Abstract
Enteroviruses are among the most common causes of viral meningitis. Enteroviral meningitis continues to represent diagnostic challenges, as cerebrospinal fluid (CSF) cell numbers (a well validated diagnostic screening tool) may be normal in up to 15% of patients. We aimed to identify potential CSF biomarkers for enteroviral meningitis, particularly for cases with normal CSF cell count. Using targeted liquid chromatography-mass spectrometry, we determined metabolite profiles from patients with enteroviral meningitis (n = 10) and subdivided them into those with elevated (n = 5) and normal (n = 5) CSF leukocyte counts. Non-inflamed CSF samples from patients with Bell’s palsy and normal pressure hydrocephalus (n = 19) were used as controls. Analysis of 91 metabolites revealed considerable metabolic reprogramming in the meningitis samples. It identified phosphatidylcholine PC.ae.C36.3, asparagine, and glycine as an accurate (AUC, 0.92) combined classifier for enterovirus meningitis overall, and kynurenine as a perfect biomarker for enteroviral meningitis with an increased CSF cell count (AUC, 1.0). Remarkably, PC.ae.C36.3 alone emerged as a single accurate (AUC, 0.87) biomarker for enteroviral meningitis with normal cell count, and a combined classifier comprising PC.ae.C36.3, PC.ae.C36.5, and PC.ae.C38.5 achieved nearly perfect classification (AUC, 0.99). Taken together, this analysis reveals the potential of CSF metabolites as additional diagnostic tools for enteroviral meningitis, and likely other central nervous system (CNS) infections.
Highlights
A variety of processes can lead to meningeal inflammation
While the enteroviral meningitis group as a whole reflected findings typical for this mild-moderately severe central nervous system (CNS) infection, the subgroup with normal cerebrospinal fluid (CSF) cell count was nearly indistinguishable from the control group on the basis of routine CSF diagnostic parameters
Enteroviral meningitis continues to present diagnostic challenges, as up to 15% of patients with this infection may present with normal CSF cell counts and turn-around of polymerase chain reaction (PCR) diagnostics may be insufficient
Summary
A variety of processes can lead to meningeal inflammation. Viruses are the most common cause of infectious meningitis, followed by bacteria. There is a variety of causes of non-infectious meningeal inflammation, such as carcinomatosis, adverse drug effects, or autoimmune diseases. Pathogens can reach the meningeal structures via the blood stream and infiltrate the membranes that surround the brain and spinal cord. Another way of infection is by infiltration per continuitatem when circumambient tissue is damaged. Typical symptoms of meningitis are headache, fever, or neck stiffness. Altered mental status or neurological deficits appear when meningitis evolves into meningoencephalitis, in which brain tissue is affected [1,2]
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