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Interleukin-8 in cerebrospinal fluid from patients with meningitis of different etiologies: its possible role as neutrophil chemotactic factor.

Interleukin (IL)-8 concentrations were analyzed in 70 cerebrospinal fluid (CSF) samples from patients with meningitis of different etiologies and in 34 normal CSF samples. Patient groups included those with pyogenic meningitis, viral meningitis, self-resolving aseptic meningitis without a specific diagnosis, and meningitis of other etiologies and normal CSF from patients with and without neurologic disease. All samples from patients with pyogenic meningitis (18) but only 3 from patients with meningitis of other etiologies and with CSF polymorphonuclear leukocyte (PMNL) counts > or = 80% had IL-8 levels > or = 2.5 ng/mL. IL-8 was above the normal level (< or = 0.5 ng/mL) in samples from 5 of 13 viral and 8 of 23 self-resolving aseptic meningitis patients and in 7 of 13 samples from patients with meningitis caused by other microorganisms. There was a significant relationship between IL-8 levels and CSF PMNL counts in patients with nonpyogenic meningitis. The data suggest a possible role of IL-8 as PMNL chemotactic factor in different infections of the subarachnoid space, not only in pyogenic meningitis.

Adolescent↗

Meningitis in the Neonate.

Group B beta-hemolytic streptococci and Escherichia coli strains account for approximately two thirds of all cases of neonatal meningitis, while bacteria that typically account for meningitis in older age groups (Haemophilus influenzae type B, Neisseria meningitidis, and Streptococcus pneumoniae) are infrequent causes of meningitis in the neonatal population. As with other medical problems in neonates, signs and symptoms of bacterial infection of the central nervous system are generally few in number and nonspecific in nature. Manifestations that can suggest meningitis, as well as other serious illnesses, include temperature instability, lethargy, respiratory distress, poor feeding, vomiting, and diarrhea. Signs suggestive of meningeal irritation, including stiff neck, bulging fontanelle, convulsions, and opisthotonus, occur only in a minority of neonates with bacterial meningitis and cannot be relied on solely to identify such patients. Ampicillin and either gentamicin or cefotaxime are recommended for initial empiric therapy of neonatal meningitis. When the results of the cerebrospinal fluid (CSF) culture and susceptibilities are known, therapy can be narrowed to cover the specific pathogen identified. In general, penicillin G or ampicillin is preferred for group B streptococcal meningitis, ampicillin for Listeria monocytogenes meningitis, and ampicillin plus either an aminoglycoside or cefotaxime for gram-negative meningitis. For the very low birth weight neonate who has been in the nursery for a prolonged period of time, organisms such as enterococci and gentamicin-resistant gram-negative enteric bacilli must also be considered. In patients with long-term vascular catheters, Staphylococcus aureus or coagulase-negative staphylococci must also be considered. Empiric combinations of antibiotics for such patients would include ampicillin or vancomycin, plus amikacin or cefotaxime. All neonates should undergo repeat CSF examination and culture at 48 to 72 hours after initiation of therapy. If organisms are observed on gram stain, modification of the therapeutic regimen should be considered, and neuroimaging should be performed. In general, therapy should be continued for 14 to 21 days for neonatal meningitis caused by group B streptococci or L. monocytogenes, and for at least 21 days for disease caused by gram-negative enteric bacilli. All patients with neonatal meningitis should have hearing and development monitored serially. The first audiologic evaluation should occur 4 to 6 weeks after resolution of the meningitis.

Journal Article↗

[Current epidemiological and clinical features meningitis in a northern Italian area]

