Brain acidosis in experimental pneumococcal meningitis

Purulent meningitis is a serious disease that often has a lethal outcome or gives lasting complications due to brain damage. The processes causing brain dysfunction or damage are still not uncovered nor are the reasons for the characteristic increase of CSF lactate, or the decrease of glucose levels and of pH. We studied rabbits with experimentally induced purulent meningitis (Streptococcus pneumoniae). Ten hours after the inoculation into cisterna magna the rabbits developed symptoms of meningitis, with stiffness of the neck, tachypnea, and fever. The CSF level of lactate and the number of leukocytes were significantly increased and the glucose level was decreased. Brain interstitial pH, as measured by ion selective microelectrodes, was significantly decreased from the normal level of 7.4 to 6.9. The levels of energy metabolites in brain cortex, including glucose, were not different between controls and infected animals, and the lactate level was not elevated more than could have been explained by passive diffusion from the CSF. This shows that the brain tissue is not the source of CSF lactate nor the sink for glucose in CSF. The marked acidification of brain interstitial space and CSF demonstrates that purulent meningitis causes a significant disturbance of brain ion homeostasis that could be, at least in part, responsible for the brain dysfunction. We suggest that activated leukocytes consume CSF glucose and produce lactic acid and secrete protons, which causes the CSF and interstitial acidosis.     

Increased glutamine synthetase immunoreactivity in experimental pneumococcal meningitis

Glutamine synthetase (GS), glial fibrillary acidic protein (GFAP) immunohistochemistry and neuronal apoptotic cell death were evaluated in a rabbit model of pneumococcal meningitis. Meningitis caused an increase of GS immunoreactivity in the cerebral cortex, but not in the hippocampal formation. GFAP immunoreactivity remained unchanged. This may represent a protective mechanism for cortical neurons. The inability of hippocampal GS to counteract the detrimental effects of glutamate may be the cause of neuronal apoptosis observed in the dentate gyrus during meningitis. Received: 23 September 1996 / Revised, accepted: 21 November 1996     

Brain Levels of neuropeptide Y in experimental pneumococcal meningitis

Neuropeptide Y (NPY), which is found in high concentrations in several regions of the brain including nuclei of the brain stem and in nerve fibers surrounding cerebral vessels, has been proposed to play a role in regulating cerebral blood flow (CBF) and systemic vegetative functions. Since CBF is altered during meningitis, we examined whether NPY concentrations changed in various regions of the rabbit brain in response to experimental pneumococcal meningitis. Changes were most pronounced in the medulla, where NPY concentration increased threefold after 48 h of infection. Concomitantly, there was an increase in NPY immunoreactive fibers surrounding small vessels in the dorsolateral medulla, especially in the nucleus tractus solitarius. These results suggest that NPY may play a role in inducing some of the hemodynamic changes seen during pneumococcal meningitis.     

Antioxidants attenuate microvascular changes in the early phase of experimental pneumococcal meningitis in rats.

BACKGROUND AND PURPOSE: We tested in a rat meningitis model 1) whether pneumococcal cell wall components are capable of producing changes in regional cerebral blood flow, brain water content, and intracranial pressure similar to those we have already observed after intracisternal inoculation of live pneumococci and 2) whether antioxidants would modulate these alterations in the early phase of meningitis. METHODS: Regional cerebral blood flow as measured by laser Doppler flowmetry and intracranial pressure were monitored continuously for 4 hours after intracisternal challenge. Brain edema formation was assessed by brain water content determinations. We investigated the following groups: rats challenged intracisternally with the whole intact pneumococcal cell wall (n = 7) or the pneumococcal cell wall hydrolyzed by the M1-muramidase (n = 7); rats injected intracisternally with phosphate-buffered saline (n = 6); rats pretreated intravenously with superoxide dismutase conjugated with polyethylene glycol (10,000 units/kg) and injected intracisternally with cell wall components (n = 5) or phosphate-buffered saline (n = 6); rats injected intracisternally with phosphate-buffered saline and pretreated intravenously with polyethylene glycol (10% solution, 1.2 ml/kg, n = 5) or continuously treated with intravenous free superoxide dismutase (22,000 units/kg per hour, n = 6); and rats continuously treated intravenously with deferoxamine mesylate (10 mg/kg per hour) and injected intracisternally with cell wall components (n = 6) or phosphate-buffered saline (n = 7). RESULTS: Both pneumococcal cell wall preparations produced a significant increase in regional cerebral blood flow, intracranial pressure, and brain water content. Conjugated superoxide dismutase as well as deferoxamine prevented the increase in intracranial pressure and brain water content. In addition, the increase in regional cerebral blood flow as observed in untreated, cell wall-challenged rats (baseline, 100%; 183.1 +/- 12.3% after 4 hours, mean +/- SEM) was significantly attenuated by administration of both conjugated superoxide dismutase (136.6 +/- 14.1%) and deferoxamine (149.8 +/- 8.2%) (p < 0.05). Polyethylene glycol-conjugated superoxide dismutase alone produced an increase in regional cerebral blood flow (125.6 +/- 8.7% after 4 hours). We found that polyethylene glycol per se accounts for this action. CONCLUSIONS: These data show that pneumococcal cell wall components containing teichoic acid produce changes in regional cerebral blood flow, intracranial pressure, and brain water content and that oxygen radicals contribute to these pathophysiological alterations in the early phase of experimental pneumococcal meningitis.     

