Studies of Spanish influenza and encephalitis lethargica
Concomitant with the Spanish influenza and extending to the 1920s encephalitis lethargica (EL), also termed von Economo's disease or sleepy sickness, occurred in epidemic proportion. A previous epidemic of encephalitis lethargica also appeared at the time of 1889 influenza pandemic. Certain clinical and pathological features of encephalitis lethargica of 1916-1920 strongly suggested a viral aetiology and subsequently it was suggested that influenza virus was the responsible pathogen (Ravenholt & Foege, 1982). Sensitive molecular techniques are now available which can be applied both to fresh tissue and old formalin fixed and paraffin blocked sections using RT-PCR. Recent genetic analyses of haemagglutinin (HA) and neuraminidase (NA) genes of 1918 influenza virus have failed to identify virulence motifs (Taubenberger et al., 1997 & 1999; Reid et al., 1999,2000 & 2002). These methods were applied to eight brain samples from patients who died of encephalitis lethargica in 1916-1920 for the presence of influenza genes. The sections of brain from eight archival, unique cases of EL had been neuropathologically reviewed and the diagnosis confirmed prior to analysis using established reverse transcription-polymerase chain reaction (RT-PCR). Although our genetic study detected ß-actin genes in the archived brains, we found no evidence of influenza genes. An animal model of influenza neuropathogenesis was established for investigations of the localisation of influenza genes in brain tissue using in situ hybridisation (ISH). Influenza gene sequences were detected in ependymal cells, choroid plexus, hippocampal neurons, periventricular regions of the lateral ventricle and cerebral aqueduct, and cells of the raphe nucleus. A persistent influenza infection in the brains of infected mice is reported. Therefore short influenza sequences could, in theory and based on a simple longevity comparison of man and mouse, be detected in brain tissues of infected subjects for a period of 1.9 -6.7 years after its initial exposure to influenza infection.