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.

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.

[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.

[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.

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.

The crossed leg sign indicates a favorable outcome after severe stroke.

OBJECTIVE: We investigated whether crossed legs are a prognostic marker in patients with severe stroke. METHODS: In this controlled prospective observational study, we observed patients with severe stroke who crossed their legs during their hospital stay and matched them with randomly selected severe stroke patients who did not cross their legs. The patients were evaluated upon admission, on the day of leg crossing, upon discharge, and at 1 year after discharge. The Glasgow Coma Scale, the NIH Stroke Scale (NIHSS), the modified Rankin Scale (mRS), and the Barthel Index (BI) were obtained. RESULTS: Patients who crossed their legs (n = 34) and matched controls (n = 34) did not differ in any scale upon admission. At the time of discharge, the GCS did not differ, but the NIHSS was better in crossed legs patients (6.5 vs 10.6; p = 0.0026), as was the mRS (3.4 vs 5.1, p < 0.001), and the BI (34.0 vs 21.1; p = 0.0073). At 1-year follow-up, mRS (2.9 vs 5.1, p < 0.001) and the BI (71.3 vs 49.2; p = 0.045) were also better in the crossed leg group. The mortality between the groups differed grossly; only 1 patient died in the crossing group compared to 18 in the noncrossing group (p < 0.001). CONCLUSION: Leg crossing is an easily obtained clinical sign and is independent of additional technical examinations. Leg crossing within the first 15 days after severe stroke indicates a favorable outcome which includes less neurologic deficits, better independence in daily life, and lower rates of death.

A prospective study on the role of CXCL13 in Lyme neuroborreliosis.

BACKGROUND: The definite diagnosis of acute Lyme neuroborreliosis (LNB) requires detection of an increased Borrelia burgdorferi-specific antibody index (AI). The B burgdorferi AI, however, is negative in up to 20% of patients with early LNB and can remain elevated for years after adequate therapy; both of these factors can make the diagnosis difficult. Recent retrospective studies suggested the chemokine CXCL13 as a potential biomarker for LNB. To evaluate its diagnostic value, we conducted a prospective study. METHODS: From March 2008 to August 2009, CSF and serum samples from all patients in whom a B burgdorferi-specific AI was requested (n=692) and CSF analysis revealed CSF pleocytosis (n=192) were included in the study. Because of the low number of patients with untreated LNB, 13 additional retrospectively selected samples of patients with untreated LNB were added. CXCL13 concentrations were measured by ELISA and receiver operating characteristic curves were generated. RESULTS: CSF CXCL13 was highly elevated in all patients with untreated acute LNB (mean=15,149 pg/mL) compared with that in the patients without LNB (mean=247 pg/mL). At a cutoff of 1,229 pg/mL, the sensitivity of CXCL13 was 94.1%, which is higher than the AI (85.7%). Only 7 patients (5 with a CNS lymphoma and 2 with bacterial meningitis) had a CXCL13 level above the cutoff, resulting in a specificity equal to the AI of 96.1%. CONCLUSIONS: CXCL13 shows high sensitivity and specificity for acute, untreated LNB. This novel marker appears to be helpful in clinically atypical cases and, in particular, in early stages of the disease when the B burgdorferi AI is (still) negative.

[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.

Therapy of community-acquired acute bacterial meningitis: the clock is running.

Despite antibiotic therapy and supportive intensive medical care, bacterial meningitis remains a disease with high mortality and morbidity. Rapid recognition of symptoms is crucial to direct physicians quickly towards appropriate diagnostic measures and, initially, empiric antibiotic therapy. It has become evident that time from arrival at the hospital to application of the first dose of antibiotics is a crucial independent factor that influences outcome. Here, we review the clinical and laboratory presentation of community-acquired bacterial meningitis and the antibiotic regiments that are currently recommended for its treatment; future therapeutic options are also discussed. Finally, suggestions for the approach to a patient with suspected bacterial meningitis are presented.

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.

