Safety Profile and Complication Rates in Emergency Off-label Use of Tirofiban in Interventional Neuroradiology : An Observational Dual Center Study.

PURPOSE: Tirofiban has been approved for the treatment of acute coronary syndrome. Meanwhile, tirofiban is frequently applied in emergency situations in interventional neuroradiology (INR). The objective of this study was to analyze the risk profile for the off-label use of tirofiban in INR patients. METHODS: Data of 86 patients, who underwent neurointerventional therapy and were treated with tirofiban at 2 neuroendovascular centers between January 2016 and July 2017 were retrospectively analyzed. Despite off-label use, recent stroke (< 30 days), recent hemorrhage, thrombocytopenia (< 150,000/µl), activated partial thromboplastin time (aPTT) > 1.3-fold, internation normalised ratio (INR) < 1.5, severe liver insufficiency (Child-Pugh C), and preceding intravenous thrombolysis were considered as contraindications. RESULTS: Median patient age was 62 years (range 26-88 years). Patients received tirofiban for extracranial (n = 35) or intracranial stenting (n = 35), coiling of ruptured cerebral aneurysms (n = 6), continuous intra-arterial nimodipine infusion via microcatheters for subarachnoid hemorrhage (SAH)-related vasospasm (n = 5), or thrombotic complications during neuroendovascular procedures (n = 5). The desired effect of preventing thrombotic complications when applying tirofiban off-label was achieved in 81 of 86 patients (94.2%). Relevant tirofiban-associated complications occurred in 14 patients (16.3%), of which 9 patients received i.v. thrombolysis for treatment of acute ischemic stroke shortly before starting therapy with tirofiban. Of the 86 patients 12 died, while the overall tirofiban-related mortality was 2.3% (2 patients died due to ICH). Logistic regression analysis revealed age to be the only parameter significantly associated with development of tirofiban-associated complications (p = 0.026). CONCLUSION: Whereas the safety profile of tirofiban when applied off-label in INR is acceptable, the highest risk for relevant tirofiban-associated complications is observed in older patients treated by emergency stenting for acute stroke.

Mechanical thrombectomy in ischemic stroke: Parameters affecting the TICI outcome.

BACKGROUND: Mechanical thrombectomy (MT) is a standard stroke treatment for patients with large vessel occlusions (LVOs). A decisive factor for a successful outcome is, among other things, timely treatment. OBJECTIVE: The objective was to analyze several time points in relation to outcomes and/or surrogate parameters. Furthermore, our data was placed in the context of other clinical trial data. METHODS: We retrospectively evaluated 133 data sets from patients who underwent MT. The correlation of various time periods with parameters, such as the ASPECTS, NIHSS, mRS, and, particularly, the TICI score, was investigated. RESULTS: A correlation was found for both the NIHSS score at discharge and the TICI score with the time periods of arrival and/or start to groin puncture as well as with arrival to the end of the intervention and the duration of the intervention. CONCLUSIONS: This retrospective study is consistent with large randomized clinical trials investigating stroke management and provides data from daily clinical practice.

MOG encephalomyelitis: distinct clinical, MRI and CSF features in patients with longitudinal extensive transverse myelitis as first clinical presentation.

BACKGROUND: Based on clinical, immunological and histopathological evidence, MOG-IgG-associated encephalomyelitis (MOG-EM) has emerged as a distinct disease entity different from multiple sclerosis (MS) and aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder (NMOSD). MOG-EM is associated with a broader clinical phenotype including optic neuritis, myelitis, brainstem lesions and acute disseminated encephalomyelitis with a substantial clinical and radiological overlap to other demyelinating CNS disorders. OBJECTIVE: To evaluate common clinical, MRI and CSF findings, as well as therapy responses in patients with longitudinal extensive transverse myelitis (LETM) as initial clinical presentation of MOG-EM. METHODS: After excluding patients with a known diagnosis of MS, we identified 153 patients with myelitis of which 7 fulfilled the inclusion criteria and were investigated for MRI, CSF and clinical parameters. RESULTS: Patients with LETM as first clinical presentation of MOG-EM display similar characteristics, namely a lack of gadolinium-enhancement in spinal cord MRI, marked pleocytosis, negative oligoclonal bands, a previous history of infections/vaccinations and response to antibody-depleting treatments for acute attacks and long-term treatment. CONCLUSIONS: We identify common pathological findings in patients with LETM as first clinical presentation of MOG-EM which distinguishes it from other forms of LETM and should lead to testing for MOG-IgG in these cases.

