Cerebral and pulmonary aspergillosis, treatment and diagnostic challenges of mixed breakthrough invasive fungal infections: case report study.

BACKGROUND: Breakthrough invasive fungal infections (bIFIs) are an area of concern in the scarcity of new antifungals. The mixed form of bIFIs is a rare phenomenon but could be potentially a troublesome challenge when caused by azole-resistant strains or non-Aspergillus fumigatus. To raise awareness and emphasize diagnostic challenges, we present a case of mixed bIFIs in a child with acute lymphoblastic leukemia. CASE PRESENTATION: A newly diagnosed 18-month-old boy with acute lymphoblastic leukemia was complicated with prolonged severe neutropenia after induction chemotherapy. He experienced repeated episodes of fever due to extended-spectrum beta-lactamase-producing Escherichia coli bloodstream infection and pulmonary invasive fungal infection with Aspergillus fumigatus (early-type bIFIs) while receiving antifungal prophylaxis. Shortly after pulmonary involvement, his condition aggravated by abnormal focal movement, loss of consciousness and seizure. Cerebral aspergillosis with Aspergillus niger diagnosed after brain tissue biopsy. The patient finally died despite 108-day antifungal therapy. CONCLUSIONS: Mixed bIFIs is a rare condition with high morbidity and mortality in the patients receiving immunosuppressants for hematological malignancies. This case highlights the clinical importance of Aspergillus identification at the species level in invasive fungal infections with multiple site involvement in the patients on antifungal prophylaxis.

Evidence that thiol group modification and reactive oxygen species are involved in hydrogen sulfide-induced mitochondrial permeability transition pore opening in rat cerebellum.

We report here the effects of hydrogen sulfide (sulfide), that accumulates in ETHE1 deficiency, in rat cerebellum. Sulfide impaired electron transfer and oxidative phosphorylation. Sulfide also induced mitochondrial swelling, and decreased ΔΨm and calcium retention capacity in cerebellum mitochondria, which were prevented by cyclosporine A (CsA) plus ADP, and ruthenium red, suggesting mitochondrial permeability transition (mPT) induction. Melatonin (MEL) and N-ethylmaleimide also prevented sulfide-induced alterations. Prevention of sulfide-induced decrease of ΔΨm and viability by CsA and MEL was further verified in cerebellum neurons. The data suggest that sulfide induces mPT pore opening via thiol modification and ROS generation.

Sex- and region-specific differences in microglia phenotype and characterization of the peripheral immune response following early-life infection in neonatal male and female rats.

Early-life infection has been shown to have profound effects on the brain and behavior across the lifespan, a phenomenon termed "early-life programming". Indeed, many neuropsychiatric disorders begin or have their origins early in life and have been linked to early-life immune activation (e.g. autism, ADHD, and schizophrenia). Furthermore, many of these disorders show a robust sex bias, with males having a higher risk of developing early-onset neurodevelopmental disorders. The concept of early-life programming is now well established, however, it is still unclear how such effects are initiated and then maintained across time to produce such a phenomenon. To begin to address this question, we examined changes in microglia, the immune cells of the brain, and peripheral immune cells in the hours immediately following early-life infection in male and female rats. We found that males showed a significant decrease in BDNF expression and females showed a significant increase in IL-6 expression in the cerebellum following E.coli infection on postnatal day 4; however, for most cytokines examined in the brain and in the periphery we were unable to identify any sex differences in the immune response, at least at the time points examined. Instead, neonatal infection with E.coli increased the expression of a number of cytokines in the brain of both males and females similarly including TNF-α, IL-1ß, and CD11b (a marker of microglia activation) in the hippocampus and, in the spleen, TNF-α and IL-1ß. We also found that protein levels of GRO-KC, MIP-1a, MCP1, IP-10, TNF-α, and IL-10 were elevated 8-hours postinfection, but this response was resolved by 24-hours. Lastly, we found that males have more thin microglia than females on P5, however, neonatal infection had no effect on any of the microglia morphologies we examined. These data show that sex differences in the acute immune response to neonatal infection are likely gene, region, and even time dependent. Future research should consider these factors in order to develop a comprehensive understanding of the immune response in males and females as these changes are likely the initiating agents that lead to the long-term, and often sex-specific, effects of early-life infection.

Prophylactic Palmitoylethanolamide Prolongs Survival and Decreases Detrimental Inflammation in Aged Mice With Bacterial Meningitis.

