Experimental bacterial meningitis in rats: Demonstration of hydrocephalus and meningeal enhancement by magnetic resonance imaging

Abstract

We investigated whether magnetic resonance imaging (MRI) is able to detect intracranial manifestations of advanced bacterial meningitis in rats. Meningitis was induced in nine animals by injecting 150 µl 10⁷ colony forming units per ml of Streptococcus pneumoniae into the cisterna magna. MRI was performed 24 h (n = 5) and 48 h (n= 4) after infection. Controls included (I) animals that were injected intracisternally with 150 µl phosphate-buffered saline or (II) animals without puncture of the cisterna magna. T2-weighted and T1-weighted MR images before and after administration of 0.3 mmol kg^-1 of gadolinium-DTPA were obtained. Hydrocephalus was found in 7 of 9 infected animals, but not in the control group. Abnormal leptomeningeal enhancement was found in all infected animals, but in none of the controls. The animals imaged after 48 h showed a more pronounced hydrocephalus and a more intense leptomeningeal enhancement than animals imaged after 24 h. Even in small animals such as rats, MRI can be used to detect the presence of bacterial meningitis and its associated complications. MRI may be a useful noninvasive method for monitoring the possible effect of adjunctive therapeutic strategies in experimental studies of meningitis. [Neurol Res 2002; 24: 307-310]     

Cerebrospinal fluid analysis in emergency patients with suspected infection of the central nervous system

Background and purpose

Meningitis and encephalitis are potentially life-threatening diseases that require fast and accurate diagnostics and therapy. The value of polymerase chain reaction (PCR) multiplex testing in clinical practice is still a matter of debate. This study aims to evaluate its benefits and limitations in emergency patients.

Methods

We assessed the value of a meningoencephalitis PCR array in the clinical routine of an emergency department.

Results

Of 1578 emergency patients who received a lumbar puncture, 43% received it for a clinically suspected central nervous system (CNS) infection. After initial workup for cerebrospinal fluid (CSF) cell count, protein and glucose, a CNS infection was still considered likely in 307 patients. In these patients, further microbiologic workup was performed. A total of 230 samples were examined by PCR and a pathogen was detected in 66 of these samples. In the case of a positive microbiologic result, a comparison between PCR array and standard method was available for 59 samples, which demonstrated an overcall agreement of 80% (n = 47/59). Of interest, exclusively array-positive results were observed for patients with meningitis found to be positive for Streptococcus pneumoniae; four out of five patients had been treated with antibiotics before the lumbar puncture. In samples with normal CSF cell count only two positive array results were obtained, both for human herpesvirus 6, and these were not clinically relevant.

Conclusion

Our data suggest that the array substantially contributes to a detection of pathogens in patients with suspected CNS infection and seems of particular interest in patients with acute bacterial meningitis under empiric antibiotic treatment. In CSF samples with normal cell count, it might be dispensable.     

An infant mouse model of brain damage in pneumococcal meningitis

Bacterial meningitis due to Streptococcus pneumoniae is associated with an significant mortality rate and persisting neurologic sequelae including sensory-motor deficits, seizures, and impairments of learning and memory. The histomorphological correlate of these sequelae is a pattern of brain damage characterized by necrotic tissue damage in the cerebral cortex and apoptosis of neurons in the hippocampal dentate gyrus. Different animal models of pneumococcal meningitis have been developed to study the pathogenesis of the disease. To date, the infant rat model is unique in mimicking both forms of brain damage documented in the human disease. In the present study, we established an infant mouse model of pneumococcal meningitis. Eleven-days-old C57BL/6 (n = 299), CD1 (n = 42) and BALB/c (n = 14) mice were infected by intracisternal injection of live Streptococcus pneumoniae. Sixteen hours after infection, all mice developed meningitis as documented by positive bacterial cultures of the cerebrospinal fluid. Sixty percent of infected C57BL/6 mice survived more than 40 h after infection (50% of CD1, 0% of BALB/c). Histological evaluations of brain sections revealed apoptosis in the dentate gyrus of the hippocampus in 27% of infected C57BL/6 and in 5% of infected CD1 mice. Apoptosis was confirmed by immunoassaying for active caspase-3 and by TUNEL staining. Other forms of brain damage were found exclusively in C57BL/6, i.e. caspase-3 independent (pyknotic) cell death in the dentate gyrus in 2% and cortical damage in 11% of infected mice. This model may prove useful for studies on the pathogenesis of brain injury in childhood bacterial meningitis.     