GFAPα IgG-associated encephalitis upon daclizumab treatment of MS.

OBJECTIVE: To describe a case of glial fibrillary acidic protein (GFAP)α immunoglobulin G (IgG)-associated encephalitis in a patient referred to us with MS on daclizumab treatment and to summarize characteristics of 5 additional recent German MS cases of serious encephalitis along with a previously published American case of CNS vasculitis associated with daclizumab. METHODS: Evaluation of cause, clinical symptoms, and treatment response. RESULTS: The 6 patients included 4 women and 2 men. The median age at onset was 38 years (range 32-51 years). Clinical presentation was marked by progressing neuropsychologic and/or neurologic deficits. Additional drug rash with eosinophilia was seen in 3 patients, whereas 2 patients showed a highly active demyelinating process. Examination of CSF samples detected pleocytosis, elevated total protein levels, and GFAPα IgG antibodies, which were not found in serum. In our case, we discovered autoimmune GFAP astrocytopathy associated with encephalitis as secondary autoimmunity, which was steroid responsive. Clinical outcome of other cases was marked by partial recovery in 4 patients and persistent foster care in 1 patient. CONCLUSIONS: Our case of GFAPα IgG-associated encephalitis along with 12 other cases of serious inflammatory brain disorders following daclizumab treatment so far indicates that interfering with NK cells and Tregs by anti-CD25 antibody therapy can result in severe secondary CNS autoimmunity in man.

Varicella zoster virus infections in neurological patients: a clinical study.

BACKGROUND: Varicella zoster virus (VZV) reactivation is a common infectious disease in neurology and VZV the second most frequent virus detected in encephalitis. This study investigated characteristics of clinical and laboratory features in patients with VZV infection. METHODS: Two hundred eighty two patients with VZV reactivation that were hospitalized in the department of neurology in the time from 2005 to 2013 were retrospectively evaluated. Results from cerebrospinal fluid (CSF) analysis were available from 85 patients. RESULTS: Trigeminal rash was the most common clinical manifestation, followed by segmental rash, CNS infection, facial nerve palsy, postherpetic neuralgia, and radiculitis. MRI of the brain performed in 25/33 patients with encephalitis/meningitis did not show any signs of infection in the brain parenchyma. Only one patient showed contrast enhancement in the hypoglossal nerve. General signs of infection such as fever or elevated CRP values were found in only half of the patients. Furthermore, rash was absent in a quarter of patients with CNS infection and facial nerve palsy, and thus, infection could only be proven by CSF analysis. Although slight inflammatory CSF changes occurred in few patients with isolated rash, the frequency was clearly higher in patients with CNS infection and facial nerve palsy. CONCLUSION: Monosegmental herpes zoster is often uncomplicated and a diagnostic lumbar puncture is not essential. In contrast, CSF analysis is an essential diagnostic tool in patients with skin lesions and cranial nerve or CNS affection. In patients with neuro-psychiatric symptoms and inflammatory CSF changes analysis for VZV should be performed even in the absence of skin lesions.

Cerebrospinal fluid abnormalities in meningeosis neoplastica: a retrospective 12-year analysis.

