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SUMMARYCentral nervous system (CNS) infections can be caused by various pathogens, including bacteria, viruses, fungi, and parasites. Molecular diagnostic methods are pivotal for identifying the different causative pathogens of these infections in clinical settings. The efficacy and specificity of these methods can vary per pathogen involved, and in a substantial part of patients, no pathogen is identified in the cerebrospinal fluid (CSF). Over recent decades, various molecular methodologies have been developed and applied to patients with CNS infections. This review provides an overview of the accuracy of nucleic acid amplification methods in CSF for a diverse range of pathogens, examines the potential value of multiplex PCR panels, and explores the broad-range bacterial and fungal PCR/sequencing panels. In addition, it evaluates innovative molecular approaches to enhance the diagnosis of CNS infections., Competing Interests: The authors declare no conflict of interest.

Metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) is an agnostic method for broad-based diagnosis of central nervous system (CNS) infections. Here we analyzed the 7-year performance of clinical CSF mNGS testing of 4,828 samples from June 2016 to April 2023 performed by the University of California, San Francisco (UCSF) clinical microbiology laboratory. Overall, mNGS testing detected 797 organisms from 697 (14.4%) of 4,828 samples, consisting of 363 (45.5%) DNA viruses, 211 (26.4%) RNA viruses, 132 (16.6%) bacteria, 68 (8.5%) fungi and 23 (2.9%) parasites. We also extracted clinical and laboratory metadata from a subset of the samples (n = 1,164) from 1,053 UCSF patients. Among the 220 infectious diagnoses in this subset, 48 (21.8%) were identified by mNGS alone. The sensitivity, specificity and accuracy of mNGS testing for CNS infections were 63.1%, 99.6% and 92.9%, respectively. mNGS testing exhibited higher sensitivity (63.1%) than indirect serologic testing (28.8%) and direct detection testing from both CSF (45.9%) and non-CSF (15.0%) samples (P < 0.001 for all three comparisons). When only considering diagnoses made by CSF direct detection testing, the sensitivity of mNGS testing increased to 86%. These results justify the routine use of diagnostic mNGS testing for hospitalized patients with suspected CNS infection., Competing Interests: Competing interests: A.P.W., B.O., T.B., B.M. and S.M. are employed by and own equity in Delve Bio. C.Y.C. is a co-founder of Delve Bio and on the scientific advisory board for Delve Bio, Flightpath Biosciences, Biomeme, Mammoth Biosciences, BiomeSense and Poppy Health. He is also an inventor on US patent 11380421, ‘Pathogen detection using next-generation sequencing’, under which algorithms for taxonomic classification, filtering and pathogen detection are used by SURPI+ software. C.Y.C. receives research support from Delve Bio and Abbott Laboratories, Inc. M.R.W. is a co-founder and on the scientific advisory board for Delve Bio. The other authors declare no competing interests., (© 2024. The Author(s).)

Objectives: To evaluate the therapeutic regimen, efficacy and safety of intrathecal or intraventricular (ITH/IVT) administration of polymyxin B for hospital-acquired central nervous system (CNS) infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB)., Methods: A retrospective study was undertaken of patients with CNS infections caused by CRAB treated with ITH/IVT combination therapy. The primary outcome was the clinical efficacy of treatment. The secondary outcomes were the bacterial clearance rate and the safety of therapy., Results: In total, 35 patients who received ITH [n=13 (37.1%)] or IVT [n=22 (62.9%)] polymyxin B as combination therapy were included in this study. The median duration of ITH/IVT polymyxin B therapy was 9 (interquartile range 7-11) days. The overall clinical cure rate and bacterial clearance rate were 77.1% and 85.7%, respectively. No adverse effects considered to be related to ITH/IVT polymyxin B were recorded. Clinical failure was independently associated with an Acute Physiology and Chronic Health Evaluation II score ≥15 [odds ratio (OR) 1.24, 95% confidence interval (CI) 1.05-1.42; P=0.038] and a Glasgow Coma Scale score ≤8 (OR 0.69, 95% CI 0.49-0.88; P=0.029). Early administration (≤4 days of infection onset) of ITH/IVT polymyxin B therapy resulted in a significantly higher clinical cure rate (OR 0.65, 95% CI 0.49-1.12; P<0.001), and may reduce the length of treatment and adverse effects., Conclusions: ITH/IVT administration of polymyxin B is a valid alternative for the treatment of CNS infections caused by CRAB. Early use of ITH/IVT polymyxin B can result in greater clinical success., (Copyright © 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Background: Tuberculous meningitis (TBM) is a severe central nervous system (CNS) infection with a challenging diagnosis due to inadequate detection methods. This study evaluated current clinical detection methods and their applicability., Methods: A cohort of 514 CNS infection patients from 2018 to 2020 was studied. Data on general demographics, Cerebrospinal Fluid (CSF) analysis, epidemiology, and clinical outcomes were collected. TBM patients were identified, and the sensitivities of mmetagenomic next-generation sequencing (NGS), GeneXpert, and microbial culture were compared. Kappa statistic assessed the consistency between methods., Results: Among the patients involved, TBM (29%) and neurosyphilis (25%) were the two most prevalent CNS infections. CSF analysis indicated that 76% of patients had leukocytosis, suggesting a potential CNS inflammation. In TBM cases, 92.5% had elevated CSF protein and leukocyte counts. Moreover, the percentage of positive mNGS results was 55.6%. GeneXpert and MTB cultures alone had lower sensitivity, but combined use resulted in a 53.4% positive rate., Conclusions: This study highlights the high sensitivity of mNGS, comparable to GeneXpert and MTB culture. The combined methods are cost-effective and straightforward, and can partially substitute for mNGS, offering valuable alternatives for TBM diagnosis and providing insights into multiple diagnostic strategies in clinical practice., (© 2024. The Author(s).)

