Cerebrospinal fluid concentrations of alpha-melanocyte-stimulating hormone in bacterial and aseptic meningitis

-Melanocyte-stimulating hormone (-MSH) has potent anti-inflammatory effects in several experimental models of inflammation. It inhibits both the actions and production of proinflammatory cytokines and neutrophil migration. We investigated whether -MSH in cerebrospinal fluid (CSF) increases during the acute stage in patients with bacterial and aseptic meningitis by measuring -MSH in CSF via radioimmunoassay. The -MSH concentrations in CSF from the children with bacterial meningitis who survived (n = 8), those with aseptic meningitis (n = 16), and the control subjects (n = 23) were all below the detection limit. However, CSF -MSH was elevated in four of the five children with bacterial meningitis who had neurological sequelae. We speculate that elevated -MSH levels in CSF during acute bacterial meningitis reflect negative feedback in response to severe inflammation associated with neurological sequelae induced by proinflammatory cytokines. Conclusion: CSF -MSH is elevated in children with severe bacterial meningitis who had neurological sequelae.     

CBC differential profile in distinguishing etiology of neonatal meningitis

A retrospective study of 72 infants under four weeks of age with meningitis evaluated over almost four years was performed to determine the predictive value of the CBC differential ratio (% lymphocytes + % monocytes/% polymorphonuclear leukocytes + % band forms) profile in distinguishing those with bacterial from those with a nonbacterial etiology. Of 18 neonates with bacterial meningitis, all had a radio lower than one; of 54 neonates with aseptic or viral meningitis, 46 (85%) had a ratio greater than one. The difference between mean ratio values of the two groups was highly significant (P less than 0.001). A CBC differential ratio less than one was more sensitive (100%) in initially identifying neonates with bacterial meningitis than were other traditionally utilized parameters, eg, presence of fever (50%), ill appearance (50%), hypoglycorrhachia (61%), elevated CSF protein (55%), or CSF Gram-stained smear revealing pathogenic organisms (45%). Statistical analysis revealed that a CBC differential ratio less than 1.5 will accurately predict all cases of neonatal bacterial meningitis with a confidence of 99.95%. The CBC differential ratio is an accurate index for distinguishing neonates with bacterial meningitis from those with nonbacterial meningitis. Utilization of this parameter in conjunction with other traditional factors is efficacious in predicting outcome.     

Detection of interleukin 1 beta but not tumor necrosis factor-alpha in cerebrospinal fluid of children with aseptic meningitis

Tumor necrosis factor-alpha and interleukin 1 beta have been shown to be mediators of meningeal inflammation in animal models of bacterial meningitis. The presence of both cytokines in cerebrospinal fluid (CSF) of patients with bacterial meningitis has been documented recently. In this study, we measured concentrations of interleukin 1 beta and tumor necrosis factor-alpha in CSF samples from 36 patients with nonbacterial (aseptic) meningitis, 13 of whom had culture-proved enteroviral meningitis, and from 14 control patients. None of the samples from patients with aseptic meningitis and from the controls had detectable tumor necrosis factor activity in CSF. Thirty-two (89%) of 36 patients with aseptic meningitis had detectable interleukin 1 beta in CSF (mean +/- SEM, 48 +/- 11 pg/mL). These concentrations were significantly smaller than those previously reported in patients with bacterial meningitis (944 +/- 128 pg/mL). Only 2 of the 14 control patients had detectable CSF interleukin 1 beta concentrations of 21 and 42 pg/mL. A significant correlation was evident between interleukin-1 beta concentrations and white blood cell counts in the CSF of patients with aseptic meningitis. Our data suggest that the initial events of CSF inflammation in children with aseptic meningitis are different than those in patients with bacterial meningitis, and the participation of these two cytokines, especially tumor necrosis factor-alpha, is less critical to the process.     