[Pain and neuroborreliosis: significance, diagnosis and treatment]. / Schmerzen bei Neuroborreliose: Bedeutung, Diagnostik und Therapie.

Lyme neuroborreliosis is a tick-borne infection of the central nervous system caused by the spirochete Borrelia burgdorferi. The most frequent manifestation of neuroborreliosis in Europe is meningoradiculitis or Bannwarth's syndrome. One of its hallmarks is intense, lancinating, radicular pain, especially at night. Its characteristics are rather different to other forms of neuropathic pain in respect to the dynamics, localisation and therapeutic responses. This review therefore summarises not only the general symptoms, diagnostic procedures and therapy of Lyme neuroborreliosis, but also revises the characteristics and therapeutic options of painful meningoradiculitis in Bannwarth's syndrome.

Nitrogen and oxygen molecules in meningitis-associated labyrinthitis and hearing impairment.

Pneumococcal meningitis remains a serious disease with a case fatality rate of 15%-25%. Furthermore, long-term residues affect up to 50% of survivors. One of the most frequent sequelae is sensorineural hearing loss, which occurs in 26% of survivors of pneumococcal meningitis. Unfortunately, sufficient treatment regimens are still missing. New insights into the pathology and pathophysiology of meningitis-associated hearing loss have come from animal models of bacterial meningitis. Most likely, bacteria reach the cochlea through the cochlear aquaeduct. Once arrived in the perilymphatic spaces, they induce a severe suppurative labyrinthitis. The blood-labyrinth barrier breaks, hair cells are damaged, and neurons in the spiral ganglion undergo cell death, leading to meningitis-associated hearing loss. Reactive oxygen and nitrogen species, in particular peroxynitrite, seem to be among the crucial mediators of cochlear damage and hearing loss during meningitis. In our rat model of pneumococcal meningitis, adjunctive therapy with the antioxidants and peroxynitrite scavengers Mn(III)tetrakis(4-bencoic acid)-porphyrin (MnTBAP) and N-Acetyl-L-Cystein (NAC) significantly attenuated acute and long-term hearing loss. In several other animal studies of pneumococcal meningitis, adjunctive antioxidant therapy also protected infected animals from intracranial complications. Therefore, the use of antioxidants seems to be a promising future treatment option in pneumococcal meningitis.

A role for the urokinase-type plasminogen activator system in amyotrophic lateral sclerosis.

There is substantial evidence, implicating extracellular matrix (ECM) regulating enzymes in the pathogenesis of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The most important ECM-degrading proteases are serine proteases (plasminogen activators, PA) and matrix metalloproteinases (MMPs). Since the role of MMPs in ALS has been addressed recently, we investigated the expression of the serine protease urokinase-type plasminogen activator (uPA) and its receptor in ALS. Employing rtPCR, zymography and immunohistochemistry we analyzed the expression of uPA and its receptor uPAR in spinal cord tissue of ALS cases and in the G93A SOD1 transgenic mouse. In the ventral horn of the spinal cord of ALS cases we found increased uPAR staining of motor neurons. In G93A mice, the expression profile of uPA and uPAR mRNA was significantly increased starting at the age of 90 days as compared to non-transgenic littermates. The uPA-dependent plasminogen activation in G93A mice at endstage increased markedly compared with controls and immunostaining of the spinal cord from G93A mice revealed increased uPAR immunostaining in neurons. To determine the functional role of uPA, we investigated the effect of intraperitoneal (i.p.) administration of the uPA inhibitor WX-340 (10 mg/kg), starting at the age of 30 days (n=18). Treatment with WX-340 prolonged (p<0.05) survival of the animals (135+/-2 vs. 126+/-3) as well as improving rotarod performance. Our experiments demonstrate that uPA and its receptor are expressed in ALS patients and in an animal model of ALS. Early inhibition with a synthetic uPA inhibitor prolonged the life of the transgenic animals. These findings indicate that the urokinase-type plasminogen activator system may play a role in the complex pathogenesis of ALS.