Continuous evaluation of single-dose moxifloxacin concentrations in brain extracellular fluid, cerebrospinal fluid, and plasma: a novel porcine model.

BACKGROUND: Knowledge regarding CNS pharmacokinetics of moxifloxacin is limited, with unknown consequences for patients with meningitis caused by bacteria resistant to beta-lactams or caused by TB. OBJECTIVE: (i) To develop a novel porcine model for continuous investigation of moxifloxacin concentrations within brain extracellular fluid (ECF), CSF and plasma using microdialysis, and (ii) to compare these findings to the pharmacokinetic/pharmacodynamic (PK/PD) target against TB. METHODS: Six female pigs received an intravenous single dose of moxifloxacin (6 mg/kg) similar to the current oral treatment against TB. Subsequently, moxifloxacin concentrations were determined by microdialysis within five compartments: brain ECF (cortical and subcortical) and CSF (ventricular, cisternal and lumbar) for the following 8 hours. Data were compared to simultaneously obtained plasma samples. Chemical analysis was performed by high pressure liquid chromatography with mass spectrometry. The applied PK/PD target was defined as a maximum drug concentration (Cmax):MIC ratio >8. RESULTS: We present a novel porcine model for continuous in vivo CNS pharmacokinetics for moxifloxacin. Cmax and AUC0-8h within brain ECF were significantly lower compared to plasma and lumbar CSF, but insignificantly different compared to ventricular and cisternal CSF. Unbound Cmax:MIC ratio across all investigated compartments ranged from 1.9 to 4.3. CONCLUSION: A single dose of weight-adjusted moxifloxacin administered intravenously did not achieve adequate target site concentrations within the uninflamed porcine brain ECF and CSF to reach the applied TB CNS target.

Oligodeoxynucleotides containing unmethylated cytosine-guanine motifs are effective immunostimulants against pneumococcal meningitis in the immunocompetent and neutropenic host.

BACKGROUND: Bacterial meningitis is a fatal disease with a mortality up to 30% and neurological sequelae in one fourth of survivors. Available vaccines do not fully protect against this lethal disease. Here, we report the protective effect of synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG ODN) against the most frequent form of bacterial meningitis caused by Streptococcus pneumoniae. METHODS: Three days prior to the induction of meningitis by intracerebral injection of S. pneumoniae D39, wild-type and Toll-like receptor (TLR9)-/- mice received an intraperitoneal injection of 100 µg CpG ODN or vehicle. To render mice neutropenic, anti-Ly-6G monoclonal antibody was daily administrated starting 4 days before infection with a total of 7 injections. Kaplan-Meier survival analyses and bacteriological studies, in which mice were sacrificed 24 h and 36 h after infection, were performed. RESULTS: Pre-treatment with 100 µg CpG ODN prolonged survival of immunocompetent and neutropenic wild-type mice but not of TLR9-/- mice. There was a trend towards lower mortality in CpG ODN-treated immunocompetent and neutropenic wild-type mice. CpG ODN caused an increase of IL-12/IL-23p40 levels in the spleen and serum in uninfected animals. The effects of CpG ODN on bacterial concentrations and development of clinical symptoms were associated with an increased number of microglia in the CNS during the early phase of infection. Elevated concentrations of IL-12/IL-23p40 and MIP-1α correlated with lower bacterial concentrations in the blood and spleen during infection. CONCLUSIONS: Pre-conditioning with CpG ODN strengthened the resistance of neutropenic and immunocompetent mice against S. pneumoniae meningitis in the presence of TLR9. Administration of CpG ODN decreased bacterial burden in the cerebellum and reduced the degree of bacteremia. Systemic administration of CpG ODN may help to prevent or slow the progression to sepsis of bacterial CNS infections in healthy and immunocompromised individuals even after direct inoculation of bacteria into the intracranial compartments, which can occur after sinusitis, mastoiditis, open head trauma, and surgery, including placement of an external ventricular drain.

[COVID-19 in old age-The geriatric perspective]. / COVID-19 im Alter ­ Die geriatrische Perspektive.

Predominantly the older population is affected by a severe course of COVID-19. The mortality of hospitalized patients with COVID-19 above the age of 80 years is up to 54% in international studies. These observations indicate the necessity to highlight the geriatric perspective on this disease. The diagnostics and treatment of COVID-19 do not differ between younger and older patients but atypical symptoms should be expected more frequently in old age. Older subjects show an increased need for rehabilitation after COVID-19. Paradoxically, increasing rehabilitation demands go along with a reduced availability of geriatric rehabilitation options, the latter being a consequence of closure or downsizing of rehabilitation departments during the pandemic. In general, measures of isolation and quarantine should be diligently balanced as the health and emotional consequences of such measures may be severe in older persons. In light of the poor prognosis of older COVID-19 patients, advanced care planning becomes even more relevant. Caregivers and physicians should be encouraged to compose advanced care directives that also reflect the specific circumstances of COVID-19. Fortunately, current data suggest that the effectiveness of the vaccination with the mRNA-vaccines approved in Germany may be equally high in older compared to younger persons.