BACKGROUND: Meningeosis neoplastica is a diffuse metastatic spread of tumor cells in the subarachnoid space. Although first recognized in 1870, systematic investigations regarding cerebrospinal fluid (CSF) constituents in this condition are scarce. METHODS: Routine CSF samples analyzed from 2001 to 2012 at the Laboratory of Clinical Neurochemistry, University of Göttingen, were re-evaluated. Patients, whose CSF contained malignant cells were included in this study. RESULTS: Patients (n = 132, age 59.1 ± 29.1, 58% women) were identified, whose CSF contained malignant cells. The most frequent primary tumor was breast cancer (32.6%), followed by lung cancer (25.0%) and hematologic malignancies (21.2%). The most frequent clinical symptoms were affections of cranial nerves (41.7%), psychiatric abmormalities (32.6%) and radicular lesions of the lower extremities (20.5%). CSF cell counts ranged from 0 to 4692 cells/µl (median 4 cells/µl) and were elevated in 50%. The CSF-to-serum albumin ratio was abnormal in 69.4%. It ranged from 1.8 to 330 x 10-3 (median 17.5 x 10-3). Total CSF protein ranged from 166 to 15,840 mg/l (median 1012 mg/l). CSF lactate was elevated (>2.4 mmol/l) in 65.2% [3.6 mmol/l (1.3/15.6 mmol/l); median (minimum/maximum)]. In 50% of all patients CSF lactate was ≥3.5 mmol/l. The CSF cell counts correlated significantly with the CSF lactate levels and the CSF protein contents. In 56 of 118 CSF samples (47.5%) ferritin was elevated, and in 25 of 65 carcinoma patients (38.5%) an intrathecal production of carcinoembryonic antigen (CEA) was detected. Granulocytes were found in 52.7% of the CSF samples. The percentages of granulocytes and lymphocytes were higher in samples with an elevated cell count. CONCLUSION: In approximately 50% of CSF samples with meningeosis neoplastica the CSF cell count is not elevated. Diagnosis may be missed when only CSF samples with elevated cell counts are subjected to cytological analysis. CSF lactate and protein and the CSF-to-serum albumin ratio are frequently increased in meningeosis neoplastica. The differential diagnosis between meningeosis neoplastica and central nervous infections, in particular tuberculous or fungal meningitis, can be difficult.

Infections in the differential diagnosis of Bell's palsy: a plea for performing CSF analysis.

PURPOSE: Peripheral facial nerve palsy (FP) is the most common single nerve affection. Most cases are idiopathic, but a relevant fraction is caused by potentially treatable aetiologies including infections. Not all current diagnosis and treatment guidelines recommend routine cerebrospinal fluid (CSF) analysis in the diagnostic workup of this symptom. In this study, we evaluated frequency of aetiologies and relevance of CSF analysis in an interdisciplinary cohort. METHODS: We retrospectively analysed all cases of newly diagnosed FP treated at a German university medical centre in a 3-year period. Diagnostic certainty was classified for infectious aetiologies according to clinical and CSF parameters. RESULTS: 380 patients with FP were identified, 63 children and 317 adults. Idiopathic Bell´s palsy was predominant in 61 %. 25 % of FP was attributed to infections, and other causes were identified in 14 %. Clinical presentation alone was not conclusive for infectious aetiology, in almost half of patients with infection-attributed FP the reported symptoms or clinical signs did not differ from common symptoms of idiopathic Bell`s palsy. Determination of C-reactive protein or white blood cell count was not helpful in the identification of infectious causes, and radiological imaging was performed in a high proportion of adult patients without conclusive results. Nuchal rigidity was found only in 7 % of patients with CSF pleocytosis. The predominant infectious agents were Borrelia burgdorferi, VZV and HSV, and in most of these cases diagnosis relied on the findings of CSF analysis. CONCLUSIONS: This study outlines the importance of careful differential diagnosis to identify infectious causes of facial nerve palsy. The high incidence and frequent unspecific clinical presentation of infectious FP underlines the importance of including CSF analysis in the diagnostic routine workup of FP.

Importance of cerebrospinal fluid analysis in the era of McDonald 2010 criteria: a German-Austrian retrospective multicenter study in patients with a clinically isolated syndrome.

The majority of patients presenting with a first clinical symptom suggestive of multiple sclerosis (MS) do not fulfill the MRI criteria for dissemination in space and time according to the 2010 revision of the McDonald diagnostic criteria for MS and are thus classified as clinically isolated syndrome (CIS). To re-evaluate the utility of cerebrospinal fluid (CSF) analysis in the context of the revised McDonald criteria from 2010, we conducted a retrospective multicenter study aimed at determining the prevalence and predictive value of oligoclonal IgG bands (OCBs) in patients with CIS. Patients were recruited from ten specialized MS centers in Germany and Austria. We collected data from 406 patients; at disease onset, 44/406 (11 %) fulfilled the McDonald 2010 criteria for MS. Intrathecal IgG OCBs were detected in 310/362 (86 %) of CIS patients. Those patients were twice as likely to convert to MS according to McDonald 2010 criteria as OCB-negative individuals (hazard ratio = 2.1, p = 0.0014) and in a shorter time period of 25 months (95 % CI 21-34) compared to 47 months in OCB-negative individuals (95 % CI 36-85). In patients without brain lesions at first attack and presence of intrathecal OCBs (30/44), conversion rate to MS was 60 % (18/30), whereas it was only 21 % (3/14) in those without OCBs. Our data confirm that in patients with CIS the risk of conversion to MS substantially increases if OCBs are present at onset. CSF analysis definitely helps to evaluate the prognosis in patients who do not have MS according to the revised McDonald criteria.