Vasopressin levels in infants during the course of aseptic and bacterial meningitis

We measured urine vasopressin (VP) once daily on days 1 through 3 in 18 patients hospitalized with meningitis. Urine VP values were 215 +/- 100, 116 +/- 44, and 69 +/- 23 pg/mL on days 1 through 3, respectively, for children with bacterial meningitis and 34 +/- 14, 20 +/- 4, and 15 +/- 4 pg/mL for those with aseptic meningitis. Urinary VP levels of infants with bacterial meningitis were significantly greater than those of healthy ambulatory subjects (n = 18) on all three study days; VP values of infants with bacterial meningitis were also greater than those of infants with aseptic meningitis on study days 2 and 3. The VP levels for the subjects with aseptic meningitis were significantly greater than those of the controls on day 1 only. None of the infants exhibited the clinical syndrome of inappropriate antidiuretic hormone secretion.     

Interleukin-6 in cerebrospinal fluid of patients with central nervous system infections

Interleukin(IL)-6 levels were measured in cerebrospinal fluid (CSF) and serum samples from pediatric patients with central nervous system (CNS) infections by means of an enzyme-linked immunosorbent assay. Mean IL-6 concentrations in CSF samples from patients with bacterial meningitis (49017 44 730 pg/ml) were significantly higher than those in patients with aseptic meningitis (10761572 pg/ml) or encephalitis (409835 pg/ml). In aseptic meningitis and encephalitis, IL-6 levels in serum were within the lower ranges (< 100 pg/ml), in contrast with the highly elevated levels found in bacterial meningitis (14 33218 385 pg/ml). In 5 of the 15 patients with encephalitis, elevated levels of IL-6 were observed in the initial CSF samples despite normal findings of routine CSF examinations. Also, sequential CSF samples revealed that there was an increase in the CSF cell count in two of the five patients. These results validated the potential of measuring IL-6 in CSF samples for the purpose of providing additional information on routine laboratory test results. D Central nervous system infection, cerebrospinal fluid, children, enzyme-linked immunosorbent assay, interleukin-6.
M Narita, Department of Pediatrics, Hokkaido University School of Medicine, N 15 W 7, Kita-ku, Sapporo 060, Japan     

The diagnostic and predictive value of cerebrospinal fluid lactate in children with meningitis. Its relation to current diagnostic methods

One hundred and thirty-three children with suspected meningitis aged from 11 days to 16 years were investigated with routine cerebrospinal fluid (CSF) laboratory methods: microscopy of a Gram-stained smear, bacterial culture, determination of leukocytes, lactate, and the CSF/blood glucose ratio. On the basis of bacterial cultures and clinical course, the children were classified into three groups: bacterial meningitis (n = 18), aseptic meningitis (n = 28), and a control group (n = 87). The main intention was to study the relation between current diagnostic methods and lactate. CSF lactate levels and cell counts, related significantly (p less than 0.01) better to the presence of bacterial meningitis than CSF/blood glucose ratios. Lactate levels exceed 2.4 mmol/l in all children with bacterial meningitis, but in none of the control group. Of 28 children with aseptic meningitis 3 had lactate in the range 2.5-2.7 mmol/l, while the others had values of 2.4 mmol/l or less. We consider CSF lactate to be the best predictor in the clinical decision to institute antibiotic treatment of children with suspected bacterial meningitis.     

Interleukin-8 levels in children with bacterial,tuberculous and aseptic meningitis

Objective : Interleukin-8 (IL-8) is produced in monocytes and vascular endothelial cells in response to stimulation with bacteria or lipopolysaccharides, and is released from these cells into blood stream or tissue fluid.Methods Cerebrospinal fluid (CSF) levels of interleukin-8 in 56 children with nonbacterial, bacterial and tuberculous meningitis (TBM), and in 15 control subjects were analyzed to evaluate the involvement of this cytokine in the pathogenesis acute bacterial meningitis and their discriminative value between different etiologies of meningitis. The kinetics of IL-8 concentrations during the course of bacterial meningitis was also evaluated in patients. IL-8 levels were significantly higher in bacterial and TBM than in aseptic meningitis and in control subjects (p<0.0001).Results: There was no difference in the levels of IL-8 between the non-bacterial meningitis and control groups. The analysis of the kinetics of production of IL-8 in patients with bacterial meningitis showed that the SSF concentrations of this cytokine decreased to undetectable values in recovery stage. Conversely in patients with TBM the concentrations of IL-8 were elevated in two weeks after beginning the specific treatment.Conclusion : The results suggest that determining IL-8 levels may be useful in the differential diagnosis.     

