Influenza caused epidemic encephalitis (encephalitis lethargica): the circumstantial evidence and a challenge to the nonbelievers

Med Hypotheses. 2010 May;74(5):798-801. doi: 10.1016/j.mehy.2009.12.012. Epub 2010 Jan 8.


Twenty years ago, circumstantial evidence was compiled to link the 1918 pandemic influenza virus to a CNS disorder called epidemic encephalitis or encephalitis lethargica. A challenge was issued to naysayers. During the past two decades, the knowledge about the influenza virus and the 1918 pandemic virus in particular has had dramatic advancement. The 1918 virus has been resurrected and reconstructed. Experimental studies of mice inoculated with a neurovirulent avian virus have delineated the neuropathology of influenza encephalitis. Review of autopsy cases of encephalitis lethargica revealed that the neuropathology during and shortly after the pandemic was unique. Surprisingly two different viruses were involved with the great pandemic. A single amino acid difference in the hemagglutinin of the two viruses changed the preferred receptor of the virus in the host cell. One virus has qualities that suggest that it is neurovirulent. Circumstantial evidence suggests that the cause of death in some influenza patients was neurogenic congestive heart failure with pulmonary edema. Theories about the pathophysiology of encephalitis lethargica and postencephalitic Parkinson's disease are offered.

Publication types

  • Case Reports
  • Historical Article

MeSH terms

  • Adult
  • Animals
  • Disease Outbreaks / history*
  • Encephalitis, Viral / epidemiology
  • Encephalitis, Viral / etiology*
  • Encephalitis, Viral / pathology
  • Fatal Outcome
  • Hemagglutinin Glycoproteins, Influenza Virus / genetics
  • History, 20th Century
  • Humans
  • Influenza A Virus, H1N1 Subtype*
  • Influenza, Human / complications*
  • Influenza, Human / epidemiology
  • Influenza, Human / history
  • Male
  • Mice
  • Mutation, Missense / genetics
  • Parkinson Disease, Postencephalitic / pathology


  • H1N1 virus hemagglutinin
  • Hemagglutinin Glycoproteins, Influenza Virus