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Clinical Microbiology Reviews Apr 2022Neonatal bacterial meningitis is a devastating disease, associated with high mortality and neurological disability, in both developed and developing countries.... (Review)
Review
Neonatal bacterial meningitis is a devastating disease, associated with high mortality and neurological disability, in both developed and developing countries. Streptococcus agalactiae, commonly referred to as group B Streptococcus (GBS), remains the most common bacterial cause of meningitis among infants younger than 90 days. Maternal colonization with GBS in the gastrointestinal and/or genitourinary tracts is the primary risk factor for neonatal invasive disease. Despite prophylactic intrapartum antibiotic administration to colonized women and improved neonatal intensive care, the incidence and morbidity associated with GBS meningitis have not declined since the 1970s. Among meningitis survivors, a significant number suffer from complex neurological or neuropsychiatric sequelae, implying that the pathophysiology and pathogenic mechanisms leading to brain injury and devastating outcomes are not yet fully understood. It is imperative to develop new therapeutic and neuroprotective approaches aiming at protecting the developing brain. In this review, we provide updated clinical information regarding the understanding of neonatal GBS meningitis, including epidemiology, diagnosis, management, and human evidence of the disease's underlying mechanisms. Finally, we explore the experimental models used to study GBS meningitis and discuss their clinical and physiologic relevance to the complexities of human disease.
Topics: Anti-Bacterial Agents; Female; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Meningitis, Bacterial; Streptococcal Infections; Streptococcus agalactiae
PubMed: 35170986
DOI: 10.1128/cmr.00079-21 -
Biomarkers in Medicine Apr 2020Infectious meningitis can be caused by viral, bacterial or fungal pathogens. Despite widely available treatments, many types of infectious meningitis are still... (Review)
Review
Infectious meningitis can be caused by viral, bacterial or fungal pathogens. Despite widely available treatments, many types of infectious meningitis are still associated with significant morbidity and mortality. Delay in diagnosis contributes to poor outcomes. Cerebrospinal fluid cultures have been used traditionally but are time intensive and sensitivity is decreased by empiric treatment prior to culture. More rapid techniques such as the cryptococcal lateral flow assay (IMMY), GeneXpert MTB/Rif Ultra (Cepheid) and FilmArray multiplex-PCR (Biofire) are three examples that have drastically changed meningitis diagnostics. This review will discuss a holistic approach to diagnosing bacterial, mycobacterial, viral and fungal meningitis.
Topics: Adult; Diagnostic Techniques and Procedures; Humans; Meningitis; Time Factors
PubMed: 32270693
DOI: 10.2217/bmm-2019-0333 -
Continuum (Minneapolis, Minn.) Oct 2018This article describes the clinical presentation, diagnostic approach (including the use of novel diagnostic platforms), and treatment of select infectious and... (Review)
Review
PURPOSE OF REVIEW
This article describes the clinical presentation, diagnostic approach (including the use of novel diagnostic platforms), and treatment of select infectious and noninfectious etiologies of chronic meningitis.
RECENT FINDINGS
Identification of the etiology of chronic meningitis remains challenging, with no cause identified in at least one-third of cases. Often, several serologic, CSF, and neuroimaging studies are indicated, although novel diagnostic platforms including metagenomic deep sequencing may hold promise for identifying organisms. Infectious etiologies are more common in those at risk for disseminated disease, specifically those who are immunocompromised because of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), transplantation, or immunosuppressant medications. An important step in identifying the etiology of chronic meningitis is assembling a multidisciplinary team of individuals, including those with specialized expertise in ophthalmology, dermatology, rheumatology, and infectious diseases, to provide guidance regarding diagnostic procedures.
SUMMARY
Chronic meningitis is defined as inflammation involving the meninges that lasts at least 4 weeks and is associated with a CSF pleocytosis. Chronic meningitis has numerous possible infectious and noninfectious etiologies, making it challenging to definitively diagnose patients. Therefore, a multifaceted approach that combines history, physical examination, neuroimaging, and laboratory analysis, including novel diagnostic platforms, is needed. This article focuses on key aspects of the evaluation of and approach to patients with chronic meningitis. Specific infectious etiologies and differential diagnoses of subacute and chronic meningitis, including noninfectious etiologies, are addressed.
Topics: Chronic Disease; Humans; Meningitis
PubMed: 30273241
DOI: 10.1212/CON.0000000000000664 -
Clinical Microbiology and Infection :... May 2016
Topics: Anti-Bacterial Agents; Community-Acquired Infections; Humans; Meningitis, Bacterial; Meningitis, Pneumococcal; Patient Participation; Practice Guidelines as Topic
PubMed: 27062097
DOI: 10.1016/j.cmi.2016.01.007 -
Journal of Leukocyte Biology Feb 2019Tuberculosis (TB) remains a leading cause of death globally. Dissemination of TB to the brain results in the most severe form of extrapulmonary TB, tuberculous... (Review)
Review
Tuberculosis (TB) remains a leading cause of death globally. Dissemination of TB to the brain results in the most severe form of extrapulmonary TB, tuberculous meningitis (TBM), which represents a medical emergency associated with high rates of mortality and disability. Via various mechanisms the Mycobacterium tuberculosis (M.tb) bacillus disseminates from the primary site of infection and overcomes protective barriers to enter the CNS. There it induces an inflammatory response involving both the peripheral and resident immune cells, which initiates a cascade of pathologic mechanisms that may either contain the disease or result in significant brain injury. Here we review the steps from primary infection to cerebral disease, factors that contribute to the virulence of the organism and the vulnerability of the host and discuss the immune response and the clinical manifestations arising. Priorities for future research directions are suggested.