Objectives: To study etiological, epidemiological and clinical features of 97 cases of acute meningitis. Methods: Ninety-seven cases of acute meningitis were examined in adult HIV-negative patients admitted to the Infectious Diseases Unit of the Azienda Ospedale-Universita S. Anna in Ferrara. Demographic, etiological, epidemiological and clinical data were analyzed. Results: All cases were divided into two groups according to the macroscopic aspect of cerebrospinal fluid (CSF): purulent CSF (50 cases) or non-purulent CSF (47 cases). Purulent CSF meningitis more frequently affected male patients (64% vs 47%) and older patients (average 52 vs 44 years). The main epidemiological features in both groups were underlying bacterial diseases (i.e. otomastoiditis and/or sinusitis in 50% of pneumococcal meningitis) and iatrogenic immunodeficiency. From a clinical point of view the following alterations in the state of consciousness (stupor, confusion and coma) were most frequently found in purulent meningitis. The following non purulent forms of meningitis were diagnosed: 5 tubercular, 3 viral infections, 2 by Listeria monocytogenes, 1 by Entoameba histolytica, 1 by Cryptococcus neoformans and 35 (74,4%) unknown causes. Purulent meningitis were: 20 (40%) Streptococcus pneumoniae, 10 Neisseria meningitidis, 3 Staphylococcus aureus, 2 Escherichia coli, 1 Haemophilus influenzae and 1 Pseudomonas aeruginosa; 13 cases were unidentified. From 1989 to 1993 and from 1994-98 both groups of meningitis increased; respectively from 17 to 30 cases for non-purulent meningitis and from 18 to 32 cases for purulent meningitis. Meningitis due to Streptococcus pneumoniae increased from 27.7% to 46.8% during the period 1994-98. Conclusions: The study shows the high incidence of pneumococcal meningitis, during 1994-98, because a large number of patients with sinusitis and otomastoiditis were observed. The incidence of meningococcal meningitis appears stable. These data confirm the importance of timely diagnosis and correct therapy for such infections with reserved prognosis.

Journal Article↗

Beta-2-microglobulin and ferritin in cerebrospinal fluid for evaluation of patients with meningitis of different etiologies.

To determine whether or not the beta-2-microglobulin (beta2-m) and/or ferritin levels in cerebrospinal fluid (CSF) can be used as markers for the differential diagnosis of meningitis and determination of the response to treatment, 122 subjects with etiologically well-characterized diagnoses were classified into three groups: bacterial meningitis (n = 5; mean age +/- SD. 1.0+/-1.0 year), viral meningitis (n = 39; 5.9+/-3.8 years), and a non-meningitis group (n = 78; 5.2+/-4.9 years). The levels of beta2-m and ferritin in CSF were determined by means of a latex photometric immunoassay. The statistical significance of the data was analyzed with the Mann Whitney U-test. A receiver operating characteristic curve was used to evaluate the diagnostic accuracy of each prediction marker. This study indicated that (1) the levels of beta2-m and ferritin in CSF were related with age in the non-meningitis group: subjects of up to 5 months of age exhibited higher concentrations of these proteins than ones of above 6 months of age (beta2-m, 1.89+/-1.13 vs. 0.84+/-0.65 mg/l. P < 0.01; ferritin, 2.97+/-2.04 vs. 1.81+/-1.34 microg/l, P = 0.09); (2) the beta2-m level was significantly higher in the CSF of patients with viral meningitis than in ones without meningitis (2.41+/-1.23 vs. 0.84+/-0.65 mg/l, P < 0.01): the best cut-off value was 1.2 mg/l (3) the ferritin level was significantly higher in the CSF of patients with bacterial meningitis than in ones with viral meningitis (43.24+/-39.49 vs. 6.81+/-7.41 microg/l, P < (.01): the best cut-off value was 7.5 microg/l; and (4) sequential measurement of the CSF ferritin level was of value for determination of the response to antibiotic treatment for bacterial meningitis. These results only apply to patients of greater than 6 months of age. beta2-m and ferritin in the CSF can be used as an ancillary tool for diagnostic guidance in the acute phase of meningitis and determination of the response to treatment for bacterial meningitis.

Adolescent↗

Absolute neutrophil count in aseptic and bacterial meningitis related to time of lumbar puncture.

Previous studies have demonstrated that during the first 24 hours of illness caused by aseptic meningitis, polymorphonuclear cells predominate in cerebrospinal fluid and decline afterward. To test the hypothesis that the absolute neutrophil count and percentage of polymorphonuclear cells in cerebrospinal fluid of bacterial meningitis patients are elevated and sustained after 24 hours compared with that of patients with aseptic meningitis. Seventy-two patients with aseptic meningitis and 13 with bacterial meningitis participated. All patients with aseptic meningitis and four patients with bacterial meningitis were followed-up prospectively. The patients were enrolled in four groups according to the interval between onset of symptoms and performance of the lumbar puncture (<12 hours, 12-24 hours, 24-36 hours, and >36 hours). In aseptic meningitis the mean absolute neutrophil count was 182, 164, 79, and 68 cells/mm(3), respectively (P = 0.025). In bacterial meningitis the absolute neutrophil count was 28, 1,466, 5,853, and 235 cells/mm(3), respectively. The mean percentage of polymorphonuclear cells in aseptic meningitis was 49%, 46%, 40%, and 26%, respectively (P = 0.038); in bacterial meningitis, 70%, 83%, 81%, and 58%, respectively. The findings suggest that the absolute neutrophil count and the polymorphonuclear cell percentage in cerebrospinal fluid have different kinetics in aseptic vs. bacterial meningitis.

