Anticonvulsant prolongation of survival in adult murine lymphocytic choriomeningitis. I. Drug treatment and virologic studies.

Lymphocytic choriomeningitis virus-induced central nervous system disease is characterized by death during a seizure approximately seven days after intracerebral inoculation. This process is mediated by thymus dependent lymphocytes, sensitized against viral antigens. Various forms of immunosuppressive treatment prevent the seizure death and produce persistently infected survivors. In this study, anticonvulsant treatment (particularly diazepam treatment) of LCM virus infected mice prolonged survival without affecting viral replication, or suppressing immune responsiveness. This prolongation of life did not lead to a reversal of pathologic processes and there were no survivors. However, anticonvulsant treatment permitted study of more advanced stages of the choriomeningitis than has previously been possible.

Anticonvulsant prolongation of survival in adult murine lymphocytic choriomeningitis. II. Ultrastructural observations of pathogenetic events.

Because previous ultrastructural studies of murine lymphocytic choriomeningitis (LCM) had revealed only mononuclear cell infiltration with no cytopathology of target cells in the choroid plexus, ependyma, and leptomeninges, diazepam treatment was used to prolong survival for characterization of late pathogenetic events. Mice which were treated with diazepam and sacrificed 8, 9, and 10 days after intracerebral inoculation with LCM virus showed an increasing amount of inflammatory infiltration into choroid plexuses, leptomeninges, Virchow-Robin spaces, and ependyma. Mononuclear cells, lymphocytes, and polymorphonuclear (PMN) leukocytes increased in number as compared with terminally infected mice sacrificed 7 days after inoculation. Ultrastructurally, choroidal epithelial cells showed cytopathological changes varying from dilated endoplasmic reticulum through necrosis. Greater numbers of PMN leukocytes, macrophages, and activated macrophages and fewer undifferentiated mononuclear cells were seen in choroid plexuses of the drug-treated survivors. Virions and larger, more numerous arenavirus inclusions were present in choroid plexus and ependyma. Ultrastructurally the leptomeningitis was characterized by large numbers of activated macrophages. Choroidal epithelial necrosis appears to be the in vivo correlate of T-cell-mediated cytotoxicity in vitro.