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Neurology AND Pneumococcal meningitis [keywords]
- Genetic variation and cerebrospinal fluid levels of mannose binding lectin in pneumococcal meningitis patients. [Journal Article]
- PLoS One 2013; 8(5):e65151.
It has been suggested that genetic variants in mannose binding lectin (MBL2) influence susceptibility and outcome of invasive pneumococcal disease. We assessed the influence of genetic variation in MBL2 on susceptibility, outcome and causative serotype of pneumococcal meningitis in a prospective nationwide cohort study including 299 white patients and 216 controls. We assessed functionality of the genetic polymorphisms by measuring levels of MBL, C3a, iC3b, C5a and sC5b-9 in cerebrospinal fluid. We also performed a meta-analysis of studies on MBL2 polymorphisms and susceptibility to invasive pneumococcal disease. The risk of contracting pneumococcal meningitis was substantially increased for white individuals homozygous with the defective MBL2 0/0 genotype (odds ratio [OR] 8.21, 95% confidence interval [CI] 1.05-64.1; p = 0.017). CSF MBL levels were significantly lower in patients with the A/0 and 0/0 genotype compared to homozygotes for the wild-type alleles (A/A; p<0.001). CSF MBL levels were positively correlated with C3a and iC3b levels, indicating complement activation by the lectin pathway. The effect of MBL2 genetic variants on susceptibility remained robust in a meta-analysis including 5 studies with 287 patients (OR 2.33, 99% CI 1.39-3.90). We conclude that MBL2 polymorphisms influence CSF MBL levels and substantially increase the risk of pneumococcal meningitis.
- Adjunctive dexamethasone in adults with meningococcal meningitis. [Journal Article]
- Neurology 2013 May 7; 80(19):1818-9.
In the article by Heckenberg et al.,(1) the authors conclude that dexamethasone did not similarly improve the unfavorable outcome in meningococcal meningitis as was seen in their previous pneumococcal cohort study.(2) The difference in the incidence of meningitis-related stroke between these meningitis populations may explain the difference in the cohorts' Glasgow Outcome Scale results.
- Bacterial meningitis in adults after splenectomy and hyposplenic States. [Journal Article]
- Mayo Clin Proc 2013 Jun; 88(6):571-8.
To examine the occurrence, disease course, prognosis, and vaccination status of patients with community-acquired bacterial meningitis with a history of splenectomy or functional hyposplenia.Patients with bacterial meningitis proven by cerebrospinal fluid culture were prospectively included in a nationwide cohort study between March 1, 2006, and September 1, 2011. Splenectomy or diseases associated with functional hyposplenia were scored for all patients. Vaccination status, clinical features, and outcome of patients with a history of splenectomy or functional hyposplenia were analyzed and compared with patients with normal spleen function.Twenty-four of 965 patients (2.5%) had an abnormal splenic function: 16 had a history of splenectomy and 8 had functional hyposplenia. All patients had pneumococcal meningitis. Pre-illness vaccination status could be retrieved for 19 of 21 patients (90%), and only 6 patients (32%) were adequately vaccinated against pneumococci. Pneumococcal serotype was known in 21 patients; 52% of pneumococcal isolates had a serotype included in the 23-valent vaccine. Vaccine failure occurred in 3 patients. Splenectomized patients more often presented with signs of septic shock compared with patients with a normal spleen (63% vs 24%; P=.02). Outcome was unfavorable in 14 patients (58%), and 6 patients died (25%).Splenectomy or functional hyposplenia is an uncommon risk factor for bacterial meningitis but results in a high rate of mortality and unfavorable outcome. Most patients were not adequately vaccinated against Streptococcus pneumoniae.
- High mobility group box 1 prolongs inflammation and worsens disease in pneumococcal meningitis. [Journal Article]
- Brain 2013 Jun; 136(Pt 6):1746-59.
Neutrophilic inflammation, which often persists over days despite appropriate antibiotic therapy, contributes substantially to brain damage in bacterial meningitis. We hypothesized that persistent inflammation is the consequence of a vicious cycle in which inflammation-induced cell injury leads to the release of endogenous danger molecules (e.g. high mobility group box 1) that drive the inflammatory response, causing further damage. The present study aimed to assess the mechanisms of high mobility group box 1 protein release and its functional relevance for the development and progression of pneumococcal meningitis. High mobility group box 1 was found in large quantities in cerebrospinal fluid samples of patients and mice with pneumococcal meningitis (predominantly in advanced stages of the disease). By using macrophages, we demonstrated that the release of high mobility group box 1 from macrophages following pneumococcal challenge is passive in nature and probably not connected with inflammasome- and oxidative stress-dependent inflammatory cell death forms. In a mouse meningitis model, treatment with the high mobility group box 1 antagonists ethyl pyruvate or Box A protein had no effect on the development of meningitis, but led to better resolution of inflammation during antibiotic therapy, which was accompanied by reduced brain pathology and better disease outcome. Additional experiments using gene-deficient mice and murine neutrophils provided evidence that high mobility group box 1 acts as a chemoattractant for neutrophils in a receptor for advanced glycosylation end products-dependent fashion. In conclusion, the present study implicated high mobility group box 1, likely released from dying cells, as a central propagator of inflammation in pneumococcal meningitis. Because persistent inflammation contributes to meningitis-associated brain damage, high mobility group box 1 may represent a promising target for adjunctive therapy of this disease.