Central nervous system (CNS) infections carry a substantial burden of morbidity and mortality worldwide, and accurate and timely diagnosis is required to optimize management. Metagenomic next-generation sequencing (mNGS) has proven to be a valuable tool in detecting pathogens in patients with suspected CNS infection. By sequencing microbial nucleic acids present in a patient's cerebrospinal fluid, brain tissue, or samples collected outside of the CNS, such as plasma, mNGS can detect a wide range of pathogens, including rare, unexpected, and/or fastidious organisms. Furthermore, its target-agnostic approach allows for the identification of both known and novel pathogens. This is particularly useful in cases where conventional diagnostic methods fail to provide an answer. In addition, mNGS can detect multiple microorganisms simultaneously, which is crucial in cases of mixed infections without a clear predominant pathogen. Overall, clinical mNGS testing can help expedite the diagnostic process for CNS infections, guide appropriate management decisions, and ultimately improve clinical outcomes. However, there are key challenges surrounding its use that need to be considered to fully leverage its clinical impact. For example, only a few specialized laboratories offer clinical mNGS due to the complexity of both the laboratory methods and analysis pipelines. Clinicians interpreting mNGS results must be aware of both false negatives-as mNGS is a direct detection modality and requires a sufficient amount of microbial nucleic acid to be present in the sample tested-and false positives-as mNGS detects environmental microbes and their nucleic acids, despite best practices to minimize contamination. Additionally, current costs and turnaround times limit broader implementation of clinical mNGS. Finally, there is uncertainty regarding the best practices for clinical utilization of mNGS, and further work is needed to define the optimal patient population(s), syndrome(s), and time of testing to implement clinical mNGS., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Central nervous system infections are due to different microorganisms such as viruses, bacteria, mycobacteria, fungi, amoebas, and other parasites. The etiology depends on multiple risk factors, and it defines the infection location because some microorganisms prefer meninges, brain tissue, cerebellum, brain stem or spinal cord. The microorganisms induce diseases in the nervous system through direct invasion, neurotoxin production, and the triggered immune response. To determine the infection etiology, there are several diagnostic tests which may be conducted with cerebrospinal fluid, blood, respiratory and stool samples. These tests include but are not limited to direct microscopic examination of the sample, stains, cultures, antigenic tests, nucleic acid amplification tests, metagenomic next-generation sequencing, immunologic biomarker and neuroimaging, especially contrast-enhanced magnetic resonance imaging. The treatment may consist of specific antimicrobial treatment and supportive standard care. Since viruses have no specific antiviral treatment, antimicrobial treatment is mainly targeted at non-viral infections. This article will focus on diagnosis and treatment of acute acquired infections of the central nervous system beyond the neonatal period. The discussion defines the disease, provides the clinical presentation, explains the etiology and risk factors, and briefly mentions potential complications. This updated review aims to provide the reader with all the elements needed to adequately approach a patient with a central nervous system infection. Mycobacterium tuberculosis infection, Cryptococcus spp. infection and vaccines are not within the scope of this article.

Objectives: Central nervous system (CNS) infections caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) present a major health and economic burden worldwide. This multicentre prospective study aimed to assess the feasibility and usefulness of CSF therapeutic drug monitoring (TDM) after intrathecal/intraventricular administration of polymyxin B in patients with CNS infections., Methods: Forty-two patients treated with intrathecal/intraventricular administration of polymyxin B against CR-GNB-induced CNS infections were enrolled. CSF trough level (Cmin) was collected beginning on Day 2 post-polymyxin B initiation and thereafter. The primary outcomes were clinical cure and 28-day all-cause mortality., Results: All patients started with intrathecal/intraventricular administration of polymyxin B at a dose of 5 g/day, corresponding to a median CSF Cmin of 2.93 mg/L (range, 0.21-25.74 mg/L). Clinical cure was 71.4%, and the median CSF Cmin of this group was higher than that of clinical failure group [3.31 (IQR, 1.73-5.62) mg/L versus 2.25 (IQR, 1.09-4.12) mg/L; P = 0.011]. In addition, with MICs ≤ 0.5 mg/L, maintaining polymyxin B CSF Cmin above 2.0 mg/L showed a higher clinical cure rate (P = 0.041). The 28-day all-cause mortality rate was 31.0% and had no association with CSF Cmin., Conclusions: After intrathecal/intraventricular administration of polymyxin B, CSF concentrations fluctuated considerably inter- and intra-individual. Polymyxin B CSF Cmin above 2.0 mg/L was associated with clinical cure when MICs were ≤ 0.5 mg/L, and the feasibility of TDM warrants additional clinical studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The application of metagenomic next-generation sequencing (mNGS) in pathogens detection of cerebrospinal fluid (CSF) is limited because clinical, microbiological, and biological information are not well connected. We analyzed the 428 enrolled patients' clinical features, pathogens diagnostic efficiency of mNGS in CSF, microbial community structure and composition in CSF, and correlation of microbial and clinical biomarkers in CSF. General characteristics were unspecific but helpful in formulating a differential diagnosis. CSF mNGS has a higher detection rate (34.6%) compared to traditional methods (5.4%). mNGS detection rate was higher when the time from onset to CSF collection was ≤20 days, the CSF leukocytes count was >200 × 10 6 /L, the CSF protein concentration was >1.3 g/L, or CSF glucose concentration was ≤2.5 mmol/L in non-postoperative bacterial CNS infections (CNSi). CSF was not strictly a sterile environment, and the potential pathogens may contribute to the dysbiosis of CSF microbiome. Furthermore, clinical biomarkers were significantly relevant to CNS pathogens. Clinical data are helpful in choosing a proper opportunity to obtain an accurate result of mNGS, and can speculate whether the mNGS results are correct or not. Our study is a pioneering study exploring the CSF microbiome in different CNSIs., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Central nervous system Infections (CNSIs) is a disease characterized by complex pathogens, rapid disease progression, high mortality rate and high disability rate. Here, we evaluated the clinical value of metagenomic next generation sequencing (mNGS) in the diagnosis of central nervous system infections and explored the factors affecting the results of mNGS. We conducted a retrospective study to compare mNGS with conventional methods including culture, smear and etc. 111 suspected CNS infectious patients were enrolled in this study, and clinical data were recorded. Chi-square test were used to evaluate independent binomial variables, taking p < 0.05 as statistically significant threshold. Of the 111 enrolled cases, 57.7% (64/111) were diagnosed with central nervous system infections. From these cases, mNGS identified 39.6% (44/111) true-positive cases, 7.2% (8/111) false-positive case, 35.1% (39/111) true-negative cases, and 18.0% (20/111) false-negative cases. The sensitivity and specificity of mNGS were 68.7% (44/64) and 82.9% (39/47), respectively. Compared with culture, mNGS provided a higher pathogen detection rate in CNSIs patients (68.7% (44/64) vs. 26.5% (17/64), p < 0.0001). Compared to conventional methods, positive percent agreement and negative percent agreement was 84.60% (44/52) and 66.1% (39/59) separately. At a species-specific read number (SSRN) ≥ 2, mNGS performance in the diagnosis of definite viral encephalitis and/or meningitis was optimal (area under the curve [AUC] 0.758, 95% confidence interval [CI] 0.663-0.854). In bacterial CNSIs patients with significant CSF abnormalities (CSF WBC > 300*10 6 /L), the positive rate of CSF mNGS is higher. To sum up, conventional microbiologic testing is insufficient to detect all neuroinvasive pathogens, and mNGS exhibited satisfactory diagnostic performance in CNSIs and with an overall detection rate higher than culture (p < 0.0001)., (© 2024. The Author(s).)