Adolescent↗

Bacterial meningitis in childhood at the Children's Hospital of Pittsburgh: 1988-1998.

Bacterial meningitis is an important acute infectious disease of childhood that remains a source of substantial morbidity and mortality. The impact of the Haemophilus influenzae type b (HIB) conjugate vaccines on the epidemiology of the other bacterial causes of meningitis in childhood has received little attention. The objective of this study is to report the experience at a tertiary-care children's hospital with the occurrence of bacterial meningitis before and after the licensure of the HIB conjugate vaccine. With use of International Classification of Diseases diagnostic codes for bacterial meningitis, a list of all children admitted to Children's Hospital of Pittsburgh with a primary or secondary diagnosis of meningitis due to H. influenzae, Streptococcus pneumoniae, and Neisseria meningitidis from January 1, 1988, to December 31, 1998, was constructed. Medical records were examined for basic patient demographic information including age, gender, race, bacterial etiology of meningitis, receipt of vaccine for HIB, underlying conditions, and fatalities. Two hundred twenty-one cases of bacterial meningitis caused by H. influenzae, N. meningitidis, and S. pneumoniae were identified. The age of infected children ranged from 1 month to 18 years, with a mean and median age of 38.1 months and 13 months, respectively. Fifty-two percent of the children were female, 83% were Caucasian and 16% were African-American. Before the routine use of HIB conjugate vaccine, HIB was the bacterial species responsible for the greatest proportion of cases (average of 58%/year). The absolute number of cases of bacterial meningitis attributable to HIB declined after 1991 to an average of 2.5 cases/year. The number of cases of meningitis caused by S. pneumoniae and N. meningitidis have remained relatively stable between 1988 and 1998. The case fatality rates for children with meningitis caused by H. influenzae, S. pneumoniae, and N. meningitidis were 0.0%, 9.2%, and 7.5%, respectively. Most cases of meningitis due to HIB occurred in children who had not been immunized. Three children who received the polysaccharide vaccine developed meningitis due to HIB; there were no failures of the conjugate vaccine.

Adolescent↗

Concentrations of interleukin-1 beta, interleukin-6, interleukin-8 and TNF-alpha in cerebrospinal fluid from children with septic or aseptic meningitis.

Cytokines at an inflammatory site may be a better indicator of the clinical severity of an infectious disease than the serum levels of the cytokines. Concentrations of interleukin-1 beta (IL-1 beta) in paired samples of cerebrospinal fluid (CSF) from 10 rabbits with experimental bacterial meningitis caused by H. influenzae type b, were measured, and compared to the concentrations of four cytokines; IL-1 beta, interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) in CSF samples from 45 children with or without meningitis. The IL-1 beta concentrations in the CSF from rabbits with experimental meningitis were significantly higher than the concentrations in control animals without meningitis (p < 0.001). The mean CSF concentrations of IL-8 from meningitic children were significantly higher than in the control group without meningitis (p < 0.005). TNF-alpha was only detected in septic meningitis. Assays of IL-6, however, were not significantly different in the septic meningitis group, the aseptic meningitis group and the non-meningitis group. These data indicate a possible role of IL-1 beta, IL-8 and TNF-alpha as mediators in the meningeal inflammatory process in patients with meningitis and TNF-alpha, in particular, may play a role in the pathogenesis of septic meningitis.

Adolescent↗

Sonographic nomogram of the leptomeninges (pia-glial plate) and its usefulness for evaluating bacterial meningitis in infants.

