Studies in the experimental pathology of louping-ill encephalitis

Abstract

Aspects of the pathogenesis and neuropathology of louping-ill encephalitis have been investigated in rodents and sheep. In animals inoculated intraperitoneally virus was detected in the circulation before being isolated from nervous tissue. There was, however, no indication as to the means by which virus particles passed from blood to brain. Replication of virus within the central nervous system appeared to be confined to the cytoplasm of nerve cells. In infant hamster cerebellum virions were found within abnormal cytoplasmic membranes in both Purkinje cells and granule cells. Neurons containing these membranes were depleted of granular endoplasmic reticulum and showed loss of Nissl substance. Chromatolysis was seen also in ventral horn cells of moribund sheep but, although viral antigen was demonstrated in the majority of such cells by immunofluorescence, virus particles were not found on ultrastructural examination. Necrosis of ventral horn cells in sheep was accompanied by diminution in acid phosphatase activity and fragmentation of the Golgi apparatus. Onset of symptoms preceded obvious neuronal loss in 75 per cent, of C57 black mice inoculated intraperitoneally. However in most other experiments nerve cell necrosis could be correlated with neurological dysfunction. In infant hamsters and moribund sheep the distribution patterns of neuronal damage and cells containing virus particles and viral antigen were similar. It is concluded that the basic cause of louping-ill is damage of nerve cells by the virus. Neuronal damage in moribund sheep was most apparent in the vestibular nuclei, the motor nuclei, the Purkinje cells of the cerebellum and the ventral horns of the spinal cord. The telencephalon was relativelyunaffected. This distribution of lesions was seen in animals that were inoculated intracerebrally or subcutaneuosly, and in natural cases. Neuropathological changes were more generalized in mice inoculated intra¬ cerebrally, and were not obviously affected either by the strain of host or the presence of concurrent lesions of scrapie. Severe neuron necrosis was seen in infant hamsters and rats, but not in those more than 14 days old at inoculation. In sheep, however, the severity of lesions was similar in all age groups. No general principle can be formulated to explain the distribution of virus infected nerve cells in animals with louping-ill. Virus was detected in nervous tissue before inflammatory changes were apparent. Severe neuron necrosis was seen in all moribund sheep, and inflammatory changes were most marked in those with the longest incubation times. There were slight generalized inflammatory lesions, which were either perivascular or associated with effete neurons, in all surviving sheep and in subclinically affected hamsters and rats. Inflammation is essentially a secondary phenomenon, which occurs after nerve cells are infected with virus. The perivascular cuff was studied intensively in moribund sheep. Histologically most constituents of the cuff appeared to be of the lymphoid type, with a few classical plasma cells and monocytes. The majority were shown to contain globulin in their cytoplasm, when stained with a fluorescent conjugate prepared against sheep IgG. Electron microscopy showed that most of the perivascular inflammatory cells were plasmacytes. Infiltrating cells were also seen to be of the plasma cell type and were observed to enter nervous tissue without causing any obvious damage to either endothelial cells or their basement membranes. Thus perivascular cuffing in sheep with louping-ill results mainly from migration of circulating plasma cells, or plasma cell precursors, into the central nervous system and is a specific response to the presence of viral antigen in the tissues. The inflammatory reaction is a protective mechanism, and is not responsible for the development of symptoms. In this respect it is unlike the histologically similar delayed allergic reaction.