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Risk of bacterial meningitis in children with cochlear implants.

BACKGROUND: In June 2002, the Food and Drug Administration received reports of bacterial meningitis in patients with cochlear implants for treatment of hearing loss. Implants that included a positioner (a wedge inserted next to the implanted electrode to facilitate transmission of the electrical signal by pushing the electrode against the medial wall of the cochlea) were voluntarily recalled in the United States in July 2002. METHODS: We identified patients with meningitis and conducted a cohort study and a nested case-control investigation involving 4264 children who had received cochlear implants in the United States between January 1, 1997, and August 6, 2002, and who were less than six years of age when they received the implants. We calculated the incidence of meningitis in the cohort and assessed risk factors for meningitis among patients and among 199 controls, using data from interviews with parents and abstracted from medical records. RESULTS: We identified 26 children with bacterial meningitis. The incidence of meningitis caused by Streptococcus pneumoniae was 138.2 cases per 100,000 person-years--more than 30 times the incidence in a cohort of the same age in the general U.S. population. Postimplantation bacterial meningitis was strongly associated with the use of an implant with a positioner (odds ratio, 4.5 [95 percent confidence interval, 1.3 to 17.9], with adjustment for medical, surgical, and environmental factors) and with the joint presence of radiographic evidence of a malformation of the inner ear and a cerebrospinal fluid leak (adjusted odds ratio, 9.3 [95 percent confidence interval, 1.2 to 94.5]). The incidence of meningitis among patients who had received an implant with a positioner remained higher than the incidence among those whose implants did not have a positioner for the duration of follow-up (24 months from the time of implantation). CONCLUSIONS: Parents and health care providers should ensure that all children who receive cochlear implants are appropriately vaccinated and are then monitored and treated promptly for any bacterial infections after receiving the implant.

Bacterial Vaccines↗

Nitric oxide in septic and aseptic meningitis in children.

To investigate the involvement of nitric oxide (NO) in childhood meningitis, we measured the concentrations of NO2- (a stable metabolite of NO) in serial samples of cerebrospinal fluid (CSF) from 11 children with septic and 7 with aseptic meningitis and 26 control patients without meningitis. The mean concentration of NO2- in samples obtained during the early stages of septic meningitis, but not aseptic meningitis, was significantly higher than in control samples. Clinical and laboratory improvement following administration of antibiotics and dexamethasone was associated with a fall in CSF [NO2-] to normal levels in these patients. CSF [NO2-] remained almost consistently within the normal range in patients with aseptic meningitis. Our findings indicate that NO production is enhanced in the CSF compartment of children with septic meningitis and support the hypothesis that NO is involved in the pathophysiology of septic meningitis.

Alanine↗

Neonatal meningitis in England and Wales: a review of routine national data.

The objective of this study was to describe trends in neonatal meningitis in England and Wales during the years 1975-91. Laboratory reports and, for the years 1983-91, data on statutory notifications and deaths from neonatal meningitis were reviewed. The mean annual total of laboratory reports of neonatal bacterial meningitis 1975-91 was 109 cases (range 69-133) with a slight upward trend apparent in the latter half of the study period. The mean annual number of reports of neonatal viral meningitis was only 14 cases with no trend apparent. The leading bacteria isolated were group B streptococci, Escherichia coli, and Listeria monocytogenes accounting for 34.1%, 28.5%, and 6.8% of reports, respectively. There was a change in the pattern of causative bacteria from 1981 onwards with the group B streptococcus displacing E coli as the leading cause. With respect to neonatal viral meningitis, echoviruses and coxsackie viruses accounted for 55.4% and 38.6% of cases, respectively. Neonatal meningitis was seriously undernotified; the ratio of laboratory reported cases to cases notified ranged from 12:1 in 1985 to 4:1 in 1989. The annual numbers of deaths ranged from 18 to 39. The laboratory reporting system provided the most useful data on secular trends and causative organisms for neonatal meningitis. The slight upward trend in the number of reports of bacterial meningitis merits continued surveillance.