[The use of benzodiazepines and Z-drugs for patients with sleeping problems - A survey among hospital doctors and nurses]. / Benzodiazepine und Z-Substanzen als Schlaf- und Beruhigungsmittel in einem Krankenhaus.

Aim | Benzodiazepines and Z-drugs are frequently prescribed sleep medications in spite of their poor risk-benefit ratio when used over a longer period of time. The aim of the study was to find out how the medical and nursing staff in a general hospital estimated the frequency of use for these drugs, and the risk-benefit ratio for elderly patients as well as the factors which positively influence the perceived use of these drugs. Methods | All members of the medical and nursing staff of a hospital received a questionnaire about their use of, and attitudes towards, benzodiazepines and Z-drugs. Absolute and relative frequencies were calculated to estimate the perceived frequency of use and the risk-benefit ratio. Multiple logistic regressions were used to analyze which factors are associated with a perceived high use of benzodiazepines or Z-drugs for insomnia. Results | More nurses than hospital doctors believed that they dispensed benzodiazepines often or always (57 % vs. 29 %) to patients with insomnia; this was also the case for Z-drugs (66 % vs. 29 %). Nearly half of the hospital doctors and 29 % of the nurses perceived more harms than benefits for benzodiazepines in the elderly. The following factors were associated with a high perceived usage of Z-drugs: working as a nurse (OR: 13,95; 95%-CI: 3,87-50,28), working in a non-surgical department (5,41; 2,00-14,61), having < 5 years of professional experience (4,90; 1,43-16,81) and feeling that the benefits of Z-drugs outweigh the risks for elderly patients (5,07; 1,48-17,35). For benzodiazepines, only the perceived positive risk-benefit ratio had an influence on the perceived use (3,35; 1,28-8.79). Conclusion | The medical and nursing staff perceived the frequency of prescription of benzodiazepines and Z-drugs and the risk-benefit ratio in different ways. Other aspects, such as working in a non-surgical department or having a smaller amount of working experience may also influence the decision to use Z-drugs.

HIV encephalopathy: glial activation and hippocampal neuronal apoptosis, but limited neural repair.

OBJECTIVES: HIV infection affects the central nervous system (CNS), frequently causing cognitive impairment. Hippocampal injury impedes the ability to transfer information into memory. Therefore, we aimed to examine neuronal injury and repair in the hippocampal formation in HIV encephalopathy. METHODS: We compared neuropathological findings in 14 autopsy cases after death from systemic complications of HIV infection and in 15 age-matched HIV-negative control cases after sudden death from nonneurological causes using immunohistochemistry. RESULTS: The density of apoptotic granule cells in the dentate gyrus was higher in HIV-infected than in control cases (P = 0.048). Proliferation of neural progenitor cells in the dentate gyrus was increased in HIV infection (P = 0.028), whereas the density of recently generated TUC-4 [TOAD (turned on after division)/Ulip/CRMP family 4]-expressing neurons in this region was not significantly elevated in HIV-infected cases (P = 0.13). HIV infection caused microglial activation and astrocytosis in the neocortex and hippocampal formation. Conversely, we were unable to detect more pronounced axonal injury in HIV-infected than in control cases. CONCLUSIONS: As in other infections involving the CNS, apoptosis of hippocampal neurons accompanied by microglial activation and astrocytosis is a prominent feature of HIV encephalopathy. The regenerative potential, assessed using the density of young neurons in the hippocampal dentate gyrus, in HIV infection appears to be lower than in acute bacterial meningitis and septic encephalitis.

[Insufficient use of anticoagulants in geriatric in-patients with atrial fibrillation and flutter (corrected)]. / Hospitalisierte geriatrische Patienten mit Vorhofflimmern sind nicht ausreichend mit Antikoagulanzien behandelt.