Bacterial hydrogen peroxide contributes to cerebral hyperemia during early stages of experimental pneumococcal meningitis.

Alterations of blood flow contribute to major clinical complications in invasive infections such as sepsis and bacterial meningitis. As a unique feature streptococci -- in particular, Streptococcus pneumoniae, the most frequent pathogen in bacterial meningitis -- release hydrogen peroxide (H(2)O(2)) because of the absence of functional catalase. In a 6 h rat model of experimental meningitis, we studied the impact of bacterial H(2)O(2) production on regional cerebral blood flow (rCBF) and intracranial pressure (ICP). Compared to wild-type D39 pneumococci, the increase of rCBF was diminished in meningitis induced by the H(2)O(2) defective SpxB(-) mutant (maximum increase, 135% +/- 17% versus 217% +/- 23% of the individual baseline; P<0.01) or after treatment of D39-induced meningitis with H(2)O(2)-degrading catalase or with tetraethylammonium (TEA), a blocker of calcium-sensitive potassium channels, which mediate H(2)O(2)-induced vasodilation. Catalase did not significantly reduce the remaining rCBF increase caused by SpxB(-), supporting the predominant role of bacterial H(2)O(2). We conclude that in addition to host-sided mediators, bacterial-derived H(2)O(2) acts as a potent vasodilator, which accounts for a certain proportion of the early cerebral hyperperfusion in pneumococcal meningitis.     

Failure of alpha-melanocyte stimulating hormone to attenuate cerebral complications in experimental pneumococcal meningitis

Alpha-melanocyte-stimulating hormone (alpha-MSH) is an endogenous neuroimmunomodulatory peptide that can inhibit a broad range of inflammatory mediators known to be involved in the pathophysiology of bacterial meningitis. We evaluated the effect of alpha-MSH in a rat model of pneumococcal meningitis. Rats were intracisternally infected with Streptococcus pneumoniae and treatment was started 6 h after infection. Both systemic and intracisternal alpha-MSH failed to influence blood-brain barrier disruption, increased intracranial pressure, brain cytokine concentrations (IL-1beta, IL-6, TNF-alpha, MIP-2, and IL-10), CSF bacterial titers, and clinical parameters of disease severity (weight loss, body temperature, and blood pressure), although the treatment strongly increased the CNS concentrations of alpha-MSH. However, systemic but not intracisternal alpha-MSH slightly reduced the CNS leukocyte accumulation, indicating that leukocyte extravasation is inhibited by alpha-MSH from the blood side. Our results show that alpha-MSH reduces the CNS leukocyte accumulation by its systemic action, but does not attenuate meningitis-associated intracranial complications.     

Increased mortality and spatial memory deficits in TNF-alpha-deficient mice in ceftriaxone-treated experimental pneumococcal meningitis

Tumor necrosis factor-alpha (TNF-alpha) is critically involved in inflammation and may participate in hippocampal injury in bacterial meningitis. In a mouse model of ceftriaxone-treated pneumococcal meningitis, spatial memory and motor performance of TNF-alpha-deficient (n = 57) and control mice (n = 55) were investigated. After infection, therapy was initiated with ceftriaxone (100 mg/kg twice daily for 5 days). Sixty-three percent TNF-alpha-deficient mice and 40% control animals died within 6 days (Fisher's exact test: P = 0.02). TNF-alpha-deficient mice surviving pneumococcal meningitis took substantially longer to reach the hidden platform than controls, and the distance of swim tracks was longer (P = 0.02). The swim speed in both groups was similar (P = 0.59). The proliferation of dentate granule cells was lower in TNF-alpha-deficient than in wild-type mice (P = 0.03). In pneumococcal meningitis, TNF-alpha deficiency caused increased mortality and stronger deficits in spatial memory possibly due to impaired neurogenesis.     

