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Influenza virus infection has been associated with a variety of neurologic complications. The objective of this study was to evaluate prospectively the role of influenza viruses in acute childhood encephalitis/encephalopathy (ACE).All children admitted to the Hospital for Sick Children, Toronto, during an 11-year period with ACE and evidence of acute influenza virus infection were included. Acute influenza virus infection was defined by detection of the organism in the nasopharynx by direct immunofluorescence microscopy or viral culture and/or by a 4-fold or greater rise in complement fixation titer.A total of 311 children with ACE were evaluated; evidence of influenza infection was detected in 7% (22 of 311). Eight were excluded from the main analysis because of evidence implicating other potential pathogens. Eleven of the 14 included subjects were <5 years of age. A respiratory prodrome was documented in 93% of subjects. In 64% neurologic manifestations developed within 5 days of onset of respiratory symptoms. Neuroimaging abnormalities were more common in children <2 years of age. Neurologic sequelae occurred in more than one-half of subjects.In this prospective registry, influenza virus infection was associated with 5% of ACE cases. The majority of children were <5 years of age and the prevalence of neuroimaging abnormalities was higher in children <2 years of age suggesting that younger children are predisposed to the neurologic complications of influenza. An acute rather than a postinfectious process was suggested by the briefness of the respiratory prodrome in most cases.