Easy-to-achieve interventions to promote healthy longevity are desired to diminish the incidence and severity of infections, as well as associated disability upon recovery. The dietary supplement palmitoylethanolamide (PEA) exerts anti-inflammatory and neuroprotective properties. Here, we investigated the effect of prophylactic PEA on the early immune response, clinical course, and survival of old mice after intracerebral E. coli K1 infection. Nineteen-month-old wild type mice were treated intraperitoneally with two doses of either 0.1 mg PEA/kg in 250 µl vehicle solution (n = 19) or with 250 µl vehicle solution only as controls (n = 19), 12 h and 30 min prior to intracerebral E. coli K1 infection. The intraperitoneal route was chosen to reduce distress in mice and to ensure exact dosing. Survival time, bacterial loads in cerebellum, blood, spleen, liver, and microglia counts and activation scores in the brain were evaluated. We measured the levels of IL-1ß, IL-6, MIP-1α, and CXCL1 in cerebellum and spleen, as well as of bioactive lipids in serum in PEA- and vehicle-treated animals 24 h after infection. In the absence of antibiotic therapy, the median survival time of PEA-pre-treated infected mice was prolonged by 18 h compared to mice of the vehicle-pre-treated infected group (P = 0.031). PEA prophylaxis delayed the onset of clinical symptoms (P = 0.037). This protective effect was associated with lower bacterial loads in the spleen, liver, and blood compared to those of vehicle-injected animals (P ≤ 0.037). PEA-pre-treated animals showed diminished levels of pro-inflammatory cytokines and chemokines in spleen 24 h after infection, as well as reduced serum concentrations of arachidonic acid and of one of its metabolites, 20-hydroxyeicosatetraenoic acid. In the brain, prophylactic PEA tended to reduce bacterial titers and attenuated microglial activation in aged infected animals (P = 0.042). Our findings suggest that prophylactic PEA can counteract infection associated detrimental responses in old animals. Accordingly, PEA treatment slowed the onset of infection symptoms and prolonged the survival of old infected mice. In a clinical setting, prophylactic administration of PEA might extend the potential therapeutic window where antibiotic therapy can be initiated to rescue elderly patients.

Meningococcal meningitis with neurological complications and meningococcemia due to serogroup W sequence type 11 complex.

Invasive meningococcal disease (IMD) caused by the serogroup W (MenW) sequence type-11 complex strain has recently emerged worldwide. Meningococcal infections due to this strain are associated with high case fatality and often atypical clinical manifestations. However, the annual IMD incidence was low, and MenW is rare in Japan. We described the first Japanese case of meningococcal meningitis and meningococcemia caused by this strain in a previously healthy 27-year-old woman. This case showed various neurological complications such as abducens palsy, cerebellitis, and cerebellar infarction, and reactive arthritis. This case provides useful information on the possibility of spreading IMD strains and the cause of various complications.

Mycobacterium bovis Cerebellar Abscess Following Treatment With Bacillus Calmette-Guérin.

Bacillus Calmette-Guérin (BCG) is a live, attenuated strain of Mycobacterium bovis that is used to treat superficial bladder cancer. Although its use is typically associated with only mild, localized side effects, rare systemic complications can occur. Disseminated mycobacterium infections after BCG therapy have been reported in over 30 cases; however, central nervous system (CNS) infections do not commonly occur. We report a 74-year-old male who developed a M. bovis cerebellar abscess after receiving intravesical BCG infusion for bladder cancer for less than 1 year. This patient was successfully treated with antituberculosis therapy and corticosteroids. This patient case demonstrates that early-onset M bovis CNS infections can occur after BCG therapy. Patients presenting with altered mental status while on BCG therapy should be evaluated for disseminated infections.

Epsilon toxin from Clostridium perfringens acts on oligodendrocytes without forming pores, and causes demyelination.

Epsilon toxin (ET) is produced by Clostridium perfringens types B and D and causes severe neurological disorders in animals. ET has been observed binding to white matter, suggesting that it may target oligodendrocytes. In primary cultures containing oligodendrocytes and astrocytes, we found that ET (10(-9) M and 10(-7) M) binds to oligodendrocytes, but not to astrocytes. ET induces an increase in extracellular glutamate, and produces oscillations of intracellular Ca(2+) concentration in oligodendrocytes. These effects occurred without any change in the transmembrane resistance of oligodendrocytes, underlining that ET acts through a pore-independent mechanism. Pharmacological investigations revealed that the Ca(2+) oscillations are caused by the ET-induced rise in extracellular glutamate concentration. Indeed, the blockade of metabotropic glutamate receptors type 1 (mGluR1) prevented ET-induced Ca(2+) signals. Activation of the N-methyl-D-aspartate receptor (NMDA-R) is also involved, but to a lesser extent. Oligodendrocytes are responsible for myelinating neuronal axons. Using organotypic cultures of cerebellar slices, we found that ET induced the demyelination of Purkinje cell axons within 24 h. As this effect was suppressed by antagonizing mGluR1 and NMDA-R, demyelination is therefore caused by the initial ET-induced rise in extracellular glutamate concentration. This study reveals the novel possibility that ET can act on oligodendrocytes, thereby causing demyelination. Moreover, it suggests that for certain cell types such as oligodendrocytes, ET can act without forming pores, namely through the activation of an undefined receptor-mediated pathway.

