Diagnostic Testing in Central Nervous System Infection

Abstract

Patients with central nervous system (CNS) infection experience very high levels of morbidity and mortality, in part because of the many challenges inherent to the diagnosis of CNS infection and identification of a causative pathogen. The clinical presentation of CNS infection is nonspecific, so clinicians must often order and interpret many diagnostic tests in parallel. This can be a daunting task given the large number of potential pathogens and the availability of different testing modalities. Here, we review traditional diagnostic techniques including Gram stain and culture, serology, and polymerase chain reaction (PCR). We highlight which of these are recommended for the pathogens most commonly tested among U.S. patients with suspected CNS infection. Finally, we describe the newer broad-range diagnostic approaches, multiplex PCR and metagenomic sequencing, which are increasingly used in clinical practice.

Fig. 1

Overview of specimen types and modalities for diagnosing CNS infection. Panel (A) represents key anatomic compartments for sampling. Panel (B) provides an overview of the major diagnostic modalities. (I) Indirect evidence of infection can be provided by pathogen-specific antibody responses. Illustrated is a generic ELISA. (II) Gram stain and culture are performed for bacterial and fungal pathogens. (III) Pathogen antigen detection is most often performed by a modification of the ELISA assay. (IV) PCR detects nucleic acid from a prespecified target. (V) Multiplex PCR expands (IV) to examine a set of predetermined targets. (VI) Metagenomic sequencing amplifies all nucleic acid directly from a biological sample, including bacteria, fungi, and viruses, as well as human nucleic acid and microbes present in reagent or laboratory environment. Bioinformatic analyses are used to identify potential pathogens. CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction.