Inhibition of DAMP signaling as an effective adjunctive treatment strategy in pneumococcal meningitis.

BACKGROUND: Pneumococcal meningitis remains a potentially lethal and debilitating disease, mainly due to brain damage from sustained inflammation. The release of danger-associated molecular patterns (DAMPs), like myeloid-related protein 14 (MRP14) and high mobility group box 1 protein (HMGB1), plays a major role in persistence of inflammation. In this study, we evaluated if paquinimod, an MRP14-inhibitor, and an anti-HMGB1 antibody can improve clinical outcome as adjunctive therapeutics in pneumococcal meningitis. METHODS: We tested the adjuvant administration of paquinimod and the anti-HMGB1 antibody in our pneumococcal meningitis mouse model assessing clinical (clinical score, open-field-test, temperature) and pathophysiological parameters (intracranial pressure, white blood cell count in CSF, bleeding area) as well as bacterial titers in blood and brain 24 h after administration and 48 h after infection. Furthermore, we explored the interactions of these two agents with dexamethasone, the standard adjuvant treatment in pneumococcal meningitis (PM), and daptomycin, a non-bacteriolytic antibiotic preventing pathogen-associated molecular pattern (PAMP) release. RESULTS: Adjunctive inhibition of MRP14 or HMGB1 reduced mortality in mice with PM. This effect was lost when the two anti-DAMP agents were given simultaneously, possibly due to excessive immunosuppression. Combining anti-PAMP (daptomycin) and anti-DAMP treatments did not produce synergistic results; instead, the anti-DAMP treatment alone was sufficient and superior. The combination of anti-HMGB1 with dexamethasone did not diminish the effect of the former. CONCLUSIONS: DAMP inhibition possesses good potential as an adjuvant treatment approach in PM, as it improves clinical outcome and can be given together with the standard adjuvant dexamethasone without drug effect loss in experimental PM.

Neuroinfectious diseases at a European neurological tertiary care center: one-third of patients require treatment in the neurological intensive care unit.

BACKGROUND AND PURPOSE: Studies on the impact of infectious diseases affecting the nervous system are sparse. METHODS: All patients with neuroinfectious diseases (NIDs) who were treated at our Department of Neurology from 2005 until 2009 were retrospectively analyzed. RESULTS: Patients with NIDs required treatment at the intensive care unit in 34.8%. The mortality rate of patients with NIDs was significantly higher than that of other inpatients with neurological diseases (5.1% vs. 3.0%, respectively, P = 0.018). CONCLUSION: In summary, this study shows that patients with NIDs are severely ill and mortality is high.

[Lyme borreliosis]. / Lyme-Borreliose.

Lyme borreliosis is a multisystem infectious disease affecting mainly the skin, nervous system, joints and heart. It is caused by spirochetes of the Borrelia burgdorferi sensu lato complex which are transmitted by ticks. The diagnosis of Lyme borreliosis is based primarily on typical clinical symptoms and signs with serological confirmation. Antibiotic therapy is beneficial for all manifestations and treatment refractory cases are rare. The diagnosis "chronic Lyme borreliosis" is increasingly being misused for all conceivable medically unexplained symptoms.

Listeria meningitis: identification of a cerebrospinal fluid inhibitor of macrophage listericidal function as interleukin 10.

