Objective:

This study aimed to investigate the underlying etiology of CNS diseases in Japanese patients.

Background:

Identifying the etiology of central nervous system (CNS) diseases, regardless of their infectious or non-infectious nature, is often intricate. Next-generation sequencing (NGS) has emerged as a powerful tool for sensitive and unbiased screening of tissue or body fluid specimens. 

Design/Methods:

Between April 2013 and October 2021, we collected brain tissue samples from 35 patients diagnosed with encephalitis or encephalitis-like CNS diseases, obtained via biopsy or autopsy. We utilized shotgun metagenomics NGS on brain tissues (mNGS-bt) to identify potential pathogens by analyzing non-human sequences against the BLAST nucleotide database. Comprehensive clinical, serological, pathological, and genetic assessments ensured the precision of pathogen identification.

Results:

Among the 35 patients, mNGS-bt elucidated pathogen-specific genomic sequences in eight cases (22.9%), including halobacteria (two cases), Balamuthia mandrillaris (one case), Epstein–Barr virus (two cases), JC polyomavirus (one case), toxoplasma gondii (one case), and herpes simplex virus (one case). Several cases exhibited concurrent infections with multiple pathogens. Fourteen cases without pathogen sequences, indicative of non-infectious CNS diseases (40%), were diagnosed with neoplastic diseases (seven cases), autoimmune/inflammatory disorders (six cases), and amyloid angiopathy (one case). 

Conclusions:

This study, featuring the most substantial brain tissue sample collection to date, demonstrates that integrating mNGS-bt with comprehensive analyses substantially improves etiological diagnoses, with 62.9% (22/35) of cases attributed to infectious or non-infectious causes. These findings highlight the potential of mNGS-bt as a primary screening tool for patients with encephalitis or encephalitis-like CNS diseases of unknown etiology.