Metagenomic Next-Generation Sequencing of Cerebrospinal Fluid in Culture-Negative Meningoencephalitis: A Review of Diagnostic Yield and Clinical Impact
DOI:
https://doi.org/10.5281/zenodo.22206002Keywords:
Metagenomic Sequencing, Meningoencephalitis, Cerebrospinal Fluid, Culture-Negative Infection, Diagnostic YieldAbstract
A large minority of meningoencephalitis is never explained. Culture, targeted polymerase chain reaction and serology each require the clinician to have guessed the organism before the test is ordered, and when the guess is wrong the patient is treated empirically and the cause is never established. Metagenomic sequencing inverts that logic by asking what nucleic acid is present rather than whether a named pathogen is. Objectives:To review the published evidence on the diagnostic yield, accuracy and clinical impact of metagenomic next-generation sequencing of f cerebrospinal fluid in patients with meningoencephalitis undiagnosed by conventional testing, and to set out what is required to interpret a result. Material and Methods:A narrative review. MEDLINE, Embase and the Cochrane Library were searched from January 2013 to May 2026 for r prospective and retrospective cohorts, diagnostic accuracy studies, validation reports and society guidance on metagenomic sequencing in central nervous system infection. Values were extracted from the primary reports and tabulated without pooling. Results:Cause remains unknown in 37% of encephalitis after extensive conventional testing. In the largest prospective study, 204 hospitalised d patients yielded 58 nervous system infections, of which sequencing alone identified 13 (22%) while conventional testing alone identified 26 (45%). Pooled sensitivity across twelve studies and 1,249 patients is 77% with specificity of 96%. Yield is concentrated in the undiagnosed, immunocompromised and pretreated, and the dominant interpretive problem is distinguishing genuine low-abundance signal from reagent and environmental contamination.
Conclusion:Metagenomic sequencing is a supplement to conventional testing rather than a replacement for it: the two modalities identify y substantially different infections. Its value is greatest in the culture-negative, immunocompromised or antibiotic-pretreated patient, and it should be reported against negative controls and confirmed orthogonally before treatment is changed.
Abbreviations:CSF – Cerebrospinal Fluid, mNGS – Metagenomic Next-Generation Sequencing, CNS – Central Nervous System, PCR –
– Polymerase Chain Reaction, HSV – Herpes Simplex Virus, ICU – Intensive Care Unit.
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