Background: Opportunistic infections in the central nervous system (CNS) can be a serious threat to people living with HIV. Early aetiological diagnosis and targeted treatment are crucial but difficult. Metagenomic next-generation sequencing (mNGS) has significant advantages over traditional detection methods. However, differences in the cerebrospinal fluid (CSF) microbiome profiles of patients living with and without HIV with suspected CNS infections using mNGS and conventional testing methods have not yet been adequately evaluated., Methods: We conducted a retrospective cohort study in the first hospital of Changsha between January 2019 and June 2022 to investigate the microbiomes detected using mNGS of the CSF of patients living with and without HIV with suspected CNS infections. The pathogens causing CNS infections were concurrently identified using both mNGS and traditional detection methods. The spectrum of pathogens identified was compared between the two groups., Results: Overall, 173 patients (140 with and 33 without HIV) with suspected CNS infection were enrolled in our study. In total, 106 (75.7%) patients with and 16 (48.5%) patients without HIV tested positive with mNGS (p = 0.002). Among the enrolled patients, 71 (50.7%) with HIV and five (15.2%) without HIV tested positive for two or more pathogens (p < 0.001). Patients with HIV had significantly higher proportions of fungus (20.7% vs. 3.0%, p = 0.016) and DNA virus (59.3% vs. 21.2%, p < 0.001) than those without HIV. Epstein-Barr virus (33.6%) was the most commonly identified potential pathogen in the CSF of patients living with HIV using mNGS, followed by cytomegalovirus (20.7%) and torque teno virus (13.8%). The top three causative pathogens identified in patients without HIV were Streptococcus (18.2%), Epstein-Barr virus (12.1%), and Mycobacterium tuberculosis (9.1%). In total, 113 patients living with HIV were diagnosed as having CNS infections. The rate of pathogen detection in people living with HIV with a CNS infection was significantly higher with mNGS than with conventional methods (93.8% vs. 15.0%, p < 0.001)., Conclusion: CSF microbiome profiles differ between patients living with and without HIV with suspected CNS infection. mNGS is a powerful tool for the diagnosis of CNS infection among people living with HIV, especially in those with mixed infections., (© 2024 British HIV Association.)

Pretransplant mortality rates in the US remain high and are connected to effective organ donation and utilization. Thus, there is a need to maximize the utilization of available donors. In some cases, this has been safely achieved using organs from donors with infectious complications. For example, several studies describe the use of organs from donors with bacterial meningitis due to pathogens such as Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenza, and Escherichia coli, with good outcomes. Listeria is an aerobic and facultatively anaerobic, nonspore-forming, Gram-positive rod that can affect the central nervous system, causing meningitis and meningoencephalitis. Due to its virulence, ability to cause intracellular infection, and lack of clinical data, people dying with listeria may not be evaluated for organ donation, may not have organs recovered, or may have their organs recovered but not transplanted. Herein, we describe the outcomes of 7 solid organ transplant recipients who received organs from 2 donors with Listeria monocytogenes central nervous system infection., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Managing health care acquired and device-associated intracranial infections in young children can be challenging given adverse antibiotic side effects and difficulties in achieving adequate central nervous system (CNS) antibiotic concentrations. Ceftaroline is a cephalosporin with a favorable safety profile and activity against methicillin-resistant Staphylococci and several Gram-negative organisms. Published data on the use of ceftaroline for CNS infections in children and adults are limited., Methods: We describe a 2-month-old infant with ventriculo-subgaleal shunt-associated methicillin-resistant Staphylococcus epidermidis ventriculitis, which was successfully treated with ceftaroline, in addition to vancomycin and rifampin. We conducted a scoping review of English-language literature retrieved from PubMed, EMBASE and Web of Science that assessed the use of ceftaroline for CNS infections., Results: We identified 22 articles for inclusion in our review, which described 92 unique patients, of whom 2 were <21 years old. Ceftaroline was commonly used in conjunction with other antibiotics to treat infections caused by Staphylococcus aureus , coagulase-negative Staphylococci and Streptococcus pneumoniae . Most case reports described clinical success with ceftaroline, though small case series and cohort studies yielded mixed efficacy assessments. Adverse effects attributed to ceftaroline were rare and included reversible myelosuppression, eosinophilia, hepatotoxicity and nephrotoxicity. Pharmacokinetic/pharmacodynamic studies suggested similar CNS penetration through inflamed meninges as other beta lactam antibiotics., Conclusions: We identified a growing body of published evidence supporting the use of ceftaroline in combination with other agents for the treatment of CNS infections. In absence of clinical trials, additional real-world data are needed to define the efficacy and safety of ceftaroline for children and adults with CNS infections., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The diagnosis of meningitis in non-surgical hospitalized patients is often difficult and diagnostic accuracy of clinical, laboratory, and radiological characteristics is unknown., Aim: To assess diagnostic accuracy for individual clinical characteristics of patients suspected of non-surgical nosocomial central nervous system (CNS) infections., Methods: In a prospective multi-centre cohort study in the Netherlands with adults suspected of CNS infections, consecutive patients who underwent a lumbar puncture for the suspicion of a non-surgical nosocomial CNS infection were included. All episodes were categorized into five final clinical diagnosis categories, as reference standard: CNS infection, CNS inflammatory disease, systemic infection, other neurological disease, or non-systemic, non-neurological disease., Findings: Between 2012 and 2022, 114 out of 1275 (9%) patients included in the cohort had suspected non-surgical nosocomial CNS infection: 16 (14%) had a confirmed diagnosis, including four (25%) with bacterial meningitis, nine (56%) with viral CNS infections, two (13%) fungal meningitis, and one (6%) parasitic meningitis. Diagnostic accuracy of individual clinical characteristics was generally low. Elevated CSF leucocyte count had the highest sensitivity (81%; 95% confidence interval (CI): 54-96) and negative predictive value (NPV) (96%; 95% CI: 90-99). When combining the presence of abnormalities in neurological or CSF examination, sensitivity for diagnosing a CNS infection was 100% (95% CI: 79-100) and NPV 100% (95% CI: 78-100). CSF examination changed clinical management in 47% of patients., Conclusion: Diagnostic accuracy for individual clinical characteristics was low, with elevated CSF leucocyte count having the highest sensitivity and NPV., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To describe the clinical features, history and association with intestinal disease in central nervous system (CNS) S. bovis infections., Methods: Four cases of S. bovis CNS infections from our institution are presented. Additionally a systematic literature review of articles published between 1975 and 2021 in PubMed/MEDLINE was conducted., Results: 52 studies with 65 cases were found; five were excluded because of incomplete data. In total 64 cases were analyzed including our four cases: 55 with meningitis and 9 with intracranial focal infections. Both infections were frequently associated with underlying conditions (70.3%) such as immunosuppression (32.8%) or cancer (10.9%). In 23 cases a biotype was identified, with biotype II being the most frequent (69.6%) and S. pasteurianus the most common within this subgroup. Intestinal diseases were found in 60.9% of cases, most commonly neoplasms (41.0%) and Strongyloides infestation (30.8%). Overall mortality was 17.1%, with a higher rate in focal infection (44.4% vs 12.7%; p=0.001)., Conclusions: CNS infections due to S. bovis are infrequent and the most common clinical form is meningitis. Compared with focal infections, meningitis had a more acute course, was less associated with endocarditis and had a lower mortality. Immunosuppression and intestinal disease were frequent in both infections., (Copyright © 2022 Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Published by Elsevier España, S.L.U. All rights reserved.)

