The Distribution of Inflammation and Virus in Human Enterovirus 71 Encephalomyelitis Suggests Possible Viral Spread by Neural Pathways

TLDR

Enterovirus 71 encephalomyelitis has been studied neuropathologically, but the detailed anatomic distribution of inflammation and viral localization in the CNS has not been examined. In seven autopsy cases, EV71 infection produced a stereotyped CNS inflammation pattern—most pronounced in spinal cord gray matter, brainstem, hypothalamus, and subthalamic/dentate nuclei, with focal motor cortex involvement and sparing of cerebellar cortex, thalamus, basal ganglia, peripheral nerves, and autonomic ganglia—characterized by perivascular cuffs, edema, neuronophagia, and microglial nodules, predominantly CD68+ macrophages, while viral antigens and RNA were confined to a few neurons and phagocytic cells, supporting neuronotropic spread via motor neural pathways rather than hematogenous routes.

Abstract

Previous neuropathologic studies of Enterovirus 71 encephalomyelitis have not investigated the anatomic distribution of inflammation and viral localization in the central nervous system (CNS) in detail. We analyzed CNS and non-CNS tissues from 7 autopsy cases from Malaysia and found CNS inflammation patterns to be distinct and stereotyped. Inflammation was most marked in spinal cord gray matter, brainstem, hypothalamus, and subthalamic and dentate nuclei; it was focal in the cerebrum, mainly in the motor cortex, and was rare in dorsal root ganglia. Inflammation was absent in the cerebellar cortex, thalamus, basal ganglia, peripheral nerves, and autonomic ganglia. The parenchymal inflammatory response consisted of perivascular cuffs, variable edema, neuronophagia, and microglial nodules. Inflammatory cells were predominantly CD68-positive macrophage/microglia, but there were a few CD8-positive lymphocytes. There were no viral inclusions; viral antigens and RNA were localized only in the somata and processes of small numbers of neurons and in phagocytic cells. There was no evidence of virus in other CNS cells, peripheral nerves, dorsal root autonomic ganglia, or non-CNS organs. The results indicate that Enterovirus 71 is neuronotropic, and that, although hematogenous spread cannot be excluded, viral spread into the CNS could be via neural pathways, likely the motor but not peripheral sensory or autonomic pathways. Viral spread within the CNS seems to involve motor and possibly other pathways.