BACKGROUND AND PURPOSE: To our knowledge, the upper limits of the thickness of normal meninges on neurosonograms are not known. We therefore established a nomogram for sonographic measurements of the leptomeninges (pia-glial plate) and assessed its usefulness in neurosonographic examinations of children with bacterial meningitis. METHODS: The pia mater-cortical glia limitans complex on the surface of the brain and in the sulcus of a frontal gyrus was measured on neurosonograms in 100 infants without meningeal disease in order to establish a nomogram of the thickness of this pia-glial plate, referred to as the leptomeninx. Effects of prematurity, age, sex, and single-layer (surface) versus double-layer (sulcus) measurements were analyzed. Meningeal thicknesses derived from a retrospective analysis of the neurosonograms of 33 patients with purulent meningitis and a prospective study of 22 patients with bacterial meningitis were compared with the nomograms. Clinical outcomes of children with meningeal thickening were compared with those of affected children with normal meninges. RESULTS: The distribution of sulci measurements was significantly asymmetrical around the mean. Statistical data showed no influence of prematurity and sex, but showed surface measurements to be more consistent than sulcal measurements. Older chronological age was related to slightly larger sulci, but did not influence the surface measurements. In children with bacterial meningitis, the surface meninges were less frequently thickened than were the sulci. Sulcal enlargement occurred often in combination with echogenic deposits in the sub-arachnoid space. CONCLUSION: Leptomeninges are best measured on the surface of a gyrus rather than in a sulcus, as the normal thickness of the sulci shows much more variability. Clinical outcome of bacterial meningitis cannot be predicted by presence or absence of meningeal thickening as the only sonographic abnormality.

Echoencephalography↗

[Concentration of proinflammatory cytokines (TNF-alpha, IL-8) in the cerebrospinal fluid and the course of bacterial meningitis].

Bacterial meningitis is still associated with high mortality rate and severe neurological sequels. The aim of the study was to assess correlation between concentration of proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-8) in the cerebrospinal fluid (CSF) and patient condition described on the basis of Glasgow Coma Scale (GCS), changes in the CSF (pleocytosis, protein and glucose level), mortality rate and occurrence of neurological complications. 42 patients with bacterial meningitis have been analysed. Control group consisted of 25 patients with viral meningitis and 23 patients without meningitis. In analysed group with bacterial meningitis the correlation between number of scores aggregated by patients in GCS and outcome has been observed. Concentration of TNF-alpha, IL-1 beta, IL-8 in CSF of patient with bacterial meningitis was significantly higher (mean value; 705.2 pg/ml, 401.1 pg/ml and 1696.0 pg/ml) than in control group (viral meningitis: 7.93 pg/ml, 31.89 pg/ml, 405.28 pg/ml, without meningitis: 0.38 pg/ml, 2.55 pg/ml, 32.56 pg/ml). Negative correlation between concentration of investigated cytokines in the CSF of patient with bacterial meningitis and GCS has been observed. Furthermore TNF-alpha and IL-8 levels correlated with pleocytosis, and protein and glucose levels, whereas IL-1 beta correlated with pleocytosis and protein level in CSF. Connection between TNF-alpha and IL-1 beta but not IL-8 level and outcome of bacterial meningitis has been observed. High TNF-alpha in the CSF (median value 953 pg/ml) was associated with significant risk of patient death. IL-1 beta has been better prognostic indicator. Patients who developed neurological sequels had median value of IL-1 beta level 401.3 pg/ml, and those who died had 585.9 pg/ml vs 244.7 pg/ml in the group who survived without any complications. Analysis of the ROC curve-revealed, that concentration of IL-1 beta > or = 289.9 pg/ml with 88.9% sensitivity and 67.7% specifity differentiate cases who at risk for death. For TNF-alpha the cut-off was > or = 538.9 pg/ml. The sensitivity for determined critical point was 77%, and specificity was 68.7%. Our investigation confirm that TNF alpha, IL-1 beta, IL-8 are useful in differential diagnosis of neuroinfections. Assessment of patients with bacterial meningitis on the basis of GCS is helpful to establish prognosis, and CGS seems to correlate with the intensity of inflammation in the CSF. High concentration of TNF-alpha, and IL-1 beta in the CSF are associated with the risk of patient death during the course of bacterial meningitis, but IL-1 beta has been the better prognostic marker.

Adolescent↗

[Significance of bromide levels in evaluation of the hemato-encephalic barrier during acute viral meningitis].

