Individual responsiveness of macrophage migration inhibitory factor predicts long-term cognitive impairment after bacterial meningitis.

BACKGROUND: Patients with pneumococcal meningitis are at risk for death and neurological sequelae including cognitive impairment. Functional genetic polymorphisms of macrophage migration inhibitory factor (MIF) alleles have shown to predict mortality of pneumococcal meningitis. METHODS: We investigated whether MIF concentrations during the acute phase of disease were predictive for death in a nationwide prospective cohort study. Subsequently, we studied whether individual ex vivo MIF response years after meningitis was associated with the development of cognitive impairment. RESULTS: We found that in the acute illness of pneumococcal meningitis, higher plasma MIF concentrations were predictive for mortality (p = 0.009). Cognitive impairment, examined 1-5 years after meningitis, was present in 11 of 79 patients after pneumococcal meningitis (14%), as compared to 1 of 63 (2%) in controls, and was consistently associated with individual variability in MIF production by peripheral blood mononuclear cells after ex vivo stimulation with various infectious stimuli. CONCLUSIONS: Our study confirms the role of MIF in poor disease outcome of pneumococcal meningitis. Inter-individual differences in MIF production were associated with long-term cognitive impairment years after pneumococcal meningitis. The present study provides evidence that MIF mediates long-term cognitive impairment in bacterial meningitis survivors and suggests a potential role for MIF as a target of immune-modulating adjunctive therapy.

Long-term neurologic and cognitive outcome and quality of life in adults after pneumococcal meningitis.

OBJECTIVES: To perform a cross-sectional cohort study on long-term neurologic, cognitive and quality-of-life outcome in adults surviving pneumococcal meningitis. METHODS: Adult survivors of community-acquired pneumococcal meningitis from a Dutch nationwide prospective cohort study were evaluated 1 to 5 years after acute illness. The control group consisted of partners or proxies of patients. Neurologic examination was performed and cognitive domains were tested with the Vienna Test System Cognitive Basic Assessment Test set (VTS COGBAT). The Research and Development (RAND)-36 and adapted Cognitive and Emotional Consequences of Stroke (CLCE)-24 questionnaires assessed perceived cognitive functioning and quality of life. Differences between group scores were tested with multivariate analyses of variance. RESULTS: A total of 80 pneumococcal meningitis patients and 69 controls were evaluated. After a median of 2 years (interquartile range, 2-3) after acute illness, 27 (34%) of 79 patients had persistent neurologic sequelae, most commonly hearing loss (21/79, 27%). On overall neuropsychologic evaluation, patients performed worse than the controls (MANCOVA; p 0.008), with alertness (z score -0.33, p 0.011) and cognitive flexibility (z score -0.33, p 0.027) as the most affected domains. Cognitive impairment was present in 11 (14%) of 79 patients. CLCE-24 questionnaires revealed cognitive impairment on all domains, most commonly for cognitive speed (53/75, 71%), attention (45/75, 60%) and memory (46/75, 61%). Patients had lower quality-of-life scores than controls (item physical functioning, (median) patients vs. controls, 80 vs. 95, p < 0.001; social functioning, (median) 81 vs. 100, p 0.003; perceived health, (mean) 59 vs. 70, p 0.005), which correlated with cognitive complaints (R = 0.66, p < 0.001). CONCLUSIONS: Adults after pneumococcal meningitis are at high risk of long-term neurologic and neuropsychologic deficits impairing daily life activities and quality of life.

Perceptions of measles, pneumonia, and meningitis vaccines among caregivers in Shanghai, China, and the health belief model: a cross-sectional study.

