Quantitation of lymphocyte subsets in cerebrospinal fluid and blood during the clinical course of aseptic and bacterial meningitis.

Mononuclear cell subsets in cerebrospinal fluid (CSF) and peripheral blood (PB) were monitored during the clinical course in 23 patients with acute meningitis using 6 monoclonal antibodies. Significant differences between aseptic and bacterial meningitis mainly consisted of a higher percentage of OKT4-positive cells in PB in the acute phase of bacterial meningitis. Significant differences between CSF and PB are found in the amount of most cell subtypes at all times except the acute phase of bacterial meningitis. The OKT4/OKT8 ratio was always significantly higher in CSF and correlated with the acuity of inflammation in bacterial meningitis.     

Persistent increase of matrix metalloproteinases in cerebrospinal fluid of tuberculous meningitis

Matrix metalloproteinase (MMP)-2 and MMP-9 were analyzed by gelatin zymography and an enzyme-linked immunosorbent assay (ELISA) in a cerebrospinal fluid (CSF) from patients with tuberculous meningitis (n=24), acute aseptic meningitis (n=23) and the control (n=10). The MMP-2 and MMP-9 levels were significantly higher in the samples from the tuberculous meningitis patients than those from either the aseptic meningitis patients or the controls. In tuberculous meningitis, the patients with late neurologic complications had higher MMP-2 and MMP-9 levels than those without. The persistent increase in the MMP-2 and MMP-9 levels was associated with the development of complications following tuberculous meningitis. Inhibiting the MMPs may be an effective strategy for preventing or reducing the complications in tuberculous meningitis.     

Interleukin-1β and tumor necrosis factor-α in cerebrospinal fluid of children with bacterial meningitis

Certain cytokines may contribute to the sequence of events that lead to meningeal inflammation in bacterial meningitis. The purpose of this study was to determine the levels of cytokines in the cerebrospinal fluid (CSF) of children with bacterial meningitis and aseptic meningitis of different etiologies. We determined the concentrations of interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF-alpha) in the CSF of 171 specimens of 144 patients whose cases were classified as follow: bacterial meningitis (n=23), aseptic meningitis (n=26) and non-meningitis (n=95). The detectable IL-1beta concentration (> or =20 pg/ml) in the bacterial meningitis, aseptic meningitis and non-meningitis groups were observed with 78.3%, 3.8%, and 8.4%, respectively. Significantly higher serum IL-1beta concentrations were detected in those with bacterial meningitis than those with aseptic meningitis (538.93+/-605.32 pg/ml vs 2.52+/-11.57 pg/ml; P<0.001) or among non-meningitis subjects (2.90+/-11.91 pg/ml; P<0.001). The mean TNF-alpha concentration was 148.74+/-338.77 pg/ml. There was significantly more TNF-alpha than aseptic meningitis (6.85+/-17.93 pg/ml; P<0.001) or non-meningitis (7.67+/-16.07 pg/ml; P<0.001). With regard to diagnosis, measurement of IL-1beta and TNF-alpha levels showed sensitivities of 78% and 74%, respectively; specificities of 96% and 81%, respectively. It is suggested that the levels of these cytokines, especially IL-1beta and TNF-alpha, are useful markers for distinguishing bacterial meningitis from aseptic meningitis.     

Cerebrospinal fluid and peripheral blood leukocyte subsets in acute inflammation of the CNS

Leukocyte subsets in CSF and peripheral blood (PB) were determined in 21 patients with acute inflammation of the CNS using the monoclonal antibodies OKT3, OKT4, OKT8, Leu12, and OKM1 in an immunoperoxidase slide assay. There was a predominance of OKT3-positive cells in nearly all samples. Significant differences between acute aseptic and bacterial meningitis only were found in CSF and represented by a higher Leu12 and a lower OKT3 percentage in aseptic inflammation and a higher absolute amount of OKT4-, OKM1- and Leu12-positive cells in bacterial meningitis. Comparison between CSF and PB showed significant differences only in aseptic meningitis with a higher percentage of Leu12-positive cells and a lower percentage of OKT8-positive cells in CSF. The OKT4/OKT8 ratio seems to be generally lower in aseptic meningitis but significant differences only were found in comparison with healthy blood donors. In a case of herpes simplex encephalitis the ratio was strongly increased in CSF during the early phase of specific antibody production because of an absolute rise of OKT4-positive cells.     