Neurogenic pulmonary edema following Cryptococcal meningoencephalitis associated with HIV infection

Neurogenic pulmonary edema (NPE) is a clinical syndrome characterized by the acute onset of pulmonary edema following a significant central nervous system insult. Only a few cases of NPE after Cryptococcal meningitis have been reported. We report a case of NPE following Cryptococcal meningoencephalitis. A 40‐year‐old man with no medical history was hospitalized for disturbance of consciousness. Blood glucose level was 124 mg/dL. Non‐contrast head computed tomography showed no abnormalities. Lumbar puncture revealed a pressure of over 300 mm H₂O and cerebrospinal fluid (CSF) confirmed a white blood cell count of 65/mm³. The CSF glucose level was 0 mg/dL. The patient was empirically started on treatment for presumptive bacterial and viral meningitis. Four days after, the patient died in a sudden severe pulmonary edema. Autopsy was performed. We found at autopsy a brain edema with small hemorrhage of the right basal ganglia, severe pulmonary edema and mild cardiomegaly. Histologically, dilated Virchow‐Robin spaces, crowded with Cryptococci were observed. In the right basal ganglia, Virchow‐Robin spaces were destroyed with hemorrhage and Cryptococci spread to parenchyma of the brain. No inflammatory reaction of the lung was seen. Finally, acute pulmonary edema in this case was diagnosed as NPE following Cryptococcal meningoencephalitis. After autopsy, we found that he was positive for serum antibodies to human immunodeficiency virus.     

Effect of induced hyperglycemia on brain cell membrane function and energy metabolism during the early phase of experimental meningitis in newborn piglets

This study was done to elucidate the mechanism of hypoglycorrhachia and elevated lactate concentrations leading to neuronal dysfunction in neonatal meningitis, and to determine the effects of induced hyperglycemia on these disturbances. Thirty-eight newborn piglets were divided into three groups: 12 in the control group (CG), 12 in the normoglycemic meningitis group (NG), and 14 in the hyperglycemic meningitis group (HG). Meningitis was induced by intracisternal injection of 108 cfu of Escherichia coli. Hyperglycemia (blood glucose 300–400 mg dl⁻¹) was induced and maintained for 60 min before induction of meningitis and throughout the experiment using modified glucose clamp technique. CSF-to-blood glucose ratio decreased significantly in NG. In HG, baseline CSF-to-blood glucose ratio was lower than two other groups, but increased at 1 h after induction of meningitis. CSF lactate concentration was increased progressively in both meningitis groups, and positively correlated with CSF leukocyte numbers (r=0.41, p<0.001) and TNF-α level (r=0.43, p<0.001). Brain glucose concentration was significantly increased in HG and showed inverse correlation with CSF leukocyte numbers (r=−0.59, p<0.01). Brain lactate concentration was not significantly different among three groups and positively correlated with the CSF TNF-α level (r=0.51, p<0.05). Lipid peroxidation products were increased in NG. Na⁺,K⁺-ATPase activity, ATP/PCr concentrations were not different among three groups. Increased intracranial pressure, CSF pleocytosis (214±59 vs. 437±214/mm³, p<0.02) and increased lipid peroxidation products observed in NG were reduced in HG. These results suggest that hypoglycorrhachia and elevated lactate concentration in the CSF during meningitis originates primarily from the increased anaerobic glycolysis in the subarachnoid space, induced by TNF-α and leukocytes. Induced hyperglycemia attenuates the inflammatory responses of meningitis and might be beneficial by providing an increased glucose delivery to meet its increased demand in meningitis.     