The killing of bacteria gaining access to the central nervous system is insufficient and requires bactericidal antibiotics for treatment. The inefficient host response in cerebrospinal fluid (CSF) is thought to be due to impaired phagocytosis in CSF, and low local concentration of antibody and complement. In addition, the CSF may contain inhibitors, disabling phagocytes to eliminate bacteria. We have assessed the bactericidal activity of macrophages in the presence of CSF from mice infected intracerebrally with Listeria monocytogenes (LM). Pretreatment of J774A.1 macrophages with interferon gamma (IFN-gamma) resulted in high levels of nitric oxide-dependent intracellular killing of LM. CSF taken from mice 24 h after infection (CSF-LM 24) contained IFN-gamma and induced killing of LM by macrophages. However, pulsing J774A.1 cells with IFN-gamma in the presence of CSF obtained from mice at later time points (48 h) rendered macrophages partly permissive for intracellular Listeria growth. The inhibitor detected in CSF-LM 48 was identified as IL-10 since: (a) IL-10 dose dependently impaired the listericidal activity of IFN-gamma-activated macrophages; (b) anti-IL-10 antibodies abrogated the bacterial growth permissive effect of CSF-LM 48; and (c) IL-10 was detected in CSF-LM 48 but not in CSF-LM 24 or CSF of mock-injected animals (CSF-Co). Likewise, IL-10 was found in the CSF of 95% of patients with bacterial meningitis.

Transforming growth factor beta 2 inhibits cerebrovascular changes and brain edema formation in the tumor necrosis factor alpha-independent early phase of experimental pneumococcal meningitis.

Macrophages and granulocytes seem to play a key role in the pathogenesis of bacterial meningitis. Transforming growth factor beta (TGF-beta) leads to macrophage deactivation, as well as to inhibition of cytokine production and of endothelial granulocyte adhesion. We have investigated the influence of TGF-beta on regional cerebral blood flow (rCBF), intracranial pressure (ICP), and brain edema formation during the early phase of experimental meningitis. Rats which were inoculated intracisternally with live pneumococci or with pneumococcal cell wall hydrolyzed by the M1 muramidase (PCW-M) developed an increase of rCBF and ICP within 4 h postintracisternal challenge. A single intraperitoneal injection of TGF-beta 2 but not of TGF-beta 2 vehicle-control prevented the changes of rCBF. Furthermore, TGF-beta 2 significantly reduced the increase of ICP in rats inoculated with PCW-M. Likewise, the elevation of brain water content after intracisternal injection of pneumococci or PCW-M was blocked by pretreatment of rats with TGF-beta 2. TGF-beta 1 exhibited similar inhibitory effects in PCW-M-injected rats. The beneficial effects of TGF-beta 2 on the initial phase after pneumococcal inoculation seem to be tumor necrosis factor alpha- (TNF-alpha) independent since (a) intracisternal or intraperitoneal injection of neutralizing anti-TNF-alpha antibodies did not significantly influence rCBF, ICP, and brain water content in PCW-M-induced meningitis; and (b) TNF-alpha was only occasionally detected at low levels in cerebrospinal fluid at 4 h after PCW-M application.

[Bacterial infections of the central nervous system]. / Bakterielle Infektionen des Zentralnervensystems.

Bacterial infections of the nervous system are often challenging for the treating physician because sensitivity and specificity of clinical signs do not reach 100%. In patients with neuroborreliosis and bacterial meningitis, investigations of the cerebrospinal fluid are necessary to confirm or rule out the diagnosis. In intracranial and spinal abscesses, the alterations of the cerebrospinal fluid are most often non-specific and imaging and neurosurgical aspiration of purulent material are additionally needed to make the diagnosis. Here, the relevant diagnostic and therapeutic aspects of three common bacterial infections of the central nervous system (neuroborreliosis, bacterial meningitis, and brain abscess) are discussed.

Adjuvant non-bacteriolytic and anti-inflammatory combination therapy in pneumococcal meningitis: an investigation in a mouse model.

