Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the proinflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. Additionally, SNPs in genes encoding complement pathway proteins have been linked to susceptibility to pneumococcal infection, although no associations with disease severity or outcome have been established. Here, we have performed a robust prospective nationwide genetic association study in patients with bacterial meningitis and found that a common nonsynonymous complement component 5 (C5) SNP (rs17611) is associated with unfavorable disease outcome. C5 fragment levels in cerebrospinal fluid (CSF) of patients with bacterial meningitis correlated with several clinical indicators of poor prognosis. Consistent with these human data, C5a receptor-deficient mice with pneumococcal meningitis had lower CSF wbc counts and decreased brain damage compared with WT mice. Adjuvant treatment with C5-specific monoclonal antibodies prevented death in all mice with pneumococcal meningitis. Thus, our results suggest C5-specific monoclonal antibodies could be a promising new antiinflammatory adjuvant therapy for pneumococcal meningitis.

IntroductionIntracranial vascular complications are an important complication of acute bacterial meningitis. Ischemic stroke in meningitis is reported as a result of vasculitis, vasospasm, endocarditis or intraarterial thrombosis. The aim of the study was to identify the value of measuring cerebral blood flow velocity (CBFv) on transracranial doppler (TCD) in the identification of patients at risk for meningitis-associated stroke.MethodsWe retrospectively studied patients with acute bacterial meningitis who were treated in our university hospital from 2000 to 2009. Data were analyzed with the main focus on the incidence of an increase of CBFv on TCD, defined as peak systolic values above 150 cm/s, and the development of stroke.ResultsIn total, 114 patients with acute bacterial meningitis were treated, 94 of them received routine TCD studies during their hospital stay. 41/94 patients had elevated CBFv values. This increase was associated with an increased risk of stroke (odds ratio (95% confidence intervall) = 9.15 (1.96-42.67); p < 0.001) and unfavorable outcome (Glasgow Outcome Score < 4; odds ratio (95% confidence intervall) = 2.93 (1.23-6.98); p = 0.018). 11/32 (34.4%) patients with an increase of CBFv who received nimodipine and 2/9 (22.2%) patients with an increase of CBFv who did not receive nimodipine developed stroke (p = 0.69).ConclusionsIn summary, TCD was found to be a valuable bedside test to detect arterial alterations in patients with bacterial meningitis. These patients have an increased risk of stroke.

In this study, we analyzed the expression and function of CXCL16 in pneumococcal meningitis. CXCL16 was found to be up‐regulated in RAW264.7 macrophages (but not in neutrophils and endothelial cells) upon pneumococcal stimulation, in the cerebrospinal fluid of patients, and in the brains as well as the cerebrospinal fluid of mice with pneumococcal meningitis. CXCL16 up‐regulation in vivo was dependent on Toll‐like receptor (TLR) 2/TLR4 and MyD88 signaling. Neutralization of CXCL16 in animals before intracisternal pneumococcal infection (using anti‐CXCL16 antibodies) resulted in reduced cerebrospinal fluid pleocytosis. In vitro, murine neutrophils expressed the CXCL16 receptor CXCR6 and showed dose‐dependant migration toward a CXCL16 gradient. Thus, this study implicates CXCL16 as an additional neutrophil chemoattractant in cerebrospinal fluid in early pneumococcal meningitis.

Despite targeted therapy, case-fatality rates and neurologic sequelae of bacterial meningitis remain unacceptably high. The poor outcome is mainly due to secondary systemic and intracranial complications. These complications seem to be both a consequence of the inflammatory response to the invading pathogen and release of bacterial components by the pathogen itself. Therefore, within the last decades, research has focused on the mechanism underlying immune regulation and the inhibition of bacterial lysis in order to identify new targets for adjuvant therapy. The scope of this article is to give an overview on current treatment strategies of bacterial meningitis, to summarize new insights on the pathophysiology of bacterial meningitis, and to give an outlook on new treatment strategies derived from experimental models.

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