Peripheral white blood cell counts and bacterial meningitis: implications regarding diagnostic efficacy in febrile children

In order to investigate the clinical value of peripheral white blood cell variables for the diagnosis of bacterial meningitis among young, febrile children, we compared total peripheral white counts, total segmented neutrophil counts, total band counts, and the ratio of immature-to-total neutrophils (I:T ratio) among 46 children with bacterial meningitis, 130 children with aseptic meningitis, and 56 febrile children with culture confirmed extrameningeal bacterial infection. Children with bacterial meningitis were comparable to those with aseptic meningitis with respect to median total white blood cell counts and median total segmented neutrophil counts but had a significantly higher median total band count (1760/microliters vs 378/microliters, P = 0.0001) and a significantly higher median I:T ratio (0.40 vs 0.09, P less than 0.001). In contrast, children with bacterial meningitis were comparable to those with an extrameningeal bacterial infection with respect to median total band count but had a significantly lower median total peripheral white count (10,650/microliters vs 15,300/microliters, P = 0.0013), a lower median total segmented neutrophil count (4511/microliters vs 6796/microliters, P = 0.023), and a significantly higher median I:T ratio (0.40 vs 0.15, P less than 0.001). Children with meningitis who were bacteremic at presentation had a significantly lower total white cell count (P = 0.001) and significantly higher I:T ratio (P = 0.005) when compared with children who had an extrameningeal infection and concurrent bacteremia at presentation.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Diagnostic and Predictive Value of Cerebrospinal Fluid Lactate in Children with Meningitis

ABSTRACT. One hundred and thirty-three children with suspected meningitis aged from 11 days to 16 years were investigated with routine cerebrospinal fluid (CSF) laboratory methods: microscopy of a Gram-stained smear, bacterial culture, determination of leukocytes, lactate, and the CSF/blood glucose ratio. On the basis of bacterial cultures and clinical course, the children were classified into three groups: bacterial meningitis (n=18), aseptic meningitis (n=28), and a control group (n=87). The main intention was to study the relation between current diagnostic methods and lactate. CSF lactate levels and cell counts, related significantly (p<0.01) better to the presence of bacterial meningitis than CSF/blood glucose ratios. Lactate levels exceed 2.4 mmol/l in all children with bacterial meningitis, but in none of the control group. Of 28 children with aseptic meningitis 3 had lactate in the range 2.5-2.7 mmol/l, while the others had values of 2.4 mmol/l or less. We consider CSF lactate to be the best predictor in the clinical decision to institute antibiotic treatment of children with suspected bacterial meningitis.     

Serum C-reactive protein in the differential diagnosis of childhood meningitis

BACKGROUND: Although determination of serum C-reactive protein (CRP) is considered one of the most useful tests for differentiating between bacterial and aseptic meningitis, its diagnostic accuracy in comparison with other laboratory parameters is yet to be further evaluated. METHODS: A total of 192 pediatric cases, aged between 2 months and 14 years, comprising patients with bacterial meningitis (n = 66) and aseptic meningitis (n = 126), were retrospectively analyzed on the basis of data from the initial examination. The area under the best fit binormal curve of the receiver operating characteristics (Az) for CRP was determined and compared with that for several other analytic parameters, including white blood cell count and erythrocyte sedimentation rate of peripheral blood, standard cerebrospinal fluid analysis variables and the combination test (probability of acute bacterial meningitis (pABM)) derived from Hoen's model. RESULTS: Compared with each of the other variables, the Az for serum CRP (0.97 +/- 0.02) was found to be significantly greater (P < 0.01) for all except pABM (0.99 +/- 0.01; P > 0.05). False-negative cases among the CRP test results were found to have been examined too early. CONCLUSIONS: The diagnostic accuracy of a single CRP determination was found to be equivalent to that of the most effective combination test. Patients with meningitis in whom serum CRP values are determined at least 12 h after the onset of fever and are < 2 mg/dL are far less likely to have bacterial meningitis.     