Small cisterno-lumbar gradient of phosphorylated Tau protein in geriatric patients with suspected normal pressure hydrocephalus.

BACKGROUND: The composition of the cerebrospinal fluid (CSF) is not homogeneous, and concentrations of proteins from different origins diverge among ventricular, cisternal and lumbar CSF fractions. Concentrations of blood-derived proteins increase and of brain-derived proteins decrease from ventricular to lumbar fractions. We studied whether the origin of the CSF portion analysed may affect results in CSF analysis for dementia. METHODS: In 16 geriatric patients with suspected normal pressure hydrocephalus [age 82.5 (76/87) years; median (25th/75th percentile)] a lumbar spinal tap of 40 ml was performed. The CSF was sequentially collected in 8 fractions of 5 ml with the 1st fraction corresponding to lumbar CSF, the 8th to cisterna magna-near CSF. Fractions were analysed for total protein, albumin, Tau protein (Tau), phosphorylated Tau (pTau), Amyloid beta 1-42 (Aß1-42), Amyloid beta 1-40 (Aß1-40), and the Aß1-42/Aß1-40 ratio. RESULTS: The concentrations of total protein and albumin increased from cisternal to lumbar fractions due to diffusion-related accumulation from blood to CSF with significantly higher concentrations in fraction 1 compared to fraction 8. The concentrations of Tau showed a non-significant trend towards decreased values in lumbar samples, and pTau was slightly, but significantly decreased in the lumbar fraction 1 [26.5 (22.5/35.0) pg/ml] compared to the cistern-near fraction 8 [27.0 (24.2/36.3) pg/ml] (p = 0.02, Wilcoxon signed rank test). Aß1-42, Aß1-40, and the Aß1-42/Aß1-40 ratio remained almost constant. CONCLUSIONS: According to the flow-related diverging dynamics of blood-derived and brain-derived proteins in CSF, the concentrations of Tau and pTau tended to be lower in lumbar compared to cisternal CSF fractions after a spinal tap of 40 ml. The differences reached statistical significance for pTau only. The small differences will not affect clinical interpretation of markers of dementia in the vast majority of cases.

Bacterial meningitis: an update of new treatment options.

The outcome of bacterial meningitis critically depends on the rapid initiation of bactericidal antibiotic therapy and adequate management of septic shock. In community-acquired meningitis, the choice of an optimum initial empirical antibiotic regimen depends on the regional resistance patterns. Pathogens resistant to antibacterials prevail in nosocomial bacterial meningitis. Dexamethasone is recommended as adjunctive therapy for community-acquired meningitis in developed countries. In comatose patients, aggressive measures to lower intracranial pressure <20 mmHg (in particular, external ventriculostomy, osmotherapy and temporary hyperventilation) were effective in a case-control study. Although many experimental approaches were protective in animal models, none of them has been proven effective in patients. Antibiotics, which are bactericidal but do not lyse bacteria, and inhibitors of matrix metalloproteinases or complement factor C5 appear the most promising therapeutic options. At present, vaccination is the most efficient method to reduce disease burden. Palmitoylethanolamide appears promising to enhance the resistance of the brain to infections.

Teaching NeuroImages: Ma2 encephalitis presenting as acute panhypopituitarism in a young man.

A 21-year-old man presented with headache, hypotonia, hypothermia, and somnolence, deteriorating to a Glasgow Coma Scale score of 3 within days. Hormonal testing revealed panhypopituitarism. His cerebral MRI showed a gadolinium-enhancing lesion in the pituitary gland with adjacent changes to the hypothalamus, midbrain, and basal ganglia (figures 1 and 2). Therapy with prednisolone resulted in rapid improvement. Ma2 antibodies were found in the patient's serum and CSF. FDG-PET demonstrated a tumor mass in the superior mediastinum and histology revealed a mediastinal seminoma. Ma2 antibody-mediated paraneoplastic disease has to be considered as a rare differential diagnosis in patients presenting with acute panhypopituitarism.(1.)