Central nervous system (CNS) infections are important causes of morbidity and mortality worldwide. In Bolivia, aetiologies, case fatality, and determinants of outcome are poorly characterised. We attempted to investigate such parameters to guide diagnosis, treatment, prevention, and health policy. From Nov-2017 to Oct-2018, we prospectively enrolled 257 inpatients (20.2% HIV-positive patients) of all ages from healthcare centers of Cochabamba and Santa Cruz, Bolivia with a suspected CNS infection and a lumbar puncture performed. Biological diagnosis included classical microbiology, molecular, serological and immunohistochemical tests. An infectious aetiology was confirmed in 128/257 (49.8%) inpatients, including, notably among confirmed single and co-infections, Cryptococcus spp. (41.7%) and Mycobacterium tuberculosis (27.8%) in HIV-positive patients, and Mycobacterium tuberculosis (26.1%) and Streptococcus pneumoniae (18.5%) in HIV-negative patients. The total mortality rate was high (94/223, 42.1%), including six rabies cases. In multivariate logistic regression analysis, mortality was associated with thrombocytopenia (Odds ratio (OR) 5.40, 95%-CI 2.40-11.83) and hydrocephalus (OR 4.07, 95%-CI 1.35-12.23). The proportion of untreated HIV patients, late presentations of neurotuberculosis, the rate of pneumococcal cases, and rabies patients who did not benefit from a post-exposure prophylaxis, suggest that decreasing the burden of CNS infections requires reinforcing health policy regarding tuberculosis, rabies, S. pneumoniae vaccination, and HIV-infections., (© 2021. The Author(s).)

Microbial penetration of the blood-brain barrier, a prerequisite for the development of central nervous system (CNS) infection, involves microbial invasion, intracellular traversal, and exocytosis. Microbial invasion of the blood-brain barrier has been investigated, but the molecular basis for microbial traversal and exit from the blood-brain barrier remains unknown. We performed transcriptome analysis of human brain microvascular endothelial cells (HBMEC) infected with Escherichia coli and Cryptococcus neoformans, representative bacterial and fungal pathogens common in CNS infections. Among the targets upregulated in response to E. coli and C. neoformans infection, PDLIM2 was knocked down by small hairpin RNA (shRNA) in HBMEC for further investigation. We demonstrated that Pdlim2 specifically regulated microbial traversal and exit from HBMEC by assessing microbial invasion, transcytosis, intracellular multiplication, and egression. Additionally, the defective exocytosis of internalized E. coli cells from the PDLIM2 shRNA knockdown cells was restored by treatment with a calcium ionophore (ionomycin). Moreover, we performed proximity-dependent biotin labeling with the biotin ligase BioID2 and identified 210 potential Pdlim2 interactors. Among the nine Pdlim2 interactors enriched in response to both E. coli and C. neoformans infection, we selected MPRIP and showed that HBMEC with knockdown of MPRIP mimicked the phenotype of PDLIM2 knockdown cells. These results suggest that the CNS-infecting microbes hijack Pdlim2 and Mprip for intracellular traversal and exocytosis in the blood-brain barrier.

We present the case of an 18-year-old female with a 1-month history of fever, headache, and double vision, whose examination revealed papilledema and cranial nerve VI palsy. Blood cultures grew Brucella abortus cattle vaccine strain RB51, which is inherently resistant to rifampin. We discuss the management of the first known case of neurobrucellosis by this strain., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Ten controlled studies evaluated antimicrobial use following implementation of the FilmArray meningitis and encephalitis panel versus usual care. Only one-half of studies identified significant reductions in antibiotic duration, with 8/10 reporting modest reductions for acyclovir. Coupling the FilmArray meningitis and encephalitis panel with interventions by antimicrobial stewardship programs may help enhance its clinical impact., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose of Review: To review recent data on the epidemiology, microbiology, diagnosis, and management of central nervous system (CNS) infections associated with neurologic devices., Recent Findings: The increasing use of implanted neurologic devices has led to an increase in associated infections. Cerebrospinal fluid (CSF) inflammation may be present after a neurosurgical procedure, complicating the diagnosis of CNS infection. Newer biomarkers such as CSF lactate and procalcitonin show promise in differentiating infection from other causes of CSF inflammation. Molecular diagnostic tests including next-generation or metagenomic sequencing may be superior to culture in identifying pathogens causing healthcare-associated ventriculitis and meningitis., Summary: Neurologic device infections are serious, often life-threatening complications. Rapid recognition and initiation of antibiotics are critical in decreasing morbidity. Device removal is usually required for cure., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Central nervous system (CNS) infections are associated with high rates of morbidity and mortality. The purpose of this review is to summarize current antimicrobial therapies, as well as, updates in the management of community-acquired meningitis and healthcare-associated meningitis and ventriculitis., Recent Findings: Due to the increasing rates of multidrug resistant and extensively-drug resistant organisms, available antimicrobials are limited. Novel treatment options include newer systemic antimicrobials and antimicrobials that have previously limited data in the management of CNS infections. Although limited by retrospective data, intrathecal (IT) and intraventricular (IVT) routes of administration offer the opportunity for antimicrobials that conventionally have minimal cerebrospinal fluid (CSF) penetration to achieve high CSF concentrations while minimizing systemic exposure., Summary: Updates in the use of systemic, IT, and IVT antimicrobials offer promise as therapeutic options for CNS infections. Additional pharmacokinetic and prospective data are needed to confirm these findings., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Significant advances to our understanding of several neuroinfectious complications after a solid organ transplant (SOT) have occurred in the last few years. Here, we review the central nervous system (CNS) infections that are relevant to SOT via a syndromic approach with a particular emphasis on recent updates in the field., Recent Findings: A few key studies have advanced our understanding of the epidemiology and clinical characteristics of several CNS infections in SOT recipients. Risk factors for poor prognosis and protective effects of standard posttransplant prophylactic strategies have been better elucidated. Newer diagnostic modalities which have broad clinical applications like metagenomic next-generation sequencing, as well as those that help us better understand esoteric concepts of disease pathogenesis have been studied. Finally, several studies have provided newer insights into the treatment of these diseases., Summary: Recent findings reflect the steady progress in our understanding of CNS infections post SOT. They provide several avenues for improvement in the prevention, early recognition, and therapeutic outcomes of these diseases., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Early diagnosis of central nervous system (CNS) infections is crucial given high morbidity and mortality. Neuroimaging in CNS infections is widely used to aid in the diagnosis, treatment and to assess the response to antibiotic and neurosurgical interventions., Recent Findings: The Infectious Diseases Society of America (IDSA) guidelines have clear recommendations for obtaining a computerized tomography of the head (CTH) prior to lumbar puncture (LP) in suspected meningitis. In the absence of indications for imaging or in aseptic meningitis, cranial imaging is of low utility. In contrast, cranial imaging is of utmost importance in the setting of encephalitis, bacterial meningitis, ventriculitis, bacterial brain abscess, subdural empyema, epidural abscess, neurobrucellosis, neurocysticercosis, and CNS tuberculosis that can aid clinicians with the differential diagnosis, source of infection (e.g., otitis, sinusitis), assessing complications of meningitis (e.g., hydrocephalus, venous sinus thrombosis, strokes), need for neurosurgical interventions and to monitor for the response of therapy. Novel imaging techniques such as fast imaging employing steady-state acquisition (FIESTA), susceptibility-weighted imaging (SWI), and chemical exchange saturation transfer (CEST) contrast are briefly discussed., Summary: Though the radiological findings in CNS infections are vast, certain patterns along with clinical clues from history and examination often pave the way to early diagnosis. This review reiterates the importance of obtaining cranial imaging when necessary, and the various radiological presentations of commonly encountered CNS infections., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Central nervous system infections cause substantial morbidity and mortality in pediatric patients. However, in approximately half of the clinical cases, the etiology is unidentified. As an unbiased molecular diagnostic technology, next-generation sequencing is gradually being applied to investigate central nervous system infections. This review summarizes and critiques the literature on this new technology for etiologic identification of unexplained central nervous system infections in pediatric patients and discusses the future prospects for development of this technology in pediatrics., Methods: A comprehensive PubMed search was conducted of articles published from January 1, 2008, to June 26, 2020 in order to retrieve all available studies on this topic. Other relevant articles were identified from recent reviews and the bibliographies of the retrieved full-text articles., Results: Among the 441 studies retrieved, 26 pediatric studies, comprising 15 case reports and 11 case series, used next-generation sequencing as a diagnostic tool. In these 26 studies, next-generation sequencing was performed on cerebrospinal fluid samples from 529 pediatric patients, and potential causal pathogens were identified in 22.1% of the cases., Conclusion: There is increasing evidence that next-generation sequencing can play a role in identifying the causes of unexplained encephalitis, meningoencephalitis, and meningitis in pediatric patients, although the diagnostic value of next-generation sequencing is difficult to quantify. There is an increasing need for close collaboration between laboratory scientists and clinicians. We believe that further clinical studies should be performed to evaluate the performance of next-generation sequencing for individual targets and in high-risk populations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Methicillin-resistant Staphylococcus aureus (MRSA)-associated central nervous system infections are potentially devastating. Linezolid has good penetration into cerebrospinal fluid and brain tissue. In clinical practice, linezolid may be used to treat central nervous system infections caused by MRSA resulting from glycopeptide intolerance or treatment failure. However, the clinical experience of linezolid in treating MRSA related central nervous system infections is scarce., Methods: From 2006 to 2016, patients aged ≥20 years who had central nervous system infections caused by MRSA treated with linezolid for more than 24 hours were retrospectively included from two medical centers. The demographic details, treatment response, side effects, and relapse of infection were reviewed., Results: Sixty-six patients with proven CNS infection caused by MRSA were treated with linezolid. The mean age was 53.3 years. The diagnoses in this cohort consisted of brain abscesses (n = 19, 28.8%), spinal epidural abscess (n = 18, 27.3%), meningitis only (n = 12, 18.2%), meningitis with brain epidural abscess (n = 9, 13.6%), and spine device-related infection (n = 5, 7.6%). The main reasons to prescribe linezolid were glycopeptide treatment failure (51.5%) and glycopeptide allergy (48.5%). Ninety-one percent of patients were treated with linezolid for more than 14 days. The in-hospital mortality rate was 13.6%. The relapse rate after treatment was 16.7%. Drug-related adverse events (mainly cytopenia) were observed in 27.3% of patients, but none of the adverse events was fatal., Conclusions: In our retrospective study, linezolid demonstrated promising effect as a salvage therapy for central nervous system infection caused by MRSA, whether due to drug allergy or glycopeptide treatment failure., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier B.V.)