Palmitoylethanolamide stimulates phagocytosis of Escherichia coli K1 by macrophages and increases the resistance of mice against infections.

BACKGROUND: Palmitoylethanolamide (PEA), an endogenous lipid and a congener of anandamide, possesses a wide range of effects related to metabolic and cellular homeostasis including anti-inflammatory and neuroprotective properties. METHODS: In vitro, we studied the ability of macrophages to phagocytose Escherichia coli K1 after stimulation with increasing doses of PEA. In vivo, wild-type mice were treated with PEA intraperitoneally 12 hours and 30 minutes before infection. Meningoencephalitis or sepsis was induced by intracerebral or intraperitoneal infection with E. coli K1. RESULTS: Stimulation of macrophages with PEA for 30 minutes increased the phagocytosis of E. coli K1 without inducing the release of TNFα or CXCL1. Intracellular killing of E. coli K1 was higher in PEA-stimulated than in unstimulated peritoneal macrophages and microglial cells. Pre-treatment with PEA significantly increased survival of mice challenged intracerebrally or intraperitoneally with E. coli K1. This effect was associated with a decreased production of CXCL1, IL-1ß and IL-6 in homogenates of spleen and cerebellum in mice treated with PEA. CONCLUSIONS: Our observations suggest that these protective effects of PEA in mice can increase the resistance to bacterial infections without the hazard of collateral damage by excessive stimulation of phagocytes.

Ruminant organotypic brain-slice cultures as a model for the investigation of CNS listeriosis.

Central nervous system (CNS) infections in ruminant livestock, such as listeriosis, are of major concern for veterinary and public health. To date, no host-specific in vitro models for ruminant CNS infections are available. Here, we established and evaluated the suitability of organotypic brain-slices of ruminant origin as in vitro model to study mechanisms of Listeria monocytogenes CNS infection. Ruminants are frequently affected by fatal listeric rhombencephalitis that closely resembles the same condition occurring in humans. Better insight into host-pathogen interactions in ruminants is therefore of interest, not only from a veterinary but also from a public health perspective. Brains were obtained at the slaughterhouse, and hippocampal and cerebellar brain-slices were cultured up to 49 days. Viability as well as the composition of cell populations was assessed weekly. Viable neurons, astrocytes, microglia and oligodendrocytes were observed up to 49 days in vitro. Slice cultures were infected with L. monocytogenes, and infection kinetics were monitored. Infected brain cells were identified by double immunofluorescence, and results were compared to natural cases of listeric rhombencephalitis. Similar to the natural infection, infected brain-slices showed focal replication of L. monocytogenes and bacteria were predominantly observed in microglia, but also in astrocytes, and associated with axons. These results demonstrate that organotypic brain-slice cultures of bovine origin survive for extended periods and can be infected easily with L. monocytogenes. Therefore, they are a suitable model to study aspects of host-pathogen interaction in listeric encephalitis and potentially in other neuroinfectious diseases.

Pontocerebellar angle aspergillosis: clinical and radiological findings.

INTRODUCTION: Cerebral aspergillosis is a rare and severe condition mostly affecting immunocompromised patients. The lesions are usually intra-axial and supratentorial; several radiologic patterns have been reported. CASE REPORT: A 65-year-old patient with chronic lymphocytic leukemia presented with fever, headache, and a pontocerebellar syndrome. A brain magnetic resonance imaging (MRI) showed a ring-enhancing left pontocerebellar mass consistent with an infectious disease. Despite broad-spectrum antibiotic therapy, the patient worsened. A follow-up MRI examination disclosed a concomitant acute ischemic lesion in the ipsilateral thalamus and an irregular narrowing of the posterior cerebral artery close to the lesion. A retrospective analysis of the first MRI revealed a small mesencephalic ischemic lesion, contiguous to the extra-axial pontocerebellar mass. At surgical inspection the mass was found to be an extra-axial granuloma, with purulent components, attached to the petrous-tentorial angle, surrounded by a thick capsule. The lesion was only partially removed because of the tight relationship with the leptomeninges of the brain stem. Cerebral aspergillosis was the final histologic and microbiological diagnosis. CONCLUSION: In immunocompromised patients, the coexistence of an infectious lesion with involvement of contiguous vessels and consequent ischemic infarction should raise the suspicion of aspergillosis, even in unusual locations such as the pontocerebellar angle.

Cerebellar bacterial brain abscess: report of eight cases.