Discrepancies between brain CT imaging and severely raised intracranial pressure proven by ventriculostomy in adults with pneumococcal meningitis

Objectives: Computed tomography (CT) of the brain is recommended for assessment of intracranial pressure (ICP) of patients with acute bacterial meningitis who are comatose or show focal neurological deficits. The aim of this report is to draw attention to the possibility of a discrepancy between CT findings and ICP values in some patients with pneumococcal meningitis. Methods: We describe three adult patients with pneumococcal meningitis who had both successive CT examinations and ICP measurements at the time of clinically evident cerebral herniation (n = 2) and/or prolonged coma (n = 2). Results: Although measurements with a ventriculostomy catheter indicated that all three patients had severely raised ICP values of 90, 44, and 45 mmHg, repeated cranial CT greatly underestimated true ICP values. Despite clinical evidence of acute cerebral herniation, it was not detected in the contemporary CT findings of two patients. Continuous ICP monitoring in the ICU helped to guide treatment for increased ICP; nevertheless, two patients died. Conclusions: The clinician must be aware that cranial CT may fail to rule out the possibility of severely raised ICP or cerebral herniation in a patient with pneumococcal meningitis. Therefore, ICP monitoring of patients with bacterial (especially pneumococcal) meningitis who are in prolonged coma should be considered early and regardless of the cranial CT appearances. Received: 7 November 2001, Received in revised form: 8 April 2002, Accepted: 16 April 2002     

Ruptured long intramedullary spinal cord abscess successfully treated with antibiotic treatment

Intramedullary spinal cord abscess (ISCA) is an extremely rare infection of the central nervous system. We report a 17-year old man with ISCA that suggested rupture confirmed by magnetic resonance imaging (MRI). The patient presented with meningeal signs, severe paraplegia, sensory impairment with a sensory level, and urinary retention. The cerebrospinal fluid (CSF) study showed pleocytosis with polymorphonuclear cells and a decreased glucose level suggesting bacterial meningitis. Computed tomography showed maxillary sinusitis and a lower respiratory tract infection. Spinal MRI showed an ISCA from Th5 to Th12. Part of the abscess seemed to have ruptured into the medullary cavity. Streptococcus intermedius was cultured from CSF, sputum, and the maxillary sinus abscess. It appeared that Streptococcus intermedius transferred from the respiratory tract to the spinal cord hematogenously, formed the ISCA, and the ISCA ruptured. The patient was treated with ampicillin, vancomycin, and meropenem. After 56 days of treatment, he could walk with a walker. In the present case, the MRI findings were helpful for early diagnosis and follow-up of the pathogenic condition. Although the present case suggested rupture of ISCA, he recovered with antibiotic therapy alone. This suggested earlier diagnosis with MRI and aggressive antibiotic therapy appear to be critical factors that determine the prognosis of patients with ISCA.     

Syringomyelia following <Emphasis Type="Italic">Listeria</Emphasis> meningoencephalitis: report of a case

A case of symptomatic syringomyelia which appeared six years after Listeria meningoencephalitis is described. Chronic spinal arachnoiditis, as shown by standard MRI and dynamic phase contrast (PC) cine-MRI, may occur after spinal infection and is likely the cause of syringomyelia. To our knowledge, there are no previous reports of delayed spinal complications following Listeria monocytogenes infection. The possibility of developing syringomyelia should be always considered in any patient with a history of central nervous system infection. Received: 12 September 2002 / Accepted in revised form: 30 January 2003 Correspondence to: R. Nardone     

Beta-2-microglobulin in the cerebrospinal fluid of patients with infections of the central nervous system

Beta-2-microglobulin was determined in 147 patients admitted to hospital because of suspicion of CNS disease. Patients with meningism were chosen as control group. The concentration of beta-2-microglobulin in the spinal fluid of control patients was correlated with age. Reference values for 0-40 years were 0.34-1.58 mg/l. Above 40 years of age the values were 0.46-3.14 mg/l. CSF beta-2-microglobulin levels of patients with meningism, aseptic and bacterial meningitis overlap too much to be relevant in distinguishing between these entities. Five patients with herpes simplex encephalitis had markedly elevated levels ranging from 4.4 to 9.0 mg/l. Ten patients with herpes zoster-associated encephalitis had values from 1.1 to 6.1 mg/l. In the patient groups with CNS infections, the ratio of serum to spinal fluid beta-2-microglobulin was significantly more frequently less than 1 as compared with the meningism group, indicating intrathecal production of the protein. Further studies on the clinical relevance of CSF beta-2-microglobulin in the diagnosis of encephalitis seem warranted.     