Initial characteristics of kawasaki disease with cerebrospinal fluid pleocytosis in febrile infants

To distinguish between febrile infants with cerebrospinal fluid pleocytosis who are finally diagnosed with Kawasaki disease and those with enterovirus meningitis poses a diagnostic challenge. We compared clinical and laboratory features at admission between two groups of infants, aged 30-90 days, to identify markers of Kawasaki disease that initially presented as cerebrospinal fluid pleocytosis. During a 2-year period, 100 patients exhibiting cerebrospinal fluid pleocytosis were studied, including six (6.0%) with Kawasaki disease and 30 (30.0%) with enterovirus meningitis. A longer duration of fever before admission (P < 0.01), higher absolute neutrophil count (P < 0.01), increased C-reactive protein level (P < 0.01), pyuria (P?=?0.02), and less prominent cerebrospinal fluid pleocytosis (P?= 0.01) were identified as initial features of infants finally diagnosed with Kawasaki disease. No significant differences were evident in white blood cell count; platelet count; levels of hemoglobin, alanine aminotransaminase, aspartate aminotransferase, albumin, and sodium; cerebrospinal fluid chemistry; or presence of a rash. Our observations may offer early indicators of Kawasaki disease for timely diagnoses in febrile infants with cerebrospinal fluid pleocytosis.     

Cerebrospinal fluid Diacron-Reactive Oxygen Metabolite levels in pediatric patients with central nervous system diseases

This study assessed the validity of cerebrospinal fluid oxidative status of pediatric patients with central nervous system diseases, using the Diacron-Reactive Oxygen Metabolites test (d-Roms; Diacron International s.r.l.; Grosseto, Italy). Eighty-seven pediatric patients (8 with bacterial meningitis, 18 with aseptic meningitis, 23 with febrile seizures, 6 with rotavirus gastroenteritis-induced convulsions, 16 with epilepsy, 2 with adrenoleukodystrophy, 2 with multiple sclerosis, and 12 control subjects) were enrolled. An analysis of the infection-associated group (bacterial meningitis, aseptic meningitis, febrile seizures, and rotavirus gastroenteritis-induced convulsions) indicated that cerebrospinal fluid Diacron-Reactive Oxygen Metabolite levels in the bacterial meningitis group were significantly higher than in other infection-associated groups. In the bacterial meningitis group, the cerebrospinal fluid Diacron-Reactive Oxygen Metabolite levels obtained after improvement were significantly decreased compared with pre-improvement values. In the noninfection-associated group (epilepsy, adrenoleukodystrophy, and multiple sclerosis), the cerebrospinal fluid Diacron-Reactive Oxygen Metabolite levels in symptomatic epilepsy patients were higher than in cryptogenic epilepsy patients and control subjects, but not significantly. Progressive patients with adrenoleukodystrophy or multiple sclerosis demonstrated high Diacron-Reactive Oxygen Metabolite levels compared with another early-stage adrenoleukodystrophy patient. Oxidative stress may be associated with the pathogenesis of various pediatric central nervous system diseases. Cerebrospinal fluid Diacron-Reactive Oxygen Metabolite levels may correlate with clinical status in these diseases.     