INTRODUCTION: Anticoagulation for the prevention of cardioembolic events is highly effective, but largely underused in frail older patients with atrial fibrillation or flutter (AF). This study aimed at identifying characteristics associated with anticoagulation use or non-use and the most frequent complications of this therapy. METHODS: Hospitalized geriatric patients treated in a one-year interval were retrospectively studied for the presence of AF and use or non-use of anticoagulation. The risk of stroke and the indication for permanent anticoagulation were assessed using the CHA2DS2-VASc score. RESULTS: In 451 of 1167 hospitalized patients (38.6%) there was a clear indication for anticoagulation. The most frequent indication for anticoagulation was AF in 381 patients (84.5% of 451 patients). Of these 381 patients, a strong indication for anticoagulation, based on CHA2DS2-VASc score, was identified in 379 patients. Of these patients, 200 (52.8%) did and 179 (47.2%) patients did not receive anticoagulation. 153 patients (40.4%) received antiplatelet therapy. 26 patients (6.7%) received neither anticoagulants nor antiplatelet therapy. The most common reason for non-implementation of anticoagulation was a high risk of falls in 93 patients (52%) of 179 patients without antocoagulation. The most frequent complications of anticoagulation were small hemorrhages without serious consequences in 8 cases. 4 patients suffered from serious bleedings. CONCLUSION: Almost half of our geriatric population did not receive anticoagulation despite a clear indication. Antiplatelet therapy use was associated with anticoagulation non-use.

[Cerebrospinal fluid diagnostics for neuroinfectious diseases]. / Liquordiagnostik bei erregerbedingten neurologischen Erkrankungen.

Cerebrospinal fluid analysis is of prime importance to establish an early diagnosis of central nervous system infections. Beside the basic diagnostics containing CSF white cell count, lactate concentration and protein analysis, the targeted search for agents of bacterial, viral or fungal CNS infectious diseases is essential. Decisive methods are bacterial and fungal staining techniques, microbiological culture methods, nucleic acid amplification and antigen detection methods or indirect identification of pathogens by serologic testings including the determination of pathogen-specific intrathecal immunoglobulin synthesis. Besides imparting basic principles of cerebrospinal fluid analysis, this article focuses on special aspects of detection of infectious agents. Well-directed questions and a close communication between clinician and laboratory allow optimal diagnostic analysis for successful confirmation of the diagnosis and for optimal treatment of the patient.

[The ageing immune system]. / Das alternde Immunsystem.

The aging of the immune system, also called immunosenescence, contributes to the increased morbidity and mortality from infections, autoimmune diseases and cancer as well as to the low efficacy of vaccination in elderly persons. Immunosenescence is characterized by a decrease in cell-mediated immune function and by reduced humoral immune responses caused by age-related changes in the innate immune system and age-dependent defects in T-and B-cell function. This paper gives an overview of the most important modifications in the different compartments of the immune system during the ageing process.

Geriatric chest imaging: when and how to image the elderly lung, age-related changes, and common pathologies.

Even in a global perspective, societies are getting older. We think that diagnostic lung imaging of older patients requires special knowledge. Imaging strategies have to be adjusted to the needs of frail patients, for example, immobility, impossibility for long breath holds, renal insufficiency, or poor peripheral venous access. Beside conventional radiography, modern multislice computed tomography is the method of choice in lung imaging. It is especially important to separate the process of ageing from the disease itself. Pathologies with a special relevance for the elderly patient are discussed in detail: pneumonia, aspiration pneumonia, congestive heart failure, chronic obstructive pulmonary disease, the problem of overlapping heart failure and chronic obstructive pulmonary disease, pulmonary drug toxicity, incidental pulmonary embolism pulmonary nodules, and thoracic trauma.

[X-linked recessive ichthyosis (XRI), cerebellar ataxia and neuropsychiatric symptoms]. / X-chromosomal-rezessive Ichthyose (XRI) mit zerebellärer Ataxie, Angsterkrankung und Depression.

X-Linked ichthyosis (XRI) is a keratinisation disorder caused by a mutation of the steroid sulfatase gene. An association with mental retardation and epilepsy has been reported earlier. Here, we report on a patient suffering from cerebellar symptoms such as yes/yes head tremor, scanning dysarthria, pronounced dysmetria and intention tremor, without any abnormalities of the cerebellum in MRI, in addition to XRI proven by molecular genetics. Furthermore, the patient suffered from anxiety disorder, depression, and a male pattern baldness. One of the patient' s brothers and a nephew showed a similar clinical presentation. Because of the fact that several members of the patient's family suffered from similar symptoms, we consider a syndromic link between XRI and cerebellar disorder to be possible.

Cerebrospinal fluid findings in geriatric patients from 2008 to 2011.

