The chemokine CXCL13 in acute neuroborreliosis

Objective Recent studies have suggested an important role of the B cell chemoattractant CXCL13 in acute neuroborreliosis (NB). Our aim was to confirm the diagnostic role of CXCL13 and to evaluate its relevance as a therapy response and disease activity marker in NB. Methods CXCL13 was measured in cerebrospinal fluid (CSF) and serum of patients with NB (n = 28), systemic borreliosis (SB, n = 9), Guillaine-Barre syndrome (GBS, n = 11), Bell's palsy (BP, n = 19), other cranial nerve palsies (CNP, n = 5), cephalgia (C, n = 20), bacterial CNS infections (B-CNS-I, n = 16) and viral CNS infections (V-CNS-I, n = 18). For follow-up studies, serial sample pairs were evaluated from 25 patients with NB (n = 56), 11 with B-CNS-I (n = 25) and 14 with V-CNS-I (n = 36). Results CSF-CXCL13 was significantly elevated in NB compared with other neurological diseases (p<0.001). Using receiver operating characteristic analysis, 337 ng/g was determined as a cut-off with a sensitivity of 96.4% and a specificity of 96.9%. Of all the parameters investigated, CSF CXCL13 showed the fastest response to antibiotic therapy, decreasing significantly (p = 0.008) within 1 week. In untreated patients, CSF CXCL13 was elevated in patients with a short duration of disease. Borrelia burgdorferi antibody index showed no significant (p = 0.356) change over follow-up. Conclusions The study confirms the relevance of CXCL13 as a diagnostic biomarker of NB and suggests that CSF CXCL13 in NB is linked to duration of disease and could be a marker of disease activity and response to antibiotic therapy

Dramatic reduction of mortality in pneumococcal meningitis

Background Acute bacterial meningitis is still a life threatening disease. Methods We performed a retrospective observational study on the clinical characteristics of consecutively admitted patients with acute pneumococcal meningitis in a single tertiary care center in central Europe (from 2003 until 2015). Data were compared with a previously published historical group of 87 patients treated for pneumococcal meningitis at the same hospital (from 1984 until 2002). Results Fifty-five consecutive patients with microbiologically proven pneumococcal meningitis were included. Most striking, mortality was down to 5.5 %, which was significantly lower than in the historical group where 24.1 % of the patients did not survive. Intracranial complications during the course of the disease were common and affected half of the patients. Unlike in the historic group, most of the intracranial complications (except ischemic stroke) were no longer associated with a low Glasgow Outcome Score at discharge. Conclusion The drastic reduction of mortality proves there have been important advances in the treatment of pneumococcal meningitis. Nevertheless, the fact that only 44.2 % of survivors had a full recovery indicates that the search for new adjunctive treatment options must be ongoing

TGFβ receptor II gene deletion in leucocytes prevents cerebral vasculitis in bacterial meningitis

In bacterial meningitis, chemokines lead to recruitment of polymorphonuclear leucocytes (PMN) into the CNS. At the site of infection in the subarachnoid space, PMN release reactive oxygen species, reactive nitrogen intermediates (RNI) and interleukin-1β (IL-1β). Although these immune factors assist in clearance of bacteria, they also result in neuronal injury associated with meningitis. Transforming growth factor beta (TGFβ) is a potent deactivator of PMN and macrophages since TGFβ suppresses the production of ROI, RNI and IL-1. Here, we report that the deletion of the TGFβ receptor II gene in PMN enhances PMN recruitment into the CNS of mice with Streptococcus pneumoniae meningitis. This was associated with more efficient clearance of bacteria, and almost complete prevention of intracerebral necrotizing vasculitis. Differences in PMN in the CNS of infected control mice and mice lacking TGFβ receptor II were not explained by altered expression of chemokines acting on PMN. Instead, TGFβ was found to impair the expression of l (leucocyte)-selectin on PMN from control mice but not from mice lacking TGFβ receptor II. l-Selectin is known to be essential for PMN recruitment in bacterial meningitis. We conclude that defective TGFβ signalling in PMN is beneficial in bacterial meningitis by ameliorating migration of PMN and bacterial clearanc

