Experimental reproduction of a spiking mortality syndrome of turkeys

We measured the levels of interleukin-6 (IL-6), albumin, C-reactive protein (CRP) and alpha 2 macroglobulin (alpha 2M), all of which have different spectrums of molecular weight, in the cerebrospinal fluid (CSF) and serum in 121 patients to evaluate damage to the blood-cerebrospinal fluid barrier (BCB) in meningitis. There was an extraordinary high level of IL-6 in the CSF when patients had bacterial or viral meningitis, but the level returned to a normal range within a week in almost all of these cases. There were no significant differences in CSF albumin levels among the different disease groups. The CRP level in CSF is considered to correlate with the serum level, and CSF CRP was higher in bacterial meningitis than in viral meningitis, however, CRP in CSF was increased in some of the infectious diseases without meningitis. The alpha 2M in CSF, which tends to be at extraordinarily high levels when there is damage to the BCB, correlated highly with CSF cell counts. CSF IL-6 seemed to be a useful indicator to identify the acute active phase of meningitis. CRP and alpha 2M in CSF are considered to be useful to differentiate bacterial meningitis, bacterial infection without meningitis and viral meningitis. Extraordinarily high levels of alpha 2M, which has a high molecular weight, in CSF is indicative of BCB damage.     

Cerebrospinal fluid leukocyte aggregation in meningitis

OBJECTIVE: To evaluate whether the difference in aggregation of cerebrospinal fluid cells from patients with bacterial, viral, aseptic and partially treated meningitis can be used for diagnostic purposes. METHODS: Cerebrospinal fluid samples of 100 patients with meningitis (15 bacterial, 13 partially treated, 10 viral and 62 aseptic) were compared on the basis of the predefined leukocyte aggregation score (LAS). RESULTS: Mean LAS was 56% in the bacterial meningitis group (range, 15 to 90%), 5.8% in the partially treated meningitis group (range, 0 to 27%), 2% in the proven viral meningitis group (range, 0 to 5%) and 2% in the aseptic meningitis group (range, 0 to 15%). All patients with bacterial meningitis had a LAS of > 15%, whereas all those with viral or aseptic meningitis had a score of < 15%. Although most patients with partially treated meningitis had a low LAS, several had higher scores, which may indicate bacterial infection. There was no statistical correlation between number of cells, type of cells (mononuclear or polymorphonuclear) or cerebrospinal fluid protein and glucose concentration and degree of leukocyte aggregation for the different groups. CONCLUSION: Measurement of the LAS may contribute to the immediate differential diagnosis of bacterial or viral meningitis, especially in patients with very high pleocytosis, as sometimes seen in enteroviral meningitis. It may also serve as a guide for the likelihood of bacterial infection in cases of partially treated meningitis. Additional studies are needed to confirm these observations.     

Basic fibroblast growth factor in experimental and clinical bacterial meningitis

Basic fibroblast growth factor (bFGF), a neurotrophic factor in the CNS, is expressed at high levels in response to seizures or strokes. We examined the expression of bFGF during experimental bacterial meningitis and the levels of bFGF in the cerebrospinal fluid (CSF) of children with bacterial meningitis. For the experimental study, a mouse model of meningitis was established by intracranial injection of Streptococcus pneumoniae. Twenty-four hours after induced meningitis, the brains were sectioned and stained immunohistochemically for bFGF. Neutrophils and macrophages infiltrating the leptomeninges and the ventricles exhibited strong bFGF immunoreactivity. The neurons in the areas adjacent to the inflamed ventricles also showed enhanced bFGF expression. For the clinical study, we used an enzyme immunoassay to measure bFGF in CSF in 18 children with bacterial meningitis, 12 with aseptic meningitis, and 18 controls. The CSF levels of bFGF were twice as high in children with bacterial meningitis (medians 6.75-7.21 pg/mL) compared with those who had aseptic meningitis (2.9 pg/mL) or in control subjects (2.65 pg/mL, p < 0.0001, respectively). In patients with bacterial meningitis who survived, CSF bFGF decreased significantly after 24-50 h of antibiotic therapy (p < 0.0005). Patients who developed major sequelae or died had much higher levels of CSF bFGF than those without (134.9 pg/mL versus 7.38 pg/mL, p < 0.05). These findings of enhanced immunoreactivity of bFGF in experimental bacterial meningitis and an association of CSF levels of bFGF with disease severity in childhood bacterial meningitis suggest a biologic role for this neurotrophic factor in the pathophysiology of bacterial meningitis.     

