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. 2016 Jan 25;11(1):e0146288.
doi: 10.1371/journal.pone.0146288. eCollection 2016.

Characteristic Cytokine and Chemokine Profiles in Encephalitis of Infectious, Immune-Mediated, and Unknown Aetiology

Free PMC article

Characteristic Cytokine and Chemokine Profiles in Encephalitis of Infectious, Immune-Mediated, and Unknown Aetiology

Benedict D Michael et al. PLoS One. .
Free PMC article


Background: Encephalitis is parenchymal brain inflammation due to infectious or immune-mediated processes. However, in 15-60% the cause remains unknown. This study aimed to determine if the cytokine/chemokine-mediated host response can distinguish infectious from immune-mediated cases, and whether this may give a clue to aetiology in those of unknown cause.

Methods: We measured 38 mediators in serum and cerebrospinal fluid (CSF) of patients from the Health Protection Agency Encephalitis Study. Of serum from 78 patients, 38 had infectious, 20 immune-mediated, and 20 unknown aetiology. Of CSF from 37 patients, 20 had infectious, nine immune-mediated and eight unknown aetiology.

Results: Heat-map analysis of CSF mediator interactions was different for infectious and immune-mediated cases, and that of the unknown aetiology group was similar to the infectious pattern. Higher myeloperoxidase (MPO) concentrations were found in infectious than immune-mediated cases, in serum and CSF (p = 0.01 and p = 0.006). Serum MPO was also higher in unknown than immune-mediated cases (p = 0.03). Multivariate analysis selected serum MPO; classifying 31 (91%) as infectious (p = 0.008) and 17 (85%) as unknown (p = 0.009) as opposed to immune-mediated. CSF data also selected MPO classifying 11 (85%) as infectious as opposed to immune-mediated (p = 0.036). CSF neutrophils were detected in eight (62%) infective and one (14%) immune-mediated cases (p = 0.004); CSF MPO correlated with neutrophils (p<0.0001).

Conclusions: Mediator profiles of infectious aetiology differed from immune-mediated encephalitis; and those of unknown cause were similar to infectious cases, raising the hypothesis of a possible undiagnosed infectious cause. Particularly, neutrophils and MPO merit further investigation.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.


Fig 1
Fig 1. Concentrations of mediators in the CSF and serum of patients with encephalitis of immune-mediated, infectious and unknown aetiologies.
Fig 2
Fig 2. Serum concentrations of mediators in patients with encephalitis of immune-mediated, infectious and unknown aetiology.
Bars represent median concentration.
Fig 3
Fig 3. CSF concentrations of mediators identified in patients with encephalitis of immune-mediated, infectious and unknown aetiology.
Fig 4
Fig 4. The heatmaps give a visual representation of how closely concentrations of different mediators correlate in the samples by nearest neighbour correlation.
Using a hierarchical cluster analysis the mediators are listed in the same order for each of the three aetiological groups to allow a visual comparison of the pattern between the groups. In the serum (a) the pattern of mediator correlations is similar for all three aetiological groups, where-as in the cerebrospinal fluid (b) the pattern differed between immune-mediated and infectious aetiologies, and the pattern for those of unknown aetiology is closer to that seen with infection.
Fig 5
Fig 5. Cerebrospinal fluid myeloperoxidase concentration and cerebrospinal fluid neutrophil count for all cases of encephalitis.
Because at low levels neutrophils are just recorded as present or absent, and at higher levels actual counts are given we looked at CSF MPO concentrations using both these parameters. CSF neutrophil counts were given for 11 patients.

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