Mechanisms of Brain Injury in Bacterial Meningitis: Workshop Summary

Morbidity and mortality associated with bacterial meningitis remain high, although antibiotic therapy has improved during recent decades. The major intracranial complications of bacterial meningitis are cerebrovascular arterial and venous involvement, brain edema, and hydrocephalus with a subsequent increase of intracranial pressure. Experiments in animal models and cell culture systems have focused on the pathogenesis and pathophysiology of bacterial meningitis in an attempt to identify the bacterial and/or host factors responsible for brain injury during the course of infection. An international workshop entitled "Bacterial Meningitis: Mechanisms of Brain Injury” was organized by the Department of Neurology at the University of Munich and was held in Eibsee, Germany, in June 1993. This conference provided a forum for the exchange of current information on bacterial meningitis, including data on the clinical spectrum of complications, the associated morphological alterations, the role of soluble inflammatory mediators (in particular cytokines) and of leukocyte-endothelial cell interactions in tissue injury, and the molecular mechanisms of neuronal injury, with potential mediators such as reactive oxygen species, reactive nitrogen species, and excitatory amino acids. It is hoped that a better understanding of the pathophysiological events that take place during bacterial meningitis will lead to the development of new therapeutic regimen

Protective Effect of a 21-Aminosteroid during Experimental Pneumococcal Meningitis

This study investigated whether the 21-aminosteroid U74389F, an inhibitor of lipid peroxidation, attenuates pathophysiologic changes in experimental pneumococcal meningitis. Infected rats injected intravenously with vehicle and U74389F developed increases in regional cerebral blood flow (rCBF), intracranial pressure (ICP), brain water content, and white blood cells (WBC) in cerebrospinal fluid (CSF) within 8 h after intracisternal challenge. Pretreatment with or administration of U74389F 4 h after infection significantly reduced the increase in ICP but had no effect on rCBF increase. Moreover, U74389F pretreatment significantly reduced brain water content and CSF WBC count. In vitro, U74389F inhibited iron-dependent lipid peroxidation of astrocyte cultures and the production of tumor necrosis factor-a, interleukin-6, and nitric oxide by stimulated macrophages. These data suggest that U74389F modulates early pathophysiologic alterations in experimental pneumococcal meningiti

Reduced spiral ganglion neuronal loss by adjunctive neurotrophin-3 in experimental pneumococcal meningitis

<p>Abstract</p> <p>Background</p> <p>Hearing loss is a frequent long-term complication of pneumococcal meningitis (PM). Its main pathological correlate is damage to the organ of Corti and loss of spiral ganglion neurons. The only current treatment option is cochlear implants which require surviving neurons. Here, we investigated the impact of systemically applied neurotrophin-3 (NT-3) on long-term hearing loss and the survival of neurons.</p> <p>Methods</p> <p>Eighteen hours after infection with <it>S. pneumoniae</it>, C57BL/6 mice were treated with a combination of ceftriaxone with NT-3 or dexamethasone or placebo. Hearing, cochlear damage, and brain damage were assessed by audiometry and histology.</p> <p>Results</p> <p>The main findings from immunohistochemical visualization of neurotrophins (NT-3, BDNF) and their receptors (TrkB, TrkC, and p75) in the cochlea were (i) enhanced staining for the cell survival-promoting receptor TrkB and (ii) increased NT-3 staining in NT-3 treated mice, showing that systemically applied NT-3 reaches the cochlea. The major effects of adjunctive NT-3 treatment were (i) a reduction of meningitis-induced hearing impairment and (ii) a reduction of spiral ganglion neuronal loss. The efficacy of NT-3 therapy was comparable to that of dexamethasone.</p> <p>Conclusion</p> <p>Systemically applied NT-3 might be an interesting candidate to improve hearing outcome after pneumococcal meningitis.</p

Adjunctive dexamethasone therapy in unconfirmed bacterial meningitis in resource limited settings: is it a risk worth taking?