Induced hypothermia in experimental traumatic spinal cord injury: an update

The use of induced hypothermia in the treatment of traumatic spinal cord injury (SCI) has been studied extensively between the 1960s and 1970s. Although the treatment showed some promise, it became less popular by the 1980s, mainly because of its adverse effects. However, a revival of hypothermia in the treatment of traumatic brain injury (TBI) in the last decade has encouraged neuroscientists to conduct experiments to reevaluate the potential benefits of hypothermia in traumatic SCI. All laboratory investigations studying the mechanisms of action and/or the efficacy of induced hypothermia in treating experimental traumatic SCI published in the last decade were reviewed. Although efficacy of hypothermia in improving functional outcome of mild to moderate traumatic SCI has been demonstrated, hypothermia may not be protective against severe traumatic SCI. At present, induced hypothermia has yet to be recognized or approved as a potential treatment having therapeutic value for traumatic SCI in humans. The continued search for a possible synergistic effect of induced hypothermia and pharmacological therapy may yield some promise. It has also been deduced from these laboratory studies that hyperthermia is deleterious and rigorous measures to prevent hyperthermia should be taken to minimize the propagation of secondary neuronal damage after traumatic SCI.     

Gene and protein expression of galectin-3 and galectin-9 in experimental pneumococcal meningitis

Inflammation of the subarachnoid and ventricular space contributes to the development of brain damage i.e. cortical necrosis and hippocampal apoptosis in pneumococcal meningitis (PM). Galectin-3 and -9 are known pro-inflammatory mediators and regulators of apoptosis. Here, the gene and protein expression profile for both galectins was assessed in the disease progression of PM. The mRNA of Lgals3 and Lgals9 increased continuously in the cortex and in the hippocampus from 22 h to 44 h after infection. At 44 h after infection, mRNA levels of Lgals9 in the hippocampus were 7-fold and those of Lgals3 were 30-fold higher than in uninfected controls (P<0.01). Galectin-9 protein did not change, but galectin-3 significantly increased in cortex and hippocampus with the duration of PM. Galectin-3 was localized to polymorphonuclear neutrophils, microglia, monocytes and macrophages, suggesting an involvement of galectin-3 in the neuroinflammatory processes leading to brain damage in PM.     

Persisting vasculitis after pneumococcal meningitis

Introduction  Bacterial meningitis is associated with a high mortality and a high incidence of neurological sequelae. Parainfectious vasculitis leading to ischemic brain damage is a known complication of bacterial meningitis but its treatment is uncertain. Methods and Results  We report the case of a 53-year-old man with pneumococcal meningitis who developed numerous ischemic lesions in the brainstem and basal ganglia caused by parainfectious vasculitis. Clinical and radiological improvement was observed after delayed corticosteroid initiation. Symptomatic vasculitis relapsed after steroid withdrawal and stabilized after reintroduction of the immunosuppressive therapy. Although the cerebrospinal fluid (CSF) contained high levels of MMP-9 at the time of symptomatic vasculitis, a significant decrease of the enzyme accompanied the introduction of corticotherapy and the regression of vasculitic symptoms. No relation between the level of MMP-9 and the white blood cell count in CSF could be found. Conclusion  Parainfectious vasculitis may respond to late corticosteroid treatment. MMP-9 level in CSF may be a marker of vasculitic complication in bacterial meningitis.     

Chronic hypothermia following tuberculous meningitis

A patient who developed chronic hypothermia following tuberculous meningitis is described. A central defect of thermoregulation was discovered, probably due to a discrete vascular lesion in the anterior hypothalmus.     

JNK is activated but does not mediate hippocampal neuronal apoptosis in experimental neonatal pneumococcal meningitis