The fluctuations of neuron-specific enolase (NSE) levels of cerebrospinal fluid during bacterial meningitis: The relationship between the fluctuations of NSE levels and neurological complications or outcome

Neuron-specific enolase (NSE) is one of the glycolytic enzymes distributed exclusively in neurons. It was measured serially in the cerebrospinal fluid (CSF) of 10 children with bacterial meningitis during the illness using radio-immunoassay. The relationship between CSF-NSE levels and neurological complications or outcome was examined. CSF-NSE levels were significantly higher in the patients with bacterial meningitis than in the patients with the other central nervous system (CNS) infectious diseases, suggesting that CNS damage in those patients with bacterial meningitis was exacerbated. As CSF-NSE levels increased to above 25 ng/mL in the acute phase, all patients except one had subdural effusion. In those patients whose CSF-NSE level rose again during the illness, CNS complications or sequelae occurred. CSF-NSE may be a useful prognostic factor for predicting CNS damage in childhood bacterial meningitis.     

Elastase-alpha 1-proteinase inhibitor: an early indicator of septicemia and bacterial meningitis in children

In 26 infants and children with septicemia or bacterial meningitis, significantly elevated plasma levels of elastase-alpha 1-proteinase inhibitor (E-alpha 1-PI) were present at time of recognition of infection, even in those patients with neutropenia (range of reference values: 25 to 190 micrograms/L, n = 142; patients: 444 to 2049 micrograms/L, n = 26). After initiation of therapy, normalization of E-alpha 1-PI levels was observed in all patients who recovered from infection. In addition, 18 of 19 children with bacterial meningitis had increased cerebrospinal fluid concentrations of E-alpha 1-PI above the range of normal (range of reference values: 0 to 39 micrograms/L, n = 62; patients: 30 to 3490 micrograms/L, n = 19); concentrations of E-alpha 1-PI in bacterial meningitis were significantly increased when compared with those in aseptic meningitis (range 25 to 194 micrograms/L; n = 15). In 30 patients with local bacterial infections (pneumonia, urinary tract infections, etc.), E-alpha 1-PI was also elevated. These data suggest that E-alpha 1-PI is a sensitive indicator of systemic and local bacterial infection in childhood.     

Cyclic adenosine-3′,5′-monophosphate concentration and enzyme activities of cerebrospinal fluid in meningitis of children

The concentration of cyclic adenosine-3,5-monophosphate (cAMP) and the activities of some enzymes of 29 children were measured from cerebrospinal fluid (CSF) and plasma at various stages of meningitis.The CSF cAMP values in acute untreated phase of aseptic and purulent meningitis were equal, but significantly higher than those of convalescent children with no pathological clinical or laboratory findings. During the whole course (up to 2 weeks) of antimicrobial treatment of the purulent meningitis CSF cAMP concentration was higher than in the convalescent phase. Of the CSF enzymes studied, the lactic dehydrogenase activity seemed to be the best indicator of changing stages of meningitis. It was clearly elevated in the acute, untreated phase of purulent meningitis then decreasing during the course of treatment. In aseptic meningitis this activity was at the normal level and the activities of creatine kinase and acid phosphatase behaved similarly. The plasma cAMP concentrations in the acute phase of purulent meningitis were in the same range as in the CSF. During the treatment no significant changes were seen. The enzyme activities in the plasma were normal. The CSF cAMP level seems to be a sensitive indicator of metabolic disturbances in meningitis and may serve as a diagnostic aid.

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Zusammenfassung Die Konzentrationen des cyclischen Adenosin-3,5-Monophosphat (cAMP) und die Aktivitäten einiger Enzymen wurden im Liquor cerebrospinalis und Plasma von 29 Kindern während verschiedener Phasen der Meningitis untersucht.Im Liquor der Kinder, die an aseptischer oder purulenter Meningitis erkrankt waren, waren die Konzentrationen von cAMP während akuter Phasen signifikant höher als im Liquor der Konvaleszenten (ohne pathologische Befunde) und blieben durch die ganze Behandlung der Meningitis (2 Wochen) erhöht. Der empfindlichste Indicator der purulenten Meningitis von allen untersuchten Enzymen im Liquor war Milchsäure-Dehydrogenase (LD), deren Aktivität während der akuten Phase mäßig erhöht war und danach sich stufenweise im Verlauf der Behandlung verminderte. Statt dessen war die Aktivität der LD bei Kindern mit aseptischer Meningitis normal. Auch die Aktivität der Kreatin-Kinase und sauren Phosphatase veränderte sich ähnlich, aber weniger stark als LD in verschiedenen Formen und Phasen der Meningitis. Die cAMP-Konzentrationen im Plasma während der akuten Phase der purulenten Meningitis entsprachen den cAMP-Werten im Liquor. Die Aktivitäten der untersuchten Enzyme im Plasma waren normal. Das cAMP im Liquor scheint ein empfindlicher Indicator der metabolischen Störungen der cerebralen Zellen und ein verwendbares Mittel für die Diagnostik der Meningitis zu sein.