Cerebrospinal fluid levels of interleukin-6 and interleukin-12 in children with meningitis

Purpose  Certain cytokines play important roles in the pathophysiology of meningitis. The main purpose of this study was to investigate if the levels of interleukin-6 (IL-6) and interleukin-12 (IL-12) in cerebrospinal fluid (CSF) could be diagnostic predictors of bacterial meningitis in children. Methods  CSF was obtained from 95 patients suspected with meningitis. These cases were classified to the bacterial meningitis (n = 12), aseptic meningitis (n = 41), and nonmeningitis (n = 42) groups. The levels of IL-6 and IL-12 in CSF were measured using the enzyme-linked immmunosorbent assays test. Results  The CSF IL-6 levels in the bacterial meningitis group (45.2 ± 50.0 pg/ml) were significantly higher than those in the aseptic meningitis group (12.9 ± 10.2 pg/ml) and the nonmeningitis group (6.5 ± 7.8 pg/ml; p < 0.05). The CSF IL-12 levels in the bacterial meningitis group (69.8 ± 67.1 pg/ml) were significantly higher than those in the aseptic meningitis group (22.9 ± 10.8 pg/ml) and the nonmeningitis group (15.3 ± 11.2 pg/ml; p < 0.05). With regard to diagnosis, the measurement of CSF IL-6 and IL-12 levels showed sensitivities of 96% and 96%, respectively, and specificities of 51% and 75%, respectively. Conclusion  It is suggested that the CSF IL-6 and IL-12 levels are useful markers for distinguishing bacterial meningitis from aseptic meningitis.     

Enriched environment fails to increase meningitis‐induced neurogenesis and spatial memory in a mouse model of pneumococcal meningitis

An increase in adult neurogenesis was observed after exposure to enriched environment (EE) and during reconvalescence from experimental pneumococcal meningitis. This study investigated neurogenesis and spatial learning performance 5 weeks after bacterial meningitis and exposure to EE. C57BL/6 mice were infected by intracerebral injection of Streptococcus pneumoniae and treated with ceftriaxone for 5 days. Forty‐eight hours after infection, one group (n = 22) was exposed to EE and the other group (n = 23) housed under standard conditions. Another set of mice was kept under either enriched (n = 16) or standard (n = 15) conditions without bacterial meningitis. Five weeks later, the Morris water maze was performed, and neurogenesis was evaluated by means of immunohistochemistry. Mice housed in EE without prior bacterial infection displayed both increased neurogenesis and improved water maze performance in comparison with uninfected control animals. Bacterial meningitis stimulated neurogenesis in the granular cell layer of the dentate gyrus: with standard housing conditions, we observed a higher density of BrdU‐immunolabeled and TUC‐4‐expressing cells 5 weeks after induction of bacterial meningitis than in the noninfected control group. EE did not further increase progenitor cell proliferation and neuronal differentiation in the subgranular cell layer of the dentate gyrus after bacterial meningitis in comparison with infected mice housed under standard conditions. Moreover, the Morris water maze showed no significant differences between survivors of meningitis exposed to EE and animals kept in standard housing. In summary, exposure to EE after pneumococcal meningitis did not further increase meningitis‐induced neurogenesis or improve spatial learning. © 2009 Wiley‐Liss, Inc.     