Coxsackievirus Infections↗

Follistatin (FS) in human cerebrospinal fluid and regulation of FS expression in a mouse model of meningitis.

OBJECTIVE: Follistatin (FS) is the specific binding protein of activin and expression of both factors is regulated by inflammatory agents. Therefore, FS concentrations were determined in cerebrospinal fluid (CSF) of patients with bacterial and viral meningitis or multiple sclerosis (MS), as well as in the CSF of patients without meningial inflammation or autoimmune diseases. Furthermore, a mouse pneumococcal meningitis model was used to localise the cellular sources of FS in brains of normal and meningitic mice. METHODS: FS concentrations in CSF were determined by ELISA; FS in mice was localised by in situ hybridisation and immunohistochemistry. RESULTS: FS concentrations were > or =0.4 microg/l in 22 of 66 CSF samples of meningitis patients versus 2 of 27 CSF samples from patients with multiple sclerosis (P<0.05) and 2 of 41 CSF specimen from patients without neuroinflammatory diseases (P<0.01). In the CSF of patients with meningitis, the concentration of FS was correlated with total protein (P<0.005) and lactate concentrations (P<0.05), but not with leukocyte counts, interval between onset of disease and CSF analysis, or clinical outcome. The CSF-to-serum ratios of FS and albumin also correlated significantly (P<0.0005). In some patients with meningitis the CSF-to-serum ratios suggested that the elevated FS in CSF did not originate from serum alone. FS was localised in mice brains to neurones of the hippocampus, dentate gyrus, neocortex, and to the choroid plexus. Analyses of brains and other organs from uninfected and infected animals sacrificed 6-36 h after infection did not reveal any obvious differences in the distribution and intensity of FS mRNA and protein expression. CONCLUSIONS: The concentration of FS in humans is elevated during meningitis. In some patients the increase is caused by a release of FS from brain into CSF. Data from the mouse meningitis model suggest that increased CSF concentrations of FS in meningitis appear not to be accompanied by an elevated number of cells containing FS mRNA or protein in the brain.

Animals↗

Incidence and prognosis of meningitis due to Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis in Sweden.

The incidence, concomitant conditions and case fatality rate of Haemophilus influenzae (Hi) and pneumococcal meningitis and of invasive meningococcal infections were studied retrospectively in Sweden (population 8.4 million) for the years 1987-89, the period before vaccination against Hi type b started. A total of 1,019 cases with culture-verified infection were found. The incidence rates per 100,000 per year were 1.8 for Hi meningitis, 1.2 for pneumococcal meningitis and 1.0 for invasive meningococcal infections. The age-specific incidence was highest in the 3-23 months age group for the 3 bacterial species. Pneumococcal meningitis was common in individuals > or = 60 years and meningococcal infections in the age-group 10-24 years. A serious concomitant condition was known in 57% of all patients with pneumococcal meningitis while this was uncommon for the other organisms. The case fatality rate was 2% for Hi meningitis, 24% for pneumococcal meningitis and 10% for meningococcal infections. All 81 pneumococcal isolates which had been serotyped belonged to serotypes in the 23-valent pneumococcal vaccine. Of the meningococcal isolates, 65% belonged to serogroup B. In conclusion, the high incidence of Hib meningitis justifies general Hib vaccination. Development of a vaccine against N. meningitidis group B should have high priority. Furthermore, improved pneumococcal vaccines are needed for patients with predisposing conditions. The currently available pneumococcal polysaccharide vaccine seems to be underused.

Adolescent↗

Cerebrospinal fluid lactate and lactate dehydrogenase activity in the rapid diagnosis of bacterial meningitis.

