Course Of Bacterial Meningitis Research Articles

A Case of Bacterial Meningitis in Which Occurrence of Ataxie Optique Led to Detection of a Small Subdural Abscess and Pialitis

We report the case of a 69-year-old man with bacterial meningitis who presented with ataxie optique in the peripheral part of the left visual field in both hands. A detailed neurological examination with contrast-enhanced brain MRI in the early stage of the clinical course identified a small subdural abscess and pialitis in the right parietal area. A favorable outcome was obtained with antibiotic therapy alone. In a case with higher brain dysfunction of unknown cause in the clinical course of bacterial meningitis, a detailed neurological examination may be helpful to identify the causative site. (Received September 25, 2023; Accepted October 31, 2023; Published March 1, 2024).

Листериозный менингоэнцефалит: особенности течения и диагностики (клиническое наблюдение)

Listeriosis has drawn the attention of doctors and scientists for many years as methods for typing the pathogen (Listeria monocytogenes), diagnosing and preventing the disease are being improved, and the emergence of new foci is being monitored. However, despite the improvement of diagnostic tools, clinicians still face difficulties in identifying listeriosis, partly due to the lack of awareness of this disease among noncore doctors, particularly during the COVID-19 pandemic. The authors describe a 54-year-old woman with severe neurolisteriosis (Listeria meningoencephalitis) after severe COVID-19 infection treated with immunosuppressants (steroids and biological agents). examination for listeriosis is reasonable in patients with an atypical course of bacterial meningitis, untypical abnormalities in the cerebrospinal fluid, and immunocompromised patients who receive immunosuppressants or comorbid patients. This case report highlights the importance of listeriosis awareness for the differential diagnosis of meningitis and meningoencephalitis of various etiologies. KEYWORDS: listeriosis, Listeria monocytogenes, differential diagnosis, bacterial meningitis, neurolisteriosis, listeriosis meningoencephalitis, COVID-19, immunosuppressive therapy. FOR CITATION: Tagirova Z.G., Nagibina M.V., Makashova V.V., Ponezheva Zh.B., Shabalina S.V., Mitrikova L.Ts. Listeria meningoenceph - alitis: specifics of its course and diagnosis (case report). Russian Medical Inquiry. 2023;7(11):766–770 (in Russ.). DOI: 10.32364/2587- 6821-2023-7-11-9.

Lack of chemokine (C-C motif) ligand 3 leads to decreased survival and reduced immune response after bacterial meningitis

Pneumococcal meningitis, caused by Streptococcus pneumoniae, is the most common type of bacterial meningitis. The clinical management of this disease has been challenged by the emergence of multidrug-resistant Streptococcus pneumoniae, requiring the urgent development of new therapeutic alternatives. Over the course of bacterial meningitis, pathogen invasion is accompanied by a massive recruitment of peripheral immune cells, especially neutrophil granulocytes, which are recruited under the coordination of several cytokines and chemokines. Here, we used chemokine (C-C motif) ligand 3 (Ccl3)-deficient mice to investigate the functional role of CCL3 in a mouse model of pneumococcal meningitis.Following intrathecal infection with Streptococcus pneumoniae Ccl3-deficient mice presented a significantly shorter survival and higher bacterial load than wildtype mice, paralleled by an ameliorated infiltration of neutrophil granulocytes into the CNS. Blood sample analysis revealed that infected Ccl3-deficient mice showed a significant decrease in erythrocytes, hemoglobin and hematocrit as well as in the number of banded neutrophils. Moreover, infected Ccl3-deficient mice showed an altered cytokine expression profile. Glial cell activation remained unchanged in both genotypes.In summary, this study demonstrates that CCL3 is beneficial in Streptococcus pneumoniae-induced meningitis. Pharmacological modulation of the CCL3 pathways might, therefore, represent a future therapeutic option to manage Streptococcus pneumoniae meningitis.

Bacterial meningitis in solid organ transplant recipients: a population-based prospective study.