Streptococcus salivarius meningitis after spinal anesthesia

Streptococcus salivarius is a usual commensal of skin, gastrointestinal tract, genitourinary tract, oral cavity and paranasal sinuses. Although it is usually considered to have low virulence, S. salivarius may cause life-threatening infections, particularly endocarditis. On the other hand, bacterial meningitis after spinal anesthesia is very rare, there being some reported cases caused by S. salivarius, S. mitis, Staphylococcus aureus and Enterococcus faecalis. We report a 57 year old man who developed meningitis symptoms within 10 h of an uncomplicated inguinal herniorrhaphy performed during spinal anesthesia. Cerebrospinal cultures grew S. salivarius sensitive to penicillin. The patient was successfully treated with penicillin G and left the hospital without sequelae. In the literature, bacterial meningitis due to S. salivarius is rarely reported. Of the 28 cases, 18 occurred after lumbar puncture for diagnostic or for spinal anesthesia, 5 occurred following a bacteriemia for upper gastrointestinal endoscopy or intestinal neoplasia, and the other 5 in patients who had dural defects. We discuss the possible etiological causes of the meningitis due to S. salivarius cases reports. The early recognition of this entity and the aseptic precautions likely to reduce the incidence of infectious complications after lumbar puncture are stressed.     

EFNS guideline on the management of community-acquired bacterial meningitis: report of an EFNS Task Force on acute bacterial meningitis in older children and adults

Acute bacterial meningitis (ABM) is a potentially life-threatening neurological emergency. An agreed protocol for early, evidence-based and effective management of community-acquired ABM is essential for best possible outcome. A literature search of peer-reviewed articles on ABM was used to collect data on the management of ABM in older children and adults. Based on the strength of published evidence, a consensus guideline was developed for initial management, investigations, antibiotics and supportive therapy of community-acquired ABM. Patients with ABM should be rapidly hospitalized and assessed for consideration of lumbar puncture (LP) if clinically safe. Ideally, patients should have fast-track brain imaging before LP, but initiation of antibiotic therapy should not be delayed beyond 3 h after first contact of patient with health service. In every case, blood sample must be sent for culture before initiating antibiotic therapy. Laboratory examination of cerebrospinal fluid is the most definitive investigation for ABM and whenever possible, the choice of antibiotics, and the duration of therapy, should be guided by the microbiological diagnosis. Parenteral therapy with a third-generation cephalosporin is the initial antibiotics of choice in the absence of penicillin allergy and bacterial resistance; amoxicillin should be used in addition if meningitis because of Listeria monocytogenes is suspected. Vancomycin is the preferred antibiotic for penicillin-resistant pneumococcal meningitis. Dexamethasone should be administered both in adults and in children with or shortly before the first dose of antibiotic in suspected cases of Streptococcus pneumoniae and H. Influenzae meningitis. In patients presenting with rapidly evolving petechial skin rash, antibiotic therapy must be initiated immediately on suspicion of Neisseria meningitidis infection with parenteral benzyl penicillin in the absence of known history of penicillin allergy.     

3-Aminobenzamide,a poly (ADP-ribose) synthetase inhibitor,attenuates the acute inflammatory responses and brain injury in experimental Escherichia coli meningitis in the newborn piglet

Abstract

The aim of the present study was to evaluate the anti-inflammatory and neuroprotective effects of a poly (ADP-ribose) synthetase inhibitor 3-aminobenzamide during the early phase of experimental bacterial meningitis in the newborn piglet. Meningitis was induced by intracisternal injection of 10⁸ colony forming units of Escherichia coli in 100 μl of saline. 3-Aminobenzamide, given 30 mg kg^–1 as a bolus i.v. injection 30 min before induction of meningitis, significantly attenuated the meningitis-induced acute inflammatory responses such as increased cerebrospinal fluid (CSF) lactate concentration, CSF leukocytosis and increased CSF tumor necrosis factor-α level. However, meningitis-induced increase in intracranial pressure and decrease in CSF glucose level were not significantly improved. Increased cerebral cortical cell membrane lipid peroxidation products (conjugated dienes) and decreased brain ATP/phosphocreatine levels observed in the meningitis group were also significantly improved with 3-aminobenzamide treatment. However, the improvement of reduced Na⁺,K⁺-ATPase activity did not reach a statistical significance (p = 0.06). In summary, 3-aminobenzamide significantly attenuated the acute inflammatory responses and the ensuing brain injury during the early phase of neonatal bacterial meningitis. These findings suggest that poly (ADP-ribose) synthetase inhibitors such as 3-aminobenzamide might be a promising novel anti-inflammatory and neuroprotective adjuvant therapy in neonatal bacterial meningitis.     