联合检测CRP,IL-6,Procalcitonin水平在成人脑膜炎诊断中的应用价值

目的 探讨联合检测C-反应蛋白(CRP)、白介素-6(IL-6)、降钙素原(Procalcitonin)水平在成人脑膜炎诊断中的应用价值。方法 选取病毒性脑膜炎患者30例为病毒组,结核性脑膜炎患者30例为结核组,化脓性脑膜炎患者30例为化脓组; 同时选取体检健康者30例为对照组,检测4组血清中CRP,IL-6,Procalcitonin的表达水平; 用ROC曲线下面积分析CRP,IL-6,Procalcitonin水平对成人脑膜炎的诊断价值。结果 健康人群血清中CRP和IL-6的表达水平均比成人脑膜炎患者低,且在病毒性脑膜炎、结核性脑膜炎和化脓性脑膜炎患者中表达水平有明显差异,血清中Procalcitonin的表达水平在化脓性脑膜炎患者中最高(P<0.05),结核性脑膜炎患者次之(P<0.05),健康人群再次之(P<0.05),病毒性脑膜炎患者中最低(P<0.05)。CRP高表达与成人脑膜炎患者脑脊液中蛋白水平呈正相关(r=0.826,P<0.001); Procalcitonin高表达与成人脑膜炎患者脑脊液中葡萄糖水平呈正相关(r=0.866,P<0.001)。诊断病毒性脑膜炎患者与体检健康者CRP,IL-6,Procalcitonin水平的灵敏度分别为83%、87%、87%,特异度为83%、87%、87%; 诊断结核性脑膜炎患者与体检健康者CRP,IL-6,Procalcitonin水平的灵敏度分别为93%、87%、87%,特异度为67%、73%、87%; 诊断化脓性脑膜炎患者与体检健康者CRP,IL-6,Procalcitonin水平的灵敏度分别为87%、87%、87%,特异度为87%、73%、87%; CRP,IL-6和Procalcitonin水平对成人脑膜炎的联合诊断的灵敏度为88.89%,特异度为83.33%,准确度为87.50%。结论 CRP,IL-6,Procalcitonin水平可作为辅助诊断成人脑膜炎的潜在标志物。     

TNF-alpha and IL-6 in the diagnosis of bacterial and aseptic meningitis in children

The objective of this study was to analyze the usefulness of tumor necrosis factor-alpha and interleukin-6 cerebrospinal fluid concentrations for the differential diagnosis between bacterial and aseptic meningitis in children and in the prognostic evaluation. A cross-sectional study was performed on 35 children between 1 month and 12 years of age with suspected meningitis. Cytokines determination was performed by enzyme-linked immunosorbent assay technique. The Mann-Whitney test and Spearman's correlation coefficients were used for statistical analysis. Six children presented bacterial meningitis, 13 aseptic, and 16 had no meningitis. The tumor necrosis factor-alpha concentrations were significantly higher in the bacterial meningitis group as compared with the aseptic group (P = 0.001) and among groups with and without meningitis (P = 0.000). There was correlation between tumor necrosis factor-alpha and cerebrospinal fluid leukocytes (P = 0.019), protein (P = 0.000), and glucose (P = 0.038). There was no association between cytokines and complications of the meningitis. The tumor necrosis factor-alpha concentrations in the cerebrospinal fluid were useful markers for distinguishing bacterial from aseptic meningitis and were demonstrated to be useful in evaluating the intensity of the inflammatory process in the central nervous system.     

Mollaret's meningitis associated with acute Epstein-Barr virus mononucleosis

A 19-year-old man developed recurrent aseptic meningitis (Mollaret's meningitis) during the course of acute Epstein-Barr virus infectious mononucleosis. Serum contained heterophil antibody and Epstein-Barr virus-specific antibodies characteristic of acute infection. Seven brief episodes of aseptic meningitis were documented over the following one-year period, in each case with a polymorphonuclear pleocytosis in the cerebrospinal fluid. Acute infection with Epstein-Barr virus, or subsequent reactivation of virus, may account for some cases of Mollaret's meningitis.     

Acid phosphatase activity of cerebrospinal fluid cells in bacterial and abacterial meningitis

Acid phosphatase staining is performed on cerebrospinal fluid cells of 365 samples from 105 patients with various types of meningitis. This enzyme activity is strongly positive in the early samples of bacterial meningitis, as far as the patients had not received a pretreatment with antibiotics for more than 24 h. It allows monitoring the response to therapy in subsequent samples. Acid phosphatase activity is positive in 2 cases of cryptococcus meningitis. It is negative in all cases of aseptic and Mycoplasma pneumoniae meningitis. The results in herpes encephalitis are variable, depending on the clinical state and the degree of brain destruction. Acid phosphatase staining is a useful and rapid cytological technique for determination of the nature of the meningitis and for monitoring the therapeutical response.     