BackgroundSolid organ transplant (SOT) recipients are at risk of infections of the central nervous system. However, the incidence and clinical course of bacterial meningitis in SOT recipients are unclear. We studied occurrence, disease course, and prognosis of bacterial meningitis in SOT recipients in the Netherlands.MethodsAll patients with a medical history of solid organ transplantation were selected from our nationwide prospective cohort study on community‐acquired bacterial meningitis in patients >16 years old, performed from March 1, 2006 to October 31, 2014. Data on patient history, symptoms and signs on admission, treatment, and outcome were collected prospectively. For transplant recipients, additional information was collected retrospectively.ResultsWe identified 6 SOT recipients, all receiving renal transplants. The annual incidence of bacterial meningitis was 7‐fold higher (95% confidence interval [CI] 2.94–17.02, P < 0.001) for renal transplant recipients as compared with the general population (9.56 [95% CI 3.98–22.96] vs. 1.35 [95% CI 1.28–1.43] per 100,000 patients per year). One of the 6 patients (17%) presented with the classic presentation of bacterial meningitis (fever, neck stiffness, and change in mental status). Seizures were common, occurring in 33% of patients. Streptococcus pneumoniae and Listeria monocytogenes were identified in 2 patients each, and Escherichia coli and Pseudomonas aeruginosa were both identified once. Four of 6 patients (67%) had an unfavorable functional outcome.ConclusionBacterial meningitis is a rare but devastating complication of solid organ transplantation. SOT recipients are at high risk for developing meningitis, and recognition of this condition may be difficult, owing to atypical clinical manifestation.

Functional polymorphisms of macrophage migration inhibitory factor as predictors of morbidity and mortality of pneumococcal meningitis

Pneumococcal meningitis is the most frequent and critical type of bacterial meningitis. Because cytokines play an important role in the pathogenesis of bacterial meningitis, we examined whether functional polymorphisms of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) were associated with morbidity and mortality of pneumococcal meningitis. Two functional MIF promoter polymorphisms, a microsatellite (-794 CATT5-8; rs5844572) and a single-nucleotide polymorphism (-173 G/C; rs755622) were genotyped in a prospective, nationwide cohort of 405 patients with pneumococcal meningitis and in 329 controls matched for age, gender, and ethnicity. Carriages of the CATT7 and -173 C high-expression MIF alleles were associated with unfavorable outcome (P= 0.005 and 0.003) and death (P= 0.03 and 0.01). In a multivariate logistic regression model, shock [odds ratio (OR) 26.0, P= 0.02] and carriage of the CATT7 allele (OR 5.12,P= 0.04) were the main predictors of mortality. MIF levels in the cerebrospinal fluid were associated with systemic complications and death (P= 0.0002). Streptococcus pneumoniae strongly up-regulated MIF production in whole blood and transcription activity of high-expression MIF promoter Luciferase reporter constructs in THP-1 monocytes. Consistent with these findings, treatment with anti-MIF immunoglogulin G (IgG) antibodies reduced bacterial loads and improved survival in a mouse model of pneumococcal pneumonia and sepsis. The present study provides strong evidence that carriage of high-expression MIF alleles is a genetic marker of morbidity and mortality of pneumococcal meningitis and also suggests a potential role for MIF as a target of immune-modulating adjunctive therapy.

Features of the course of nosocomial meningitis in patients of neurosurgical intensive care unit

To determine the incidence rate and risk factors of nosocomial meningitis in patients with complicated postoperative period. We report the results of prospective observation of the course of bacterial meningitis in patients with complicated postoperative period at neurosurgical intensive care unit in 2010-2014. Nosocomial meningitis (NM) developed in 146 patients, which accounted for 12.6±1.0% (CI, 10.74-14.66). Patients with meningitis were characterized by longer stay at ICU, prolonged mechanical ventilation, need for central venous access and invasive hemodynamic monitoring, as well as longer course of antibacterial therapy. Frequency of invasive monitoring of intracranial pressure was similar in these two groups of patients. Bloodstream infections (14.8% vs. 4.9%; p<0.000), respiratory tract infections (55% vs. 35.6%; p<0.000), and urinary tract infections (56.4% vs. 30.9%; p<0.000) were more frequently observed in patients with NM. The following significant differences were observed between the group of NM patients and the control group: more frequent use of external ventricular drain (72.5% vs. 26.1%; p<0.000), number of reoperations (64.7% vs. 36.3%; p<0.000), and the total operating room time (417.3 min vs. 337.5 min; p<0.000). Etiology was ascertained in 61.0±4.0% of cases of nosocomial meningitis. CoNS (33.0%) and Acinetobacter baumannii (21.3%) were the main pathogens isolated from cerebrospinal fluid. The mortality in patients with meningitis was 31.5±3.8%. External ventricular drain, repeated surgery, long-term stay in the operating room, as well as other types of infections may be considered as risk factors for developing nosocomial meningitis in neurosurgical patients at ICU.

