Neutrophil extracellular trap-associated protein in cerebrospinal fluid for prognosis evaluation of adult bacterial meningitis: a retrospective case-control study.

BACKGROUND AND OBJECTIVES: Central nervous system infections, typified by bacterial meningitis, stand as pivotal emergencies recurrently confronted by neurologists. Timely and precise diagnosis constitutes the cornerstone for efficacious intervention. The present study endeavors to scrutinize the influence of inflammatory protein levels associated with neutrophils in cerebrospinal fluid on the prognosis of central nervous system infectious maladies. METHODS: This retrospective case series study was undertaken at the Neurology Department of the Second Hospital of Shandong University, encompassing patients diagnosed with infectious encephalitis as confirmed by PCR testing and other diagnostic modalities spanning from January 2018 to January 2024. The quantification of MPO and pertinent inflammatory proteins within patients' cerebrospinal fluid was accomplished through the utilization of ELISA. RESULTS: We enlisted 25 patients diagnosed with bacterial meningitis, ascertained through PCR testing, and stratified them into two groups: those with favorable prognoses (n = 25) and those with unfavorable prognoses (n = 25). Following assessments for normality and variance, notable disparities in CSF-MPO concentrations emerged between the prognostic categories of bacterial meningitis patients (P < 0.0001). Additionally, scrutiny of demographic data in both favorable and unfavorable prognosis groups unveiled distinctions in CSF-IL-1ß, CSF-IL-6, CSF-IL-8, CSF-IL-18, CSF-TNF-α levels, with correlation analyses revealing robust associations with MPO. ROC curve analyses delineated that when CSF-MPO ≥ 16.57 ng/mL, there exists an 83% likelihood of an adverse prognosis for bacterial meningitis. Similarly, when CSF-IL-1ß, CSF-IL-6, CSF-IL-8, CSF-IL-18, and CSF-TNF-α levels attain 3.83pg/mL, 123.92pg/mL, 4230.62pg/mL, 35.55pg/mL, and 35.19pg/mL, respectively, there exists an 83% probability of an unfavorable prognosis for bacterial meningitis. CONCLUSION: The detection of neutrophil extracellular traps MPO and associated inflammatory protein levels in cerebrospinal fluid samples holds promise in prognosticating bacterial meningitis, thereby assuming paramount significance in the prognostic evaluation of patients afflicted with this condition.

Cerebrospinal fluid biomarkers implicated in the pathogenesis of anti-neutrophil cytoplasmic antibody-related hypertrophic pachymeningitis.

OBJECTIVE: Hypertrophic pachymeningitis (HP) related to anti-neutrophil cytoplasmic antibody (ANCA) is the most frequently seen immune-mediated HP. We investigated cerebrospinal fluid (CSF) biomarkers related to the pathogenesis of ANCA-related HP (ANCA-HP). METHODS: The levels of B cell activation factor of the tumor necrosis factor family (BAFF), a proliferation-inducing ligand (APRIL), and transforming growth factor beta 1 (TGF-ß1) in the CSF were compared between patients with ANCA-HP (n = 12), other types of immune-mediated HP (other HP; n = 12), multiple sclerosis (MS; n = 14), and non-inflammatory neurological disorders (NIND; n = 10). In addition, we evaluated whether ANCA would be detected in CSF. RESULTS: CSF levels of BAFF, APRIL, and TGF-ß1 were significantly increased in ANCA-HP and other HP. In particular, BAFF and APRIL levels were significantly correlated with the IgG index in ANCA-HP. In other HP, BAFF and APRIL levels were significantly correlated with cell counts and protein levels in CSF. Of 12 patients with ANCA-HP, the CSF of 7 patients (58%) tested positive for myeloperoxidase (MPO)- or proteinase 3 (PR3)-ANCA, while none of the CSF samples from other HP, MS, or NIND patients tested positive. CONCLUSION: The levels of BAFF, APRIL, and TGF-ß1 may serve as useful CSF biomarkers for assessing the disease activity of immune-mediated HP. Moreover, BAFF and APRIL in the CSF may be implicated in the pathogenesis of ANCA-HP via promoting autoreactive B cells, while detecting MPO- or PR3-ANCA in the CSF may be found in some patients with ANCA-HP.Key Points• CSF BAFF, APRIL, and TGF-ß1 levels increase significantly in immune-mediated HP.• CSF BAFF and APRIL levels are significantly correlated with IgG index in ANCA-HP.• Detection of MPO- or PR3-ANCA in the CSF is found in some patients with ANCA-HP.• BAFF, APRIL, and ANCA in the CSF may be implicated in the pathogenesis of ANCA-HP.

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

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.

Matrix metalloproteinase inhibition lowers mortality and brain injury in experimental pneumococcal meningitis.