BACKGROUND: The chemical composition of the cerebrospinal fluid (CSF) is age-dependent. METHODS: Routine CSF parameters, the indications for lumbar puncture (LP), and the most frequent complications were retrospectively studied in patients older (n = 167) and younger (n = 36) than 65 years. RESULTS: In the absence of meningeal inflammation, the mean CSF lactate level of patients older than 65 years was slightly but significantly higher than the mean CSF lactate level of younger patients. The lactate level of patients with otherwise normal CSF findings correlated significantly with the age of the patients. In the absence of meningeal inflammation, the CSF-to-serum albumin ratio (QAlbumin) was significantly higher in older patients than in younger ones. The most frequent indication for LP, suspected infection of the central nervous system (CNS) (n = 110), was confirmed in 12.7% of patients. The only LP complication documented was headache in two patients. CONCLUSIONS: Elevations of QAlbumin and CSF lactate levels appear to be nonspecific findings in elderly patients. Suspected infections, the most frequent indication for LP, were confirmed by CSF analysis in more than 10% of patients. The very low complication rate of LP makes it a very valuable tool in the diagnostic routine for older patients with CNS diseases.

Distributed, limbic gray matter atrophy in patients after bacterial meningitis.

BACKGROUND AND PURPOSE: The structural basis of cognitive sequelae after bacterial meningitis in humans is still poorly understood. In animal models and human autopsy cases, neuronal apoptosis of the hippocampal formation in particular seems to play an important role. Here, we aimed to analyze if BM entails MR imaging structural consequences in humans in vivo. MATERIALS AND METHODS: We applied voxel-based morphometry in a cohort of BM survivors with normal conventional MR imaging after resolution of the acute inflammation to assess morphologic differences. RESULTS: We found clear gray matter volume loss in the limbic system including the hippocampal formation, thalamus, and cingulate gyri bilaterally as well as in the temporal lobe. These results were corroborated by an alternative atlas-based method. CONCLUSIONS: Even in patients with normal routine MR imaging results, clear-cut gray matter atrophy with a mesial temporal/limbic pattern was evident. The anatomic distribution is compatible with the neuropsychological deficit commonly observed in patients after BM. The similarity of the observed atrophy may point to causal link between BM and mesial temporal epilepsy.

Candida esophagitis as the cause of swallowing disturbances in an 85-year-old patient with myasthenia gravis.

An 85-year-old man with myasthenia gravis was successfully treated with methotrexate (10 mg/week), pyridostigmine and prednisolone (0-30 mg/day) for over 10 years. Then, he developed dysphagia and lost weight. Gastroscopy revealed Candida esophagitis. The patient received nystatin for 2 weeks. Methotrexate was stopped, and immunosuppressive therapy was continued with prednisolone alone. The patient has now remained in good condition for over 1 year. Although dysphagia is a typical symptom of myasthenia gravis, swallowing disturbances should not be attributed hastily to this disease, since they may also be a complication of therapy.

Septic metastatic encephalitis: coexistence of brain damage and repair.

AIMS: Septic metastatic encephalitis (SME) arises from systemic bacterial infections and is a severe complication of sepsis with a high mortality. In this study, we examined the neuropathological findings in humans suffering from SME including white matter pathology and proliferation of neural precursor cells in the hippocampal dentate gyrus. METHODS: The brains of 10 autopsy cases with SME and 10 control cases after sudden death from non-neurological causes were studied by means of immunohistochemistry. RESULTS: We found diffuse axonal injury and demyelination in the frontal cortex (P = 0.01) as well as increased numbers of recently generated TUC-4 expressing neurones in the hippocampal dentate gyrus in SME cases (P = 0.01). The median density of apoptotic granule cells in the dentate gyrus also was higher in SME cases, the difference, however, failed to reach statistical significance (P = 0.25). CONCLUSION: The coexistence of degenerative processes predominantly in the neocortex and regenerative activity in the hippocampal formation known from bacterial meningitis also characterizes the pathology of SME.

The diagnostic spectrum in patients with suspected chronic Lyme neuroborreliosis--the experience from one year of a university hospital's Lyme neuroborreliosis outpatients clinic.