Modulation of Hippocampal Neuroplasticity by Fas/CD95 Regulatory Protein 2 (Faim2) in the Course of Bacterial Meningitis

Fas-apoptotic inhibitory molecule 2 (Faim2) is a neuron-specific membrane protein and a member of the evolutionary conserved lifeguard apoptosis regulatory gene family. Its neuroprotective effect in acute neurological diseases has been demonstrated in an in vivo model of focal cerebral ischemia. Here we show that Faim2 is physiologically expressed in the human brain with a changing pattern in cases of infectious meningoencephalitis.In Faim2-deficient mice, there was increased caspase-associated hippocampal apoptotic cell death and an increased extracellular signal-regulated kinase pattern during acute bacterial meningitis induced by subarachnoid infection with Streptococcus pneumoniae type 3 strain. However, after rescuing the animals by antibiotic treatment, Faim2 deficiency led to increased hippocampal neurogenesis at 7 weeks after infection. This was associated with improved performance of Faim2-deficient mice compared to wild-type littermates in the Morris water maze, a paradigm for hippocampal spatial learning and memory. Thus, Faim2 deficiency aggravated degenerative processes in the acute phase but induced regenerative processes in the repair phase of a mouse model of pneumococcal meningitis. Hence, time-dependent modulation of neuroplasticity by Faim2 may offer a new therapeutic approach for reducing hippocampal neuronal cell death and improving cognitive deficits after bacterial meningitis.

Transcellular migration of neutrophil granulocytes through the blood-cerebrospinal fluid barrier after infection with Streptococcus suis

BackgroundA critical point during the course of bacterial meningitis is the excessive influx of polymorphnuclear neutrophils (PMNs) from the blood into the brain. Both paracellular and transcellular routes of leukocyte transmigration through the blood-brain barrier have been described in CNS diseases so far. Thus, we investigated the mechanism of PMN transmigration through the blood-CSF barrier under inflammatory conditions.MethodsIn an "inverted" Transwell culture model of the blood-CSF barrier, the zoonotic agent Streptococcus suis (S. suis) was used to stimulate porcine choroid plexus epithelial cells (PCPECs) specifically from the physiologically relevant basolateral side. Barrier function was analyzed by measuring TEER and TR-dextran-flux, and tight junction morphology was investigated by immunofluorescence. Route and mechanism of PMN transmigration were determined by immunofluorescence, electron microscopy and FACS analysis. Quantitative real time-PCR was used to determine expression levels of ICAM-1 and VCAM-1.ResultsHere, we show that the transmigration of PMNs through PCPECs was significantly higher after stimulation with TNFα or infection with S. suis strain 10 compared to its non-encapsulated mutant. Barrier function was not significantly affected by PMN migration alone, but in combination with S. suis infection. Tight junction and cytoskeletal actin reorganisation were also observed after stimulation with S. suis or TNFα. Most strikingly, PMNs preferentially migrated across PCPECs via the transcellular route. Extensive sequential analyses of the PMN transmigration process with Apotome®-imaging and electron microscopy revealed that paracellular migrating PMNs stop just before tight junctions. Interestingly, PMNs subsequently appeared to proceed by transcellular migration via funnel-like structures developing from the apical membrane. It is noteworthy that some PMNs contained bacteria during the transmigration process. Flow cytometric and transmigration inhibition studies with integrin-specific antibodies showed that PMN traversal is dependent on CD11b/CD18. Analysis of cell adhesion molecules in PCPECs revealed a significant increase of ICAM-1 and VCAM-1 expression after TNFα and S. suis stimulation.ConclusionOur data underline the relevance of the blood-CSF barrier as a gate for leukocyte entry into the CNS and suggest a novel transcellular migration step during the pathogenesis of bacterial meningitis.