Background: Bacterial meningitis is associated with significant morbidity and mortality despite advances in medical care. The main objective of this study was to assess the association of adjunctive dexamethasone treatment with discharge outcome of patients treated as bacterial meningitis in low income setting. Methods: A retrospective study was conducted at four teaching hospitals across Ethiopia. Patients of age 14 years and older treated as cases of bacterial meningitis between January 1, 2011 and April 30, 2015 were included in this study. Information regarding sociodemographic data, clinical presentations, laboratory data, treatments given and status at hospital discharge were retrieved from patients' medical records using a structured questionnaire. Predefined outcome variables at discharge were analysed using descriptive statistics. Multivariable logistic regression was used to identify factors independently associated with poor outcome. Results: A total of 425 patients treated with the presumptive clinical diagnosis of bacterial meningitis were included in this study (lumbar puncture done in 56 %;only 19 % had CSF findings compatible with bacterial meningitis, and only 3 % had proven etiology). The overall in hospital mortality rate was 20.2 %. Impaired consciousness, aspiration pneumonia, and cranial nerve palsy at admission were independently associated with increased mortality. Adjuvant dexamethasone, which was used in 50.4 % of patients, was associated with increased in-hospital mortality (AOR = 3.38;95 % CI 1.87-6.12, p < 0.001) and low Glasgow outcome scale (GOS) at discharge (AOR = 4.46 (95 % CI 1.98-10.08). This association between dexamethasone and unfavorable outcome was found to be more pronounced in suspected but unproven cases and in those without CSF alterations compatible with bacterial meningitis. Conclusion: Most patients treated for suspected bacterial meningitis did not receive proper diagnostic workup. Adjuvant dexamethasone use in clinically suspected but unproven cases of bacterial meningitis was associated with an increased mortality and poor discharge GOS. These findings show that there are potential deleterious effects in unconfirmed cases in this setting. Physicians practising under such circumstances should thus abide with the current recommendation and defer the use of adjuvant corticosteroid in suspected cases of bacterial meningitis

Outcome of patients with acute bacterial meningitis in a teaching hospital in Ethiopia: A prospective study

Background: The mortality and neurologic sequelae associated with acute bacterial meningitis (ABM) remain high despite advances in medical care. The main aim of this study was to evaluate short-term outcome in patients treated as bacterial meningitis at a teaching hospital in Ethiopia to identify factors that could be focused on to improve outcome in this setting. Methods: A hospital based longitudinal study was conducted at Jimma University Hospital in southwest Ethiopia from March 1, 2013 to December 31, 2015. Participants of this study were patients of age 18 years and older who were treated as confirmed or possible cases of ABM. Patients were followed throughout their hospital stay for change in their clinical course and predefined end points. A multivariable analysis was done to identify factors associated with unfavorable outcomes. Result: 90 patients admitted with diagnosis of acute bacterial meningitis were included in the study;cerebrospinal fluid was analysed for 85 (94.4%) of them. Causative bacteria were isolated in 26 (28.9%) patients only;most of these isolates (84.6%) were either Streptococcus pneumoniae or Neisseria meningitidis. Patients managed as cases of ABM at the hospital suffered from a high rate of unfavorable outcome (36.7%) and an overall mortality rate of 22.2%. Impaired level of consciousness (AOR = 0.766, 95% CI = 0.589-0.995), dexamethasone therapy (AOR = 4.676, 95% CI = 1.12-19.50) and fever persisting after two days of admission (AOR = 24.226, 95% CI = 5.24-111.96) were found to be independently associated with unfavorable outcome. Conclusion: Outcome in patients treated for ABM at the hospital was found to be poor. Impaired mentation, treatment with adjunctive dexamethasone and persistent fever were found to be associated with poor outcome. Thus, development of clinical guidelines for treatment of ABM that suit the local context is essential to improve patient management and outcome