后颅窝开颅术后无菌性脑膜炎的临床分析

目的探讨后颅窝开颅术后无菌性脑膜炎的诊断和治疗。方法回顾性分析16例后颅窝开颅术后无菌性脑膜炎患者的临床特点和治疗方式。结果16例患者均有发热，体温37.5～40.1℃，白细胞计数（45～110）×10^6/L，脑脊液糖定量（2.2～3.9）mmol/L，细菌培养阴性；所有患者均接受地塞米松静脉注射和鞘内注射治疗；6例间断腰穿，10例腰穿置管持续引流；16例患者均治愈，其中14例院内治愈，2例自动出院，4月内自愈。结论术后3d开始发热，脑脊液白细胞数增高，糖定量正常和细菌培养阴性可以诊断为无菌性脑膜炎；激素治疗和脑脊液引流是治疗无菌性脑膜炎的主要手段。     

Value of second lumbar puncture in confirming a diagnosis of aseptic meningitis. A prospective study.

In patients with viral meningitis, polymorphonuclear leukocytes sometimes predominate in the CSF on initial examination. In a prospective analysis of this phenomenon, 16 consecutive patients with viral meningitis were followed up with serial CSF studies. The percentage of polymorphonuclear leukocytes showed a significant fall between initial and second examinations (41.75 +/- 27.0 to 8.6 +/- 8.78 [mean +/- 2 SD], P less than .001), while total WBC counts and the protein and sugar content levels remained unchanged. Based mainly upon this "polymorph shift," antibiotic therapy was correctly withheld from 100% of patients reexamined. On subsequent examinations, the percentage of polymorphonuclear cells remained low. All patients recovered completely without any specific treatment. In otherwise healthy subjects with the aseptic meningitis syndrome, antibiotic therapy can be withheld even when polymorphonuclear cells predominate on initial CSF examination. If suspicion arises regarding the diagnosis, another examination will demonstrate a significant fall in polymorphonuclear cells if the initial impression was correct.     

NF-kappaB activation in cerebrospinal fluid cells from patients with meningitis

We examined whether or not NF-kappaB, a factor that regulates expression of the genes that code for pro-inflammatory cytokines, is activated in cerebrospinal fluid (CSF) cells to investigate the production of pro-inflammatory cytokines by CSF cells in patients with meningitis. Western blotting demonstrated that NF-kappaB was more activated in CSF cells of patients with bacterial meningitis than in those of patients with aseptic meningitis. NF-kappaB was hardly activated in carcinomatous meningitis. The NF-kappaB activation in CSF cells of patients with meningitis tended to be correlated with the CSF interleukin-6 concentration. Our data suggested that CSF cells produce pro-inflammatory cytokines through NF-kappaB activation in meningitis, and that increased NF-kappaB activation in CSF cells indicate infectious meningitis rather than carcinomatous meningitis.     

Decrease of Leu7 positive cells in peripheral blood from patients with aseptic meningitis]

In order to clarify the role of natural killer cell in the central nervous system (CNS) infection, we examined Leu7 positive cells in peripheral blood of aseptic meningitis by flow cytometry. We studied 10 patients with aseptic meningitis (5 echo virus type 6 and 5 suspected viral meningitis). Also 3 patients with Japanese encephalitis, 3 with fungal meningitis, each one with bacterial meningitis, tuberculous meningitis and brainstem encephalitis were analyzed. Blood samples of acute phase and after recovery were obtained by the first examination on admission and the latest examination after normalization of cerebrospinal fluid findings, respectively. All aseptic meningitis patients showed decrease of Leu7 positive cells in acute phase (mean +/- SD = 6.8 +/- 3.12%, from 3 to 25 days of illness) and continued after recovery (8.3 +/- 4.27%, from 35 to 503 days of illness) in all but one. The number of the cells found in the aseptic meningitis patients during the acute phase and after recovery was significantly lower than in normal subjects (p less than 0.01). The change did not differ statistically between the acute phase and post recovery. The date suggest that decreased Leu7 positive cells is present before infection. As concerning other CNS infections, the positive cells decreased from acute phase to after recovery in two Japanese encephalitis and one tuberculous patients. But because of small number, it was not decided whether the decrease significantly was low value or not. Since natural killer cells is related to defence mechanism of viral infection in acute phase, it seems that low natural killer activity may develop the viral infection. Therefore the date raises the possibility that the people who has originally less the natural killer cells tend to be susceptible, as far as viral meningitis.     