Increased Expression of Tyrosine Phosphatase SHP2 in Experimental Pneumococcal Meningitis: Correlation With Tumor Necrosis Factor-Alpha and Cerebrospinal Fluid Pleocytosis

Protein tyrosine phosphatase SHP2 plays a crucial role in the development of the central nervous system. To explore the expression and possible role of SHP2 during the course of bacterial meningitis, this article reports a juvenile rat bacterial meningitis model established by direct intracisternal injection of Streptococcus pneumoniae. Expression of SHP2 at both mRNA and protein levels were assessed. White blood cell count and concentration of tumor necrosis factor-alpha (TNF-alpha) in cerebrospinal fluid (CSF) were also measured. In the cortex, bacterial meningitis led to a significant upregulation of mRNA encoding SHP2. SHP2 protein levels and CSF white blood cell count were positively correlated. However, there was no significant correlation between the levels of SHP2 protein and TNF-alpha concentrations in CSF. These findings do not support an essential role of SHP2 in the pathogenesis of experimental pneumoniae meningitis, but it is possible that SHP2 protein expression may be used as a marker of disease activity.

The effects of superoxide dismutase in gerbils with bacterial meningitis

Inflammatory products, such as oxygen radicals generated during the course of bacterial meningitis, can damage nerve endings, hair cells, and/or supporting cells in the cochlea. Superoxide dismutase (SOD), an O2-scavenger, has been shown to play an important role in the protection against radical toxicity in various animal experiments. To study the antioxidant effects of SOD on the inflammatory response of gerbils with bacterial meningitis. Meningitis was induced in three groups of 10 gerbils by intrathecal (IT) injection of Streptococcus pneumoniae into the cisterna magna. Group 1 received IT SOD, group 2 received intramuscular (IM) SOD, and group 3, the control group, received IM normal saline. Histologic data and auditory brainstem responses (ABR) were obtained from each gerbil. Fibrosis and/or neo-ossification were near absent in the IT SOD group and significantly less fibrosis occurred in the IM group (IT vs. IM: P = 0.010; IT vs. control group: P = 0.001). The amount of surviving spiral ganglion cells correlated inversely with the extent of fibrosis (r = -0.753, P < 0.00001). IT injection of SOD significantly reduced cochlear fibrosis and neo-ossification, reduced the spiral ganglion cell loss, and decreased damage of the cochlear components following bacterial meningitis.

Interferon-gamma differentially modulates the release of cytokines and chemokines in lipopolysaccharide- and pneumococcal cell wall-stimulated mouse microglia and macrophages.

During bacterial infections of the CNS, activated microglia could support leucocyte recruitment to the brain through the synthesis of cyto- and chemokines. In turn, invading leucocytes may feedback on microglial cells to influence their chemokine release pattern. Here, we analyzed the capacity of interferon-gamma (IFNgamma) to serve as such a leucocyte-to-microglia signal. Production of cyto- and chemokines was stimulated in mouse microglia cultures by treatments with lipopolysaccharide (LPS) from Gram-negative Escherichia coli or cell walls from Gram-positive Streptococcus pneumoniae (PCW). IFNgamma presence during the stimulation (0.1-100 ng/mL) modulated the patterns of LPS- and PCW-induced cyto- and chemokine release in a dose-dependent, potent and complex manner. While amounts of TNFalpha and IL-6 remained nearly unchanged, IFNgamma enhanced the production of IL-12, MCP-1 and RANTES, but attenuated that of KC, MIP-1alpha and MIP-2. Release modulation was obtained with IFNgamma preincubation (treatment of cells before LPS or PCW administration), coincubation and even delayed addition to an ongoing LPS or PCW stimulation. Together the changes observed for the microglial chemokine release under IFNgamma would shift the chemoattractive profile from favouring neutrophils to a preferential attraction of monocytes and T lymphocyte populations--as actually seen during the course of bacterial meningitis. The findings support the view of activated microglia as a major intrinsic source for an instant production of a variety of chemokines and suggest that leucocyte-derived IFNgamma could potentially regulate the microglial chemokine release pattern.

Expression of death-related proteins in dentate granule cells in human bacterial meningitis.