Bacterial meningitis: new therapeutic approaches.

Bacterial meningitis remains a disease with high mortality and long-term morbidity. Outcome critically depends on the rapid initiation of effective antibiotic therapy. Since a further increase of the incidence of pathogens resistant to antibacterials can be expected both in community-acquired and nosocomial bacterial meningitis, the choice of an optimum initial empirical antibiotic regimen will gain significance. In this context, the use of antibiotics which are bactericidal but do not lyse bacteria, may emerge as a therapeutic option. Conversely, the role of corticosteroids, which decrease the entry of hydrophilic antibacterials into the cerebrospinal fluid, as adjunctive therapy will probably decline as a consequence of the increasing antibiotic resistance of bacteria causing meningitis. Consequent vaccination of all children at present is the most efficient manner to reduce disease burden.

α-Synuclein in human cerebrospinal fluid is principally derived from neurons of the central nervous system.

The source of Parkinson disease-linked α-synuclein (aSyn) in human cerebrospinal fluid (CSF) remains unknown. We decided to measure the concentration of aSyn and its gradient in human CSF specimens and compared it with serum to explore its origin. We correlated aSyn concentrations in CSF versus serum (Q(aSyn)) to the albumin quotient (Q(albumin)) to evaluate its relation to blood-CSF barrier function. We also compared aSyn with several other CSF constituents of either central or peripheral sources (or both) including albumin, neuron-specific enolase, ß-trace protein and total protein content. Finally, we examined whether aSyn is present within the structures of the choroid plexus (CP). We observed that Q(aSyn) did not rise or fall with Q(albumin) values, a relative measure of blood-CSF barrier integrity. In our CSF gradient analyses, aSyn levels decreased slightly from rostral to caudal fractions, in parallel to the recorded changes for neuron-specific enolase; the opposite trend was recorded for total protein, albumin and ß-trace protein. The latter showed higher concentrations in caudal CSF fractions due to the diffusion-mediated transfer of proteins from blood and leptomeninges into CSF in the lower regions of the spine. In postmortem sections of human brain, we detected highly variable aSyn reactivity within the epithelial cell layer of CP in patients diagnosed with a range of neurological diseases; however, in sections of mice that express only human SNCA alleles (and in those without any Snca gene expression), we detected no aSyn signal in the epithelial cells of the CP. We conclude from these complementary results that despite its higher levels in peripheral blood products, neurons of the brain and spinal cord represent the principal source of aSyn in human CSF.

Cerebrospinal fluid findings in adults with acute Lyme neuroborreliosis.

Presence of BB-specific antibodies in the cerebrospinal fluid (CSF) with evidence of their intrathecal production in conjunction with the white cell count in the CSF and typical clinical symptoms is the traditional diagnostic gold standard of Lyme neuroborreliosis (LNB). Few data are available on the CSF lactate concentration in European adults with the diagnosis of acute LNB. The objective of the study was to investigate the CSF changes during acute LNB. Routine CSF parameters [leukocyte count, protein, lactate and albumin concentrations, CSF/serum quotients of albumin (Q(Alb)), IgG, IgA and IgM, and oligoclonal IgG bands] and the Borrelia burgdorferi (BB)-specific antibody index were retrospectively studied in relation to the clinical presentation in patients diagnosed with acute LNB. A total of 118 patients with LNB were categorized into the following groups according to their symptoms at presentation; group 1: polyradiculoneuritis (Bannwarth's syndrome), group 2: isolated facial palsy and group 3: predominantly meningitic course of the disease. In addition to the CSF of patients with acute LNB, CSF of 19 patients with viral meningitis (VM) and 3 with neurolues (NL) were analyzed. There were 97 patients classified with definite LNB, and 21 as probable LNB. Neck stiffness and fever were reported by 15.3% of patients. Most of these patients were younger than 50 years. Polyradiculoneuritis was frequently found in patients older than 50 years. Lymphopleocytosis was found in all patients. Only 5 patients had a CSF lactate ≥3.5 mmol/l, and the mean CSF lactate level was not elevated (2.1 ± 0.6 mmol/l). The patients with definite LNB had significantly higher lactate levels than patients with probable LNB. Elevated lactate levels were accompanied by fever and headache. In the Reiber nomograms, intrathecal immunoglobulin synthesis was found for IgM in 70.2% followed by IgG in 19.5%. Isoelectric focussing detected an intrathecal IgG synthesis in 83 patients (70.3%). Elevated BB AIs in the CSF were found in 97 patients (82.2%). Patients with VM showed lower CSF protein concentration and CSF/serum quotients of albumin than LNB patients. In acute LNB, all patients had elevated cerebrospinal fluid (CSF) leukocyte counts. In contrast to infections by other bacteria, CSF lactate was lower than 3.5 mmol/l in all but 5 patients. The CSF findings did not differ between polyradiculoneuritis, facial palsy, and meningitis. The CSF in LNB patients strongly differed from CSF in VM patients with respect to protein concentration and the CSF/serum albumin quotient.