Objective: To review the current literature describing pharmacology, pharmacokinetics/pharmacodynamics (PK/PD), efficacy, and safety of linezolid and daptomycin for the treatment of central nervous system (CNS) infections caused by vancomycin-resistant Enterococcus (VRE) faecium ., Data Sources: A literature search of PubMed/MEDLINE databases was conducted (from 1950 to April 2020) utilizing the following key terms: vancomycin-resistant Enterococcus, VRE, meningitis, ventriculitis, CNS infection, daptomycin , and linezolid ., Study Selection and Data Extraction: All relevant studies and case reports describing the treatment of VRE faecium from the CNS with linezolid or daptomycin were included., Data Synthesis: A total of 17 reports describing 22 cases were identified. There were 15 of 19 cases involving linezolid that reported clinical cure, of which 53.3% were monotherapy. Only 5 of 9 cases involving intravenous (IV) daptomycin resulted in cure; all 4 cases reporting daptomycin administration via the intrathecal or intraventricular route achieved clearance from the cerebrospinal fluid (CSF)., Relevance to Patient Care and Clinical Practice: The preferred treatment option for VRE faecium infections involving the CNS remains unclear. Supporting evidence through observational case reports have described varying outcomes with linezolid and daptomycin. This review compares reported outcomes between the 2 agents and provides a thorough discussion on drug- and patient-specific variables to consider., Conclusions: Linezolid monotherapy appears to be safe and effective for the treatment of susceptible-VRE faecium CNS infections, with consideration of therapeutic drug monitoring in special populations and with prolonged treatment duration. Daptomycin is an effective treatment option via intrathecal or intraventricular administration when neurosurgical access is available. The role of IV daptomycin remains inconclusive.

A 48-year-old man who worked in mining in remote, northern Australia was transferred from a rural hospital 5 days after the onset of headaches, subjective fevers and flaccid paralysis of the left upper limb. Initial investigations demonstrated inflammatory cerebrospinal fluid (CSF) changes and a longitudinally extensive cervical cord lesion. Given two serial negative blood and CSF cultures, he was treated as inflammatory myelitis with intravenous methylprednisolone. Despite the initial improvement in pain and left arm power, the patient's neurological deficit plateaued and then deteriorated with worsening neck pain, diaphragmatic dysfunction and dysphagia requiring intubation and respiratory support. A third CSF culture isolated Burkholderia pseudomallei confirming a diagnosis of neuro-melioidosis. Repeat imaging revealed the rostral extension of the original spinal cord lesion into the medulla and pons. Over the next 4 weeks, the patient's neurological deficits slowly improved with continued intravenous antibiotic therapy with meropenem and oral trimethoprim/sulfamethoxazole., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The genera Acremonium and Sarocladium comprise a high diversity of morphologically and genetically related fungi generally found in the environment, although a few species, mainly Sarocladium kiliense and Acremonium egyptiacum, can also be involved in many human infections. Clinical management of opportunistic infections caused by these fungi is very complex, since their correct identification is unreliable, and they generally show poor antifungal response. More than 300 clinical cases involving a broad range of Acremonium/Sarocladium infections have so far been published, and with this review we aim to compile and provide a detailed overview of the current knowledge on Acremonium/Sarocladium human infections in terms of presentation, diagnosis, treatments and prognoses. We also aim to summarise and discuss the data currently available on their antifungal susceptibility, emphasising the promising results obtained with voriconazole as well as their impact in terms of animal infections., (© 2020 Wiley‐VCH GmbH.)

Central nervous system (CNS) infections cause substantial morbidity and mortality worldwide, with mounting concern about new and emerging neurologic infections. Stratifying etiologies based on initial clinical and laboratory data would facilitate etiology-based treatment rather than relying on empirical treatment. Here, we report the epidemiology and clinical outcomes of patients with CNS infections from a prospective surveillance study that took place between 2013 and 2016 in Singapore. Using multiple correspondence analysis and random forest, we analyzed the link between clinical presentation, laboratory results, outcome and etiology. Of 199 patients, etiology was identified as infectious in 110 (55.3%, 95%-CI 48.3-62.0), immune-mediated in 10 (5.0%, 95%-CI 2.8-9.0), and unknown in 79 patients (39.7%, 95%-CI 33.2-46.6). The initial presenting clinical features were associated with the prognosis at 2 weeks, while laboratory-related parameters were related to the etiology of CNS disease. The parameters measured were helpful to stratify etiologies in broad categories, but were not able to discriminate completely between all the etiologies. Our results suggest that while prognosis of CNS is clearly related to the initial clinical presentation, pinpointing etiology remains challenging. Bio-computational methods which identify patterns in complex datasets may help to supplement CNS infection diagnostic and prognostic decisions.

