Concentrations of nucleotides, nucleosides, purine bases and urate in cerebrospinal fluid of children with meningitis

The release of agents mediating inflammation in meningitis may bring about neuronal hypoxia, under which circumstances ATP concentrations decrease and its degradation products increase and are released into the cerebrospinal fluid. In this study of alterations in neuronal energy metabolism in meningitis, AMP, IMP, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine and urate were determined by high performance liquid chromatography in the cerebrospinal fluid of 54 children aged between 1 month and 13 years suffering from meningitis (25 viral, 24 bacterial and 5 tuberculous cases) and 63 controls. Compared to the controls, patients with viral meningitis exhibited high concentrations of IMP, adenosine, guanosine, adenine, guanine and xanthine; patients with bacterial meningitis exhibited high concentrations of IMP, inosine, guanosine, adenosine, hypoxanthine, xanthine and urate; and patients with tuberculous meningitis exhibited high concentrations of AMP, guanosine, xanthine and uratc. Viral and bacterial cases did not differ significantly for any of the metabolites studied. AMP and urate concentrations were significantly higher in patients with tuberculous cases compared with viral or bacterial meningitis cases.     

不同中枢神经系统感染患儿脑脊液肝细胞生长因子水平变化的意义

目的通过观察病毒性脑炎、细菌性脑膜炎及结核性脑膜炎患儿脑脊液肝细胞生长因子(HGF)水平变化,探讨其是否可以作为一个鉴别诊断的生化指标,为临床疾病的诊断提供依据。方法选择临床确诊病毒性脑炎30例、细菌性脑膜炎21例、结核性脑膜炎19例及对照组24例,采用酶联免疫吸附试验双抗体夹心法检测各组患儿脑脊液HGF水平。同时将HGF水平分别与脑脊液中白细胞计数和蛋白定量进行直线相关分析,观察脑脊液中HGF水平与脑脊液中白细胞计数和蛋白定量的关系。结果细菌性脑膜炎组、结核性脑膜炎组脑脊液HGF水平高于病毒性脑炎组和对照组,结核性脑膜炎组高于细菌性脑膜炎组患儿,细菌性脑膜炎组、结核性脑膜炎组及病毒性脑炎组与对照组患儿比较均有显著性差异(Pa<0.05),病毒性脑炎组与对照组患儿比较差异无统计学意义(P>0.05)。结论 HGF有可能成为鉴别细菌性脑膜炎、结核性脑膜炎及病毒性脑炎的指标之一。     

神经元特异性烯醇化酶对脑膜炎患儿的诊断价值

目的探讨脑脊液神经元特异性烯醇化酶(CSF-NSE)对脑膜炎患儿的诊断价值。方法采用ELISA对18例化脓性脑膜炎(化脑)、13例结核性脑膜炎(结脑)及25例病毒性脑膜炎(病脑)及18例正常儿童CSF-NSE进行测定。结果与对照组比较,化脑及结脑患儿CSF-NSE水平均显著升高(P均<0.05);病脑患儿无显著性差异(P>0.05);化脑及结脑患儿CSF-NSE水平较病脑患儿显著升高(P<0.05);化脑、结脑、病脑患儿CSF-NSE与其CSF白细胞数及蛋白水平均无相关性(P>0.05)。结论CSF-NSE测定可作为鉴别化脑和病脑的重要参考指标之一,也可作为评价脑膜炎患儿病情严重程度及预后的生化指标。     

Postmortem time and storage temperature affect the concentrations of hypoxanthine, other purines, pyrimidines, and nucleosides in avian and porcine vitreous humor

An HPLC method was used to determine whether postmortem time and storage temperature affect the concentrations of purines, pyrimidines, and nucleosides in avian and porcine vitreous humor. Inosine, hypoxanthine, xanthine, uric acid, uracil, uridine, and thymine were identified in the vitreous humor of chickens (Gallus domesticus). Time from death to sample collection (0-192 h) influenced the concentrations of all seven compounds (p less than 0.01 to less than 0.0001). The storage temperature of chicken carcasses before sampling (6 or 20 degrees C) had a significant influence on the concentrations of inosine, hypoxanthine, xanthine, uric acid, uracil, and thymine (p less than 0.05 to less than 0.0001). The interaction of postmortem time with temperature was significant for all seven compounds (p less than 0.01), with the rate of increase in concentration over time being higher at 20 than 6 degrees C. At 0 h postmortem, the vitreous humor of pigs (Sus scrofa) contained detectable levels of hypoxanthine, uracil, and uridine. Inosine, hypoxanthine, xanthine, guanosine, guanine, uracil, and uridine were detected after storage of pig eyes for 24 h at 20 degrees C. Between 0 and 24 h postmortem, there was a 22-fold increase in hypoxanthine concentration and a 13-fold increase in uracil concentration (p less than 0.0001). It was concluded that postmortem time and temperature are factors that must be taken into consideration when making comparisons of purines, pyrimidines, and nucleosides between groups and in relating postmortem vitreous humor hypoxanthine concentrations to antemortem hypoxia.     