Neuronal apoptosis in the dentate gyrus has been observed in animal models of bacterial meningitis and in humans dying in the course of the disease. To evaluate the mechanisms of neuronal cell death, hippocampal sections of 20 patients dying from bacterial meningitis were investigated by immunohistochemistry using antibodies against the proform of caspase-3 and the active enzyme, bcl-2, bax and p53. In the dentate granule cell layer, the median density of neurons with an apoptotic morphology was 7.6/mm2 (0-15.6/mm2). The median density of immunoreactive neurons was 2.3/mm2 (procaspase-3), 0.9/mm2 (activated caspase-3), 1.8/mm2 (bcl-2), 1.1/mm2 (bax) and 0.4/mm2 (p53). 80% of neurons immunoreactive for active caspase-3 had an apoptotic morphology, whereas only 10% of all procaspase-3 stained neurons showed signs of apoptosis. Apoptotic cell death is present in humans dying in the course of bacterial meningitis in the dentate gyrus of the Formatio hippocampi. Neuronal expression of caspase-3, bcl-2 and bax suggests an involvement of these proteins in neuronal death.

Excess glutamate levels in the cerebrospinal fluid predict clinical outcome of bacterial meningitis.

The clinical course of bacterial meningitis still is characterized by a high mortality and frequent neurological deficits in survivors. In addition to other potentially neurotoxic mediators of inflammation, the excitatory amino acid glutamate, which has been implicated in neuronal death in a variety of other neurological diseases, may also be involved in the pathological process of bacterial meningitis. To investigate the prognostic value of the glutamate concentration in the cerebrospinal fluid (CSF) of patients with bacterial meningitis. Thirty consecutive patients with bacterial meningitis were included in a prospective study. The clinical severity of the disease was assessed on admission and 14 days after the beginning of antibiotic treatment by means of the Glasgow Coma Scale. Studies of CSF were performed on admission and after 3 to 6 days. In addition to standard CSF investigations, including cell count, cytologic findings, protein analysis, glucose and lactate levels, and microbiological tests, the concentration of glutamate in the CSF was measured by an enzymatic assay. At admission, both CSF cell count and concentration of glutamate correlated well with the severity of the disease. After treatment, glutamate concentrations decreased significantly to normal or only slightly elevated levels in 23 patients. However, in 7 patients glutamate levels remained markedly increased. In this group, clinical outcome was significantly worse than in the group of patients with low glutamate levels in the second CSF analysis. A prolonged increase of glutamate levels in the CSF may predict poor clinical outcome in patients with bacterial meningitis, possibly because of the sustained neurotoxic effects of this excitatory neurotransmitter.

Acute phase proteins in serum and cerebrospinal fluid in the course of bacterial meningitis

We carried out estimations of the following acute phase proteins: C-reactive protein (CRP), alpha-l-antitrypsin (AAT), alpha-1-acid glycoprotein (AAG), alpha-2-ceruloplasmin (CER), and alpha-2-haptoglobin (HPT) in serum and in cerebrospinal fluid (CSF) in patients with bacterial meningitis (BM, n = 30) and viral meningitis (VM, n = 30). We have shown that determinations of concentrations of AAG and CRP in serum and CER in CSF are useful in differentiation between BM and VM. The diagnostic power of these three tests (the areas under their ROC curves equal 0.942, 0.929, and 0.931, respectively) is bigger, though statistically not significantly, than that of traditional parameters of BM in CSF, i.e., total protein concentration and white blood cell count. Determination of AAG, CRP, and AAT in serum is a valuable monitoring marker in the course of BM treatment. Convenience of serum sampling constitutes an advantage over traditional BM parameters in CSF.

The use of adjunctive therapy to alter the pathophysiology of bacterial meningitis.

The inflammation in the subarachnoid space (SAS) that develops in the course of bacterial meningitis may have a role in eradicating the infection, but also, ultimately, is the cause of the neurological sequelae associated with this infection. The presence of an inflammatory exudate in the SAS leads to alterations in the blood-brain barrier, altered cerebrospinal fluid dynamics, cerebral edema and increased intracranial pressure, and loss of cerebral auto-regulation. Our increasing understanding of the pathophysiology of meningeal inflammation has led to therapeutic interventions to limit the degree of meningeal inflammation and neurologic sequelae. The inflammatory cascade that leads to alterations in central nervous system physiology will be reviewed as well as the experimental evidence and clinical trials demonstrating the efficacy of adjunctive therapy in reducing meningeal inflammation and decreasing the incidence and severity of neurological sequelae in bacterial meningitis.

