Abstract
BackgroundThe epidemic of encephalitis lethargica (EL), called classical EL, was rampant throughout the world during 1917–1926, affecting half a million persons. The acute phase was lethal for many victims. Post-encephalitic parkinsonism (PEP) affected patients for decades. Our purpose was to investigate the cause of classical EL by studying the few available brain specimens. Cases of PEP and modern EL were also studied. Transmission electron microscopy (TEM) and immunohistochemistry were employed to examine brain from four classical EL cases, two modern EL cases and one PEP case.MethodsStandard methods for TEM, immunohistochemistry and RTPCR were applied.Results27 nm virus-like particles (VLP) were observed in the cytoplasm and nuclei of midbrain neurons in all classical EL cases studied. Large (50 nm) VLP and 27 nm intranuclear VLP were observed in the modern EL cases and the PEP case. Influenza virus particles were not found. VLP were not observed in the control cases. TEM of cell cultures inoculated with coxsackievirus B4 and poliovirus revealed both small and large intranuclear virus particles and small cytoplasmic particles, similar to the VLP in EL neurons. In the EL brains, nascent VLP were embedded in putative virus factories and on endoplasmic reticulum (ER). The VLP in the cases of classical EL survived, whereas ribosomes underwent autolysis due to the lack of refrigeration and slow formaldehyde fixation of whole brain. The VLP were larger than ribosomes from well preserved brain. Immunohistochemistry of classical EL cases using anti-poliovirus and anti-coxsackievirus B polyclonal antibodies showed significant staining of cytoplasm and nuclei of neurons as well as microglia and neuropil. Purkinje cells were strongly stained.A 97-bp RNA fragment of a unique virus was isolated from brain tissue from acute EL case #91558. Sequence analysis revealed up to 95% identity to multiple human Enteroviruses. Additional cases had Enterovirus positive reactions by real time PCR.ConclusionsThe data presented here support the hypothesis that the VLP observed in EL tissue is an Enterovirus.
Highlights
The epidemic of encephalitis lethargica (EL), called classical EL, was rampant throughout the world during 1917–1926, affecting half a million persons
Analysis by Transmission electron microscopy (TEM) A selection of TEM images is presented of control human brain, brain from classical EL, two modern EL cases and one case of Post-encephalitic parkinsonism (PEP)
1) The developing virus-like particles (VLP) were either in putative virus factories or nascent VLP particles attached to endoplasmic reticulum (ER) membranes
Summary
The epidemic of encephalitis lethargica (EL), called classical EL, was rampant throughout the world during 1917–1926, affecting half a million persons. Cases of PEP and modern EL were studied. Encephalitis lethargica occurred suddenly in 1916–17 as an epidemic that was simultaneously reported in Vienna and in France, and continued until 1926, when it gradually disappeared. Church et al [3], reporting on a series of modern EL cases, suggested that EL is an autoimmune disorder. They based this on clinical presentation, intrathecal oligoclonal bands (OCB), anti-streptolysin-O titers and autoantibodies reactive against human basal ganglia antigens in EL patients. While Dale et al offer indirect evidence (see Discussion), our study presents direct evidence for a specific Enterovirus etiology for both classical and modern EL
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