Tumour necrosis factor-alpha in infectious meningitis.

During a one year period tumour necrosis factor-alpha (TNF-alpha) was prospectively determined in the cerebrospinal fluid of 49 patients with infectious meningitis. TNF-alpha was found in the cerebrospinal fluid of 15 of 18 patients with bacterial meningitis. In 11 patients who had cerebrospinal fluid positive for TNF-alpha it was detected in only one serum (in low concentration). There was no significant correlation between the concentration of TNF-alpha in cerebrospinal fluid and the patient''s age, duration of illness and fever, body temperature, and serum C reactive protein. However, cerebrospinal fluid protein concentrations of greater than or equal to 2 g/l and leucocyte values of greater than or equal to 2.5 X 10(9)/l were more often associated with high TNF-alpha concentrations (greater than or equal to 500 pg/ml). In contrast with bacterial meningitis, none of the 31 samples of cerebrospinal fluid from patients with viral meningitis was positive for TNF-alpha. Thus this investigation supports the conclusion, drawn from animal studies on TNF-alpha in the cerebrospinal fluid, that the presence of TNF-alpha is indicative of bacterial meningitis. Absence of TNF-alpha cerebrospinal fluid, however, was found here not to exclude a bacterial aetiology of the infection.     

Value of C reactive protein measurement in tuberculous,bacterial, and viral meningitis.

The value of C reactive protein measurement in the differential diagnosis of meningitis was assessed in a population where tuberculous meningitis is prevalent. C reactive protein was measured serially with a sensitive radioimmunoassay in sera from 31 children with bacterial meningitis, 15 with tuberculous meningitis (6 with miliary tuberculosis), and 28 with viral meningitis. Concentrations of C reactive protein in patients with tuberculous meningitis lay between those of patients with bacterial and viral meningitis--a finding which detracts from the virtually absolute discrimination C reactive protein measurement allows between bacterial and viral meningitis. In all but two of the patients with tuberculous meningitis, C reactive protein concentrations fell rapidly after treatment began and became normal after 10 days. This fall did not, however, exclude the development of hydrocephalus as a complication. Measurement of C reactive protein remains a useful additional parameter in the diagnosis and management of the various types of meningitis.     

Plasma and cerebrospinal fluid arginine vasopressin in patients with and without fever.

Hyponatraemia has been described in association with a number of acute infectious diseases, mainly bacterial and tuberculous meningitis and pneumonia, and has been attributed to inappropriate secretion of arginine vasopressin (AVP). The mechanism of inappropriate AVP production is uncertain, but there is experimental evidence to suggest that fever may stimulate secretion of AVP into plasma and cerebrospinal fluid. In this study, AVP concentrations in plasma and cerebrospinal fluid from 37 febrile children with infections have been compared with those from 27 afebrile control subjects. Ten of the febrile children had meningitis (eight bacterial, two viral) and the remainder a variety of other infectious diseases. Seventy four per cent of febrile infected children were hyponatraemic (serum sodium less than 135 mmol/l) compared with only 8% of the afebrile controls. Plasma AVP concentrations were significantly higher in the febrile patients (median 2.92 pmol/l, range 1.0-23.25, n = 28) than in controls (median 1.67 pmol/l, range 0.57-6.0, n = 14) but there was no significant difference in cerebrospinal fluid AVP concentrations. There was no difference in plasma AVP concentrations between patients with meningitis and those with infections not involving the central nervous system. Careful attention should be paid to fluid and electrolyte balance in all children with acute infections.     