Infections of the central nervous system

Recent clinical studies and review articles concerning the epidemiology, clinical features, and antibiotic and adjunctive therapy of bacterial meningitis and brain abscess are presented. The type and frequency of complications that may occur during the course of bacterial meningitis are reported, and their intensive care management is discussed. The role of the polymerase chain reaction in viral diseases of the central nervous system is briefly presented, and further areas of research are mentioned.

Akut-entzündliche Erkrankungen des Zentralnervensystems

The most important acute inflammatory diseases of the central nervous system include bacterial meningitis, herpes-simplex encephalitis, brain abscess, intracranial subdural empyema (and epidural abscess), spinal abscess, acute disseminated postinfectious encephalomyelitis, tick-borne encephalitis, poliomyelitis and viral meningitis. The prognosis of bacterial meningitis and herpes-simplex encephalitis depends on early diagnosis and prompt initiation of therapy within a few hours. The unfavourable course of bacterial meningitis is often due to intracranial complications including brain edema, cerebrovascular arterial or venous involvement, or hydrocephalus. They may require adjunctive therapy including administration of hyperosmolar agents, dexamethasone, anticoagulation using heparin, or ventricular drainage.

Movement disorders in bacterial meningitis

Movement disorders developed in five children, ages 6 to 21 months, during the course of bacterial meningitis caused by Hemophilus influenzae (one), Streptococcus pneumoniae (one), Neisseria meningitidis (one), or Mycobacterium tuberculosis (two). Athetosis, choreoathetosis, and hemiballismus occurred, ranging in duration from hours to months. Cranial computed tomography, performed in four cases, showed no lesion of the basal ganglia. The movements were of such abrupt onset and severity that in four cases they were initially misinterpreted as seizures, and anticonvulsant therapy was contemplated. It is important to recognize the potential development of movement disorders during the acute phase of bacterial meningitis to preclude the inappropriate administration of anticonvulsant medication.

The role of complement in inflammation during experimental pneumococcal meningitis

The mechanism whereby an effective bactericidal inflammatory reaction develops in the subarachnoid space is not clearly defined. While normal cerebrospinal fluid is deficient in complement, immunoglobulin and leukocytes, these serum components appear in cerebrospinal fluid (CSF) during the course of bacterial meningitis. Using a rabbit model of pneumococcal meningitis we examined the role of the alternate complement pathway in three early events important to the defense of the subarachnoid space: leukocyte chemotaxis, phagocyte mediated bacterial killing, and clearance of bacterial components from the cerebrospinal fluid space. Rabbits treated with cobra venom factor to deplete complement were inoculated intracisternally with encapsulated (type II or XIX) pneumococci. Following complement depletion, there was a dramatic (at least 100-fold) decrease in the LD 50 for these strains. Nevertheless, complement depletion did not affect the magnitude of CSF leucocytosis or the rate of clearance of bacterial particles from CSF. A short delay in the appearance of leukocytes in CSF was found in the absence of complement. The major effect of complement depletion, however, was to diminish the efficiency of leukocyte mediated killing of encapsulated bacteria in the CSF. Although the short delay in the onset of leukocytosis in the complement depleted animals is consistent with a chemotactic role of complement in the normal animal, the quantitatively normal leukocytosis in the complement depleted rabbits clearly indicates that important chemotaxins other than complement function in CSF. Inhibition of leukocytosis by indomethacin and diclofenac suggests that metabolite(s) of the arachidonic acid pathway may perform such a chemotactic role. A major role of complement in the defense of the subarachnoid space appears to be as an opsonin needed for the effective bactericidal activity of leukocytes. It is the lack of this function that best explains the greatly decreased LD 50 value of encapsulated pneumococci in the complement depleted animal.

Onset of Hearing Loss in Children with Bacterial Meningitis

Auditory brainstem responses were evaluated in 37 children with bacterial meningitis within 48 hours of admission. Four children (two with Haemophilus influenzae type b, and two with Streptococcus pneumoniae) had definite abnormalities of hearing detected at admission. Two of these children had severe-to-profound hearing losses which have persisted. Hearing losses were greatly reduced in the other two children (one child also was ataxic) when repeat testing was performed. Auditory brainstem responses in two additional children suggested brainstem dysfunction at admission (one child died and the other has had severe sequelae). Hearing losses occur early in the course of bacterial meningitis in some children. Further studies are required to confirm the use of auditory brainstem responses in detecting hearing losses early in high-risk children with bacterial meningitis.