Bacterial contamination and the transport vial material affect cerebrospinal fluid concentrations of ß-Amyloid and Tau protein as determined by enzyme immunoassay.

BACKGROUND/AIMS: Determination of marker proteins of neuronal degeneration in cerebrospinal fluid (CSF) is of increasing importance. However, preanalytical problems may compromise the results. METHODS: We studied the influence of the transport tube material and shaking at room temperature on the CSF concentrations of ß-amyloid and tau protein determined by enzyme immunoassays. RESULTS: The materials of the transport tube moderately influenced the CSF concentrations of ß-amyloid and tau protein. Polyethylene and polypropylene tubes were well suited, but glass, polycarbonate and polystyrene tubes caused a decrease in the CSF ß-amyloid and tau protein concentrations. The strongest impact, however, was caused by bacterial contamination of samples. Contamination with high concentrations of Pseudomonas aeruginosa and related species rendered ß-amyloid undetectable and strongly diminished tau protein concentrations. The effects of several Gram-positive bacteria were less pronounced. Addition of 0.1% sodium azide prior to bacterial contamination increased the interval at which CSF could be kept at room temperature without a substantial reduction of the ß-amyloid or tau protein concentration. CONCLUSION: Polyethylene or polypropylene tubes are suitable transport vessels for CSF samples. Bacterial contamination during sampling and portioning must be avoided. Addition of sodium azide may be an option when transport of the sample is delayed.

The use of S100B and Tau protein concentrations in the cerebrospinal fluid for the differential diagnosis of bacterial meningitis: a retrospective analysis.

BACKGROUND: Patients with meningitis are often difficult to classify into bacterial (BM) or benign viral (VM) meningitis. To facilitate the differential diagnosis, S100B and Tau protein in the cerebrospinal fluid (CSF) were measured and compared with standard laboratory parameters. METHODS: S100B(CSF), Tau(CSF), and routine parameters (CSF leukocyte count, protein(CSF), lactate(CSF), serum C-reactive protein, blood leukocyte count and body temperature) were analyzed in 33 patients with microbiologically confirmed BM and in 19 with VM. Their classification accuracy, sensitivity and specificity were studied by receiver operating characteristic (ROC) curves. RESULTS: S100B(CSF) concentrations were higher in BM than in VM patients (p = 0.03) and showed a promising accuracy (90%) for the differential diagnosis of BM versus VM. Its discriminative properties were comparable to routine parameters. Of all parameters, S100B(CSF) showed the highest specificity (100%) with an optimal cut-off of 3.1 ng/ml. Tau(CSF) concentrations were useless for the discrimination (p = 0.64). CONCLUSIONS: In contrast to Tau(CSF), S100B(CSF) concentrations ≥3.1 ng/ml are promising to discriminate bacterial from viral meningitis.

Long-term intrathecal infusion of outer surface protein C from Borrelia burgdorferi causes axonal damage.

Lyme neuroborreliosis (LNB) is the most frequent tick-borne infectious disease of the central nervous system. In acute LNB and the rare chronic state of infection, patients can experience cognitive deficits such as attention and memory disturbances. During LNB, single compounds of Borrelia burgdorferi sensu lato are released into the subarachnoid space.To investigate the pathogenesis of neurologic dysfunction in LNB, we determined that the outer surface protein C (OspC), a major virulence factor of B. burgdorferi, stimulated mouse microglial cells in a dose-dependent manner to release nitric oxide (EC50 = 0.24 mg/L) in vitro. To mimic pathophysiologic conditions of long-term release of this bacterial component in vivo, we treated C57BL/6 mice with recombinant OspC from Borrelia garinii or buffer by intraventricular infusion and tested them for behavioral deficits. After 4weeks, brains were examined by routine histology and immunohistochemistry. Assessment of spatial learning and memory of treated mice during OspC exposure did not reveal significant differences from controls. Continuous exposure to intrathecal B. burgdorferi OspC led to activation of microglia and axonal damage without demonstrable cognitive impairment in experimental mice. These results suggest that long-term intrathecal exposure to OspC resulted in axonal damage that may underlie the neurologic manifestations in chronic LNB.