Background: While increases in overdoses, viral hepatitis, and endocarditis associated with drug use have been well-documented in North Carolina, the full scope of invasive drug-related infections (IDRIs) has not. We characterized trends in IDRIs among hospitalized patients in North Carolina., Methods: We compared invasive infections that were related or not related to drug use among hospitalized patients aged 18-55 years based on retrospective review of administrative records from 2010-2018. Hospitalizations for endocarditis, central nervous system/spine infections, osteomyelitis, and septic arthritis were labeled as IDRIs if discharge codes included opioid and/or amphetamine misuse. Trends, rates, and distributions were calculated., Results: Among 44 851 hospitalizations for the specified infections, 2830 (6.3%) were IDRIs. The proportion of infections attributable to drug use increased from 1.5% (2010) to 13.1% (2018), and the rate grew from 1.2 to 15.1 per 100 000. Compared with those who had non-drug-related infections, patients with IDRIs were younger (median age, 35 vs 46 years), more likely to be non-Hispanic white (81% vs 56%), and had longer hospitalizations (median, 8 vs 6 days). 43% of hospitalizations for IDRIs involved infective endocarditis., Conclusions: The rate of IDRIs in North Carolina increased substantially during 2010-2018, indicating an urgent need for enhanced infection prevention, harm reduction, and addiction services aimed at community and inpatient settings., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction : Central nervous system (CNS) infections can be life-threatening and are often associated with disabling sequelae. One important factor in most CNS infections is a timely pathogen-specific treatment. The diagnostic methods available, however, do not always reach a satisfying sensitivity and specificity. In these cases, there is need for additional diagnostic biomarkers. Chemokines represent potential candidates as biomarkers, since they are an important pillar of the host immune response. The aim of this review is to discuss the diagnostic potential of cerebrospinal fluid (CSF) CXCL13 in patients with CNS infections. Areas covered : Data were obtained from a literature search in PubMed up to October 2019. This review focusses on articles on the potential of CXCL13 as a diagnostic tool. The majority of identified studies aimed to characterize its role in two diseases, namely Lyme neuroborreliosis and neurosyphilis. Expert opinion : CSF CXCL13 has a significant potential as a diagnostic and monitoring add-on marker in Lyme neuroborreliosis. Differences in study design, control groups and clinical parameters between studies, however, affect sensitivity, specificity and cutoff values, underlining the need of further studies to address these issues and pave the way for a generalized clinical practice.

Background: Listeriosis is a rare but severe foodborne infectious disease. Perinatal listeriosis is often associated with septicemia, central nervous system (CNS) infection, and serious adverse pregnancy outcomes (miscarriage and neonate death). Here we report the characteristics and outcomes of perinatal listeriosis cases treated over 6 years at Beijing Obstetrics and Gynecology Hospital (BOGH), the largest maternity hospital in China., Methods: We retrospectively reviewed the records of laboratory-confirmed, pregnancy-associated listeriosis cases treated from January 1, 2013 to December 31, 2018. The clinical manifestations, laboratory results, perinatal complications and outcomes (post-natal follow-up of 6 months) were investigated., Results: In BOGH, 12 perinatal listeriosis cases were diagnosed based on Listeria monocytogenes positive culture, including 10 single pregnancies and 2 twin pregnancies. The corresponding incidence of pregnancy-associated listeriosis was 13.7/100,000 deliveries. Among those cases, four pregnant women and four newborns had septicemia, and two of the neonates with septicemia also suffered CNS infection. All the maternal patients recovered. Two inevitable miscarriages and four fetal stillbirths occurred. Of the eight delivered newborns, six survived, and two died within 2 days from birth. None of the survivors had neurological sequelae during a 6-month follow-up. The overall feto-neonatal fatality rate was 57.1%; notably, this rate was 100% for infections occurring during the second trimester of pregnancy and only 14.3% for those occurring in the third trimester., Conclusions: Perinatal listeriosis is associated with high feto-neonatal mortality, and thus, a public health concern. Additional large-scale studies are needed to strengthen the epidemiological understanding of listeriosis in China.

The etiology of central nervous system (CNS) infections such as meningitis and encephalitis remains unknown in a large proportion of cases partly because the diversity of pathogens that may cause CNS infections greatly outnumber available test methods. We developed a metagenomic next generation sequencing (mNGS)-based approach for broad-range detection of pathogens associated with CNS infections suitable for application in the acute care hospital setting. The analytical sensitivity of mNGS performed on an Illumina MiSeq was assessed using simulated cerebrospinal fluid (CSF) specimens (n = 9). mNGS data were then used as a training dataset to optimize a bioinformatics workflow based on the IDseq pipeline. For clinical validation, residual CSF specimens (n = 74) from patients with suspected CNS infections previously tested by culture and/or PCR, were analyzed by mNGS. In simulated specimens, the NGS reads aligned to pathogen genomes in IDseq were correlated to qPCR C T values for the respective pathogens (R = 0.96; p < 0.0001), and the results were highly specific for the spiked pathogens. In clinical samples, the diagnostic accuracy, sensitivity and specificity of the mNGS with reference to conventional methods were 100%, 95% and 96%, respectively. The clinical application of mNGS holds promise to benefit patients with CNS infections of unknown etiology.

In the last two decades, central nervous system (CNS) cryptococcosis (CNSc) has emerged as a major opportunistic infection in the immunocompromised population of India. We have analyzed the clinical features of CNSc and epidemiology of Cryptococcus neoformans and Cryptococcus gattii. A total of 160 clinical isolates of C. neoformans/gattii recovered from CNSc patients were analyzed. The origin, clinical parameters, and imaging features of the patients were recorded, and clinical parameters were analyzed based on their human immunodeficiency virus (HIV) status and infecting species, namely, C. neoformans or C. gattii. Serotypes and mating types of the isolates were determined. Molecular typing was performed by polymerase chain reaction (PCR) fingerprinting using M13 microsatellite primer (GTG)5, and multilocus sequence typing (MLST). Majority of the patients were from Bangalore Urban, Karnataka. Among 160 cases 128 (80%) were HIV seropositive, and 32 (20%) were HIV negative. Middle-aged males (36-55 years) were highly affected. There were statistically significant differences in the clinical manifestations, imaging and CSF parameters of HIV coinfected and noninfected cases, whereas limited differences were observed in these parameters in the cases infected with C. neoformans and C. gattii. We identified 80% C. neoformans VNI, 8.75% VNII and 22.5% C. gattii (VGI), 8.75% C. tetragattii (VGIV) among clinical strains. This comprehensive study will contribute toward a better prognosis of CNS cryptococcosis patients during the hospital stay, treatment strategies for HIV coinfected and noninfected cases and will provide the molecular epidemiology of these two pathogenic fungal species in south India, which was unclear in this part of the country., (© The Author(s) 2019. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Introduction: Central nervous system (CNS) infections have considerable morbidity and mortality. Fosfomycin is a broad spectrum bactericidal antibiotic with favorable pharmacokinetic properties and low toxicity, satisfactory penetration in the cerebrospinal fluid and is authorized for the treatment of bacterial meningitis., Areas Covered: The objective of this analysis was to evaluate the available data regarding the effectiveness and safety of intravenous fosfomycin for the treatment of CNS infections. Thirty-two relevant publications were identified. Data from 224 patients who received intravenous fosfomycin as treatment for CNS infections were evaluated. Overall, 93.8% of patients were cured from the infection. Staphylococcus was the most frequent pathogen; Streptococcus pneumoniae, Neisseria meningitidis, and several other microbial agents, including multi-drug resistant and extensively drug-resistant bacteria, were also implicated. Fosfomycin was given as part of a combination treatment in the vast majority of the patients. The dosage of fosfomycin ranged between 4 g and 24 g per day; a regimen with 14-16 g per day was used in the majority of the cases. Fosfomycin was generally well tolerated., Expert Opinion: The evaluation of the published evidence suggests that fosfomycin may be beneficial in the treatment of patients with CNS infections.

