Medical and molecular perspectives into a forgotten epidemic: Encephalitis lethargica, viruses, and high-throughput sequencing

• Encephalitis lethargica was an epidemic polioencephalitis (1920s) followed by parkinsonism.
• A viral etiology is supported by clinical, histopathological, and epidemiological data.
• Several candidate organisms have been proposed without promising or confirmed results.
• Current expanding high-throughput sequencing methods may offer new etiological insight.

The emergence of encephalitis lethargica (EL), an acute-onset polioencephalitis of unknown etiology as an epidemic in the years 1917–1925 is still unexplainable today. Questioned by the first descriptor of EL himself, Constantin von Economo, there has been much debate shrouding a possible role of the “Spanish” H1N1 influenza A pandemic virus in the development of EL. Previous molecular studies employing conventional PCR for the detection of influenza A virus RNA in archived human brain samples from patients who died of acute EL were negative. However, the clinical and laboratory characteristics of EL and its epidemiology are consistent with an infectious disease, and recently a possible enterovirus cause was investigated. With the rapid development of high-throughput sequencing, new information about a possible viral etiology can be obtained if sufficient specimens for analysis were still available today. Here, we discuss the implications of these technologies for the investigation of a possible infectious cause of EL from archived material, as well as a prospectus for future work for acquiring viral nucleic acids from these sources.