INTRODUCTION: Inflammatory diseases of the CNS are associated with increased permeability of blood-brain barrier due to vasculitis of cerebral blood vessels leading to regional ischaemia and necrosis. Many substances pass easily from the serum into the CSF through inflamed and damaged blood-brain barrier. Bromide partition test is one of the parameters for evaluation of the blood-brain barrier integrity during CNS inflammatory diseases. As early as 1929 Walter published a monograph on blood-brain barrier accentuating the value of bromide partition test for evaluation of the functional status of blood-brain barrier. In healthy individuals bromide partition test usually ranges from 2.9-3.5. In most patients with TB meningitis bromide partition test remains below 1.6 while it is usually higher in patients with serous meningitis of other aetiologies. However, the low bromide partition test may associate also some other viral and other serous meningitides accompanied with severe lesions of the blood-brain barrier, resulting in increased passage of sodium bromide from the serum into the CSF, so that the serum/CSF ratio is lower. The aim of th study was to calculate and analyze the results of bromide partition test in patients with acute viral meningitis and hyperproteinorachia above 0.70 g/l and to calculate and analyze the results of bromide partition test in patients with TB and parasitic meningitis. The results of bromide patirion tests were compared with results of other parameters for evaluation of the blood-brain barrier function. METHOD: Titration method was used to determine the serum sodium bromide and CSF ratio. Sodium bromide oxidation into sodium bromate was the principle, where addition of potassium iodide is followed by release of equivalent amount of elementary iodide. Iodide is titrimetrically evidenced with thyosulphate, with starch as an indicator. In addition to bromide partition test functional condition of blood-brain barrier was also evaluated by albumin coefficients, albuminorachia and total proteinorachia. RESULTS: In 6 of 30 patients (20%) with acute viral meningitis the bromide partition ratio was below 1.6, suggesting severe damage of blood-brain barrier in these patients: albumin coefficients exceeded 16.7 (mean = 24.7), albuminorachia was over 0.90 (mean = 1.38 g/l), and total proteinorachia over 3.0 g (mean = 3.1 g/l). The aetiology was confirmed in all patients: lymphocyte choriomeningitis virus in 5, COX B1 in one. Values of bromide partition test were higher on follow-up examination, and values of other parameters decreased, suggesting restitution of blood-brain barrier. The results are given in Table 1. Most severe damage of blood-brain barrier was evidenced in patients with lymphocyte choriomeningitis. Parameters for evaluation of functional condition of blood-brain barrier in patients with lymphocyte choriomeningitis and TB meningitis with most severe damage of the barrier, were compared. The results are given in Table 2. No differences between the compared parameters were found, i.e. no difference in the severity of blood-brain damage. Bromide patition test values were below 1.6 in all patients with TB meningitis and in 3 of 5 patients with parasitic meningitis. DISCUSSION: Numerous studies have shown that bromide patition test value during TB meningitis was usually below 1.6. This is probably due to hypersensitivity reaction of the meninges to tuberculin which is located intrathecally and leads to blood-brain barrier damage. Use of antituberculous drugs does not affect the bromide partition test values in early stages of the disease. In all of our 15 patients with TB meningitis the bromide partition test values were below 1.6, coinciding with reference reports. However, we also measured bromide partition test values below 1.6 in 6 (20%) of 30 patients with acute viral meningitis with proteinorachia above 0,70 g/l (ABSTRACT TRUNCATED).

Acute Disease↗

The rational clinical examination. Does this adult patient have acute meningitis?