Cerebrospinal fluid C-reactive protein measurement--a bedside test in the rapid diagnosis of bacterial meningitis

C-reactive protein (C-RP) determinations were performed by the Latex agglutination method on the cerebrospinal fluid (CSF) samples of 212 patients with clinical features suggestive of meningitis. Patients were grouped as follows Group I: bacterial meningitis and partially treated bacterial meningitis (n = 22). Group II: viral encephalitis (n = 11). Group III: tuberculous meningitis (n = 18). Group IV: (i) febrile convulsions (n = 87); (ii) epileptic seizures (n = 70); (iii) intracranial haemorrhage (n = 4). C-RP was a better indicator of bacterial meningitis (sensitivity 91 per cent) than the Gram's stain (sensitivity 46 per cent). C-RP was positive in 91 per cent of patients in Group I, none in Groups II and III and 0.6 per cent in Group IV. C-RP determination in CSF proved to be a useful indicator of bacterial meningitis and served to distinguish it from viral encephalitis, tuberculous meningitis, febrile convulsions and other central nervous system disorders.     

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.     

Purine and pyrimidine metabolism and electrocortical brain activity during hypotension in near-term lambs

BACKGROUND: Insufficient cerebral O2 supply leads to cellular energy failure and loss of brain cell function. The relationship between the severity of cellular energy failure due to hemorrhagic hypotension and the loss of electrocortical brain activity (ECBA), as a measure of brain cell function, is not yet fully elucidated in near-term born lambs. OBJECTIVES: To study the relationship between cerebral purine and pyrimidine metabolism, as a measure of brain cell energy failure, and brain cell function after hemorrhagic hypotension in near-term born lambs. METHODS: Eight near-term lambs (term 147 days) were delivered at 131 days of gestation. After a stabilization period, mean arterial blood pressure was reduced till 30% of baseline by withdrawal of blood. Cerebrospinal fluid (CSF) was obtained at the end of the hypotensive period (2.5 h). CSF from 8 siblings was used for comparison. HPLC was used to determine purine and pyrimidine metabolites in CSF, as a measure of cellular energy failure. ECBA was calculated as the root mean square value of a band-filtered (2-16 Hz) one-channel EEG. RESULTS: Values of guanosine, inosine, hypoxanthine, xanthine and uridine were significantly higher, while ECBA was significantly lower after hemorrhagic hypotension than control values. The concentrations of inosine, hypoxanthine, xanthine and uridine were significantly negatively linearly related to ECBA. CONCLUSIONS: Brain cell function is negatively related to concentrations of inosine, hypoxanthine, xanthine and uridine in the CSF after hemorrhagic hypotension in near-term born lambs.     

Diagnosis of meningitis with reagent strips

OBJECTIVE: To determine the usefulness of reagent strips in the evaluation of pleocytosis, cerebrospinal fluid glucose and protein levels for early and rapid diagnosis of meningitis in children. METHODS: We included cerebrospinal fluid samples of 164 children admitted to the outpatient clinic of Communicable Diseases of the General Pediatric Center (Funda??o Hospitalar do Estado de Minas Gerais, CGP-FHEMIG) during the daytime hours from May of 1997 to May 1999, and who presented with clinical suspicion of meningitis. Patients ranged in age from one month to 12 years (median 12 months). Results from the cytological and biochemical assay (cellularity, cerebrospinal fluid glucose and protein levels) were obtained from 154 patients. These results were subsequently compared with the reaction of cerebrospinal fluid in reagent strips. RESULTS: The cytological and biochemical assay identified 43 cases of probable bacterial meningitis, 19 of probable viral meningitis, and 83 with no alterations. According to the reagent strips, there were 41 cases of probable bacterial meningitis, 2 of probable viral meningitis, and 71 with no alterations. By comparing the results of reagent strips and those of the cytological and biochemical assay, we obtained values for sensitivity, specificity, positive and negative predictive values, and accuracy (respectively 90.7; 98.1; 95.1; 96.4; and 96.1). Statistical analysis using McNemer test did not indicate significant differences between the two methods in the diagnosis of bacterial meningitis (P=0.68). Kappa statistics indicated a high level of agreement between the tests (P<0.0001). CONCLUSIONS: Our results suggest that reagent strips may be a useful additional resource in the diagnosis of bacterial meningitis, especially when it is difficult to collect a sufficient amount of cerebrospinal fluid or to indicate the initial treatment.     