The value of cerebrospinal fluid (CSF) lactate and lactate dehydrogenase (LD) activity in the rapid diagnosis of meningitis was investigated in three groups of patients--a 'no meningitis', an aseptic meningitis and a bacterial meningitis group. The sensitivity achieved in the detection of bacterial meningitis by CSF lactate values of 2.85 mmol/l (93.8%) and 3.9 mmol/l (89.6%) was greater than that reached by conventional chemical investigations using a CSF protein value of 1 g/l (81.5%) or a CSF glucose value of 2.2 mmol/l (68.8%) as the indicator. The sensitivity of an absolute CSF LD value of 40 U/l (86.3%) in the detection of bacterial meningitis was slightly lower than that of a CSF protein value of 1 g/l (87%) and better than the sensitivity of either a CSF/serum LD ratio of 0.1:1.0 (83.9%) or a CSF glucose level of 2.2 mmol/l (76.3%). As with conventional CSF chemistry, both investigations may give normal values in the presence of bacterial meningitis.

Child↗

The many causes of meningitis.

Meningitis should be suspected in a patient who presents with fever, meningism, or severe headache. A careful physical examination should be performed of perimeningeal foci, with emphasis on the sinuses, ears, throat, neck, and lungs. A history of exposure to tuberculosis, viral disease, rodents, or suspicious dairy products or farm animals may give clues to the source of the meningitis. Immunosuppression through the use of corticosteroids or chemotherapy for such conditions as Hodgkin's disease, lymphoma, leukemia, malnutrition, or acquired immunodeficiency syndrome (AIDS) should also be noted and alert the clinician to the possible presence of an unusual pathogen. Meningitis associated with leukemia or most of the non-T-cell lymphomas is likely to be from a common bacterial agent (often Listeria), unless the patient is being treated with a steroid or is receiving other chemotherapy. Patients with Hodgkin's disease or AIDS or who have been treated with a steroid are more likely to have cryptococcal or tuberculous meningitis. Neonates and the very elderly may present with only irritability or lethargy and fever, without any of the other common symptoms. In neonates up to one week of age, group B streptococcal infection should be suspected. Gram-negative organisms should be suspected in elderly patients and those who have had neurosurgery. In patients with CSF shunts, infection with coagulase-negative Staphylococcus should be assumed and these patients are treated empirically until results of cultures are received. Several noninfectious conditions may mimic infectious meningitis, as may some unusual causes of infectious meningitis (eg, syphilis and schistosomiasis), which have not been discussed in this article.

Anti-Bacterial Agents↗

Increased total concentration of amino acids in the cerebrospinal fluid of patients with purulent meningitis.

Total concentrations of amino acids, as measured by fluorometry of primary amino nitrogen with the use of fluorescamine, were determined in the cerebrospinal fluid (CSF) of 50 patients with purulent meningitis, 40 patients with aseptic meningitis, and 36 control subjects. On admission total concentrations of amino acids in the CSF were significantly higher in patients with purulent meningitis (mean +/- SEM, 2.27 +/- 0.27 mM) than in patients with aseptic meningitis (1.07 +/- 0.03 mM, P less than 0.001) or in control subjects (1.16 +/- 0.04 mM, P less than 0.001). This value was higher when the patients with purulent meningitis were reexamined one to two days later and reached a maximum after three to four days of illness. The fluorometry method proved to be simple, rapid, and precise and may be used as an additional test in diagnosing bacterial meningitis, especially in patients who are treated with antibiotics before admission. For patients with bacterial meningitis, a high concentration of amino acids in the CSF on admission may indicate a poor outcome.

Adolescent↗

The changing spectrum of neonatal meningitis over a fifteen-year period.

One hundred seventy-seven cases of neonatal meningitis treated at the University of Texas Medical Branch at Galveston over a 15-year period (1974-1988) were reviewed. Over this period, the incidence of bacterial meningitis decreased, the incidence of aseptic meningitis remained stable, and the diagnosis of enteroviral meningitis increased in frequency. During 1984-1988, enterovirus was the most common cause of meningitis in neonates older than seven days and accounted for one third of all cases of neonatal meningitis. Half of all neonates with bacterial meningitis had negative blood cultures. We recommend that 1) diagnostic lumbar puncture remain part of the routine assessment of the neonate with suspected sepsis, and 2) CSF be cultured for enterovirus as well as for bacteria when a neonate older than seven days presents with suspected sepsis.

Age Factors↗

Patients with malignant meningitis presenting with neuropsychiatric manifestations.

