Safety and effectiveness of selective carotid angioplasty prior to cardiac surgery: a single-centre matched case-control study.

OBJECTIVES: Reducing the rate of postoperative stroke after cardiac surgery remains challenging, especially in patients with occlusive cerebrovascular disease. Angioplasty in all patients with high-grade carotid artery stenosis has not been shown to be effective in reducing the post-surgical stroke rate. In this study, we present the initial results of a different approach using selective carotid angioplasty only in patients with poor intracranial collaterals. METHODS: We conducted a single-centre study to assess the safety of this procedure. The postangioplasty complication rate of the study group was compared to that of patients who were scheduled for symptomatic carotid artery angioplasty. To determine the effectiveness of this procedure, the post-cardiac surgery complication rate of the study group was compared with that of the matched case controls. RESULTS: Twenty-two patients were treated with selective carotid angioplasty without developing persistent major neurological complications. All patients except 1 patient subsequently underwent surgery without developing persistent major neurological disabilities. Two patients died of cardiogenic shock within 30 days. CONCLUSIONS: Selective carotid angioplasty prior to cardiac surgery in patients with a presumed high risk of stroke was relatively safe and effective in this study group. Although this strategy does not prevent stroke in these high-risk patients, data suggest that this approach shifts the postoperative type of stroke from a severe haemodynamic stroke towards a minor embolic stroke with favourable neurological outcomes. Larger studies are needed to determine whether this strategy can effectively eliminate the occurrence of haemodynamic stroke after cardiac surgery.

Cerebrospinal fluid complement activation in patients with pneumococcal and meningococcal meningitis.

BACKGROUND: Recent research into the treatment of bacterial meningitis has examined the innate immune system, specifically the complement system, as a potential target for adjuvant therapy. However, the effects of blocking the complement system may be pathogen dependent. METHODS: We measured cerebrospinal fluid (CSF) levels of complement components C1q, C3a, iC3b, C5a, sC5b-9, CFH and MBL in 310 patients with pneumococcal and meningococcal meningitis from a prospective nationwide cohort study. The CSF complement component levels were successfully determined for between 289 (93%) and 307 (99%) patients, depending on available volumes of stored CSF. RESULTS: Complement factors C1q and MBL as well as common complement pathway factors C3a, iC3b, C5a, sC5b-9 and complement regulator CFH were all elevated in patients with bacterial meningitis as compared to the controls. CSF levels of complement components C5a and sC5b-9 were higher in patients with pneumococcal meningitis compared to those with meningococcal meningitis. After correction for age, immunocompromised state and level of consciousness, the CSF concentrations of C5a and sC5b-9 remained different between causative microorganisms (P = 0.006 and P = 0.016 respectively). In pneumococcal meningitis high C5a and C5b-9 levels are associated with the occurrence of systemic complications, unfavorable outcome and death, whereas an inverse relationship between C5b-9 levels and mortality is observed in meningococcal meningitis. CONCLUSIONS: Our study shows striking variations in complement activation depending on the pathogen responsible for the bacterial meningitis. In pneumococcal meningitis, high CSF complement levels were a strong indicator of disease severity and mortality, however in meningococcal meningitis, an inverse relationship between sC5b-9 and mortality was observed.

Inflammasome activation mediates inflammation and outcome in humans and mice with pneumococcal meningitis.

BACKGROUND: Inflammasomes are multi-protein intracellular signaling complexes that have recently been hypothesized to play a role in the regulation of the inflammation response. We studied associations between inflammasome-associated cytokines IL-1ß and IL-18 in cerebrospinal fluid (CSF) of patients with bacterial meningitis and clinical outcome, and pneumococcal serotype. In a murine model of pneumococcal meningitis we examined the pathophysiological roles of two inflammasome proteins, NLRP3 (Nod-like receptor protein-3) and adaptor protein ASC (apoptosis-associated speck-like protein). METHODS: In a nationwide prospective cohort study, CSF cytokine levels were measured and related to clinical outcome and pneumococcal serotype. In a murine model of pneumococcal meningitis using Streptococcus pneumoniae serotype 3, we examined bacterial titers, cytokine profiles and brain histology at 6 and 30 hours after inoculation in wild-type (WT), Asc and Nlrp3 deficient mice. RESULTS: In patients with bacterial meningitis, CSF levels of inflammasome associated cytokines IL-1ß and IL-18 were related to complications, and unfavorable disease outcome. CSF levels of IL-1ß were associated with pneumococcal serotype (p<0.001). In our animal model, Asc and Nlrp3 deficient mice had decreased systemic inflammatory responses and bacterial outgrowth as compared to WT mice. Differences between Asc⁻/⁻ and WT mice appeared sooner after bacterial inoculation and were more widespread (lower pro-inflammatory cytokine levels in both blood and brain homogenate) than in Nlrp3⁻/⁻ mice. Nlrp3 deficiency was associated with an increase of cerebral neutrophil infiltration and cerebral hemorrhages when compared to WT controls. CONCLUSIONS: Our results implicate an important role for inflammasome proteins NLRP3 and ASC in the regulation of the systemic inflammatory response and the development of cerebral damage during pneumococcal meningitis, which may dependent on the pneumococcal serotype.