Lactoferrin, C-reactive Protein, α-1-Antitrypsin and Immunoglobulin GA in Cerebrospinal Fluid in Meningitis

ABSTRACT. Cerebrospinal fluid measurements of lactoferrin and α-1-antitrypsin showed significant elevation in bacterial meningitis in children. 8 of 10 lactoferrin values and 6 of 11 α-1-antitrypsin values were above the upper range of controls. Both proteins correlated well with the total number of leukocytes in the cerebrospinal fluid. C-reactive protein, measured by either agglutination or radial immunodiffusion in the cerebrospinal fluid, failed to demonstrate any asefulness in diagnosing bacterial meningitis. Neither elevated serum C-reactive protein in cases of bacterial meningitis, nor sepsis, gave detectable concentrations of C-reactive protein in the cerebrospinal fluid.     

Evaluation of adenosine deaminase activity and antibody to Mycobacterium tuberculosis antigen 5 in cerebrospinal fluid and the radioactive bromide partition test for the early diagnosis of tuberculosis meningitis.

A number of different biochemical and serological tests have been described recently for the early and accurate diagnosis of tuberculous meningitis. None of these tests has yet gained widespread acceptance in clinical medicine or in microbiology laboratories. To investigate this problem we evaluated adenosine deaminase activity (ADA), an enzyme linked immunosorbent assay (ELISA) that detects antibody to antigen 5 of Mycobacterium tuberculosis, and the radioactive bromide partition test (BPT) in the cerebrospinal fluid (CSF). Cerebrospinal fluid specimens from children with tuberculous, pyogenic, and viral meningitis as well as from patients with pulmonary tuberculosis without meningitis and from controls with normal CSFs were included inn the study. In addition, we estimated ADAs in serum samples from selected children in these groups. The sensitivity and specificity of the three tests evaluated in the CSF were: ADA assay 73% and 71%; BPT 92% and 92%; and ELISA for antibody to antigen 5, 53% and 90%, 40% and 94%, and 27% and 100%, respectively, at tires of more than or equal to 1:20, 1:40, and 1:80. The serum ADA was lower (11.0 +/- 6.15 IU/l) in children with tuberculous meningitis when compared with those with pulmonary tuberculosis alone (25.8 +/- 20.9 IU/l). The BPT was found to be the most reliable test in the early differentiation of tuberculous from other causes of meningitis and remained abnormal for a period of up to five months after the beginning of treatment. Accordingly, we believe that the BPT should be used in conjunction with bacterial and fungal antigen detection systems for the initial differentiation of clinically suspicious tuberculous meningitis from Gram or culture negative cases, or both, of bacterial and fungal meningitis.     

Lactoferrin, C-reactive protein, alpha-1-antitrypsin and immunoglobulin GA in cerebrospinal fluid in meningitis

Cerebrospinal fluid measurements of lactoferrin and alpha-1-antitrypsin showed significant elevation in bacterial meningitis in children. 8 of 10 lactoferrin values and 6 of 11 alpha-1-antitrypsin values were above the upper range of controls. Both proteins correlated well with the total number of leukocytes in the cerebrospinal fluid. C-reactive protein, measured by either agglutination or radial immunodiffusion in the cerebrospinal fluid, failed to demonstrate any usefulness in diagnosing bacterial meningitis. Neither elevated serum C-reactive protein in cases of bacterial meningitis, nor sepsis, gave detectable concentrations of C-reactive protein in the cerebrospinal fluid.     

Cerebrospinal fluid lactic acid dehydrogenase activity. Levels in untreated and partially antibiotic-treated meningitis.

High levels of cerebrospinal fluid (CSF) lactic acid dehydrogenase (LDH) activity were found in 23 cases of bacterial meningitis, but significantly lower levels of CSF LDH activity were observed in 11 patients with viral meningitis and in 13 patients with no central nervous system infection. No correlation was found between levels of CSF LDH activity and specific agents or the amounts of CSF white blood cell, protein, and glucose. The number of meningitis cases of unknown cause that could be classified as probably bacterial or viral was increased by determination of the level of CSF LDH activity. The level of CSH LDH activity is useful in differentiating bacterial from viral meningitis and, along with determination of the CSF blood cell counts and protein and glucose levels, aids in classification of meningitis before culture results are available.     