OBJECTIVES: Therapy with antibiotics, dexamethasone, and supportive intensive care has improved the prognosis of pneumococcal meningitis, but mortality remains high. Here, we investigated an adjunctive combination therapy of the non-bacteriolytic antibiotic daptomycin plus several anti-inflammatory agents to identify the currently most promising adjunctive combination therapy for pneumococcal meningitis. METHODS: C57BL/6 mice were infected by injection of pneumococci into the cisterna magna. Treatment was begun 21 h after infection, and consisted of ceftriaxone plus (a) dexamethasone, (b) dexamethasone plus daptomycin, (c) daptomycin, (d) daptomycin plus an anti-IL1 antibody, (e) daptomycin plus roscovitine, or (f) daptomycin plus an anti-C5 antibody. Animals were followed until 45 h after infection. Furthermore, adjunctive daptomycin plus anti-C5 antibodies were assessed in a long-term follow-up. RESULTS: Adjunctive treatment with daptomycin and an anti-C5 antibody was superior to adjunctive dexamethasone and reduced disease symptoms (clinical score 1.1 ± 1.1 versus 5.0 ± 2.7, p < 0.0083), improved explorative activity (open field test 17.8 ± 8.2 versus 7.4 ± 4.3 crossed fields/2 minutes, p < 0.0083), and reduced hearing impairment (thresholds for click stimulus 96.1 ± 14.7 versus 114.8 ± 9.3 dB SPL, p < 0.0083) in the acute stage. Furthermore, explorative activity (14.4 ± 7.3 crossed fields/2 minutes versus 6.3 ± 7.2, p < 0.05) and cognitive function (t-maze test, exploration time previously unknown alley 72.4 ± 14.3 versus 48.7 ± 25.6%, p < 0.05) was improved at 2 weeks after infection. Treatment with daptomycin plus an anti-IL-1ß antibody or roscovitine was not of significant benefit in comparison to adjunctive therapy with dexamethasone. CONCLUSIONS: An adjunctive combination of the non-lytic antibiotic daptomycin plus an anti-C5 antibody was superior to standard therapy with adjunctive dexamethasone in the treatment of pneumococcal meningitis.

Mimicking of cerebral herniation through gamma-hydroxybutyric acid therapy.

Besides being a treatment option for narcolepsy, gamma-hydroxybutyrate is used as an adjuvant during anesthesia in Europe. In addition, it is illegally used as a recreational drug. Fixed and dilated, asymmetric pupils developed in 2 patients during continuous therapy with intravenous gamma-hydroxybutyrate, which was added to the long-term anesthetics fentanyl and midazolam. Cerebral herniation as an alternative cause for the pupillary changes was ruled out by using continuous intracranial pressure monitoring and computed tomography. In both patients, the pupillary abnormalities resolved after discontinuation of gamma-hydroxybutyrate. Thus, fixed and dilated pupils that are asymmetric seem to be an important side effect of gamma-hydroxybutyrate therapy that may mimic cerebral herniation in deeply anesthetized patients.

[Bacterial meningitis in adults in emergency and rescue services]. / Bakterielle Meningitis bei Erwachsenen im Notfall- und Rettungswesen.

The cardinal symptoms of bacterial meningitis are headache, fever, impaired consciousness and nuchal stiffness (meningism); however, the diagnosis of acute bacterial meningitis can only be confirmed or ruled out by investigation of cerebrospinal fluid. The recommended empirical antibiotic regimen for community-acquired acute bacterial meningitis in adults in Germany is a combination of ceftriaxone and ampicillin plus adjuvant dexamethasone. An important influenceable factor for treatment success of acute bacterial meningitis is a rapid induction of antibiotic therapy, which must be initiated directly after lumbar puncture. When this is delayed for any reason, e. g. because of the necessity of cerebral computed tomography imaging before lumbar puncture, antibiotics should be started even before acquisition of cerebrospinal fluid.

Spectrum and Prevalence of Pathological Intracranial Magnetic Resonance Imaging Findings in Acute Bacterial Meningitis.