- Controversies in neurology, Vienna, 2012: steroids in bacterial meningitis: no. [Comment, Journal Article]
- J Neural Transm 2013 Feb; 120(2):343-6.
In acute bacterial meningitis long-term morbidity and mortality are still high, in particular, in low and middle income countries where meningococci are the most frequent causative agents of this disease. If at all, dexamethasone has been shown to be helpful in pneumococcal meningitis, i.e., in elderly Europeans and not in adolescent African, Asian or South American patients. Since deranged glucose, in particular, glucose variability and deranged coagulation homeostasis are known to be deleterious in patients with bacterial meningitis, dexamethasone--being capable to cause both--might add to morbidity and mortality. After more than 20 prospective trials evidence still lacks that dexamethasone improves outcome in the majority of patients. Dexamethasone only exerts a positive effect, if given prior to the first dose of antibiotic; therefore, the introduction of empiric antimicrobial chemotherapy into the emergency (= pre-hospital) management of patients with suspected bacterial meningitis, the discussion on dexamethasone in acute bacterial meningitis is rendered almost futile.
- Paroxysmal autonomic instability with dystonia after pneumococcal meningoencephalitis. [Journal Article]
- Case Report Med 2012.:965932.
Streptococcus pneumoniae is a common cause of bacterial meningitis, frequently resulting in severe neurological impairment. A seven-month-old child presenting with Streptococcus pneumoniae meningoencephalitis developed right basal ganglia and hypothalamic infarctions. Daily episodes of agitation, hypertension, tachycardia, diaphoresis, hyperthermia, and decerebrate posturing were observed. The diagnosis of paroxysmal autonomic instability with dystonia was established. The patient responded to clonidine, baclofen, and benzodiazepines. Although this entity has been reported in association with traumatic brain injury, and as a sequel to some nervous system infections, this is the first case, to our knowledge, associated with pneumococcal meningoencephalitis.
- Effects of B7-H3 on the inflammatory response and expression of MMP-9 in mice with pneumococcal meningitis. [Journal Article, Research Support, Non-U.S. Gov't]
- J Mol Neurosci 2013 May; 50(1):146-53.
B7-H3, a new member of the B7 superfamily, plays a key role in the regulation of T cell-mediated immune responses. Our previous work showed that B7-H3 strongly augmented both LPS- and bacterial lipoprotein-induced NF-κB activation and inflammatory response, and soluble B7-H3 was elevated in CSF and plasma of patients with bacterial meningitis. MMP-9 has been implicated in blood-brain barrier disruption, inflammation, and vasculitis during the pathogenesis of bacterial meningitis. In this study, we report that in a murine model of pneumococcal meningitis, B7-H3 treatment enhances inflammatory response in the meninges, upregulates MMP-9 expression in cerebral parenchyma, and deteriorates clinical disease status indicated by weight loss and impaired movement ability. In vitro results showed that B7-H3 augmented MMP-9 secretion from Streptococcus pneumoniae-stimulated microglia cells. Thus, our data indicate that B7-H3 contributes to the development of pneumococcal meningitis by exaggerating inflammatory responses and upregulating MMP-9 activity in CNS, which ultimately lead to neuronal injury.
- Genetic variation in inflammasome genes is associated with outcome in bacterial meningitis. [Journal Article, Research Support, Non-U.S. Gov't]
- Immunogenetics 2013 Jan; 65(1):9-16.
Bacterial meningitis is a severe and deadly disease, most commonly caused by Streptococcus pneumoniae. Disease outcome has been related to severity of the inflammatory response in the subarachnoid space. Inflammasomes are intracellular signaling complexes contributing to this inflammatory response. The role of genetic variation in inflammasome genes in bacterial meningitis is largely unknown. In a prospective nationwide cohort of patients with pneumococcal meningitis, we performed a genetic association study and found that single-nucleotide polymorphisms in the inflammasome genes CARD8 (rs2043211) and NLRP1 (rs11621270) are associated with poor disease outcome. Levels of the inflammasome associated cytokines interleukin (IL)-1β and IL-18 in cerebrospinal fluid also correlated with clinical outcome, but were not associated with the CARD8 and NLRP1 polymorphisms. Our results implicate an important role of genetic variation in inflammasome genes in the regulation of inflammatory response and clinical outcome in patients with bacterial meningitis.
- Intrathecal treatment with the anti-phosphorylcholine monoclonal antibody TEPC-15 decreases neuronal damage in experimental pneumococcal meningitis. [Journal Article, Research Support, Non-U.S. Gov't]
- Chemotherapy 2012; 58(3):212-6.
Neuronal injury in pneumococcal meningitis is a consequence of microglial activation and direct toxicity by bacterial products and systemic inflammation.The treatment effect of the TEPC-15 antibody recognizing teichoic and lipoteichoic acids was investigated in murine microglial cells and in a rabbit model of pneumococcal meningitis.In vitro, the TEPC-15 antibody recognizing teichoic and lipoteichoic acids increased Streptococcus pneumoniae phagocytosis by murine microglial cells. In rabbit ceftriaxone-treated S. pneumoniae meningitis, intracisternal TEPC-15 reduced the density of apoptotic neurons in the hippocampal dentate gyrus (116 ± 70 vs. 221 ± 132/mm(2); p = 0.03). Cerebrospinal fluid inflammatory parameters (protein, lactate, leukocytes, prostaglandins) were not reduced in TEPC-15-treated rabbits.Intracisternal treatment with the TEPC-15 antibody reduced neuronal damage probably by promoting rapid phagocytosis of bacterial products.