Matrix metalloproteinases contribute to the blood-brain barrier disruption during bacterial meningitis

In this study, we investigated the involvement of matrix metalloproteinases (MMPs) in the pathophysiology of bacterial meningitis. By using an enzyme immunoassay, high concentrations of MMP-9 were detected in the cerebrospinal fluid (CSF) of adult patients with bacterial meningitis but not in controls, and in patients with Guillain-Barré syndrome. Moreover, we observed significantly elevated concentrations of the tissue inhibitor of metalloproteinase-1 (TIMP-1) in the CSF of patients with bacterial meningitis, compared with controls. In a rat model of meningococcal meningitis, intracisternal injection of heat-killed meningococci caused a disruption of the blood-brain barrier (BBB), an increase in intracranial pressure, and CSF pleocytosis paralleled by the occurrence of MMP-9 activity in the CSF 6 hours after meningococcal challenge. The MMP inhibitor batimastat (BB-94) significantly reduced the BBB disruption and the increase in intracranial pressure irrespective of the time of batimastat administration (15 minutes before and 3 hours after meningococcal challenge) but failed to significantly reduce CSF white blood cell counts. In conclusion, our results suggest that MMPs are involved in the alterations of BBB permeability during experimental meningococcal meningitis.     

Increased creatine kinase brain isoenzyme concentration in cerebrospinal fluid with meningitis

CPK-BB (CK-BB) isoenzyme is an intracellular enzyme released in various neurologic conditions, including central nervous system (CNS) infections. Activity of CK-BB in cerebrospinal fluid (CSF) was determined in 80 children by electrophoresis and densitometry. The possible correlation between CNS infection and CK concentrations was assessed. Significantly elevated concentrations of CK activity (P < 0.01) in the CSF were found in children with bacterial meningitis as compared with children with either aseptic meningitis or normal CSF findings. The data suggest the possibility of utilizing CSF CK activity to differentiate between bacterial and viral meningitis in situations where a routine CSF examination is inconclusive.     

Intraoral non-Hodgkin''s lymphoma in seven patients with acquired immunodeficiency syndrome

Transcranial Doppler sonography (TCD) of the middle, anterior and posterior cerebral arteries and of the basilar artery was used to evaluate the mean blood velocity (V mean) and the pulsatility index [PI = (V systolic-V diastolic)/V mean] as a vascular resistance index in 63 patients (male 40, female 23, mean age 43 +/- 19 y) with bacterial meningitis (n = 33, including 2 patients with fungal meningitis) and viral meningitis (n = 30) within 12 h after admission of the patients. The findings were similar for all intracranial arteries. Compared with reference values of 69 healthy volunteers [V mean of middle cerebral artery [MCA] 57 +/- 13 cm/s, MCA-PI 0.83 +/- 0.15], MCA-V mean was increased in patients with Glasgow coma scale (GCS) scores of 14 and 15 (71 +/- 18 cm/s; t-test: p < 0.001), not significantly different in the patients with GCS scores of 10-13 (55 +/- 21 cm/s) and decreased in those with GCS scores of 3-9 (42 +/- 21 cm/s, p < 0.01). The MCA-PI increased from 0.93 +/- 0.22 in the patients with GCS scores of 14-15 to 2.81 +/- 2.06 in those with GCS scores of 3-9 (p < 0.001 vs. controls). By regression analysis, MCA-V mean decreased and MCA-PI increased with decreasing GCS scores (p < 0.001). Only in patients with bacterial meningitis was the Glasgow outcome scale (GOS) score lower the more the MCA-PI was increased (regression analysis p < 0.001). We conclude that in patients with bacterial and viral meningitis, and in a good clinical state, the cerebral blood flow seems increased by hyperemia; with clinical deterioration the cerebral haemodynamics worsen. However, the early assessment of the cerebral blood flow by TCD seems useful for predicting outcome in bacterial meningitis only.     