     

Neonatal meningitis in England and Wales: 10 years on

OBJECTIVES: To determine the incidence of neonatal meningitis in England and Wales. DESIGN: A national postal survey using the British Paediatric Surveillance Unit (BPSU) card scheme supplemented by information from other sources. SETTING: England and Wales 1996-1997. SUBJECTS: A total of 274 babies less than 28 days of age who were treated for meningitis. RESULTS: The incidence of neonatal meningitis in England and Wales has not changed since our previous study in 1985-1987. However, the acute phase mortality has fallen from 19.8% in 1985-1987 to 6.6% in this study. Group B streptococci (42%) and Escherichia coli (16%) remain the most common infecting microorganisms. Eight of 69 (12%) babies with group B streptococci and 4/26 (15%) with E coli died. Antibiotic regimens based on the third generation cephalosporins, notably cefotaxime, were most commonly used (84%). The BPSU scheme identified 72% of cases during the study period. Most cases of viral meningitis were not reported through the BPSU. Less than a third of samples from aseptic meningitis were examined for viruses; 56% of these were positive. CONCLUSIONS: Although the incidence of neonatal meningitis remains unchanged, mortality from this infection has fallen significantly. If this improvement is maintained as reflected in the level of sequelae at 5 years of age, then the fear surrounding meningitis during the neonatal period will have been dramatically reduced.     

Serum C-reactive protein in childhood meningitis in countries with limited laboratory resources: a Chilean experience.

Quantitative C-reactive protein (CRP) was determined sequentially by nephelometry and photometry from a finger prick serum sample in 67 children with bacterial meningitis (BM) and 16 children with aseptic meningitis (AM). The initial mean CRP value of 180 mg/liter in children with BM differed significantly from the 12 mg/liter found in those with AM (P less than 0.001). In BM a slow descent instead of rapid normalization or a secondary increase in sequential CRP values were early indicators of complications during recovery, such as resistance to the antibiotic. A significant difference in the mean CRP values between uneventful and complicated courses of BM was observed from the fourth day on (P less than 0.001). The measurements obtained with nephelometry correlated reliably with the more widely available photometry (r = 0.99). Easily performed rapid CRP determinations can considerably improve the quality of care in meningitis patients, especially in those situations where facilities for performing bacterial cultures or antibiotic susceptibility testing are not available.     

Cerebrospinal fluid concentrations of interleukin-1 beta, tumour necrosis factor-alpha, and interferon gamma in bacterial meningitis

To investigate the role of the inflammatory cytokines, the cerebrospinal fluid concentrations of interleukin (IL)-1 beta, tumour necrosis factor-alpha (TNF-alpha), and interferon gamma (IFN-gamma) were measured in 11 children with bacterial meningitis and two with mycoplasmic meningoencephalitis and compared with those in 50 children with aseptic meningitis and 15 with non-pleocytotic cerebrospinal fluid. Concentrations of IL-1 beta and TNF-alpha were each significantly higher in the cerebrospinal fluid of patients with bacterial meningitis than in those with aseptic meningitis or those with non-pleocytotic cerebrospinal fluid. IFN-gamma was detected at low concentrations in the cerebrospinal fluid of only 2/11 of those with bacterial meningitis. On the other hand, the IFN-gamma concentration was the highest in the cerebrospinal fluid of patients with aseptic meningitis. These results suggest that the inflammatory cytokines are differently released in the intrathecal space infected with viruses or bacteria.     

Cerebrospinal fluid concentrations of interleukin-1 beta, tumour necrosis factor-alpha, and interferon gamma in bacterial meningitis.