BACKGROUND: Malignant meningitis is often thought of as a late event in the course of cancer. At one time, it was thought to be rare, but it has been recognized more frequently in recent times. Clinical suspicion of malignant meningitis is prompted by neurologic symptoms and signs in patients at risk for this oncologic complication. Neuropsychiatric symptoms previously were not considered as presenting symptoms of malignant meningitis. METHODS: Three patients with cancer with no neurologic symptoms were examined for malignant meningitis based on neuropsychiatric symptoms. Cerebrospinal fluid was examined for malignant cells to confirm the diagnosis of malignant meningitis. RESULTS: The clinical presentation of malignant meningitis for three patients was neuropsychiatric. None of the patients had delirium during their initial presentation. CONCLUSIONS: It is important that clinicians recognize that psychiatric symptoms without neurologic findings may indicate malignant meningitis and that malignant meningitis needs to be included in the differential diagnosis of neuropsychiatric disorders in patients with cancer.

Female↗

"Meningeal sign": a characteristic finding of meningiomas on contrast-enhanced MR images.

In meningiomas, a flat, contrast-enhancing, probably dural structure adjacent to the tumor can occasionally be observed on Gadolinium-DTPA enhanced MR images. This so called "meningeal sign" was evaluated with respect to the differential diagnosis of meningiomas in MR imaging. The study included 29 patients with intracranial meningiomas and 24 patients with non-meningeal brain tumors. In all meningiomas, MR studies included T2-weighted as well as unenhanced and Gadolinium-DTPA-enhanced T1-weighted images. In all non-meningeal tumors, Gd-DTPA-enhanced MR images were available. All images were evaluated with respect to the presence of the "meningeal sign". In meningiomas, a "meningeal sign" was seen in 15/29 cases on Gadolinium-DTPA-enhanced images. No abnormalities corresponding to the areas of contrast enhancement were found on unenhanced T2- and T1-weighted MR images. In non-meningeal tumors only 2/24 cases showed a "meningeal sign". In conclusion, with a sensitivity of 52% and a specificity of 92%, the demonstration of the "meningeal sign" improved the differential diagnosis of intracranial meningiomas in contrast-enhanced MR imaging.

Adult↗

Validation of a clinical prediction rule for the differential diagnosis of acute meningitis.

OBJECTIVE: To attempt to validate a previously reported clinical prediction rule derived to assist in distinguishing between acute bacterial meningitis and acute viral meningitis. DESIGN: Retrospective chart review of patients treated at five hospitals between 1981 and 1990. The criterion standard for bacterial meningitis was a positive cerebrospinal fluid (CSF) or blood culture or a positive test for bacterial antigen in the CSF. For viral meningitis, the criterion standard was a positive viral culture from CSF, stool, or blood or a discharge diagnosis of viral meningitis with no other etiology evident. SETTING: Two Department of Veterans Affairs (VA) hospitals, two county hospitals, and one private hospital, each affiliated with one of two medical schools. PATIENTS: All persons aged more than 17 years who were hospitalized over a ten-year period at one of five academically affiliated hospitals for the management of acute meningitis. MEASUREMENTS AND MAIN RESULTS: Sixty-two cases of bacterial meningitis and 98 cases of viral meningitis were confirmed. With all patients included, the discriminatory power of the model as measured by the area under the receiver operating characteristic curve (AUC) was 0.977 (95% CI, 0.957-0.997), compared with the AUC of 0.97 in the derivation set of the original publication. The AUCs (95% CIs) for data subsets were: Dallas cases 0.994 (0.986-1.0). Milwaukee cases 0.912 (0.834-0.990); ages 18-39 years 0.952 (0.892-1.0), ages 40-59 years 0.99 (0.951-1.0), and age > or = 60 years 0.955 (0.898-1.0). CONCLUSIONS: The authors conclude that the clinical prediction rule proved robust when applied to a geographically distinct population comprised exclusively of adults. There was sustained performance of the model when applied to cases from each city and from three age strata. Prospective validation of this prediction rule will be necessary to confirm its utility in clinical practice.