BACKGROUND: In China, the measles vaccine is offered for free whereas the pneumococcal vaccine is a for-fee vaccine. This difference has the potential to influence how caregivers evaluate whether a vaccine is important or necessary for their child, but it is unclear if models of health behavior, such as the Health Belief Model, reveal the same associations for different diseases. This study compares caregiver perceptions of different diseases (measles, pneumonia and meningitis); and characterizes associations between Health Belief Model constructs and both pneumococcal vaccine uptake and perceived vaccine necessity for pneumonia, measles, and meningitis. METHODS: Caregivers of infants and young children between 8 months and 7 years of age from Shanghai (n = 619) completed a written survey on their perceptions of measles, pneumonia, and meningitis. We used logistic regression models to assess predictors of pneumococcal vaccine uptake and vaccine necessity. RESULTS: Only 25.2% of children had received a pneumococcal vaccine, although most caregivers believed that pneumonia (80.8%) and meningitis (92.4%), as well as measles (93.2%), vaccines were serious enough to warrant a vaccine. Perceived safety was strongly associated with both pneumococcal vaccine uptake and perceived vaccine necessity, and non-locals had 1.70 times higher odds of pneumonia vaccine necessity than non-locals (95% CI: 1.01, 2.88). CONCLUSIONS: Most factors had a similar relationship with vaccine necessity, regardless of disease, indicating a common mechanism for how Chinese caregivers decided which vaccines are necessary. Because more caregivers believed meningitis needed a vaccine than pneumonia, health care workers should emphasize pneumococcal vaccination's ability to protect against meningitis.

The kynurenine pathway contributes to long-term neuropsychological changes in experimental pneumococcal meningitis.

Pneumococcal meningitis is a lethal form of bacterial infection in the central nervous system that often causes lifelong neurological sequelae, despite therapeutic advances. The contemporary view is that the inflammatory response to infection contributes to the functional disabilities among survivors of this disease. We previously have established a mouse model of neurobehavioural deficits, using an automated IntelliCage™ system that revealed long-term behavioural and cognitive deficits in C57BL/6J female mice cured of meningitis by ceftriaxone treatment. We now have investigated the roles of two kynurenine pathway enzymes, indoleamine dioxygenase-1 (IDO1) and tryptophan dioxygenase-2 (TDO2), in the pathomechanisms of pneumococcal meningitis. Since tryptophan metabolism has long been implicated in behavioural and cognitive modulation through the production of neuroactive compounds, we hypothesised that preventing the actions of these enzymes through gene knockout would be beneficial in mice subjected to pneumococcal infection. We found no significant effect of IDO1 or TDO2 on mortality. Post-meningitic wild-type mice showed long-term diurnal hypoactivity and nocturnal hyperactivity when they were exposed to an Intellicage adaptation test throughout both the light and dark phases. These changes were not apparent in IDO1(-/-) survivors, but were present in the TDO2(-/-) survivors. Both IDO1(-/-) and TDO2(-/-) survivors were not protected against developing long-term cognitive deficits as measured in IntelliCage-based patrolling or reversal tasks. Collectively, these observations suggest (i) involvement of the kynurenine pathway in causing some behavioural sequelae of pneumococcal meningitis and (ii) that this pathway might operate synergistically with, or independently of, other pathways to cause other aspects of neurological sequelae.

A novel automated test battery reveals enduring behavioural alterations and cognitive impairments in survivors of murine pneumococcal meningitis.