Multicenter evaluation of the Amplicor Enterovirus PCR test with cerebrospinal fluid from patients with aseptic meningitis. The European Union Concerted Action on Viral Meningitis and Encephalitis

The Amplicor Enterovirus PCR test was compared with viral culture for the detection of enteroviruses in cerebrospinal fluid (CSF) specimens. In a multicenter study in which nine laboratories participated, a total of 476 CSF specimens were collected from patients with suspected aseptic meningitis. Sixty-eight samples were positive by PCR (14.4%), whereas 49 samples were positive by culture (10.4%), demonstrating that the Amplicor Enterovirus PCR test was significantly more sensitive than culture (P < 0.001). After discrepancy analysis the sensitivity and specificity of the Amplicor Enterovirus PCR test obtained by using viral culture as the "gold standard" were 85.7 and 93.9%, respectively. Our results with the CSF specimens collected in different countries demonstrate that the Amplicor test is capable of detecting a large variety of enterovirus serotypes and epidemiologically unrelated isolates in CSF specimens from patients with aseptic meningitis. The Amplicor Enterovirus PCR test is a rapid assay which can be routinely performed with CSF samples and is an important improvement for the rapid diagnosis of enteroviral meningitis.     

Hypouricemia in patients with meningitis

Serum urate and sodium concentrations were measured in 23 patients with acute viral and bacterial meningitis. Serum urate level was 3.0 +/- 0.2 mg/dl (mean +/- S.D.) (3.6 +/- 1.2 mg/dl in male and 2.5 +/- 0.9 mg /dl in female) on admission, but gradually elevated with improvements of meningitis. It turned to 4.8 +/- 0.2 mg/dl after recovery, and the value on admission was significantly lower than that after recovery (p < 0.0001). Serum sodium level was 137.6 +/- 2.9 mEq/l on admission and 139.7 +/- 2.7 mEq/l after recovery; also lower in the former (p < 0.01). These results show that patients develop transient hypouricemia, which may be explained by SIADH (syndrome of inappropriate secretion of ADH), although SIADH is subclinical in most cases of meningitis.     

Diagnosis of meningococcal meningitis by broad-range bacterial PCR with cerebrospinal fluid

We used broad-range bacterial PCR combined with DNA sequencing to examine prospectively cerebrospinal fluid (CSF) samples from patients with suspected meningitis. Fifty-six CSF samples from 46 patients were studied during the year 1995. Genes coding for bacterial 16S and/or 23S rRNA genes could be amplified from the CSF samples from five patients with a clinical picture consistent with acute bacterial meningitis. For these patients, the sequenced PCR product shared 98.3 to 100% homology with the Neisseria meningitidis sequence. For one patient, the diagnosis was initially made by PCR alone. Of the remaining 51 CSF samples, for 50 (98.0%) samples the negative PCR findings were in accordance with the negative findings by bacterial culture and Gram staining, as well as with the eventual clinical diagnosis for the patient. However, the PCR test failed to detect the bacterial rRNA gene in one CSF sample, the culture of which yielded Listeria monocytogenes. These results invite new research efforts to be focused on the application of PCR with broad-range bacterial primers to improve the etiologic diagnosis of bacterial meningitis. In a clinical setting, Gram staining and bacterial culture still remain the cornerstones of diagnosis.     