Acute Disease↗

Rapid diagnosis of bacterial meningitis with reagent strips.

Laboratory examination of cerebrospinal fluid (CSF) is not available in many parts of the world, and without knowledge of CSF glucose, protein, and cells, a diagnosis of meningitis may be missed. Testing CSF with urine reagent strips that measure glucose and protein has given variable results. We tested CSF samples from 234 children with suspected meningitis for glucose, protein, and leucocytes with Combur9 reagent strips. The results were compared with those obtained from the laboratory and also interpreted as indicating bacterial or viral meningitis. There was good agreement between the strip and laboratory method of estimating CSF glucose, protein, and leucocytes. All but 4 of the cases of meningitis were correctly identified by the strip method (sensitivity 97%). 2 (2.9%) of 69 cases of bacterial meningitis were judged by an independent observer to be viral, and 2 (3.3%) of 60 cases of viral meningitis as normal. No normal CSF was diagnosed as meningitis (specificity 100%). The results indicate that Combur9 reagent strips can distinguish normal from infected CSF and are of value in the diagnosis of meningitis.

Cerebrospinal Fluid↗

Application of PCR for various neurotropic viruses on the diagnosis of viral meningitis.

BACKGROUND: Epidemiological studies have indicated that the majority of cases of aseptic meningitis result from viral infections. However, specific viral pathogens for aseptic meningitis can be identified in only some cases even if consistent conventional diagnostic methodologies rare used. OBJECTIVES: To clarify the etiological agents of aseptic meningitis by means of polymerase chain reaction (PCR) for various neurotropic viruses. STUDY DESIGN: Cerebrospinal fluid (CSF) samples were collected from 73 children suspected of having meningitis from November 1991 to December 1994. The samples were examined for infectious viruses by cell culture and for viral genomes by PCR. RESULTS AND CONCLUSIONS: Of 45 samples from patients diagnosed with aseptic meningitis, positive PCR results for enterovirus, mumps virus, cytomegalovirus, and varicella-zoster virus were obtained from respectively 25, 14, 1, and 1. Viral pathogens were thus identified in 41 (91.1%) of the 45 CSF samples. By the combination of PCR methods with conventional virological methods, the diagnosis of viral meningitis was established in 97.8% of the 45 cases. Our findings prove that the application of PCR methods is useful for etiological study of aseptic meningitis, and that the vast majority of cases of aseptic meningitis result from viral infection.

Cerebrospinal Fluid↗

Anti-interleukin-8 auto-antibodies in cerebrospinal fluid of children with purulent meningitis.

BACKGROUND: Cerebrospinal fluid (CSF) of patients with purulent meningitis contains a high concentration of interleukin (IL)-8. Recently, the presence of anti-IL-8 auto-antibodies was noted in blood and alveolar fluid. Therefore, measurement of the concentration of anti-IL-8 auto-antibodies was attempted in CSF of children with and without meningitis. METHODS AND RESULTS: We measured the concentration of anti-IL-8 auto-antibodies in CSF of children with purulent or aseptic meningitis and those without meningitis. The CSF obtained on admission showed a significantly higher concentration of anti-IL-8 IgG and IgM auto-antibodies in children with purulent meningitis, compared with those with aseptic meningitis or without meningitis. Among the three groups of children, the concentration of IL-8 was also significantly higher in CSF of children with purulent meningitis. CONCLUSION: Because the anti-IL-8 IgG auto-antibody binds to IL-8 and inhibits IL-8 interaction with specific receptors on neutrophils, the presence of anti-IL-8 auto-antibodies seems to provide a mechanism that limits the bioavailability of free IL-8 in CSF.

Autoantibodies↗

Benefits of management strategy adjustments during an outbreak of enterovirus meningitis in adults.