The pro-inflammatory cytokine interferon-gamma is an important driver of neuropathology and behavioural sequelae in experimental pneumococcal meningitis

Interferon-gamma is known to play a complex modulatory role in immune defence during microbial infections. Its actions in pneumococcal meningitis, however, remain ill-defined. Here, a pathological role for IFN-γ was demonstrated using a murine model of pneumococcal meningitis, in that C57BL/6J mice deficient in this pro-inflammatory cytokine (IFN-γ^−/−) showed less severe acute and long-term neuropathology following intracerebral challenge with Streptococcus pneumoniae. The absence of IFN-γ significantly lengthened the survival of mice that otherwise would have developed fatal clinical signs within two days of CNS infection. Compared to their wild-type counterparts, IFN-γ^−/− mice showed a diminished inflammatory response (attenuated levels of pro-inflammatory cytokines in the cerebrospinal fluid) and milder brain pathologies (less BBB permeability to protein and brain haemorrhage) during the acute phase of disease. Following a full regime of antibiotic treatment, we found substantial brain injuries in the wild-type mice 10 days after infection. IFN-γ^−/− mice, however, showed decreased neuronal damage in both hippocampus and cortex. In the longer term (≈10 weeks p.i.), the wild-type mice that had survived meningitis due to antibiotic treatment had neurobehavioural abnormalities including diurnal hypoactivity, nocturnal hyperactivity and impaired performance in a discrimination reversal task. IFN-γ^−/− mice, concomitantly tested in the automated IntelliCage platform, had reduced behavioural and cognitive disorders compared to wild-type mice. Both IFN-γ^−/− and wild-type survivors of pneumococcal meningitis showed impaired working memory in the IntelliCage-based complex patrolling task. These observations indicate an association between IFN-γ-driven acute brain pathology and the long-term neurological sequelae resulting from pneumococcal meningitis.     

Recurrent Streptococcus Pneumoniae Meningoencephalitis in a Patient With a Transethmoidal eningoencephalocele

We report a case of recurrent Streptococcus Pneumoniae meningoencephalitis with a transethmoidal meningoencephalocele (TEME) but without cerebrospinal fluid (CSF) leakage.A 35-year-old man was admitted with S. pneumoniae meningitis. He had suffered from four episodes of recurrent pneumococcal meningitis during the previous 4 years. A computed tomography scan of the paranasal sinus showed the TEME protruding through a bony defect of the right frontal base. However, the patient did not have symptoms that could be attributable to CSF leakage, and radioisotope cisternography did not identify a leak. Brain magnetic resonance imaging revealed cortical lesions overlying the TEME, and electroencephalography revealed epileptiform discharges in frontal regions. Appropriate antibiotics therapy without steroids was given to improve his condition.The presented case suggests that even in the absence of clinically demonstrable CSF leakage, an occult skullbase defect and its associated meningoencephalocele should be considered in patients with recurrent bacterial meningitis.     

Aseptic Meningitis in Kikuchi's Disease

The involvement of the nervous system in Kikuchi''s disease (KD) is rare. Although some reports of meningeal involvement in KD were described in the literature from Japan, it has rarely been reported in Korea. A 23-year-old man presented with severe headache, fever, and vomiting. Cerebrospinal fluid (CSF) analysis revealed an opening pressure 300 mmH₂O, WBC 283/mm³, glucose 44 mg/dl and protein 86 mg/dl. Multiple tender lymph nodes on the left anterior neck were found on the 9^th day of his hospital stay. The lymph node biopsy disclosed histopathologic features typical of KD. We report a patient with KD accompanied by aseptic meningitis, emphasizing the importance of recognizing this disorder in diagnosing patients with meningitis.