Gelatinase B [matrix metalloproteinase (MMP)-9] and collagenases (MMP-8/-13) are upregulated in cerebrospinal fluid during aseptic and bacterial meningitis in children

We investigated the protein expression of gelatinases [matrix metalloproteinase (MMP)-2 and -9] and collagenases (MMP-8 and -13) in cerebrospinal fluid (CSF) from patients with bacterial (BM, n = 17) and aseptic (AM, n = 14) meningitis. In both, MMP-8 and -9 were increased in 100% of patients, whereas MMP-13 was detectable in 53% and 82% respectively. Three patients with clinical signs of meningitis, without CSF pleocytosis, scored positive for all three MMPs. MMP-8 appeared in two isoforms, granulocyte-type [polymorphonuclear cell (PMN)] and fibroblast/macrophage (F/M) MMP-8. Analysis of kinetic changes from serial lumbar punctures showed that these MMPs are independently regulated, and correlate only partly with CSF cytosis or levels of the endogenous inhibitor, tissue inhibitor of matrix metalloproteinase-1. In vitro, T cells, peripheral blood mononuclear cells (PBMCs) and granulocytes (PMN) release MMP-8 and -9, whereas MMP-13 could be found only in the former two cell types. Using models of exogenous (n-formyl-Met-Leu-Phe, T cell receptor cross-linking) and host-derived stimuli (interleukin-2), the kinetics and the release of the MMP-8, -9 and -13 showed strong variation between these immune cells and suggest release from preformed stocks. In addition, MMP-9 is also synthesized de novo in PBMCs and T cells. In conclusion, invading immune cells contribute only partially to MMPs in CSF during meningitis, and parenchymal cells are an equally relevant source. In this context, in patients with clinical signs of meningitis, but without CSF pleocytosis, MMPs seem to be a highly sensitive marker for intrathecal inflammation. The present data support the concept that broad-spectrum enzyme inhibition targeting gelatinases and collagenases is a potential strategy for adjunctive therapy in infectious meningitis.     

Antibody neutralization of vascular endothelial growth factor (VEGF) fails to attenuate vascular permeability and brain edema in experimental pneumococcal meningitis

To determine the contribution of vascular endothelial growth factor (VEGF) to cerebral edema formation in bacterial meningitis, we used a VEGF neutralizing antibody to block VEGF in rabbits, following induction of meningitis by intracisternal inoculation with 10⁹ heat-killed pneumococci. At 8 h, cerebrospinal fluid (CSF) VEGF was significantly elevated in infected untreated animals, and correlated with CSF white blood cell (WBC) count (r=0.56, P=0.004), and brain water content (r=0.42, P=0.04). Blocking of VEGF did not attenuate brain edema, blood–brain barrier disruption, or CSF pleocytosis. The functional role of VEGF in the pathophysiology of BM remains elusive.     