Genetic variation in inflammasome genes is associated with outcome in bacterial meningitis.

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)-1ß 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.

Intracerebral hemorrhages in adults with community associated bacterial meningitis in adults: should we reconsider anticoagulant therapy?

OBJECTIVE: To study the incidence, clinical presentation and outcome of intracranial hemorrhagic complications in adult patients with community associated bacterial meningitis. METHODS: Nationwide prospective cohort study from all hospitals in the Netherlands, from 1 March 2006, through 31 December 2010. RESULTS: Of the 860 episodes of bacterial meningitis that were included, 24 were diagnosed with intracranial hemorrhagic complications: 8 upon presentation and 16 during clinical course. Clinical presentation between patients with or without intracranial hemorrhage was similar. Causative bacteria were Streptococcus pneumoniae in 16 patients (67%), Staphylococcus aureus in 5 (21%), Pseudomonas aeruginosa and Listeria monocytogenes both in 1 patient (4%). Occurrence of intracranial hemorrhage was associated with death (63% vs. 15%, P<0.001) and unfavorable outcome (94% vs. 34%, P<0.001). The use of anticoagulants on admission was associated with a higher incidence of intracranial hemorrhages (odds ratio 5.84, 95% confidence interval 2.17-15.76). CONCLUSION: Intracranial hemorrhage is a rare but devastating complication in patients with community-associated bacterial meningitis. Since anticoagulant therapy use is associated with increased risk for intracranial hemorrhage, physicians may consider reversing or temporarily discontinuing anticoagulation in patients with bacterial meningitis.

Pathogenesis and pathophysiology of pneumococcal meningitis.

Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae, which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy.

Macrophage migration inhibitory factor, infection, the brain, and corticosteroids.

Bacterial meningitis is a complex disorder in which injury is caused, in part, by the causative organism and, in part, by the host's own inflammatory response. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine and a neuro-endocrine mediator that might play a role in pneumococcal meningitis. Here, we discuss the role of MIF in infection, the brain, and corticosteroids and conclude that experimental meningitis studies have to determine whether MIF is a potential target for adjunctive therapy in pneumococcal meningitis.

Daptomycin in experimental murine pneumococcal meningitis.

BACKGROUND: Daptomycin, a lipopeptide antibiotic, could be an alternative to vancomycin for treatment of pneumococcal meningitis. We determined the activity of daptomycin versus vancomycin, with dexamethasone as an adjuvant, in a murine model of pneumococcal meningitis. METHODS: Ninety-six 25-30 gram mice were inoculated intracisternally with serotype 3 Streptococcus pneumoniae modified by the integration of a luminescent lux operon. All mice were treated with either dexamethasone 1 mg/kg intraperitoneally every 6 hours alone or in combination with either vancomycin or daptomycin, also administered intraperitoneally. Serum antimicrobial concentrations were selected to approximate those achieved in humans. Following treatment, bioluminescence and cerebrospinal fluid (CSF) bacterial concentrations were determined. Caspase-3 staining was used to assess apoptosis on brain histopathology. RESULTS: Sixteen hours post intracisternal inoculation, bacterial titers in CSF were 6.8 log10 cfu/ml. Amongst the animals given no antibiotic, vancomycin 50 mg/kg at 16 and 20 hours or daptomycin 25 mg/kg at 16 hours, CSF titers were 7.6, 3.4, and 3.9 log10 cfu/ml, respectively, at 24 hours post infection (p-value, < 0.001 for both vancomycin or daptomycin versus no antibiotic); there was no significant difference in bactericidal activity between the vancomycin and daptomycin groups (p-value, 0.18). CSF bioluminescence correlated with bacterial titer (Pearson regression coefficient, 0.75). The amount of apoptosis of brain parenchymal cells was equivalent among treatment groups. CONCLUSION: Daptomycin or vancomycin, when given in combination with dexamethasone, is active in the treatment of experimental pneumococcal meningitis.