Topics: Central Nervous System; HIV Infections; Humans; Immunity; Mycobacterium tuberculosis; Tuberculosis, Meningeal; Virulence
PubMed: 30645042
DOI: 10.1002/JLB.MR0318-102R -
Microbiology Spectrum Mar 2017Central nervous system tuberculosis (CNS-TB) takes three clinical forms: meningitis (TBM), intracranial tuberculoma, and spinal arachnoiditis. TBM predominates in the... (Review)
Review
Central nervous system tuberculosis (CNS-TB) takes three clinical forms: meningitis (TBM), intracranial tuberculoma, and spinal arachnoiditis. TBM predominates in the western world and presents as a subacute to chronic meningitis syndrome with a prodrome of malaise, fever, and headache progressing to altered mentation and focal neurologic signs, followed by stupor, coma, and death within five to eight weeks of onset. The CSF formula typically shows a lymphocytic pleocytosis, and low glucose and high protein concentrations. Diagnosis rests on serial samples of CSF for smear and culture, combined with CSF PCR. Brain CT and MRI aid in diagnosis, assessment for complications, and monitoring of the clinical course. In a patient with compatible clinical features, the combination of meningeal enhancement and any degree of hydrocephalus is strongly suggestive of TBM. Vasculitis leading to infarcts in the basal ganglia occurs commonly and is a major determinant of morbidity and mortality. Treatment is most effective when started in the early stages of disease, and should be initiated promptly on the basis of strong clinical suspicion without waiting for laboratory confirmation. The initial 4 drug regimen (isoniazid, rifampin, pyrazinamide, ethambutol) covers the possibility of infection with a resistant strain, maximizes antimicrobial impact, and reduces the likelihood of emerging resistance on therapy. Adjunctive corticosteroid therapy has been shown to reduce morbidity and mortality in all but late stage disease.
Topics: Anti-Inflammatory Agents; Antitubercular Agents; Arachnoiditis; Brain; Cerebrospinal Fluid; Humans; Magnetic Resonance Imaging; Mycobacterium; Polymerase Chain Reaction; Tomography, X-Ray Computed; Tuberculoma, Intracranial; Tuberculosis, Meningeal
PubMed: 28281443
DOI: 10.1128/microbiolspec.TNMI7-0044-2017 -
Clinical Microbiology and Infection :... Sep 2017Infections complicating neurosurgery pose unacceptable mortality and morbidity. (Review)
Review
BACKGROUND
Infections complicating neurosurgery pose unacceptable mortality and morbidity.
AIMS
To summarize what is known about the epidemiology, diagnosis and treatment of post-neurosurgical meningitis (PNM).
SOURCES
PubMed, references of identified studies and reviews, and personal experience when evidence was lacking.
CONTENT
The incidence and pathogen distribution of PNM is highly variable. A shift towards Gram-negative bacteria has been observed with use of antibiotic prophylaxis and antibiotic-coated devices directed mainly against Gram-positive bacteria. However, knowledge of the local epidemiology is necessary to treat PNM. The diagnosis of PNM is difficult because, unlike community-acquired meningitis, symptoms are less specific; patients are ill at baseline and many neurosurgical conditions mimic meningitis and cause cerebrospinal fluid (CSF) abnormalities. Pivotal CSF findings for diagnosis of PNM are the CSF glucose, CSF lactate and Gram stain. CSF leucocyte counts are not specific in PNM. Current diagnostic capabilities leave a non-negligible category of patients with microbiologically negative, uncertain diagnosis of PNM. There is no high-quality evidence on several cardinal issues in PNM management, including the effectiveness of intraventricular or intrathecal (IV/IT) antibiotics, effectiveness of dual antibiotic therapy for multidrug-resistant Gram-negative bacteria; clinical benefit of routine therapeutic drug monitoring; and safest timing of shunt replacement. Some data point to a potential benefit of IV/IT antibiotic treatment, mainly for PNM caused by carbapenem-resistant Gram-negative bacteria. Carbapenem-colistin combination therapy is suggested for PNM caused by carbapenem-resistant Gram-negative bacteria with a carbapenem MIC ≤8 mg/L.
IMPLICATIONS
Guiding the optimal management of PNM will necessitate collaborative multicentre efforts and unique study designs.