PURPOSE: Aim of this study was to determine the spectrum and prevalence of pathological intracranial magnetic resonance imaging (MRI) findings in patients with acute bacterial meningitis. METHODS: We retrospectively identified all consecutive patients with cerebral spinal fluid proven bacterial meningitis who presented at our neurology department between 2007 and 2012. Pathogenic agents and clinical symptoms were noted. MR-examinations were evaluated regarding presence and localization of pathological signal alterations in the different sequences by two neuroradiologists in consensus. RESULTS: A total of 136 patients with purulent bacterial meningitis were identified. In 114 cases the bacterial pathogen agent was proven and in 75 patients an MRI was available. In 62 of the 75 (82.7 %) patients meningitis-associated pathologic imaging findings were evident on MRI. Overall, intraventricular signal alterations, i.e., signs of pyogenic ventriculitis, were present in 41 cases (54.7 %), while sulcal signal changes were found in 22 cases (29.3 %). Intraparenchymatous signal alterations affected the cortex in 15 cases (20 %), and the white matter in 20 patients (26.7 %). The diffusion-weighted imaging and fluid attenuated inversion recovery sequences were most sensitive in the detection of these changes and showed any pathologic findings in 67.6 and 79.6 %, respectively. Patients with streptococcal meningitis showed significantly more often (n = 29 of 34, 85.3 %) intraventricular and/or sulcal diffusion restrictions than patients with meningitis caused by other agents (n = 12 of 37, 32.4 %) (p< 0.0001). CONCLUSION: Pathological MR findings are frequently found in patients with acute bacterial meningitis. Intraventricular diffusion restrictions, i.e., signs of pyogenic ventriculitis, are more often found in patients with streptococcal, especially pneumococcal, infection.

Evaluation of cerebrospinal fluid uPA, PAI-1, and soluble uPAR levels in HIV-infected patients.

To evaluate the potential role of the uPAR/uPA/PAI-1 system in HIV-induced blood-brain-barrier (BBB) disruption, CSF uPA-dependent plasminogen activation (PdPA) was analyzed by casein zymography, and CSF protein levels of all three molecules were measured by ELISA. CSF uPAR, but not uPA, PAI-1, or PdPA levels was significantly increased in neurologically compromised HIV+ patients. Only individual patients with severe AIDS dementia complex had increased levels of uPA (but not PAI-1) which fell upon initiation of antiretroviral therapy. The levels of all three molecules did not correlate with the CSF to serum albumin ratio suggesting not an important role in HIV-induced BBB disruption.

[Gadolinium enhancement of the cauda equina following ischemia of the lumbar cord]. / Kontrastmittelaufnahme der Cauda equina nach Ischämie im Conus medullaris.

Enhancement of the cauda equina is a well-recognized finding, in particular in patients with inflammatory diseases of the peripheral nervous system. However, we report an unusual case of a woman with an ischemic lesion in the lumbar intumescence who developed enhancement of the cauda equina 18 days after disease onset. Seventy-six days after the onset of illness, contrast uptake was no longer detectable. Severe injury to the motor neurons in the lumbar intumescence was evident clinically and electromyographically. We propose that the enhancement of the cauda equina was due to blood-nerve barrier disruption during Wallerian degeneration following ischemic injury to the motor neurons of the lumbar cord.

Lack of endothelial nitric oxide synthase aggravates murine pneumococcal meningitis.

Nitric oxide (NO) plays a central role in the pathogenesis of bacterial meningitis. However, the role of NO produced by endothelial NO synthase (eNOS) in meningitis is still unclear. We investigated the influence of eNOS depletion on the inflammatory host response, intracranial complications, and outcome in experimental pneumococcal meningitis. Leukocyte accumulation in the cerebrospinal fluid was more pronounced in infected eNOS-deficient mice than in infected wild type mice. This effect could be attributed to an increased expression of P-selectin, macrophage inflammatory protein-2, keratinocyte-derived cytokine, and interleukin (IL)-1beta in the brain of infected eNOS-deficient mice. However, no differences in the cerebral expression of intercellular adhesion molecule-1, tumor necrosis factor-alpha, and IL-6 as well as of neuronal NOS and inducible NOS could be detected between infected wild type and mutant mice. In addition to enhanced leukocyte infiltration into the CSF, meningitis-associated intracranial complications including blood-brain barrier disruption and the rise in intracranial pressure were significantly augmented in infected eNOS-deficient mice. The aggravation of intracranial complications was paralleled by a worsening of the disease, as evidenced by a more pronounced hypothermia, an enhanced weight reduction, and an increased death rate. The current data indicate that eNOS deficiency is detrimental in bacterial meningitis. This effect seems to be related to an increased expression of (certain) cytokines/chemokines and adhesion molecules; thus leading to increased meningeal inflammation and, subsequently, to aggravated intracranial complications.