CONTEXT: Early clinical recognition of meningitis is imperative to allow clinicians to efficiently complete further tests and initiate appropriate therapy. OBJECTIVE: To review the accuracy and precision of the clinical examination in the diagnosis of adult meningitis. DATA SOURCES: A comprehensive review of English- and French-language literature was conducted by searching MEDLINE for 1966 to July 1997, using a structured search strategy. Additional references were identified by reviewing reference lists of pertinent articles. STUDY SELECTION: The search yielded 139 potentially relevant studies, which were reviewed by the first author. Studies were included if they described the clinical examination in the diagnosis of objectively confirmed bacterial or viral meningitis. Studies were excluded if they enrolled predominantly children or immunocompromised adults or focused only on metastatic meningitis or meningitis of a single microbial origin. A total of 10 studies met the criteria and were included in the analysis. DATA EXTRACTION: Validity of the studies was assessed by a critical appraisal of several components of the study design. These components included an assessment of the reference standard used to diagnose meningitis (lumbar puncture or autopsy), the completeness of patient ascertainment, and whether the clinical examination was described in sufficient detail to be reproducible. DATA SYNTHESIS: Individual items of the clinical history have low accuracy for the diagnosis of meningitis in adults (pooled sensitivity for headache, 50% [95% confidence interval [CI], 32%-68%]; for nausea/vomiting, 30% [95% CI, 22%-38%]). On physical examination, the absence of fever, neck stiffness, and altered mental status effectively eliminates meningitis (sensitivity, 99%-100% for the presence of 1 of these findings). Of the classic signs of meningeal irritation, only 1 study has assessed Kernig sign; no studies subsequent to the original report have evaluated Brudzinski sign. Among patients with fever and headache, jolt accentuation of headache is a useful adjunctive maneuver, with a sensitivity of 100%, specificity of 54%, positive likelihood ratio of 2.2, and negative likelihood ratio of 0 for the diagnosis of meningitis. CONCLUSIONS: Among adults with a clinical presentation that is low risk for meningitis, the clinical examination aids in excluding the diagnosis. However, given the seriousness of this infection, clinicians frequently need to proceed directly to lumbar puncture in high-risk patients. Many of the signs and symptoms of meningitis have been inadequately studied, and further prospective research is needed.

Acute Disease↗

Destruction of meningeal cells over the medial cerebral hemisphere of newborn hamsters prevents the formation of the infrapyramidal blade of the dentate gyrus.

Meningeal cells participate in the development of the cerebellum both by stabilizing the extracellular matrix of the pial surface and by organizing the radial glial scaffold and the lamination of the cerebellar cortex. In the present study we investigated possible influences of meningeal cells on the development of the dentate gyrus, whose ontogenesis has many similarities to that of the cerebellum. Meningeal cells were selectively destroyed by injecting newborn hamsters with 25 micrograms 6-hydroxydopamine (6-OHDA) into the interhemispheric fissure. Twenty-four hours postinjection (p.i.) the meningeal cells over the medial cerebral hemispheres were completely destroyed. Thirty days p.i. the infrapyramidal blade of the dentate gyrus was almost completely missing, while the suprapyramidal blade was hypertrophied, extending with its medial tip almost up to the medial surface of the cortex. In order to ascertain that this maldevelopment was caused by the destruction of meningeal cells, another group of hamsters was pretreated with normetanephrine (NMN) which inhibits the extraneuronal uptake of 6-OHDA into meningeal cells. In this group the meningeal cells were unaffected by the treatment, and the morphology of the dentate gyrus was normal 30 days p.i. of 6-OHDA plus NMN. When the meningeal cells were destroyed in later stages of development (postnatal days 1-5), alterations of the dentate gyrus could be induced only up to the fourth postnatal day; thereafter, 6-OHDA treatment left it unchanged. This indicates a critical period of meningeal cell influence that coincides with the period of existence of the subpial dentate matrix. Analysis of the time course of the defective development revealed that in the first 5 days p.i. 1) meningeal cells over the medial cerebral hemisphere were destroyed and removed, 2) the pial basement membrane over both the dentate anlage and the diencephalon thinned and ruptured, and the adjacent brain parts fused focally, 3) many cells of the subpial dentate matrix disappeared from their subsurface position, 4) the number of "immature" cells increased in the hilus and the subgranular zone of the suprapyramidal blade, 5) the suprapyramidal blade elongated and thickened considerably, while the infrapyramidal blade did not form. Beyond 5 days p.i. those parts of the pial surface of the dentate anlage that had not fused with the diencephalon were repopulated with meningeal cells. This reappearance of meningeal cells was accompanied by 1) the restitution of the normal morphology of the basement membrane, 2) the reappearance of neuronal and glial cells below the pial surface, and 3) the formation of fragments of the infrapyramidal blade which later developed a normal appearing lamination.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Expression of vascular endothelial growth factor in tuberculous meningitis.