Pneumococcal meningitis is associated with caspase 3-dependent apoptosis of recently post-mitotic immature neurons in the dentate gyrus of the hippocampus. The death of these cells is implicated in the learning and memory deficits in patients surviving the disease. The stress-activated protein kinase c-Jun N-terminal kinase (JNK) has been shown to be an important mediator of caspase 3-dependent neuronal apoptosis. However, whether JNK is involved in hippocampal apoptosis caused by pneumococcal meningitis has so far not been investigated. Here we show in a neonatal rat model of pneumococcal meningitis that JNK3 but not JNK1 or JNK2 is activated in the hippocampus during the acute phase of infection. At the cellular level, JNK3 activation was accompanied in the dentate gyrus by markedly increased phosphorylation of its major downstream target c-Jun in early immature (Hu-positive) neurons, but not in migrating (doublecortin-positive) neurons, the cells that do undergo apoptosis. These findings suggested that JNK may not be involved in pneumococcal meningitis-induced hippocampal apoptosis. Indeed, although intracerebroventricular administration of D-JNKI-1 or AS601245 (two highly specific JNK inhibitors) inhibited c-Jun phosphorylation and protein expression in the hippocampus, hippocampal apoptosis was unaffected. Collectively, these results demonstrate that JNK does not mediate hippocampal apoptosis in pneumococcal meningitis, and that JNK may be involved in processes unrelated to apoptosis in this disease.     

Neuroprotective effects of brain-derived neurotrophic factor (BDNF) on hearing in experimental pneumococcal meningitis

Bacterial meningitis is still one of the most common causes of acquired profound sensorineural deafness in children despite antibiotic treatment. We investigated the neuroprotective effects of brain-derived neurotrophic factor on hearing function in experimental bacterial meningitis. We implanted stainless steel tubes into both cerebral ventricles of Sprague-Dawley rats aged 21 days. Bacterial meningitis was induced by inoculating a strain of serotype III Streptococcus pneumoniae into the cisterna magna. Six micrograms per day of brain-derived neurotrophic factor (groups 1 and 3) or albumin (groups 2 and 4) was injected into the cerebral ventricles 24 hours after or before infection, respectively, for a duration of 7 days. Additionally, all rats received antibiotic subcutaneous treatment starting 24 hours after infection for 7 days. Brainstem auditory evoked potentials were recorded 24 hours before and 24 hours after infection and after 7 days of treatment with brain-derived neurotrophic factor or placebo and antibiotics, respectively, to determine hearing threshold. Our results showed that the hearing thresholds of animals in each group increased significantly 24 hours after infection compared with the results recorded 24 hours before infection (P < .01). After 7 days of treatment with brain-derived neurotrophic factor, brainstem auditory evoked potential responses recurred in 16 ears when stimulated at 75 dB hearing level in groups 1 and 3. Their hearing thresholds significantly decreased compared with the control group 2 (P < .05) and group 4 (P < .01). However, 13 of 14 ears absent brainstem auditory evoked potential responses could still not be identified at 75 dB hearing level in control groups 2 and 4. The improvement of the hearing thresholds in group 3 (treated before infection) was greater than that of group 1 (treated after infection) (P < .05), but there was no significant difference found between the control groups before and after infection (P > .05). Our study supports the hypothesis that the administration of exogenous brain-derived neurotrophic factor can be effective in preventing or treating hearing loss following bacterial meningitis.     

Cauda equina syndrome complicating pneumococcal meningitis

A 14-month-old female with pneumococcal meningitis presented with flaccid paraplegia, saddle anesthesia, and bladder and bowel dysfunction. Magnetic resonance imaging of the spine demonstrated intense gadolinium enhancement of the cauda equina, whereas the conus medullaris appeared normal. This finding indicated that lumbosacral polyradiculopathy caused her symptoms.     

Experimental pneumococcal meningitis. Effects of neuraminidase and other pneumococcal constituents on cerebrospinal fluid in the intact dog.

The intracisternal administration of a Type I pneumococcus to mongrel dogs resulted in spinal fluid abnormalities and clinical course and outcome similar to those of meningitis in humans. In order to define the pathogenic role of pneumococcal neuraminidase and other pneumococcal extracts in experimental meningitis, the following preparations were derived from the same Type I pneumococcus: crude neuraminidase, partially purified neuraminidase, heat-inactivated crude neuraminidase, and heat-killed pneumococci. These preparations were administered intracisternally daily for 5 days to a series of mongrel dogs. These substances did not produce clinical morbity similar to that observed in infected animals, even though there was significant decrease in the NANA content of cortical brain subcellular structures in the neuraminidase-treated dogs. It was concluded that the substances investigated were not responsible for morbidity and mortality in experimental pneumococcal meningitis. Both heat-killed pneumococci and the crude neuraminidase preparation elicited significant alterations in spinal fluid glucose and protein concentrations which were similar to those recorded in infected animals; however these abnormalities were not associated with significant morbidity. It is proposed that spinal fluid glucose and protein abnormalities may not be directly linked to brain damage or dysfunction in this experimental model, or in man.