Pneumococcal meningitis, caused by Streptococcus pneumoniae infection, is a major form of lethal bacterial meningitis. Survivors are predisposed to developing lifelong disabling sequelae, including cognitive impairment, psychological problems and motor deficits. In our experimental model, ventricular inoculation of 10(5) colony-forming units of S. pneumoniae type 3 caused 90% of mice to develop life-threatening meningitis within 48 h. Antibiotic treatment with ceftriaxone 20 h post infection reduced the incidence of severe meningitis to <10%. At the time of treatment, upregulation of pro-inflammatory cytokines was detected, including interleukin-1ß, interleukin-6 and tumour necrosis factor. We evaluated the long-term behavioural and cognitive sequelae in control mice and those surviving meningitis using an automated system (the IntelliCage) in which mice perform a range of behavioural and spatial tasks to obtain water rewards from conditioning units in their home cage. Surviving mice showed a number of altered behaviours relative to controls, including (i) hypoexploration when first exposed to the IntelliCage, (ii) altered activity patterns (fewer visits to conditioning stations during the light phase and more in the dark phase), (iii) avoidance of light (a constant or flashing LED stimulus), (iv) impaired spatial learning (a complex patrolling task), and (v) impaired discrimination reversal learning. Overall these results suggest photophobia and weakened learning ability in post-meningitic mice, particularly on tasks engaging hippocampal and prefrontal neural substrates. This study also demonstrates a standardised and comprehensive battery of tests that can be readily used to investigate neurological sequelae in undisturbed mice residing in a complex home cage environment.

Inhibition of indoleamine 2,3-dioxygenase prevented cognitive impairment in adult Wistar rats subjected to pneumococcal meningitis.

Streptococcus pneumoniae is a common cause of forms of bacterial meningitis that have a high mortality rate and cause long-term neurologic sequelae. We evaluated the effects of an indoleamine 2,3-dioxygenase (IDO) inhibitor on proinflammatory mediators and memory in Wistar rats subjected to pneumococcal meningitis. The animals were divided into 4 groups: sham, sham treated with IDO inhibitor, meningitis, and meningitis treated with IDO inhibitor. During the first experiment, the animals were killed 24 hours later, and the hippocampus was isolated for the analysis of tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, IL-10, and cytokine-induced neutrophil chemoattractant 1 (CINC-1) levels. The survival rate was 56.296% in the meningitis group and 29.616% in the meningitis group with IDO inhibitor. In the control group, we found a mean of 14.29 white blood cells/mL cerebrospinal fluid, whereas the mean was 80.00 white blood cells/mL cerebrospinal fluid in the sham IDO inhibitor group, 1167.00 white blood cells/mL cerebrospinal fluid in the meningitis group, and 286.70 white blood cells/mL cerebrospinal fluid in the meningitis IDO inhibitor group. In the meningitis group with IDO inhibitor, the levels of TNF-α and CINC-1 were reduced. In the second experiment, animals were subjected to a behavioral task and cytokine analysis 10 days after meningitis induction. In the meningitis group, there was an impairment of aversive memory. However, in the meningitis group that received adjuvant treatment with the IDO inhibitor, animals demonstrated preservation of aversive memory. These findings showed dual effects of the IDO inhibitor on a pneumococcal meningitis animal model because the inhibitor impaired survival but also produced beneficial effects, including anti-inflammatory activity and neuroprotection against the latter behavioral deficits.

Cannabidiol reduces host immune response and prevents cognitive impairments in Wistar rats submitted to pneumococcal meningitis.

Pneumococcal meningitis is a life-threatening disease characterized by an acute infection affecting the pia matter, arachnoid and subarachnoid space. The intense inflammatory response is associated with a significant mortality rate and neurologic sequelae, such as, seizures, sensory-motor deficits and impairment of learning and memory. The aim of this study was to evaluate the effects of acute and extended administration of cannabidiol on pro-inflammatory cytokines and behavioral parameters in adult Wistar rats submitted to pneumococcal meningitis. Male Wistar rats underwent a cisterna magna tap and received either 10µl of sterile saline as a placebo or an equivalent volume of S. pneumoniae suspension. Rats subjected to meningitis were treated by intraperitoneal injection with cannabidiol (2.5, 5, or 10mg/kg once or daily for 9 days after meningitis induction) or a placebo. Six hours after meningitis induction, the rats that received one dose were killed and the hippocampus and frontal cortex were obtained to assess cytokines/chemokine and brain-derived neurotrophic factor levels. On the 10th day, the rats were submitted to the inhibitory avoidance task. After the task, the animals were killed and samples from the hippocampus and frontal cortex were obtained. The extended administration of cannabidiol at different doses reduced the TNF-α level in frontal cortex. Prolonged treatment with canabidiol, 10mg/kg, prevented memory impairment in rats with pneumococcal meningitis. Although descriptive, our results demonstrate that cannabidiol has anti-inflammatory effects in pneumococcal meningitis and prevents cognitive sequel.