中性粒细胞与淋巴细胞比值预测急性腔隙性脑梗死患者病情进展的临床价值

目的分析中性粒细胞与淋巴细胞比值(NLR)对急性腔隙性脑梗死患者病情进展的预测价值。方法根据病情进展与否将2012年2月～2017年1月收治的230例急性腔隙性脑梗死患者分为进展组(40例)与非进展组(190例),记录各组中性粒细胞绝对值、淋巴细胞绝对值等指标,计算NLR。受试者工作特征(ROC)曲线分析NLR等对急性腔隙性脑梗死患者病情进展预测的特异度、敏感度,Pearson相关性分析NLR等指标与mRS评分的关系。结果进展组NLR、白细胞计数、中性粒细胞绝对值均显著高于非进展组(P 0. 05);淋巴细胞绝对值显著低于非进展组(P 0. 05)。NLR对进展性腔隙性脑梗死(PLI)预测曲线下面积(AUC)为0. 800,最佳临界值3. 25,敏感度85. 06%,特异度70. 68%;白细胞计数、中性粒细胞绝对值、淋巴细胞绝对值对PLI预测AUC分别为0. 650、0. 745、0. 615。进展组预后良好率显著低于非进展组(P 0. 05)。NLR、中性粒细胞绝对值、白细胞计数与mRS评分正相关(P 0. 05)。结论 NLR值对急性腔隙性脑梗死患者病情进展有一定的预测价值,有可能作为患者预后评估的有效指标。     

Level of transforming growth factor beta 1 is elevated in cerebrospinal fluid of children with acute bacterial meningitis

We investigated the levels of transforming growth factor beta 1 (TGF-β1) in cerebrospinal fluid (CSF) in children with meningitis, with a view to prognostic relevance. CSF TGF-β1 levels on admission were measured by a sandwich enzyme immunoassay in children with bacterial meningitis (n = 16), aseptic meningitis (n = 12), and control subjects without evidence of central nervous system (CNS) infection (n = 16). Patients were followed up for a mean duration of 13 months, and neurodevelopmental sequelae was determined for those with bacterial meningitis. On admission, CSF TGF-β1 levels were significantly higher in children with bacterial meningitis (mean, standard error, 32.92, 2.36 pg/ml) as opposed to those with aseptic meningitis (25.26, 1.72 pg/ml) (P = 0.0155), or control subjects (20.53, 1.05 pg/ml) (P < 0.0001). The CSF TGF-β1 levels in children with aseptic meningitis were higher than those in the control group, but without significance (P = 0.02). No apparent correlation existed between CSF TGF-β1 levels and CSF protein or cell counts in patients with bacterial meningitis. No significant difference in CSF TGF-β1 levels was found between patients with or without major sequelae following bacterial meningitis. Received: 19 March 1997 Received in revised form: 24 June 1997 Accepted: 20 August 1997     

ACID MONOAMINE METABOLITES OF CEREBROSPINAL FLUID IN MENINGITIS AND ENCEPHALITIS

The concentrations of the acid monoamine metabolites homovanillic acid (HVA) and 5-hydroxyindolcacetic acid (5-HIAA) were measured by spectrophotofluorometric techniques in lumbar cerebrospinal fluid obtained from patients with meningitis and encephalitis. Very high concentrations of HVA were found in 4 patients with bacterial meningitis in the acute stage and a marked fall was observed after treatment. The levels found in 3 patients with aseptic meningitis and in 2 out of 4 patients with encephalitis were also above the control values. Interference with the active transport mechanism for acid monoamine metabolites from cerebrospinal fluid to blood may account for the high concentrations of HVA found in patients with meningitis. In a limited material investigated there was no obvious difference between the levels of 5-HIAA found in cerebrospinal fluid obtained from meningitic patients as compared to controls.     

NF-κB activation in cerebrospinal fluid cells from patients with meningitis

Abstract

We examined whether or not NF-κB, a factor that regulates expression of the genes that code for pro-inflammatory cytokines, is activated in cerebrospinal fluid (CSF) cells to investigate the production of pro-inflammatory cytokines by CSF cells in patients with meningitis. Western blotting demonstrated that NF-κB was more activated in CSF cells of patients with bacterial meningitis than in those of patients with aseptic meningitis. NF-κB was hardly activated in carcinomatous meningitis. The NF-κB activation in CSF cells of patients with meningitis tended to be correlated with the CSF interleukin-6 concentration. Our data suggested that CSF cells produce pro-inflammatory cytokines through NF-κB activation in meningitis, and that increased NF-κB activation in CSF cells indicate infectious meningitis rather than carcinomatous meningitis.