Oxidative stress in bacterial meningitis.

Fifty years after the advent of antibiotics for clinical use, the rates of morbidity and mortality associated with bacterial meningitis remain high. The unfavourable clinical outcome is often due to intracranial complications including cerebrovascular insults, raised intracranial pressure, hydrocephalus, and brain edema. Reactive oxygen species (ROS) are known effector molecules in the antimicrobial armature of polymorphonuclear and mononuclear phagocytes. However, over the last decade, there has been a substantial body of work implicating a central role of ROS in the development of intracranial complications and brain damage in bacterial meningitis. Recently, it also became evident that reactive nitrogen species (RNS), especially nitric oxide, are important mediators of meningitis-associated pathophysiological changes, at least during the early phase of the disease. There is now substantial evidence that much of the oxidative injury associated by simultaneous production of superoxide and nitric oxide is mediated by the strong oxidant peroxynitrite. ROS and peroxynitrite can be cytotoxic via a number of independent mechanisms. Their cytotoxic effects include initiation of lipid peroxidation and induction of DNA single strand breakage. Damaged DNA activates poly(ADP-ribose) polymerase (PARP). Recent experimental data propose a role of lipid peroxidation and PARP activation in the development of meningitis-associated intracranial complications and brain injury. Agents which interfere with the production of ROS and peroxynitrite, as well as with PARP activation and lipid peroxidation may represent novel, therapeutic strategies to limit meningitis-associated brain damage, and, thus, to improve the outcome of this serious disease.

7-Nitroindazole inhibits pial arteriolar vasodilation in a rat model of pneumococcal meningitis.

This study investigates how the neuronal and inducible nitric oxide synthase (NOS) pathways contribute to the cerebrovascular changes in the early phase of experimental pneumococcal meningitis in rats. Using a closed cranial window preparation, the diameters of pial arterioles were measured during 4 hours after intracisternal injection of heat-killed pneumococci and compared with controls (n = 6). Injection of pneumococci (n = 7) caused a significant increase in pial arteriolar diameter (157 +/- 22% after 4 hours; P < 0.05, compared with 104 +/- 11% in controls), intracranial pressure, CSF white blood cell counts, and brain water content. Treatment with the neuronal NOS inhibitor 7-nitroindazole (50 mg/kg given intraperitoneally, n = 5) prevented pneumococci-induced vasodilation (107 +/- 20% at 4 hours), whereas S-methylisothiourea (SMT; 0.1 mg/kg given intraperitoneally, n = 5), which predominantly inhibits the inducible NOS, did not influence pneumococci-induced vasodilation (154 +/- 38% at 4 hours). S-methylisothiourea at a dose of 1.0 mg/kg (n = 5), attenuated the vasodilation (124 +/- 18% at 4 hours). However, the increase in mean arterial blood pressure after SMT at 1.0 mg/kg, but not at 0.1 mg/kg, suggests that the higher dose of SMT influenced the constitutive NOS activity, causing inhibition of the pneumococci-induced vasodilation. Neither SMT (at both doses) nor 7-nitroindazole influenced the increase in brain water content, intracranial pressure, and CSF white blood cell counts in pneumococci-challenged rats. Our study suggests that pial arteriolar vasodilation in the early phase of experimental pneumococcal meningitis is mediated by the neuronal NOS pathway.

Endothelin B receptor-mediated increase of cerebral blood flow in experimental pneumococcal meningitis.