Background: Patients harboring an external ventricular drain (EVD) who develop signs of infection require screening for infection in the central nervous system (CNS). The cerebrospinal fluid (CSF) can be collected by the EVD or by lumbar puncture (LP). If only one sample is analyzed, the diagnosis might be dubious or false-negative. The objective of this study was to compare the diagnosis accuracy of CNS infection of CSF samples collected from EVD and LP., Methods: We conducted a transversal study where data were prospectively collected from 2016 to 2019. Patients harboring EVD with signs of infection were submitted to the CSF analysis collected by LP and EVD. Diagnosis sensibility and results correlation were analyzed using the kappa index., Results: The 141 samples from LP and 141 samples from EVD were collected from 108 patients. Among the 282 samples, a total of 77 had infection. Seventy CSF samples from LP fulfilled infection criteria. However, only 32 EVD samples demonstrated infection. Among the 70 cases of infection based on the LP sample, 25 CSF samples collected from the EVD were also suggestive of infection; but in 45 patients only the CSF samples from LP met infection criteria. Seven patients had diagnosis of infection only in the EVD sample. The kappa correlation index of the results obtained from LP and EVD was 0.260 and the McNemar χ 2 test was <0.01., Conclusions: The CSF analysis exclusive from the EVD has a low sensibility and negative predictive value. CSF collected from LP has a sensibility 2.18 times higher than EVD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The clinical and laboratory characteristics of AIDS-associated Talaromyces marneffei infection, a rare but a fatal mycosis disease of the central nervous system, remain unclear., Case Presentation: Herein, we conducted a retrospective study of ten AIDS patients with cerebrospinal fluid culture-confirmed central nervous system infection caused by Talaromyces marneffei. All 10 patients were promptly treated with antifungal treatment for a prolonged duration and early antiviral therapy (ART). Among them, seven patients were farmers. Nine patients were discharged after full recovery, while one patient died during hospitalization, resulting in a mortality rate of 10%. All patients initially presented symptoms and signs of an increase in intracranial pressure, mainly manifesting as headache, dizziness, vomiting, fever, decreased muscle strength, diplopia or even altered consciousness with seizures in severe patients. Nine patients (90%) showed lateral ventricle dilatation or intracranial infectious lesions on brain CT. Cerebrospinal fluid findings included elevated intracranial pressure, increased leukocyte count, low glucose, low chloride and high cerebrospinal fluid protein. The median CD4 + T count of patients was 104 cells/μL (IQR, 36-224 cells/μL) at the onset of the disease. The CD4 + T cell counts of three patients who eventually died were significantly lower (W = 6.00, p = 0.020) than those of the patients who survived., Conclusions: The common clinical symptoms of T. marneffei central nervous system infection are associated with high intracranial pressure and intracranial infectious lesions. Earlier recognition and diagnosis and a prolonged course of amphotericin B treatment followed by itraconazole combined with early ART might reduce the mortality rate.

Background: Central nervous system (CNS) infections are important contributors to morbidity and mortality and the causative agents for ~50% patients are never identified. The causative agents of some CNS infections have distinct spatial and temporal patterns., Methodology/principal Findings: Here we present the results of a spatial epidemiological and ecological analysis of CNS infections in Lao PDR (2003-2011). The data came from hospitalizations for suspected CNS infection at Mahosot Hospital in Vientiane. Out of 1,065 patients, 450 were assigned a confirmed diagnosis. While many communities in Lao PDR are in rural and remote locations, most patients in these data came from villages along major roads. Japanese encephalitis virus ((JEV); n = 94) and Cryptococcus spp. (n = 70) were the most common infections. JEV infections peaked in the rainy season and JEV patients came from villages with higher surface flooding during the same month as admission. JEV infections were spatially dispersed throughout rural areas and were most common in children. Cryptococcus spp. infections clustered near Vientiane (an urban area) and among adults., Conclusions/significance: The spatial and temporal patterns identified in this analysis are related to complex environmental, social, and geographic factors. For example, JEV infected patients came from locations with environmental conditions (surface water) that are suitable to support larger mosquito vector populations. Most patients in these data came from villages that are near major roads; likely the result of geographic and financial access to healthcare and also indicating that CNS diseases are underestimated in the region (especially from more remote areas). As Lao PDR is undergoing major developmental and environmental changes, the space-time distributions of the causative agents of CNS infection will also likely change. There is a major need for increased diagnostic abilities; increased access to healthcare, especially for rural populations; and for increased surveillance throughout the nation., Competing Interests: The authors have declared that no competing interests exist.

Nosocomial Central Nervous System (CNS) infections are often serious complications of neurosurgical procedures. Their diagnosis is complex and frequently based on microbiological culture. The aim of this work was to evaluate the effectiveness of the FilmArray® Blood Culture Identification (BCID) panel, a multiplex PCR designed to identify the most common etiologic agents of sepsis involved with nosocomial CNS infections. A total of ninety samples were analyzed with the BCID panel. The sensitivity and specificity achieved were 77.4% and 100% respectively, when compared with the reference method (culture). Based on the analysis of the melting curves, another cut-off was established improving sensitivity to 83.9% whilst maintaining 98.3% specificity. The BCID panel seems to be a helpful tool for the prompt diagnosis of CNS nosocomial infections. The cut-off proposed here can increase sensitivity, but further studies are required to confirm its effectiveness and its applicability in clinical microbiology laboratories., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Central nervous system (CNS) infection by Histoplasma capsulatum is a rare disease in immunocompromised individuals in endemic areas. About one quarter of cases result from hematogenous dissemination. A 23-year-old upholsterer with chronic occipital headache had developed intracranial hypertension and dizziness, incoordination with ataxic gait, and acute confusion 5 months prior to admission. Laboratory examinations and chest roentgenogram were normal. Postcontrast T1-weighted MRI of the brain revealed a multiple ring-enhancing cerebellar, brain stem and parietal lobe lesions, and meningeal contrast enhancement. Cerebrospinal fluid culture was positive for H. capsulatum species complex, which was confirmed by phylogenetic analysis. Thirteen years after the diagnosis and treatment, there was no H. capsulatum recurrence; sequels related to complications due to the ventriculoperitoneal shunt. This case shows a primary neurological presentation of cerebral histoplasmosis, without meningitis or disseminated disease in nonimmune-compromised patient. The authors propose a categorization of the diagnosis of CNS histoplasmosis. Routine diagnostics of sibling species within the H. capsulatum complex proved to be difficult.