To investigate the role of the inflammatory cytokines, the cerebrospinal fluid concentrations of interleukin (IL)-1 beta, tumour necrosis factor-alpha (TNF-alpha), and interferon gamma (IFN-gamma) were measured in 11 children with bacterial meningitis and two with mycoplasmic meningoencephalitis and compared with those in 50 children with aseptic meningitis and 15 with non-pleocytotic cerebrospinal fluid. Concentrations of IL-1 beta and TNF-alpha were each significantly higher in the cerebrospinal fluid of patients with bacterial meningitis than in those with aseptic meningitis or those with non-pleocytotic cerebrospinal fluid. IFN-gamma was detected at low concentrations in the cerebrospinal fluid of only 2/11 of those with bacterial meningitis. On the other hand, the IFN-gamma concentration was the highest in the cerebrospinal fluid of patients with aseptic meningitis. These results suggest that the inflammatory cytokines are differently released in the intrathecal space infected with viruses or bacteria.     

2‘,5’-oligoadenylate synthetase activity and T cell subset in the cerebrospinal fluid and peripheral blood of aseptic meningitis

2′,5′-oligoadenylate synthetase activity, which is assumed to be induced by interferon, is reported to be one of the useful markers reflecting interferon activity. The enzyme activity of patients with aseptic meningitis and febrile convulsion were compared in order to evaluate interferon activity as one of the local immuno-defense mechanisms of aseptic meningitis. The surface antigen of mononuclear cells in cerebrospinal fluid and peripheral blood of some patients with aseptic meningitis was also measured. The enzyme activity of patients with aseptic meningitis was 191.4 pmol/dL in the cerebrospinal fluid and 395.8 pmol/dL in the serum during the acute phase, while that of patients with febrile convulsion was 45.2 pmol/dL in the cerebrospinal fluid and 326.0 pmol/dL in the serum. The enzyme activity of the former patients significantly decreased during the recovery phase in both the cerebrospinal fluid and serum. CD3 positive cells in the peripheral blood were 56.3% of the total mononuclear cells during the acute phase and 65.2% during the recovery phase, whereas in the cerebrospinal fluid mononuclear cells, they were 87.1 and 85.5%, respectively. During the acute phase, CD4 positive cells were the predominant T lymphocyte subset in the cerebrospinal fluid cells, while CD8 positive cells were predominant during the recovery phase. The relative proportions of CD4 positive and CD8 positive cells during the acute and recovery phase in the cerebrospinal fluid mononuclear cells were quite high compared to the recovery phase, although that ratio of peripheral blood mononuclear cells was not changed throughout the course. It was concluded that T lymphocytes and increased 2′,5′-oligoadenylate synthetase activity in the cerebrospinal fluid may be one of the important components in the local inflammatory process independent of the systemic host defense mechanism in aseptic meningitis.     

Cerebrospinal fluid immunoglobulins in children.

Cerebrospinal fluid (CSF) immunoglobulins were measured in 62 normal children, in 9 children with purulent meningitis, and in 10 children with presumptive viral meningitis. The mean values in normal children were IgA 0, IgM 0, and IgG 0.84 +/- 1.4 mg/100 ml (+/- SD). The mean levels of all CSF immunoglobulins were raised in acute bacterial meningitis and were significantly greater than the levels found in viral meningitis. CSF IgM was 0.16 +/- 0.5 mg/100 ml in viral meningitis compared with 2.64 +/- 2.06 mg/100 ml in bacterial meningitis (P less than 0.01). However, these values overlapped to a considerable extent and, generally, measurement of CSF immunoglobulins did not enhance diagnostic accuracy in this group of children.     

Cerebrospinal fluid immunoglobulins in children

Cerebrospinal fluid (CSF) immunoglobulins were measured in 62 normal children, in 9 children with purulent meningitis, and in 10 children with presumptive viral meningitis. The mean values in normal children were IgA 0, IgM 0, and IgG 0.84 +/- 1.4 mg/100 ml (+/- SD). The mean levels of all CSF immunoglobulins were raised in acute bacterial meningitis and were significantly greater than the levels found in viral meningitis. CSF IgM was 0.16 +/- 0.5 mg/100 ml in viral meningitis compared with 2.64 +/- 2.06 mg/100 ml in bacterial meningitis (P less than 0.01). However, these values overlapped to a considerable extent and, generally, measurement of CSF immunoglobulins did not enhance diagnostic accuracy in this group of children.