Study investigates the role of endothelin (ET) receptors in mediating early changes in cerebral blood flow--as measured by laser Doppler flowmetry (CBFLDF)--during experimental pneumococcal meningitis. Meningitis was induced with heat-killed pneumococci and confirmed by a significant increase in CBFLDF (baseline 100%; 225.3 +/- 21.8% after 6 hours; mean +/- SD), intracranial pressure (ICP), brain water content, and white blood cell count in the CSF. Intravenous administration of the selective endothelin B (ETB) receptor antagonist BQ-788 immediately before pneumococcal challenge (but not 4 hours afterward) significantly attenuated these pathophysiologic alterations (e.g., CBFLDF 6 hours after pneumococcal challenge: 116.7 +/- 17.4%). Pretreatment with BQ-123, a selective endothelin A receptor antagonist, had no significant effect on ICP and brain water content, but augmented the increase in CBFLDF and CSF white blood cell count. Since ET is known to trigger the release of nitric oxide (NO) by ETB receptor activation, we examined specific ET-NO interactions in primary rat cerebromicrovascular endothelial cells after stimulation with heat-killed pneumococci. Pneumococci induced a significant increase in both ET and NO concentrations in endothelial cell culture medium. Treatment with phosphoramidon, an inhibitor of the endothelin-converting enzyme, prevented the production of endothelin and markedly reduced NO generation. Our data provide evidence that ET is involved as a mediator in early pneumococcal meningitis in the rat and contributes to the increase in CBFLDF, ICP, brain water content, and CSF pleocytosis, presumably through ETB receptor-mediated NO production.

Global cerebral ischemia in the rat: online monitoring of oxygen free radical production using chemiluminescence in vivo.

Using online in vivo chemiluminescence (CL), we studied for the first time continuously the production of reactive oxygen species (ROS) after global cerebral ischemia and the relationship of ROS production to CBF. In anesthetized rats equipped with a closed cranial window, the CL enhancer, lucigenin (1 mM), was superfused onto the brain topically. CL was measured through the cranial window with a cooled photomultiplier, and CBF was measured simultaneously with laser-Doppler flowmetry. Reperfusion after 10 min (n = 8) of global cerebral ischemia led to a CL peak to 188 +/- 77% (baseline = 100%) within 10 +/- 4 min. After 2 h of reperfusion, CL had returned to 102 +/- 28%. Reperfusion after 20 min (n = 8) of ischemia increased CL to 225 +/- 48% within 12 +/- 3 min. After 2 h, CL was still increased (150 +/- 44%, p < 0.05 compared with 10 min of ischemia). CL after 10 min of ischemia was neither affected by brain topical free CuZn-superoxide dismutase (SOD) (100 U/ml, n = 3) nor by i.v. administration of free CuZn-SOD (104 U/kg, followed by 104 U/kg/h, n = 3). The CBF hyperfusion peak on reperfusion preceded the CL peak in all experiments by several minutes. In additional in vitro experiments we investigated the source of CL: Intracellular loading of lucigenin was demonstrated in cultured CNS cells, and a very similar pattern of CL as in the in vivo preparation after ischemia developed in rat brain slices after 15 min of hypoxia, which was unaffected by free CuZn-SOD (100 U/ml) but strongly attenuated by liposome-entrapped CuZn-SOD. We conclude that lucigenin-enhanced CL is a promising tool to study ROS production continuously from the in vivo brain of experimental animals and brain slices, and that the CL signal most likely derives from the intracellular production of superoxide. The production of ROS is preceded by reperfusion, is burst-like, and is dependent on the duration of the ischemic interval.

Microvascular changes during the early phase of experimental bacterial meningitis.