Antioxidant treatment prevents cognitive impairment and oxidative damage in pneumococcal meningitis survivor rats.

Pneumococcal meningitis is associated with the highest fatality case ratios in the world. Most of patients that survive present neurologic sequelae at later times as well as biochemicals alterations such as oxidative stress in both earlier and later times after central nervous system infection. In this context, we evaluated the effect of antioxidant treatment on memory and oxidative parameters in the hippocampus of meningitis survivor rats 10 days after infection. To this aim, the animals underwent a magna cistern tap receiving either 10 µL sterile saline as a placebo or an equivalent volume of a Streptococcus pneumoniae suspension at the concentration 5x10(9) cfu/mL. The animals submitted to meningitis were divided into the following groups: 1) treated with antibiotic, 2) treated with basic support plus N-acetylcysteine, 3) treated with basic support plus deferoxamine, 4) treated with basic support plus N-acetylcysteine and deferoxamine, or 5) treated with N-acetylcysteine plus deferoxamine. Ten days after meningitis, the animals underwent inhibitory avoidance and habituation to an open field tasks and, immediately after, were assessed for oxidative damage in the hippocampus and cortex. The meningitis group showed significantly decreased performance in latency retention compared with the sham group in the inhibitory avoidance task. In the open-field task, the meningitis group presented memory impairment after meningitis. All these memory impairments were prevented by N-acetylcysteine plus deferoxamine with or without basic support and its isolate use. In addition, there was an increase of lipid phosphorylation in cortex and hippocampus and all the combined antioxidants attenuated lipid phosphorylation in both structures. On the other hand, there was an increase of protein phosphorylation in cortex and N-acetylcysteine plus deferoxamine with or without basic support prevented it. Thus, we hypothesize that oxidative stress may be related to cognitive impairment in pneumococcal meningitis.

Periodic Lateralized Epileptiform Discharges (PLEDs) and pneumococcal meningoencephalitis.

Pneumococcal meningoencephalitis (PME) is a life-threatening condition of the central nervous system (CNS), and is often the result of a complicated upper airway infection. Periodic Lateralized Epileptiform Discharges (PLEDs) are a typical electroencephalographic (EEG) pattern found in some acutely acquired brain insults. Within the pediatric population they are frequently seen in association with herpetic encephalitis, a CNS infection with a high morbidity and mortality rate. We report the case of a 3-year-old girl with a bilateral ear infection who developed convulsions and coma. She had early PLEDs lateralized to the right on the EEG and microbiological criteria for Streptococcus pneumoniae infection. Concomitant herpetic encephalitis was ruled out. Intensive antibiotic and antiepileptic treatment resulted in a remarkable improvement, with the patient being able to resume her normal activities within months. To our knowledge, the association of PME and PLEDs has not been previously described in children. On the other hand, EEG has scarcely been used in the management of acute CNS infections. Hence, non-herpetic CNS encephalitis with potentially more favorable outcomes ought to be considered in the differential diagnosis of PLEDs. Continuous EEG monitoring should be considered in children with CNS infections presenting with altered sensorium, independent of the presence of seizures.

Imipramine reverses depressive-like parameters in pneumococcal meningitis survivor rats.

