No Metagenomic Evidence of Causative Viral Pathogens in Postencephalitic Parkinsonism Following Encephalitis Lethargica.

Dániel Cadar,Peter Riederer,Camelia-Maria Monoranu,Dennis Tappe,Sabrina Strobel,Kurt A Jellinger

doi:10.3390/microorganisms9081716

Abstract

Postencephalitic parkinsonism (PEP) is a disease of unknown etiology and pathophysiology following encephalitis lethargica (EL), an acute-onset polioencephalitis of cryptic cause in the 1920s. PEP is a tauopathy with multisystem neuronal loss and gliosis, clinically characterized by bradykinesia, rigidity, rest tremor, and oculogyric crises. Though a viral cause of EL is likely, past polymerase chain reaction-based investigations in the etiology of both PEP and EL were negative. PEP might be caused directly by an unknown viral pathogen or the consequence of a post-infectious immunopathology. The development of metagenomic next-generation sequencing in conjunction with bioinformatic techniques has generated a broad-range tool for the detection of unknown pathogens in the recent past. Retrospective identification and characterization of pathogens responsible for past infectious diseases can be successfully performed with formalin-fixed paraffin-embedded (FFPE) tissue samples. In this study, we analyzed 24 FFPE brain samples from six patients with PEP by unbiased metagenomic next-generation sequencing. Our results show that no evidence for the presence of a specific or putative (novel) viral pathogen was found, suggesting a likely post-infectious immune-mediated etiology of PEP.

Highlights

Encephalitis lethargica (EL, von Economo disease) was an epidemic polioencephalitis of unknown etiology with an acute-onset
Is a tauopathy with multisystem neuronal loss and gliosis accompanied by widespread neurofibrillary lesions, consisting of 3- and 4-repeat (3R and 4R) hyperphosphorylated tau isoforms [4]
postencephalitic parkinsonism (PEP) does not show alpha-synuclein pathology and, differs from idiopathic Parkinson’s disease [5,6]

Summary

Introduction

Encephalitis lethargica (EL, von Economo disease) was an epidemic polioencephalitis of unknown etiology with an acute-onset. The disease was responsible for more than 1 million human cases and half a million deaths during 1917–1925. PEP does not show alpha-synuclein pathology and, differs from idiopathic Parkinson’s disease [5,6]. In the 1920s–1930s, PEP was the most frequent form of parkinsonism. Despite the frequency of EL and PEP, their etiology and pathogenesis are unknown. A viral pathogen or a post-infectious immune-mediated mechanism is probably the cause of PEP, whereas EL is likely of direct viral etiology [1]. As a wide range of viruses is capable of causing acute or delayed neuropathology in humans [7], including, as Microorganisms 2021, 9, 1716.

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