We investigated the temporal profile of the changes in regional CBF (rCBF) and intracranial pressure (ICP) during the early phase of pneumococcal meningitis in the rat. rCBF, as measured by laser-Doppler flowmetry, and ICP were continuously monitored during 6 h post infection (p.i.). Brain edema formation was assessed by brain water content determinations. Meningitis was induced by intracisternal injection of 75 microliters of 10(7) colony-forming units/ml pneumococci (n = 7). In control animals (n = 6), saline was injected. There was no change in the rCBF or ICP of controls throughout the experiment. However, there was a dramatic increase in rCBF and ICP associated with brain edema formation in untreated meningitis animals. rCBF increased to 135.3 +/- 33.8% (mean +/- SD) in the untreated animals at 1 h p.i. and reached 211.1 +/- 40.5% at 6 h p.i. (p less than 0.05 compared with controls). ICP increased from 2.9 +/- 1.4 to 10.4 +/- 4.7 mm Hg at 6 h p.i. (p less than 0.05 compared with controls). Brain water content was significantly elevated (79.69 +/- 0.24 compared with 78.94 +/- 0.16% in the control group, p less than 0.05). We investigated the effect of dexamethasone (3 mg/kg i.p.), which was given prior to the induction of meningitis (n = 3) or at 2 h after pneumococcal injection (n = 5), indomethacin (10 mg/kg i.v., n = 5), and superoxide dismutase (SOD; 132,000 U/kg i.v. per 6 h, n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Spectrum of complications during bacterial meningitis in adults. Results of a prospective clinical study.

OBJECTIVE: To determine systematically central nervous system and systemic complications during the acute phase of adult bacterial meningitis. DESIGN: Prospective clinical study. SETTING: University referral center, Department of Neurology. PATIENTS: A total of 86 consecutive patients between the ages of 15 and 87 years who had bacterial meningitis. MEASUREMENTS: Central nervous system complications, including brain swelling, hydrocephalus, brain abscess, subdural empyema, or subdural effusion (using computed tomography) and cerebrovascular involvement (using cerebral angiography), systemic complications, including septic shock, disseminated intravascular coagulation, adult respiratory distress syndrome, or septic or reactive arthritis, and typical complications arising during intensive care therapy. RESULTS: Of the 86 adult patients with bacterial meningitis, complications developed in 43 patients. The major central nervous system complications included angiographically documented cerebrovascular involvement (15.1% of the patients [13/86 patients]), brain swelling (14.0% [12/86]), hydrocephalus (11.6% [10/86]), and intracerebral hemorrhage (2.3% [2/86]), while septic shock (11.6% [10/86]), adult respiratory distress syndrome (3.5% [3/86]), and disseminated intravascular coagulation (8.1% [7/86]) dominated among the patients with systemic complications. Seven patients had cerebral herniation, three with a lethal course. The overall mortality was 18.6% [16/86] and was 10 of 30 (3.33%) in pneumococcal meningitis. CONCLUSIONS: Clinical and autopsy studies showed that the major determinants for the lethal outcome were primarily central nervous system complications in six patients, systemic complications in five, and a combination of both in another five. The identification of the various complications and their time of expected occurrence may help to develop additional treatment regimens in bacterial meningitis in adults.

Cefotaxime vs penicillin G for acute neurologic manifestations in Lyme borreliosis. A prospective randomized study.

We randomly assigned 21 patients with painful Lyme neuroborreliosis radiculitis (Bannwarth's syndrome) and neuroborreliosis meningitis to a 10-day treatment with either penicillin G. 4 x 5 million U/d (n = 10) or cefotaxime sodium, 3 x 2 g/d (n = 11), intravenously. We were not able to demonstrate clinical differences between groups, either during the 10-day treatment period or at follow-up examination a mean of 7.7 months after antibiotic therapy. Cerebrospinal fluid cefotaxime concentrations reached the minimum inhibitory concentration at the 90% level for Borrelia burgdorferi in all patients, while none of the patients treated with penicillin G had cerebrospinal fluid concentrations above the minimum inhibitory concentration at the 90% value. We conclude that patients with acute neurologic manifestations of Lyme borreliosis may benefit from a 10-day treatment with cefotaxime or penicillin G. Cerebrospinal fluid antibiotic concentrations above the minimum inhibitory concentration at the 90% value, as observed in all patients treated with cefotaxime, offer the most hope for long-term prognosis.