Cerebrospinal fluid pyrazinamide concentrations in children with tuberculous meningitis

Cerebrospinal fluid pyrazinamide concentrations were determined by high pressure liquid chromatography in 53 samples from 13 children who had tuberculous meningitis complicated by increased intracranial pressure. Peak concentrations of up to 50 micrograms/ml were achieved between 1 1/2 and 2 1/2 hours after pyrazinamide administration and in most cases a concentration of 20 micrograms/ml or more was achieved. We conclude that pyrazinamide easily gains entry into the cerebrospinal fluid of children with tuberculous meningitis and should be included in treatment regimens for that disease.     

可溶性DLL1在儿童颅内感染性疾病诊断中的意义

目的：探讨脑脊液（CSF）及血清中可溶性DLL1的水平在儿童颅内感染诊断中的意义。方法：选择颅内感染患儿50例（结脑20例,病脑20例,化脑10例）以及非颅内感染患儿（对照组）20例,采用酶联免疫吸附试验定量测定患儿CSF及血清中可溶性DLL1的水平。结果：结脑组患儿CSF中可溶性DLL1的水平明显高于病脑组、化脑组及对照组（2.89±1.72 ng/mL vs 0.14±0.14 ng/mL, 0.27±0.21 ng/mL, 0.13±0.12 ng/mL; P＜0.01）;结脑组患儿血清中可溶性DLL1的水平也明显高于病脑组、化脑组及对照组（12.61±6.45 ng/mL vs 2.28±2.27 ng/mL, 2.38±1.79 ng/mL, 2.26±2.10 ng/mL; P＜0.01）;病脑组、化脑组与对照组相比,CSF及血清中可溶性DLL1的水平差异无统计学意义（P>0.05）。结论：可溶性DLL1的检测作为一种新的指标,在结脑诊断中可能有潜在重要价值。     

Simultaneous recovery of bacterial and viral pathogens from cerebrospinal fluid

Mixed bacterial infection in meningitis is well-documented, but there have been few previous reports of mixed viral-bacterial meningitis. A retrospective analysis of the bacterial and viral cerebrospinal fluid (CSF) cultures from a 1-year period in a 315-bed children's hospital revealed 5 patients with mixed viral-bacterial meningitis among 276 patients with viral and/or bacterial culture-positive meningitis. These 5 accounted for 2.8% of the patients with positive CSF viral cultures and 4.8% of those with positive CSF bacterial cultures. All of the viruses were identified as enteroviruses, and the bacteria were Group B Streptococcus, Group D Salmonella, Streptococcus pneumoniae, Haemophilus influenzae type b and Staphylococcus aureus. The ages of the patients ranged from 10 days to 22 years. The clinical course of each of the illnesses was typical of bacterial meningitis. This relatively high frequency of mixed viral-bacterial meningitis could affect the utility of rapid viral diagnostic tests for CSF viruses.     

C-reactive protein is useful in distinguishing Gram stain-negative bacterial meningitis from viral meningitis in children.

OBJECTIVE: To clarify to what extent Gram stain-negative bacterial meningitis can be distinguished from viral meningitis by assessment of cerebrospinal fluid (CSF) and blood indices and serum C-reactive protein (CRP) in children over 3 months of age. DESIGN: Common CSF indices, blood leukocyte counts, and serum CRP values were compared between patients with bacterial meningitis who had a positive CSF bacterial culture but a negative Gram stain and patients with viral meningitis. POPULATION: Three hundred twenty-five consecutive patients with CSF culture-proven bacterial meningitis, for whom Gram stain was negative in 55 cases, and 182 children with proven or presumed viral meningitis. RESULTS: Significant differences between patients with bacterial and viral meningitis were found in all indices with large overlap in all except serum CRP. In patients with bacterial meningitis, the mean CSF glucose concentration, protein concentration, leukocyte count, blood leukocyte count, and serum CRP were 2.9 mmol/L (52 mg/dL), 1.88 g/L, 4540 x 10(6)/L, 18.0 x 10(9)/L, and 115 mg/L; and in those with viral meningitis, mean values were 3.3 mmol/L (59 mg/dL), 0.52 g/L, 240 x 10(6)/L, 10.6 x 10(9)/L, and <20 mg/L, respectively. Of the tests investigated in this study, only serum CRP was capable of distinguishing Gram stain-negative bacterial meningitis from viral meningitis on admission with high sensitivity (96%), high specificity (93%), and high negative predictive value (99%). CONCLUSION: Exclusion of bacterial meningitis with only the conventional tests is difficult. Combined with careful physical examination and CSF analyses, serum CRP measurement affords substantial aid.