Chemotactic activity on mononuclear cells in the cerebrospinal fluid of patients with viral meningitis is mediated by interferon-gamma inducible protein-10 and monocyte chemotactic protein-1

In viral meningitis the inflammatory response involves activated T cells and monocytes which are recruited into the subarachnoid space. To identify the chemotactic signals attracting the cells to the site of infection in the meninges, we measured the levels of two CXC chemokines, interferon-gamma (IFN-gamma) inducible protein (IP)-10 and monokine induced by IFN-gamma, four CC chemokines, monocyte chemotactic protein (MCP)-1, RANTES, macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta, as well as the cytokines interleukin (IL)-15 and IL-16 in the cerebrospinal fluid (CSF) of patients suffering from viral meningitis. The results point to an involvement of two chemokines, MCP-1 and IP-10, since (1) unlike the other cytokines, MCP-1 and IP-10 were present in 97% and 79% of the CSF, respectively, at concentrations sufficient to induce chemotaxis of mononuclear cells; (2) more than 90% of the CSF of viral meningitis induced chemotaxis of peripheral blood mononuclear cells (PBMC) and all of them induced chemotaxis of activated T cells, and (3) the CSF-mediated chemotaxis of PBMC was inhibited by anti-MCP-1 antibodies and chemotaxis of activated T cells was abolished by the combination of anti-MCP-1 and anti-IP-10 antibodies. Our data provide evidence that MCP-1 and IP-10 lead to accumulation of activated T cells and monocytes in the CSF compartment in viral meningitis.     

No triazolam-induced expression of Fos protein in raphe nuclei of the male Syrian hamster

The levels of soluble interleukin-2 receptors (sIL-2R), beta-2 microglobulin (beta-2M), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured in the serum of 50 previously untreated patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) as well as in 25 age and sex-matched normal controls. Compared to normal controls, mean serum levels of sIL-2R and beta-2M were significantly increased in both NHL and CLL (p < 0.001) while the increase in ESR and CRP was less marked (p < 0.01 and p < 0.05, respectively). Comparison of these tumor markers with histologic grading showed statistically significant differences only for CRP between low, intermediate and high-grade lymphomas (p < 0.001 and p < 0.05). More advanced stages exhibited higher mean values of all serum markers than early stages (p < 0.001 for sIL-2R, beta-2M and ESR and p < 0.05 for CRP). An association with the presence of b-symptoms was observed only for sIL-2R (p < 0.05). In addition, sIL-2R as well as beta-2M were able to predict time to progression in patients with diffuse large-cell lymphomas. We conclude that of the four tumor markers tested sIL-2R and beta-2M more frequently showed increased serum levels and were associated with clinical stage and/or presence of b-symptoms. Both sIL-2R and beta-2M were also found to have prognostic significance for survival.     

Clinical applications of C-reactive protein in pediatrics

The body of literature concerning studies of the applications of CRP measurement in the pediatric population continues to grow. Based on current data serial CRP measurements appear to be most useful for monitoring patient response to therapy after the primary diagnosis of invasive infectious or inflammatory diseases, for monitoring patients after major surgical procedures and those with serious burns. Monitoring CRP over time may be used to assess for recrudescent disease, a secondary process or ineffective therapy. In addition CRP appears to be suited to most applications for which the ESR is used but offers many advantages. At present there are no objective outcome-based clinical trial data to justify using CRP values alone, whether elevated or normal, as a basis for management decisions regarding instituting or withholding antimicrobial therapy, or its early discontinuance for patients suspected of having neonatal sepsis, meningitis, bacteremia or pneumonia, regardless of immune status. In addition, because of significant inconsistencies among studies for which CRP has been applied to differential diagnosis of bacterial vs. viral diseases, including meningitis, acute otitis media and lower respiratory tract infection, we cannot recommend it for this purpose. Data do not support a role for CRP in differential diagnosis of acute appendicitis or for localizing urinary tract infections.     