Toll-like receptor stimulation enhances phagocytosis and intracellular killing of nonencapsulated and encapsulated Streptococcus pneumoniae by murine microglia.

Toll-like receptors (TLRs) are crucial pattern recognition receptors in innate immunity that are expressed in microglia, the resident macrophages of the brain. TLR2, -4, and -9 are important in the responses against Streptococcus pneumoniae, the most common agent causing bacterial meningitis beyond the neonatal period. Murine microglial cultures were stimulated with agonists for TLR1/2 (Pam(3)CSK(4)), TLR4 (lipopolysaccharide), and TLR9 (CpG oligodeoxynucleotide) for 24 h and then exposed to either the encapsulated D39 (serotype 2) or the nonencapsulated R6 strain of S. pneumoniae. After stimulation, the levels of interleukin-6 and CCL5 (RANTES [regulated upon activation normal T-cell expressed and secreted]) were increased, confirming microglial activation. The TLR1/2, -4, and -9 agonist-stimulated microglia ingested significantly more bacteria than unstimulated cells (P < 0.05). The presence of cytochalasin D, an inhibitor of actin polymerizaton, blocked >90% of phagocytosis. Along with an increased phagocytic activity, the intracellular bacterial killing was also increased in TLR-stimulated cells compared to unstimulated cells. Together, our data suggest that microglial stimulation by these TLRs may increase the resistance of the brain against pneumococcal infections.

Short-term rifampicin pretreatment reduces inflammation and neuronal cell death in a rabbit model of bacterial meningitis.

OBJECTIVE: In bacterial meningitis, severe systemic and local inflammation causes long-term impairment and death of affected patients. The current antibiotic therapy relies on cell wall-active beta-lactam antibiotics, which rapidly sterilize the cerebrospinal fluid (CSF). However, beta-lactams inhibit cell wall synthesis, induce bacteriolysis, and thereby evoke a sudden release of high amounts of toxic and proinflammatory bacterial products. Because tissue damage in bacterial meningitis is the result of bacterial toxins and the inflammatory host response, any reduction of free bacterial compounds promises to prevent neuronal damage. DESIGN: In vitro experiments and randomized prospective animal study. SETTING: University research laboratories. SUBJECTS: Streptococcus pneumoniae broth cultures and New Zealand White rabbits. INTERVENTIONS: We evaluated a concept to improve bacterial meningitis therapy in which a short-term pretreatment with the protein synthesis-inhibiting antibiotic rifampicin precedes the standard antibiotic therapy with ceftriaxone. First, logarithmically growing pneumococcal cultures were subdivided and exposed to different antibiotics. Then, rabbits suffering from pneumococcal meningitis were randomized to receive rifampicin pretreatment or ceftriaxone alone. MEASUREMENTS AND MAIN RESULTS: In pneumococcal cultures, quantitative immunoblotting and real-time polymerase chain reaction revealed a reduced release of pneumolysin and bacterial DNA by rifampicin pretreatment for 30 minutes in comparison with ceftriaxone treatment alone. In vivo, a 1-hour rifampicin pretreatment reduced the release of bacterial products and attenuated the inflammatory host response, as demonstrated by decreased CSF levels of prostaglandin E2 and total protein and increased glucose CSF/plasma ratios. Rifampicin pretreatment reduced infection-associated neuronal apoptotic cell loss compared with ceftriaxone-treated controls. CONCLUSIONS: A short-term pretreatment with rifampicin reduced the beta-lactam-induced release of deleterious bacterial products, attenuated inflammation, and thereby decreased neuronal cell loss in experimental bacterial meningitis. This concept has the potential to reduce inflammation-associated neuronal injury in bacterial meningitis and should be evaluated in a clinical trial.