Pneumococcal meningitis (PM) results in high mortality rates and long-lasting neurological deficits. Hippocampal apoptosis and cortical necrosis are histopathological correlates of neurofunctional sequelae in rodent models and are frequently observed in autopsy studies of patients who die of PM. In experimental PM, inhibition of matrix metalloproteinases (MMPs) and/or tumor necrosis factor (TNF)-converting enzyme (TACE) has been shown to reduce brain injury and the associated impairment of neurocognitive function. However, none of the compounds evaluated in these studies entered clinical development. Here, we evaluated two second-generation MMP and TACE inhibitors with higher selectivity and improved oral availability. Ro 32-3555 (Trocade, cipemastat) preferentially inhibits collagenases (MMP-1, -8, and -13) and gelatinase B (MMP-9), while Ro 32-7315 is an efficient inhibitor of TACE. PM was induced in infant rats by the intracisternal injection of live Streptococcus pneumoniae. Ro 32-3555 and Ro 32-7315 were injected intraperitoneally, starting at 3 h postinfection. Antibiotic (ceftriaxone) therapy was initiated at 18 h postinfection, and clinical parameters (weight, clinical score, mortality rate) were recorded. Myeloperoxidase activities, concentrations of cytokines and chemokines, concentrations of MMP-2 and MMP-9, and collagen concentrations were measured in the cerebrospinal fluid. Animals were sacrificed at 42 h postinfection, and their brains were assessed by histomorphometry for hippocampal apoptosis and cortical necrosis. Both compounds, while exhibiting disparate MMP and TACE inhibitory profiles, decreased hippocampal apoptosis and cortical injury. Ro 32-3555 reduced mortality rates and cerebrospinal fluid TNF, interleukin-1ß (IL-1ß) and collagen levels, while Ro 32-7315 reduced weight loss and cerebrospinal fluid TNF and IL-6 levels.

Hypertrophic pachymeningitis: significance of myeloperoxidase anti-neutrophil cytoplasmic antibody.

The aim of this study was to elucidate the characteristics, pathogenesis and treatment strategy of hypertrophic pachymeningitis that is associated with myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA). We retrospectively investigated clinical, radiological, immunological and pathological profiles of 36 patients with immune-mediated or idiopathic hypertrophic pachymeningitis, including 17 patients with myeloperoxidase-ANCA, four patients with proteinase 3-ANCA, six patients with other immune-mediated disorders, and nine patients with 'idiopathic' variety. Myeloperoxidase-ANCA-positive hypertrophic pachymeningitis was characterized by: (i) an elderly female predominance; (ii) 82% of patients diagnosed with granulomatosis with polyangiitis (previously known as Wegener's granulomatosis) according to Watts' algorithm; (iii) a high frequency of patients with lesions limited to the dura mater and upper airways, developing headaches, chronic sinusitis, otitis media or mastoiditis; (iv) a low frequency of patients with the 'classical or generalized form' of granulomatosis with polyangiitis involving the entire upper and lower airways and kidney, or progressing to generalized disease, in contrast to proteinase 3-ANCA-positive hypertrophic pachymeningitis; (v) less severe neurological damage according to the modified Rankin Scale and low disease activity according to the Birmingham Vasculitis Activity Score compared with proteinase 3-ANCA-positive hypertrophic pachymeningitis; (vi) increased levels of CXCL10, CXCL8 and interleukin 6 in cerebrospinal fluids, and increased numbers of T cells, neutrophils, eosinophils, plasma cells and monocytes/macrophages in autopsied or biopsied dura mater with pachymeningitis, suggesting TH1-predominant granulomatous lesions in hypertrophic pachymeningitis, as previously reported in pulmonary or renal lesions of granulomatosis with polyangiitis; and (vii) greater efficacy of combination therapy with prednisolone and cyclophosphamide compared with monotherapy with prednisolone. Proteinase 3-ANCA may be considered a marker for more severe neurological damage, higher disease activity and a higher frequency of the generalized form compared with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. However, categorization into 'granulomatosis with polyangiitis' according to Watts' algorithm and immunological or pathological features were common in both proteinase 3- and myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. These data indicate that most patients with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis should be categorized as having the central nervous system-limited form of ANCA-associated vasculitis, consistent with the concept of ophthalmic-, pulmonary- or renal-limited vasculitis.

[Characteristics of some links of the antioxidant system in patients with complicated cerebral stroke]. / Osobennosti nekotorykh zven'ev antioksidantnoi sistemy organizma u bol'nykh s oslozhnennym mozgovym insul'tom.

The state was studied of some constituent parts of the antioxidant system of cerebrospinal fluid and blood in 101 patient with ischemic and hemorrhagic cerebral insult. Correlation has been established between clinical status of cerebral insult and activity of the antioxidant system during the early stage of acute brain derangements. Those patients who ran a grave course of secondary affection of trancus cerebri demonstrated low activity of the antioxidant system of cerebrospinal fluid and blood.

Experimental pneumococcal meningitis. II. Characterization and quantitation of the inflammatory process.

For the systematic study of the role of inflammation in the morbidity and mortality associated with bacterial meningitis, techniques for quantitation of the inflammatory reaction in the meninges of rabbits with experimental pneumococcal infection were developed. The brains of 19 infected animals were removed intact, and the area of inflammation in microscopic sections was quantitated by an electronic X-Y plotter connected to a computer. Exudate was maximal along the ventral surface of the brain at the level of the cerebellum. Inflammation increased progressively with time and peaked at 72 hr. In a separate group of 29 animals, lactic acid dehydrogenase concentrations in cerebrospinal fluid increased significantly during infection, and the rate of increase wirh time coincided with the increase in inflammation documented histologically. The described method of quantitating inflammation in the meninges during experimental meningitis makes it possible to study the increase in granulocyte involvement with time. The establishment of a direct relation between the concentration of lactic acid dehydrogenase in the cerebrospinal fluid and the inflammatory mass validates the use of lactic acid dehydrogenase as an indicator of inflammation.