Hypothetical pathophysiology of acute encephalopathy and encephalitis related to influenza virus infection and hypothermia therapy

BACKGROUND: To establish a treatment strategy for acute encephalopathy and encephalitis associated with influenza virus infection, the pathophysiology of the disease was investigated through manifestations and laboratory findings of patients. PATIENTS AND METHODS: A child with central nervous system (CNS) complications during the course of influenza virus infection was analyzed in view of immunologic abnormalities. In addition, four children with acute encephalopathy and encephalitis were enrolled in the hypothermia treatment for the purpose of stabilizing the cytokine storm in the CNS. RESULTS: The CNS symptoms preceded the systemic progression to the failure of multiple organs (MOF) and disseminated intravascular coagulopathy (DIC). The mild hypothermia suppressed the brain edema on computed tomography (CT) scanning and protected the brain from the subsequent irreversible neural cell damage. CONCLUSION: The replicated viruses at the nasopharyngeal epithelium may disrupt the olfactory mucosa and gain access to the brain via the olfactory nerve system. The direct virus-glial cell interaction or viral stimulation of the glial cells induces the production and accumulation of the pro-inflammatory cytokines, especially tumor necrosis factor (TNF)-alpha, in the CNS. The cytokine storm results in neural cell damage as well as the apoptosis of astrocytes, due to the TNF-alpha-induced mitochondrial respiratory failure. The disruption of the blood-brain barrier progresses to the systemic cytokine storm, resulting in DIC and MOF. Mild hypothermia appears promising in stabilizing the immune activation and the brain edema to protect the brain from ongoing functional, apoptotic neural and glial damage and the systemic expansion of the cytokine storm.