Encephalitis lethargica and influenza: was there a relationship?

Joel A. VILENSKY1, Sherman McCALL2 and Sid GILMAN3
1Indiana School of Medicine, Ft. Wayne, USA.  vilensk AT ipfw.edu
2Department of Molecular Pathology and genetics, Armed Forces Institute of Pathology, Washington, DC, USA.  Sherman.McCall AT afip.osd.mil
3Department of Neurology, University of Michigan, Ann Arbor, USA.  sgilman AT umich.edu

Encephalitis lethargica (EL) was a highly polymorphic neurological epidemic disease that occurred primarily 1916-1925 and killed as many as 500,000 people worldwide. During the epidemic period some investigators posited an etiological and/or epidemiological relationship between this disease and the approximately contemporaneous “Spanish” influenza epidemic. Others were certain the two diseases were unrelated. Since the epidemic period this debate has continued with a few publications beginning in the 1970s describing the use of modern molecular/biochemical techniques to examine brain tissue/serum from EL victims and/or postencephalitic parkinsonian (a sequel of EL) patients to investigate whether influenza caused EL. The majority of these studies have concluded that there is no evidence that the influenza virus caused EL.

Although the data supporting a causal relationship between influenza and EL are weak, the data negating such a relationship are not as strong as generally perceived. Most important is that the clinical data on the subjects are often limited or problematic, making it possible that the subjects did not have EL. In addition, there is a myriad of technical limitations that might have caused false negatives in the experimental studies. Probably the most important is stage of infection; most cases available for testing were stricken with EL a lengthy period before their deaths, so viral fragments may no longer have been present.

Also, viral degradation undoubtedly occurred due to tissue autolysis during the postmortem interval: 1) formalin fixation is suboptimal for molecular studies; 2) samples were stored 80 years without climate control; and, 3) lysate processing from formalin-fixed, paraffin-embedded tissue is difficult. All of these factors adversely affect the amount of RNA that can be extracted.

Current empirical studies provide little evidence of influenza causation, but technical limitations and the shortage of appropriate historical material for testing make it difficult to exclude a relationship between EL and influenza with confidence.

Symposium.  Encephalitis Lethargica
Thursday, 21 June 2007, 9:30 - 11:15 am

12th Annual Meeting of the International Society for the History of the Neurosciences   (ISHN)
Los Angeles, California, USA, 19-23 June 2007