The role of plasma metagenomic sequencing in identification of Balamuthia mandrillaris encephalitis

Balamuthia mandrillaris is a rare, free-living amoeba (FLA) that causes granulomatous amoebic encephalitis, a disease with close to 90% mortality. The geographical ranges of many FLA are expanding, potentially increasing human exposure to B. mandrillaris. Here, we report a case of a 58-year-old woman with progressive neurological symptoms, ultimately diagnosed postmortem with B. mandrillaris encephalitis through plasma metagenomic next-generation sequencing (mNGS) despite negative results on both cerebrospinal fluid (CSF) mNGS and CSF PCR testing. Histologic analysis and real-time PCR (qPCR) studies on postmortem brain tissue confirmed B. mandrillaris infection with significant vascular clustering of trophozoites. Retrospective analysis of CSF mNGS data demonstrated subthreshold reads for B. mandrillaris, emphasizing the challenges of interpreting low-level pathogen signals. A systematic review of 159 published B. mandrillaris cases revealed only two reports of B. mandrillaris diagnosed using plasma mNGS, both of which also had diagnostic CSF studies. This case demonstrates the diagnostic challenges of B. mandrillaris infections, highlights its vascular tropism, and suggests that plasma mNGS may warrant evaluation as a diagnostic tool for B. mandrillaris.