Pneumococcal meningitis is a severe infectious disease of the central nervous system, associated with acute inflammation and might cause damage to the host, such as deafness, blindness, seizure, and learning deficits. However, infectious diseases can play a significant role in the etiology of neuropsychiatric disturbances. In this context, we evaluated depressive-like parameters; corticosterone and ACTH levels in pneumococcal meningitis surviving rats. Wistar rats underwent a magna cistern tap receiving either 10 µL sterile saline or a Streptococcus pneumoniae suspension at the concentration of 5 × 10(9) cfu/mL. After 3 days of meningitis induction procedure, the animals were treated with imipramine at 10 mg/kg or saline for 14 days (3rd-17th day). The consumption of sweet food was measured for 7 days (10th-17th day). The meningitis group decreased the sucrose intake and increased the levels of corticosterone and ACTH levels in the serum and TNF-α in the cortex; however, the treatment with imipramine reverted the reduction of sweet food consumption, normalized hormonal levels and TNF-α in the cortex. Our results supported the hypothesis that the pneumococcal meningitis surviving rats showed depressive-like behavior and alterations in the hypothalamus-pituitary-adrenal axis.

Long-term outcomes of pneumococcal meningitis in childhood and adolescence.

A vaccine to prevent pneumococcal meningitis (PM) has recently been introduced. However, contemporary data to inform cost-effectiveness analysis and justify its routine use are sparse. We examined the cognitive, educational, psychological and social outcomes of PM in childhood. We completed a population-based case-control study in two regions of the UK. Children and young people currently between 3 and 20 years of age that had been diagnosed with PM ≤14 years of age were identified from active regional surveillance. Controls were siblings or neighbours of similar age. Standardised questionnaires and neuropsychological testing was administered to assess IQ, educational attainments, memory, psychological distress, quality of life and hearing impairment. Data were available on 97 patients and 93 controls. Eighty-four patients had a sibling/neighbour-matched control. Both matched and unmatched analyses were completed, and results of the 84 matched comparisons were highly similar to the unmatched. For the total sample, controls were similar in age, ethnicity and socioeconomic status. Median age at meningitis was 11 months. Median time between meningitis and assessment was 6.0 years. In the matched analysis, partial or profound hearing impairment was reported in 14% of patients and 1% of controls. Patients had significantly lower mean full-scale IQ (p = 0.05), verbal IQ (p = 0.0008), numeracy (p = 0.02), total quality of life (p = 0.04), school functioning (p = 0.005), psychosocial functioning (p = 0.001) and psychological difficulties (p = 0.01). Parents of patients reported greater functional disability (p = 0.008), impairment in all aspects of quality of life (p = 0.001) and psychological difficulties (p < 0.0006). Findings for IQ were not materially different when analyses were repeated only in those without hearing impairment. In multivariate regression analysis that included both case-control status and hearing status, both being a patient (p = 0.001) and having profound hearing impairment (p = 0.001) were independently associated with lower full-scale IQ. Conclusions Pneumococcal meningitis is associated with major sequelae. Our findings strongly support the introduction of pneumococcal conjugate vaccine as part of routine childhood vaccination programmes internationally.

Cognitive functioning and quality of life nine years after bacterial meningitis.

OBJECTIVE: To examine recovery of psychological functioning nine years after meningitis. METHODS: In a follow-up study, cognitive functioning and quality of life were evaluated in 28 adults 8-10 years after recovery from bacterial meningitis (n=17 due to Streptococcus pneumoniae; n=11 due to Neisseria meningitidis), and 13 controls. Test results were compared with those performed one year after the disease. All patients were well recovered at discharge (defined as a score on the Glasgow Outcome Scale of 5), but some pneumococcal patients still showed cognitive slowness and low quality of life one year after bacterial meningitis. RESULTS: At follow-up, psychological functioning and quality of life of patients and controls were similar. On group level, cognitive functioning had normalized. This was also true for patients after pneumococcal meningitis, although some cognitive slowness persisted on an individual level. CONCLUSION: Psychological functioning continues to improve slowly during the first decade after bacterial meningitis.

Time-dependent behavioral recovery after pneumococcal meningitis in rats.