BACKGROUND AND PURPOSE: Studies addressing the diagnostic relevance of anti-Borrelia burgdorferi (BB) serum antibodies in patients with non-specific symptoms and suspected chronic Lyme neuroborreliosis (LNB) are scarce. METHODS: In this study, we enrolled within 1 year 122 patients with suspected chronic LNB. One hundred and fourteen patients had previously tested positive for BB. All patients had previously received antibiotic treatment. Each patient received a clinical examination and measurement of BB-specific antibodies. The diagnosis of neuroborreliosis was made according to the national guidelines of the German Society of Neurology. Nine patients had acute borreliosis. One of the nine met the criteria of acute LNB. Of the remaining 113 patients, 85 patients underwent a lumbar puncture. Ten seronegative subjects without lumbar puncture were also considered. In 61.8% of these 95 patients the quality of life, of sleep, mood, and anxiety were assessed. RESULTS: Of 95 patients, 25.3% had symptoms without a somatic cause or evidence of borreliosis, 38.9% had a well-defined illness unrelated to BB infection, and 29.5% suffered from symptoms without a detectable somatic cause, displaying antibodies against BB. Six patients were grouped as post-LNB syndrome. Most common symptoms in all categories were arthralgia, myalgia, dysaesthesia, depressive mood and chronic fatigue. CONCLUSION: Patients with persistent symptoms with elevated serum antibodies against BB but without signs of cerebrospinal fluid inflammation require further diagnostic examinations to exclude ongoing infection and to avoid co-infections and other treatable conditions (e.g. autoimmune diseases). One patient with acute LNB, who was treated with ceftriaxone for 3 weeks suffered from LNB with new headaches and persistent symptoms 6 months later. These data should encourage further studies with new experimental parameters.

S100B in the cerebrospinal fluid--a marker for glial damage in the rabbit model of pneumococcal meningitis.

The rabbit model provides an important experimental setting for the evaluation of antibiotic agents against pneumococcal meningitis. One of the primary targets of this model is the study of neuronal and glial cell damage in bacterial meningitis. The aim of this investigation was to evaluate whether a significant increase of S100B in the cerebrospinal fluid (CSF) as an indicator of white matter damage could be observed in this meningitis model. Seven rabbits were infected intracisternally with S. pneumoniae, and CSF S100B concentrations were examined serially before infection, at 12h, 14h, 17h, 20h, and at 24h after infection. The course of CSF S100B increase and its relation to other parameters of brain tissue destruction and CSF inflammation were measured. Axonal damage was visualized by amyloid precursor protein (APP) immunostaining and demyelination by Luxol Fast Blue/Periodic Acid Schiff (LFB-PAS) stain. In each animal, we observed a distinct rise in S100B concentration in the CSF due to pneumococcal meningitis. We conclude that the CSF concentration of the glial S100B protein can be used as an additional parameter for future interventional studies focusing on glial cell damage in the rabbit model of bacterial meningitis.

Increased neuronal proliferation in human bacterial meningitis.

OBJECTIVE: Neurogenesis is increased in experimental models of bacterial meningitis. In this study, neurogenesis was examined after bacterial infection of the CNS, and after stroke and brain trauma in humans. METHODS: Brain sections of patients after death from bacterial meningitis, stroke, or brain trauma and from autopsy cases after death from nonneurologic diseases were investigated by immunohistochemistry. RESULTS: In the dentate gyrus, the density of proliferating cellular nuclear antigen-expressing cells was higher after bacterial meningitis compared to the control group (p = 0.0075). Furthermore, the number of cells expressing the immature neuronal marker proteins TUC-4 and doublecortin were increased in brain sections of patients after death from meningitis compared to control cases (p = 0.0067 and p = 0.045). After stroke and brain trauma, higher densities of proliferating cells were observed (p = 0.031 and p = 0.018), while an increase of TUC-4-expressing cells was detected after stroke only (p = 0.0012 and p = 0.47). CONCLUSIONS: The increased proliferation of neural progenitors suggests an endogenous mechanism in response to noxious stimuli. Stimulation of neurogenesis might help to alleviate the consequences of neuronal destruction in bacterial meningitis and other diseases of the brain.

Evidence for frequent focal and diffuse acute axonal injury in human bacterial meningitis.

AIMS: We aimed at quantifying acute axonal injury in victims of bacterial meningitis. METHODS: The brains of 26 autopsies with bacterial meningitis and of 10 control cases were studied by histology and quantitative immunohistochemistry for amyloid-beta precursor protein (APP). RESULTS: Mild to severe axonal injury in the white matter was present in 25 of 26 victims of meningitis. The area of axonal damage ranged from 0.0% to 1.38% (median = 0.08%, mean = 0.36%) of the total area studied in each individual case. In 4 of 10 age- and sex-matched control brains small areas also stained for APP (p = 0.0007). Axonal injury in meningitis was most prominent in the basal ganglia and pons, followed by the hippocampal formation, neocortex and the cervical spinal cord. The cerebellum was least affected. CONCLUSION: Axonal injury is a frequent complication of bacterial meningitis probably contributing to long-term sequelae in survivors.