Diagnostic value of atypical lymphocytes in cerebrospinal fluid from adults with enteroviral meningitis

We have noted two morphologically distinct types of atypical lymphocytes (AL) in the cerebrospinal fluid (CSF) of adult patients with meningitis: one, which we designate type-I AL, with multilobulated nuclei resembling those of the abnormal cells in adult T-cell leukaemia (ATL); and another, type-II AL, characterized by large lymphocytes with basophilic cytoplasm and nuclei containing coarse chromatin. Type-I AL were detected in 25 of 39 patients (64%) with enteroviral and in 11 of 109 (11%) with aseptic meningitis presumed to be caused by other viruses, but not in meningitis resulting from Cryptococcus neofirmans (n = 14), Mycobacterium tuberculosis (n = 19) or acute bacterial infection (n = 49). Type-I AL were not seen in herpes zoster (n = 15) aseptic meningeal reactions (n = 15), or in leptomeningeal carcinomatosis (n = 14). Type-II AL were often present in meningitis of various aetiologies and in aseptic meningeal reactions, but not in leptomeningeal carcinomatosis. The presence of type-I AL in the CSF was found to be indicative of enteroviral meningitis with the highest predictive value (69%), while type-II AL had a lower diagnostic positive predictive value in meningitis of the five aetiologies above. Type-I AL immunostained for CD4, while type-II AL were stained for CD8. The presence of type-I AL in CSF strongly suggests enteroviral meningitis, which warrants careful follow-up without antifungal, antituberculous or antibacterial agents. However, type-I AL, which are likely to be virally transformed lymphocytes, must be distinguished from ATL cells, which frequently involve the meninges.     

Impact of deltamethrin impregnated mosquito nets on the transmission of malaria in the coastal lagoon area, Benin]

Neopterin has been determined in blood as a marker of cellular immune system activation. We studied cerebrospinal fluid (CSF) neopterin levels in children with neurologic diseases, and the following results were obtained: (1) CSF neopterin levels markedly increased at the acute phase of bacterial meningitis, aseptic meningitis, and encephalitis as compared with those in patients without neurologic diseased. (2) In the CSF of patients with bacterial meningitis and aseptic meningitis, neopterin levels decreased more rapidly than the total cell count and 2'5' oligoadenylate synthetase (2-5 AS) did. (3) CSF neopterin in patients with non-infectious neurologic diseases was almost equal to that in patients without neurologic diseases. (4) There was no correlation between CSF neopterin and other CSF values, such as total cell count, mononuclear cell count, protein, and 2-5 AS. These results suggest that CSF neopterin is a useful marker of inflammatory central nervous diseases.     

Lysozyme activity in cerebrospinal fluid. Studies in inflammatory and non-inflammatory CNS disorders

Lysozyme activity was measured in cerebrospinal fluid (CSF) from 114 patients with inflammatory (bacterial and serous meningitis, polyradiculitis, encephalitis) and non-inflammatory (multiple sclerosis, CNS tumors, cerebral vascular diseases) CNS diseases. Highly elevated values were found consistently in patients with bacterial meningitis. Elevated values were found also in patients with encephalitis, polyradiculitis, multiple sclerosis and CNS tumors, but a considerable overlapping between these groups and normal controls precludes the use of CSF lysozyme measurements as a diagnostic aid in the latter disease groups. Simultaneous measurements of lysozyme, albumin and IgG in CSF and serum suggested that the mechanism for increased CSF lysozyme values in bacterial meningitis is mainly a breakdown of the blood/brain barrier, whereas the increased CSF lysozyme values in the remaining groups of patients are more likely caused by production of lysozyme by cells within the meninges (neutrophilic granulocytes, monocytes?).     