The pathogenesis of tuberculous meningitis is still unclear. Recently, vascular endothelial growth factor (VEGF) was found to be associated with inflammatory diseases and we found the increased serum level of VEGF in pulmonary tuberculosis. We hypothesized that VEGF might be associated with the pathogenesis of tuberculous meningitis and measured serum and cerebrospinal fluid (CSF) levels of VEGF in 28 patients with tuberculous meningitis and 31 non-tuberculous infectious meningitis patients (13 bacterial meningitis patients, eight fungal meningitis patients and 10 patients with viral meningitis) before therapy. We examined the CSF VEGF levels 3 months after in 12 tuberculous meningitis patients. The serum and CSF levels of VEGF were significantly higher in tuberculous meningitis than in other meningitis. The decrease in titer of CSF VEGF paralleled the clinical improvement of tuberculous meningitis. Immunohistochemical staining of autopsied brains demonstrated the presence of VEGF in the inflammatory mononuclear cells of the dense fibroconnective tissue both in the subarachnoid space and surrounding the vasculitis lesion. We found the expression of VEGF in tuberculous meningitis and think that VEGF reflects its activity.

Adolescent↗

Clinical predictors of bacterial meningitis in infants and young children in The Gambia.

BACKGROUND: Bacterial meningitis is an important cause of childhood morbidity and mortality world-wide. In the developing world, where the burden of acute meningitis and its long-term sequelae are especially high, staff with limited training at primary health care facilities must be able to recognize the symptoms and signs of meningitis, so that suspected cases can be referred urgently to hospitals. METHODS: Children who presented with possible invasive bacterial infection to health facilities in The Gambia, West Africa, between 1993 and 1995 were investigated in a standardized manner and clinical findings were documented. Bacterial meningitis was defined as the growth of bacteria from the cerebrospinal fluid. Clinical findings were compared between cases of meningitis and other children. RESULTS: Of 2097 children between 2 months and 3 years of age investigated, 51 had a confirmed diagnosis of bacterial meningitis. In multivariate analysis using a model adjusting for age but not including respiratory signs, the variables associated independently with meningitis were appearance of being very sick (odds ratio for meningitis vs. no meningitis or no lumbar puncture performed (OR) 4.1, 95% CI 1.5-11.1), being lethargic or unconscious (OR 5.2, 95% CI 2.1-13), a stiff neck (OR 29.3, 95% CI 12.2-70.3), a bulging fontanel (OR 3.2, 95% CI 1.2-8.5) and reduced feeding as a prompted complaint (OR 2.9, 95% CI 1.3-6.7). A combination model of a history of convulsions, or being lethargic or unconscious, or having a stiff neck, as used in the WHO-Integrated Management of Childhood Illness (IMCI) guidelines, had a sensitivity of 98% and a specificity of 72% to predict meningitis. CONCLUSIONS: A combination of a limited number of signs is sufficient to predict meningitis with high sensitivity, without a large number of children who do not have meningitis being unnecessarily referred.

Child, Preschool↗

Bacterial meningitis in the United States in 1995. Active Surveillance Team.

BACKGROUND: Before the introduction of the conjugate vaccines, Haemophilus influenzae type b was the major cause of bacterial meningitis in the United States, and meningitis was primarily a disease of infants and young children. We describe the epidemiologic features of bacterial meningitis five years after the H. influenzae type b conjugate vaccines were licensed for routine immunization of infants. METHODS: Data were collected from active, population-based surveillance for culture-confirmed meningitis and other invasive bacterial disease during 1995 in laboratories serving all the acute care hospitals in 22 counties of four states (total population, more than 10 million). The rates were compared with those for 1986 obtained by similar surveillance. RESULTS: On the basis of 248 cases of bacterial meningitis in the surveillance areas, the rates of meningitis (per 100,000) for the major pathogens in 1995 were Streptococcus pneumoniae, 1.1; Neisseria meningitidis, 0.6; group B streptococcus, 0.3; Listeria monocytogenes, 0.2; and H. influenzae, 0.2. Group B streptococcus was the predominant pathogen among newborns, N. meningitidis among children 2 to 18 years old, and S. pneumoniae among adults. Pneumococcal meningitis had the highest case fatality rate (21 percent) and in 36 percent of cases was caused by organisms that were not susceptible to penicillin. From these data, we estimate that 5755 cases of bacterial meningitis were caused by these five pathogens in the United States in 1995, as compared with 12,920 cases in 1986, a reduction of 55 percent. The median age of persons with bacterial meningitis increased greatly, from 15 months in 1986 to 25 years in 1995, largely as a result of a 94 percent reduction in the number of cases of H. influenzae meningitis. CONCLUSIONS: Because of the vaccine-related decline in meningitis due to H. influenzae type b, bacterial meningitis in the United States is now a disease predominantly of adults rather than of infants and young children.

