoantibodies in the serum of patients with various epilepsy syndromes have been studied, and patients with focal epilepsy of “unknown cause” are proposed to be candidates for immune therapy.
In our research history of Rasmussen syndrome and acute limbic encephalitis with antibodies to N-methyl-d-aspartate (NMDA)-type glutamate receptor (GluR), we have developed methods for detecting antibodies to glutamate receptors (GluN2B, GluN1, GluD2, etc) by immunoblot, enzyme-linked immunosorbent assay (ELISA), etc. Triheteromeric NMDA-type GluRs (GluN1/GluN2A/GluN2B) constitute the major population of NMDA-type GluRs in adult hippocampal synapses and Glu2B is prominent in adult hippocampal synapses as an integral part of NR1/NR2A/NR2B receptors. Therefore, we investigated antibodies against NMDA-type GluR in the CSF of patients with ES to investigate the immunological mechanisms involved in epilepsy and developmental delay in these patients.
Discussion We studied antibodies against peptides of NMDA-type GluR subunits, mainly GluN2B-NT2 and GluN2B-CT, in the CSF of patients with ES to elucidate the contribution of immunological mechanisms to the clinical features. We found higher CSF levels of antibodies to GluN2B-NT2, GluN2B-CT, and GluN1-NT in ES patients, and levels of antibodies against GluN2B-NT2 and GluN2B-CT GluN2B-NT2 and GluN2B-CT showed positive correlation with intervals from the onset of ES to the examination in a linear regression model until 25 months after the onset of ES. These data suggest that some patients with ES may have antibodies against several kinds of NMDA-type GluR subunits in the CSF and these antibodies are produced after the onset of ES, probably associated with neural damages, similar to the antibodies in Rasmussen syndrome. In Rasmussen syndrome, the antibodies increase to the highest levels from 12 to 23 months after epilepsy onset, and are associated with seizure aggravation. In patients with ES and Rasmussen syndrome, continuation of epileptic seizures may induce seizure-related neural damages, resulting in increasing supply of neural antigens and immunomodulatory factors. These may contribute to the production of antibodies to neural molecules, including NMDA-type GluRs.