Cerebrospinal fluid pleocytosis in children with pneumonia but lacking evidence of meningitis

Headache, nuchal rigidity, positive Kernig's sign, and even convulsions may be observed during severe bacterial infections such as pneumonia, pyelonephritis, typhoid fever, and bacillary dysentery. In such cases, meningitis can be excluded only by documentation of normal cerebrospinal fluid (CSF). The authors describe four children with lobar pneumonia in whom the clinical signs of meningeal irritation were associated with a mild increase in the white blood cell count in the CSF (pleocytosis) although there was no other evidence of meningeal infection.     

Subdural effusion in type B Haemophilus influenzae meningitis. A study of 38 cases

OBJECTIVE: Studying clinical, laboratory and radiologic findings, as well as outcome, observed in patients with meningitis caused by Hib, and its relationship with subdural effusion. MATERIAL AND METHODS: Retrospective study of 38 meningitis caused by Hib. Patients were aged between 3 months and 5 years. Imaging was performed in 26 cases (68%): CT in 21 children (55%) and cranial sonography in 11 cases (29%). EEG was made in 29 patients (76%) and auditory-evoked potentials in 13 (34%). The mean follow-up period after discharge was 24 months. RESULTS: Sixty-six per cent were male and 34% female. Eight cases had subdural effusion. These patients showed higher white cell counts in blood and CSF, higher levels of proteins in CSF, and lower levels of glucose in the same medium. They also had seizures before or during hospitalization, with higher frequency than those without subdural effusion (50% vs 26%) as well as more prolonged fever (127 vs 73 hours). No specific treatment was required in any case. CONCLUSIONS: Subdural effusion is one of the most frequent complications observed in meningitis. Patients frequently present more important clinical and laboratory alterations. This finding is not related with neurologic sequelae and they resolve spontaneously with time.     

Effect of the bradykinin B2 receptor antagonist Hoe140 in experimental pneumococcal meningitis in the rat

To elucidate the role of bradykinin in the complex pathophysiology of bacterial meningitis we investigated the effect of the bradykinin B2 receptor antagonist Hoe140, icatibant (D-Arg[Hyp3-Thi5-D-Tic7-Oic8]-bradykinin), on pathophysiological alterations in experimental pneumococcal meningitis. Untreated rats injected intracisternally (i.c.) with heat-killed pneumococci developed an increase of regional cerebral blood flow (185.4 +/- 27.4%, baseline 100%, mean +/- S.D.), brain water content (79.16 +/- 0.23%), intracranial pressure (21.4 +/- 6.0 mm Hg), and white blood cell count in the cerebrospinal fluid (CSF) (4621 +/- 1894 cells/microliter) within 6 h after i.c. challenge. Treatment with Hoe140 (0.1 mg/kg i.v. at baseline and 0.05 mg/kg s.c. at 2 h after i.c. challenge) attenuated the increase of brain water content (78.53 +/- 0.28%; P < 0.05), intracranial pressure (7.5 +/- 2.2 mm Hg; P < 0.05), and regional cerebral blood flow (128.6 +/- 23.1%; P < 0.05), and reduced CSF pleocytosis (2690 +/- 1898 cells/microliter. N.S.). When treatment was started 4 h after i.c. challenge Hoe140 reduced intracranial pressure (P < 0.05), but was no more capable to significantly influence the other pathophysiological parameters. Treatment with lower (0.01 mg/kg i.v. at baseline, followed by 0.005 mg/kg s.c. at 2 h) and higher (2 mg/kg i.v., followed by 1 mg/kg s.c. at 2 h) concentrations of Hoe140 was ineffective. Likewise, i.c. injection of Hoe140, at different dosages (4 nmol, 40 nmol, 400 nmol) did not significantly alter the pathophysiological parameters in pneumococci-induced meningitis, but caused changes in mean arterial blood pressure at dosages greater than 4 nmol. We conclude that bradykinin is involved as an inflammatory mediator of microvascular changes, brain edema, and increased intracranial pressure during the early phase of experimental pneumococcal meningitis.