Adolescent↗

Empiric therapy for bacterial meningitis.

Population studies from three counties indicate that meningitis occurs with a frequency of approximately 10 episodes per 100,000 population annually in the United States. Estimates based on this prevalence and a population of 2.3 X 10(8) suggest that approximately 23,000 episodes of meningitis occur annually in the United States. Available studies indicate that rapid and reasonably accurate identification of the etiologic agent can be made in greater than or equal to 75% of patients with meningitis by gram-staining of the cerebrospinal fluid, counterimmunoelectrophoresis, or other antigen detection techniques. These means of rapid diagnosis theoretically leave only approximately 7,000 episodes of meningitis annually in the United States in which empiric, as opposed to specific, therapy is necessary. Age-dependent variation in etiologic agents of meningitis markedly influences selection of therapeutic regimens. The preponderance of Enterobacteriaceae and group B streptococci as causes of meningitis in neonates has resulted in utilization of a penicillin (often ampicillin) combined with an aminoglycoside for empiric therapy. Continued high morbidity and mortality, especially in neonatal meningitis caused by Enterobacteriaceae, have been felt to reflect inadequate penetration of aminoglycosides into the cerebrospinal fluid, but careful prospective randomized studies of intrathecal and intraventricular administration of aminoglycosides failed to demonstrate any enhancement of therapeutic results. Ampicillin appeared to be an ideal agent for empiric therapy in older children, in whom meningitis is usually caused by Haemophilus influenzae, with Streptococcus pneumoniae and Neisseria meningitidis being less frequently implicated as etiologic agents. The occurrence of beta-lactamase-mediated resistance to ampicillin in as high as 15% of isolates of H. influenzae has resulted in combined use of ampicillin and chloramphenicol for meningitis in children. This approach is complicated by evidence of clinically important antagonism between ampicillin and chloramphenicol. Since almost all community-acquired meningitis in otherwise healthy adults is caused by meningococci and pneumococci, penicillin remains the agent of choice. In contrast, meningitis following trauma to and surgery involving the central nervous system and in the elderly is often caused by gram-negative bacilli and other "unusual" organisms; therapeutic problems in this group parallel those observed in neonatal meningitis.

Anti-Bacterial Agents↗

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.

Adolescent↗

Outcome of penicillin-nonsusceptible Streptococcus pneumoniae meningitis: a nested case-control study.

BACKGROUND: There are few data comparing the clinical features, management and outcome of penicillin-nonsusceptible (PNSP) meningitis patients with penicillin-susceptible (PSSP) meningitis patients. METHODS: We performed a retrospective, nested case-control study comparing cases with PNSP meningitis with controls with PSSP meningitis obtained from the Immunization Monitoring Program, Active (IMPACT) cross-Canada surveillance study of invasive infections. RESULTS: There were 30 PNSP meningitis cases (10.1% of total) and 45 PSSP meningitis controls from 6 centers obtained from 297 meningitis cases in the IMPACT database from 1991 through 1999. Vancomycin was used for empiric therapy in no cases and controls in 1991 to 1993 and in all cases in 1999. A third generation cephalosporin was used in 93.3% of confirmed PNSP cases, and 70.0% also received vancomycin and/or rifampin. Penicillin was used in 66.7% of confirmed PSSP cases. PNSP cases were more likely than PSSP controls to have a second lumbar puncture (odds ratio, 4.1; P= 0.01). PNSP cases were treated with intravenous antibiotics for an average of 15.6 days compared with 12.3 days for controls ( P= 0.04). Among PNSP cases, those patients who did not receive empiric vancomycin were treated with intravenous antibiotics for an average of 18.5 days compared with 12.0 days for those who did receive empiric vancomycin ( P= 0.04). The overall mortality was 5.3%, and 36.6% of survivors had >or=1 neurologic sequelae, including 19.7% with hearing loss. In multivariate statistical models, PNSP was not a risk factor for intensive care unit admission or neurologic sequelae. CONCLUSIONS: Management of suspected bacterial meningitis and confirmed meningitis in Canadian children changed in the past decade. Treatment of PNSP meningitis is significantly different from that for PSSP meningitis. These changes have occurred in response to the emergence of PNSP in Canada. Neurologic sequelae remain common after meningitis, but there are no differences between PNSP cases and PSSP cases.

Adolescent↗