Enteroviruses (EVs) are the most common identifiable cause of the aseptic meningitis syndrome. Widespread seasonal outbreaks of EV meningitis result in a high financial cost to the community, in part because of the difficulty of discriminating between viral and bacterial meningitis. During a nationwide outbreak of EV meningitis due to echovirus 30 in France we tested the hypothesis that a management strategy including early testing of cerebrospinal fluid (CSF) by means of EV PCR in all adult patients with acute aseptic meningitis on admission might reduce the duration of hospitalization and thus the expenditure on health resources. We compared the characteristics of adult patients with acute aseptic meningitis seen in our institution before (n = 21) and after (n = 27) implementation of this strategy. The strategy was cost-effective in that it significantly reduced (i) the mean duration of hospital stay (from 103 to 80 h; p = 0.04); and (ii) the mean duration of antibacterial treatment (from 115 to 69 h; p = 0.02). Systematic testing of CSF in adult patients with aseptic meningitis by means of EV PCR may be cost-effective during an outbreak of EV meningitis.

Adolescent↗

Experimental pneumococcal meningitis in mice: a model of intranasal infection.

Effective laboratory animal models of bacterial meningitis are needed to unravel the pathophysiology of this disease. Previous models have failed to simulate human meningitis by using a directly intracerebral route of infection. Hyaluronidase is a virulence factor of Streptococcus pneumoniae. In this study, a novel model of murine meningitis is described. Intranasal administration of S. pneumoniae with hyaluronidase induced meningitis in 50% of inoculated mice, as defined by a positive cerebrospinal fluid (CSF) culture and an inflammatory infiltrate in the meninges. None of the mice inoculated without hyaluronidase developed meningitis. Hyaluronidase was found to facilitate pneumococcal invasion of the bloodstream after colonization of the upper respiratory tract. Meningitis was characterized by pleocytosis of CSF and the induction of proinflammatory cytokines and CXC chemokines in brain tissue. These results indicate that this murine model mimics important features of human disease and allow for the use of this model for studying issues related to the pathophysiology and the treatment of pneumococcal meningitis.

Animals↗

Levels of vancomycin in cerebrospinal fluid of adult patients receiving adjunctive corticosteroids to treat pneumococcal meningitis: a prospective multicenter observational study.

BACKGROUND: Evidence from a recent randomized controlled trial suggests that dexamethasone as adjunct therapy in adult pneumococcal meningitis reduces mortality and neurological sequelae. However, adding dexamethasone has the potential to reduce penetration of vancomycin into the cerebrospinal fluid (CSF). We sought to determine concentrations of vancomycin in serum and CSF of patients with suspected or proven pneumococcal meningitis receiving dexamethasone to assess the penetration of vancomycin into the CSF during steroid therapy. METHODS: In an observational open multicenter study, adult patients admitted to the intensive care unit because of suspected pneumococcal meningitis received recommended treatment for pneumococcal meningitis, comprising intravenous cefotaxime (200 mg per kg of body weight per day), vancomycin (administered as continuous infusion of 60 mg per kg of body weight per day after a loading dose of 15 mg per kg of body weight), and adjunctive therapy with dexamethasone (10 mg every 6 h). Vancomycin levels in CSF were measured on day 2 or day 3 of therapy and were correlated with protein levels in CSF and vancomycin levels in serum (determined at the same time as levels in CSF). RESULTS: Fourteen patients were included. Thirteen had proven pneumococcal meningitis; 1 patient, initially suspected of having pneumococcal meningitis, was finally determined to have meningitis due to Neisseria meningitidis. Mean levels of vancomycin in serum and CSF were 25.2 and 7.2 mg/L, respectively, and were positively correlated (r=0.6; P=.025). A positive correlation was also found between the ratio of vancomycin in CSF to vancomycin in serum and the level of protein in CSF (r=0.66; P=.01). CONCLUSIONS: Appropriate concentrations of vancomycin in CSF may be obtained even when concomitant steroids are used. Dexamethasone can, therefore, be used without fear of impeding vancomycin penetration into the CSF of patients with pneumococcal meningitis, provided that vancomycin dosage is adequate. This study is registered at http://www.ClinicalTrials.gov/ (registration number NCT00162578).

Adrenal Cortex Hormones↗