Purpose: We assessed the performance of metagenomic next-generation sequencing (mNGS) in the diagnosis of infectious encephalitis and meningitis. Methods: This was a prospective multicenter study. Cerebrospinal fluid samples from patients with viral encephalitis and/or meningitis, tuberculous meningitis, bacterial meningitis, fungal meningitis, and non-central nervous system (CNS) infections were subjected to mNGS. Results: In total, 213 patients with infectious and non-infectious CNS diseases were finally enrolled from November 2016 to May 2019; the mNGS-positive detection rate of definite CNS infections was 57.0%. At a species-specific read number (SSRN) ≥2, mNGS performance in the diagnosis of definite viral encephalitis and/or meningitis was optimal (area under the curve [AUC] = 0.659, 95% confidence interval [CI] = 0.566-0.751); the positivity rate was 42.6%. At a genus-specific read number ≥1, mNGS performance in the diagnosis of tuberculous meningitis (definite or probable) was optimal (AUC=0.619, 95% CI=0.516-0.721); the positivity rate was 27.3%. At SSRNs ≥5 or 10, the diagnostic performance was optimal for definite bacterial meningitis (AUC=0.846, 95% CI = 0.711-0.981); the sensitivity was 73.3%. The sensitivities of mNGS (at SSRN ≥2) in the diagnosis of cryptococcal meningitis and cerebral aspergillosis were 76.92 and 80%, respectively. Conclusion: mNGS of cerebrospinal fluid effectively identifies pathogens causing infectious CNS diseases. mNGS should be used in conjunction with conventional microbiological testing. Trial Registration: Chinese Clinical Trial Registry, ChiCTR1800020442., (Copyright © 2020 Xing, Zhang, Ma, He, Yao, Wang, Qi, Chen, Wu, Wang, Huang, Du, Wang, Wang, Yang and Yu.)

Background: In patients at high risk of opportunistic infections who present with isolated. neurological symptoms, it is lifesaving to consider Central Nervous System Aspergillosis (CNS-A). Ibrutinib use in chronic lymphocytic leukemia (CLL) has previously been associated with CNS-A. We provide a case report of a patient that presented with primary CNS-A on Ibrutinib therapy without any prior pulmonary or local paranasal signs of infection., Case Presentation: 74-year-old Caucasian male with CLL and no prior chemotherapy on ibrutinib for 6 months presented with three months of unsteady gait, occipital headache, and confusion. He has a history of pulmonary sarcoidosis on chronic prednisone 5 mg daily and chronic obstructive pulmonary disease (COPD). He was found to have a "brain abscess" on imaging. Emergent craniotomy confirmed Aspergillus and patient was treated with Voriconazole for 6 months. At six-month follow up, repeat magnetic resonance imaging (MRI) confirmed complete resolution of CNS lesion., Conclusions: Our case reinforces the importance of being vigilant for isolated CNS-A in CLL patients on ibrutinib who present with neurological symptoms and signs, without prior or co-infection of sino-pulmonary tissue.

A 60-year-old female had a frontal bone intraosseous meningioma resected 10 years previously. On follow up CT head, an enlarging intraosseous frontal bone lesion was noted. This was thought to be a recurrent frontal meningioma. Intraooperatively, she was found to have an abscess deep to the cranioplasty.

Acute infections of the intracranial central nervous system (CNS) often present as neurological emergencies, where missed or delayed diagnosis and treatment can be catastrophic to the patient. Accurate and timely identification of the underlying etiologies, which are critical in directing life-saving therapies, can be achieved through neuroimaging. This article will provide a thorough review of radiologic findings in common infections of the brain, from primarily compartmentalized infections of multimicrobial etiologies, to CNS manifestations of specific immunocompromised-selective pathogens, of herpes simplex virus, and of tuberculosis. We also briefly discuss the epidemiology, etiology, clinical features, treatment guidelines, complications, and long-term sequelae of these infections., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Microbiological diagnosis of central nervous system (CNS) infections is challenging due to limited access to CNS samples, overlap between meningitis and encephalitis, and the multiplicity of pathogens potentially involved. We aimed to estimate the impact of a commercial multiplex PCR assay (FilmArray® meningitis/encephalitis) on the management of patients with suspicion of meningitis or encephalitis, in terms of time to diagnosis, antimicrobial agents use, duration of hospitalization, and costs. This prospective observational study was conducted at Saint Joseph Hospital (Paris, France) from December 2016 to December 2017. All CSF samples sent to the microbiology laboratory for suspicion of meningitis and/or encephalitis, with CSF cells count > 5 cells/μL, were tested by meningitis/encephalitis multiplex PCR assay. One hundred thirty patients were included. The multiplex PCR assay was positive in 33 patients (25%). Main pathogens found were Enterovirus (n = 12), Varicella-Zoster virus (n = 7), Herpes simplex virus-2 (n = 6), and Listeria monocytogenes (n = 3) as main pathogens. The multiplex PCR assay reduced time to microbiological diagnosis by 3.3 ± 1.6 days and allowed an earlier discontinuation of empirical anti-infective drugs in 42 patients (32%) and an earlier hospital discharge in 23 patients (18%), with an estimated saving of 82 hospital days overall, and a management cost reduction of 26,242 € (201 €/patient). The systematic use of the FilmArray® meningitis/encephalitis multiplex PCR assay may allow earlier diagnosis, earlier discontinuation of empirical treatment, reduced duration of stay, and costs reduction.

Listeria monocytogenes is a facultative, intracellular foodborne pathogen that causes listeriosis and is prevalent worldwide. However, our knowledge of this bacterium and the listeriosis it causes is still extremely limited until now. Therefore, this retrospective study of patients in mainland China over 10 years (2008-2017) was performed to better understand the demographic trends and clinical features of listeriosis in China. Both electronic and manual retrieval systems were used to collect the relevant literature on listeriosis in mainland China. A total of 759 cases were reported from 22 provinces. Among the clinical cases, septicemia was the most common presentation (49%), followed by central nervous system infection (25%). The overall case fatality rate was 18%, with a higher rate among neonatal patients (73%). In recent years, listeriosis has been reported annually and even peaked in 2014. The median age of nonperinatal cases was 36 years (range, 0-102), with a predominance of male cases (52%). Sporadic cases were frequent from March to May. Efforts to prevent and control the spread of listeriosis are required through further research and collaborative efforts to improve the capacities of clinical diagnosis and treatment.

CNS infections continue to rise in incidence in conjunction with increases in immunocompromised populations or conditions that contribute to the emergence of pathogens, such as global travel, climate change, and human encroachment on animal territories. The severity and complexity of these diseases is impacted by the diversity of etiologic agents and their routes of neuroinvasion. In this review, we present historical, clinical, and molecular concepts regarding the mechanisms of pathogen invasion of the CNS. We also discuss the structural components of CNS compartments that influence pathogen entry and recent discoveries of the pathways exploited by pathogens to facilitate CNS infections. Advances in our understanding of the CNS invasion mechanisms of different neurotropic pathogens may enable the development of strategies to control their entry and deliver drugs to mitigate established infections., (Copyright © 2019. Published by Elsevier Inc.)