Alterations in hippocampus frequently occur following bacterial meningitis, despite antibiotic treatment. We investigated the cognitive performance in rats submitted to bacterial meningitis after 10, 30, and 60 days. To this aim, we utilized male Wistar rats submitted to either sham (control) or meningitis by Streptococcus pneumoniae, and followed by the initiation of the antibiotic treatment at 16 h after inoculation. The animals underwent six behavioral tasks 10, 30 and 60 days after surgery. We demonstrated that some of the learning and memory impairment, demonstrated 10 days after the induction of meningitis, persists up to 30 days, but not 60 days after induction.

Correlation between behavioral deficits and decreased brain-derived neurotrophic [correction of neurotrofic] factor in neonatal meningitis.

We investigated the correlation between memory impairment and hippocampal brain-derived neurotrophic factor (BDNF) levels in adult rats submitted to experimental meningitis (Streptococcus pneumoniae) in the neonatal period. Sixty days after inoculation the animals were submitted to the behavior tasks and hippocampal BDNF protein were evaluated. In the meningitis group, there was impairment in habituation and avoidance memory and a decrease in the BDNF levels. The decrease in hippocampal BDNF levels correlated to impairment in memory in adult animals submitted to experimental meningitis in the neonatal period.

Dexamethasone and long-term outcome in adults with bacterial meningitis.

OBJECTIVE: This follow-up study of the European Dexamethasone Study was designed to examine the potential harmful effect of adjunctive dexamethasone treatment on long-term neuropsychological outcome in adults with bacterial meningitis. METHODS: Neurological, audiological, and neuropsychological examinations were performed in adults who survived pneumococcal or meningococcal meningitis. RESULTS: Eighty-seven of 99 (88%) eligible patients were included in the follow-up study; 46 (53%) were treated with dexamethasone and 41 (47%) with placebo. Median time between meningitis and testing was 99 months. Neuropsychological evaluation showed no significant differences between patients treated with dexamethasone and placebo. The proportions of patients with persisting neurological sequelae or hearing loss were similar in the dexamethasone and placebo groups. The overall rate of cognitive dysfunction did not differ significantly between patients and control subjects; however, patients after pneumococcal meningitis had a higher rate of cognitive dysfunction (21 vs 6%; p = 0.05) and experienced more impairment of everyday functioning due to physical problems (p = 0.05) than those after meningococcal meningitis. INTERPRETATION: Treatment with adjunctive dexamethasone is not associated with an increased risk for long-term cognitive impairment. Adults who survive pneumococcal meningitis are at significant risk for long-term neuropsychological abnormalities.

The free radical scavenger alpha-phenyl-tert-butyl nitrone aggravates hippocampal apoptosis and learning deficits in experimental pneumococcal meningitis.

The effect of adjuvant therapy with the radical scavenger alpha-phenyl-tert-butyl nitrone (PBN; 100 mg/kg given intraperitoneally every 8 h for 5 days) on brain injury and learning function was evaluated in an infant rat model of pneumococcal meningitis. Meningitis led to cortical necrotic injury (median, 3.97% [range, 0%-38.9%] of the cortex), which was reduced to a median of 0% (range, 0%-30.9%) of the cortex (P<.001) by PBN. However, neuronal apoptosis in the hippocampal dentate gyrus was increased by PBN, compared with that by saline (median score, 1.15 [range, 0.04-1.73] vs. 0.31 [range, 0-0.92]; P<.001). Learning function 3 weeks after cured infection, as assessed by the Morris water maze, was decreased, compared with that in uninfected control animals (P<.001). Parallel to the increase in hippocampal apoptosis, PBN further impaired learning in infected animals, compared with that in saline-treated animals (P<.02). These results contrast with those of an earlier study, in which PBN reduced cortical and hippocampal neuronal injury in group B streptococcal meningitis. Thus, in pneumococcal meningitis, antioxidant therapy with PBN aggravates hippocampal injury and learning deficits.