PURPOSE: To analyze the clinical characteristics and therapeutic outcome of patients with solely cerebellar bacterial brain abscess (BBA). CASE REPORT: Eight patients with solely cerebellar BBA, collected during a period of 23 years from 210 BBA patients, were included in this study. The eight patients were five men and three women, aged 5-54 years (mean, 36.6 years). Six of them were adults, one was a child, and one was an adolescent. Six patients had underlying medical/surgical problems. Of the clinical presentations, dizziness was the most common (87.5%, 7/8), followed by headache (62.5%, 5/8), altered consciousness (62.5%, 5/8), fever (50%, 4/8), ataxia (25%, 2/8), hearing impairment (12.5%, 1/8), dysarthria (12.5%, 1/8), and hemiparesis (12.5%, 1/8). The Image Severity Index (ISI) scores of these eight patients ranged from 6 to 12 points. All eight patients received both medical and surgical treatment. One patient died owing to a complication in the neurosurgical procedure and the remaining patients survived. The therapeutic outcome was quantified one month after discharge by modified Rankin scale (mRS) and the result showed six of the seven survivors had good outcomes, while the other one had a poor outcome (ataxic gait). CONCLUSION: Cerebellar BBA accounted for 3.8% (8/210) of the overall BBA. In cerebellar BBA, dizziness is a frequent symptom. Early diagnosis and a combination of antimicrobial and neurosurgical intervention is important for its treatment. The small case number is a limitation of this study; therefore, further large-scale study of cerebellar BBA is needed for better delineation of the clinical characteristics, therapeutic outcome, and prognostic factors.

A novel case of Fusarium oxysporum infection in an Atlantic bottlenose dolphin (Tursiops truncatus).

A necropsy was performed on a captive-born, 10-yr-old male Atlantic bottlenose dolphin (Tursiops truncatus) after it died acutely. Gross necropsy findings revealed hemorrhage within the right cerebrum, right cerebellum, and right eye. Histopathologic findings revealed a moderate multifocal acute necrotizing meningoencephalitis with intralesional fungal hyphae. Several pieces of cerebrum and cerebellum and cerebrospinal fluid were sent to the Fungus Testing Laboratory in San Antonio, Texas (U.S.A.). The culture yielded Fusarium oxysporum, which was confirmed by internal transcribed spacer and D1-D2 sequencing. Fusarium oxysporum infection has been reported in marine mammals. No cases of noncutaneous F. oxysporum infection in a cetacean that was not on long-term antimicrobials have been reported in the literature.

Comparative pathology of nocardiosis in marine mammals.

Nocardia spp. infections in mammals cause pyogranulomatous lesions in a variety of organs, most typically the lung. Members of the Nocardia asteroides complex are the most frequently recognized pathogens. Nine cases of nocardiosis in free-ranging pinnipeds and 10 cases of nocardiosis in cetaceans were evaluated. Host species included the hooded seal (Cystophora cristata, n = 8), leopard seal (Hydrurga leptonyx, n = 1), Atlantic bottlenose dolphin (Tursiops truncatus, n = 4), beluga whale (Delphinapterus leucas, n = 4), and killer whale (Orcinus orca, n = 2). The most common presentation of nocardiosis in both pinnipeds and cetaceans was the systemic form, involving 2 or more organs. Organs most frequently affected were lung and thoracic lymph nodes in 7 of 9 cases in pinnipeds and 8 of 10 cases in cetaceans. Molecular identification and bacterial isolation demonstrated a variety of pathogenic species. N. asteroides, N. farcinica, N. brasiliensis, and N. otitisdiscaviarum are pathogenic for pinnipeds. In cetaceans N. asteroides, N. farcinica, N. brasiliensis, N. cyriacigeorgica, and N. levis are pathogenic. Hematoxylin and eosin and acid fast staining failed to reveal bacteria in every case, whereas modified acid fast and Grocott's methenamine silver consistently demonstrated the characteristic organisms. In both pinnipeds and cetaceans, juvenile animals were affected more often than adults. Hooded seals demonstrated more cases of nocardiosis than other pinnipeds.

A 13-year-old girl with a cystic cerebellar lesion: consider the hydatid cyst.

We report a 13-year-old girl with a hydatid cyst located in the posterior fossa. The pre-operative diagnosis was a cerebellar tumour; the cyst was operated on using puncture, aspiration, irrigation and resection. Sixteen months post-operatively, the patient is in a good health. A hydatid cyst must always be considered in the differential diagnosis of cystic lesions of the cranium, especially for those children living in rural areas.

Transient dysautonomia and cerebellitis in childhood enteric fever.

A case of childhood enteric fever complicated by transient dysautonomia and cerebellitis is reported. The child was treated with intravenous antibiotics, and the complications were managed conservatively. Dysautonomia and cerebellitis resolved by day 5 and day 8 after admission, respectively. Results of a neurologic examination at the end of 6 months were normal. Dysautonomia complicating the course of childhood enteric fever is previously unreported.