Topics: Anti-Bacterial Agents; Humans; Injections, Spinal; Meningitis; Neurosurgical Procedures; Postoperative Complications
PubMed: 28529027
DOI: 10.1016/j.cmi.2017.05.013 -
Clinical Microbiology and Infection :... Sep 2017The existing heterogeneity in diagnostic work-up and treatment strategies in bacterial meningitis was the incentive to develop a European evidence-based guideline, which... (Review)
Review
BACKGROUND
The existing heterogeneity in diagnostic work-up and treatment strategies in bacterial meningitis was the incentive to develop a European evidence-based guideline, which was published in 2016 by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group on Infections of the Brain (ESGIB).
AIMS
To summarize salient features of the guideline, identify recent developments and challenges currently faced.
SOURCES
The ESCMID guideline, ongoing trial registries.
CONTENT
Epidemiology, clinical symptoms, diagnostic work-up and therapy strategies of acute bacterial meningitis.
IMPLICATIONS
The incidence of bacterial meningitis has decreased following pneumococcal and meningococcal conjugate vaccine introduction. In the diagnosis of bacterial meningitis the clinical characteristics and laboratory parameters are of limited diagnostic accuracy and therefore cerebrospinal fluid analysis remains the principal contributor to the final diagnosis. The ESCMID guideline advises to start empiric treatment within one hour of arrival in all suspected meningitis cases, and choice of antibiotics needs to be differentiated according to the patient's age, risk factors, and local resistance rates of pneumococci. Dexamethasone is the only proven adjunctive treatment and should be started together with the antibiotics. The follow-up of surviving patients should include evaluation for hearing loss and pneumococcal vaccination to prevent recurrences. Future perspectives include further development and implementation of vaccines, and new treatments aimed at further reducing the inflammatory response. Studies on implementation of the new guideline should determine adherence and evaluate whether improved prognosis can be achieved by following protocolled management strategies.
Topics: Community-Acquired Infections; Humans; Meningitis, Bacterial; Practice Guidelines as Topic
PubMed: 28478238
DOI: 10.1016/j.cmi.2017.04.019 -
The Cochrane Database of Systematic... Apr 2016Tuberculous meningitis is a serious form of tuberculosis (TB) that affects the meninges that cover a person's brain and spinal cord. It is associated with high death... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tuberculous meningitis is a serious form of tuberculosis (TB) that affects the meninges that cover a person's brain and spinal cord. It is associated with high death rates and with disability in people who survive. Corticosteroids have been used as an adjunct to antituberculous drugs to treat people with tuberculous meningitis, but their role has been controversial.
OBJECTIVES
To evaluate the effects of corticosteroids as an adjunct to antituberculous treatment on death and severe disability in people with tuberculous meningitis.
SEARCH METHODS
We searched the Cochrane Infectious Diseases Group Specialized Register up to the 18 March 2016; CENTRAL; MEDLINE; EMBASE; LILACS; and Current Controlled Trials. We also contacted researchers and organizations working in the field, and checked reference lists.
SELECTION CRITERIA
Randomized controlled trials that compared corticosteroid plus antituberculous treatment with antituberculous treatment alone in people with clinically diagnosed tuberculous meningitis and included death or disability as outcome measures.
DATA COLLECTION AND ANALYSIS
We independently assessed search results and methodological quality, and extracted data from the included trials. We analysed the data using risk ratios (RR) with 95% confidence intervals (CIs) and used a fixed-effect model. We performed an intention-to-treat analysis, where we included all participants randomized to treatment in the denominator. This analysis assumes that all participants who were lost to follow-up have good outcomes. We carried out a sensitivity analysis to explore the impact of the missing data.
MAIN RESULTS
Nine trials that included 1337 participants (with 469 deaths) met the inclusion criteria.At follow-up from three to 18 months, steroids reduce deaths by almost one quarter (RR 0.75, 95% CI 0.65 to 0.87; nine trials, 1337 participants, high quality evidence). Disabling neurological deficit is not common in survivors, and steroids may have little or no effect on this outcome (RR 0.92, 95% CI 0.71 to 1.20; eight trials, 1314 participants, low quality evidence). There was no difference between groups in the incidence of adverse events, which included gastrointestinal bleeding, invasive bacterial infections, hyperglycaemia, and liver dysfunction.One trial followed up participants for five years. The effect on death was no longer apparent at this time-point (RR 0.93, 95% CI 0.78 to 1.12; one trial, 545 participants, moderate quality evidence); and there was no difference in disabling neurological deficit detected (RR 0.91, 95% CI 0.49 to 1.69; one trial, 545 participants, low quality evidence).One trial included human immunodeficiency virus (HIV)-positive people. The stratified analysis by HIV status in this trial showed no heterogeneity, with point estimates for death (RR 0.90, 95% CI 0.67 to 1.20; one trial, 98 participants) and disability (RR 1.23, 95% CI 0.08 to 19.07; one trial, 98 participants) similar to HIV-negative participants in the same trial.
AUTHORS' CONCLUSIONS
Corticosteroids reduce mortality from tuberculous meningitis, at least in the short term.Corticosteroids may have no effect on the number of people who survive tuberculous meningitis with disabling neurological deficit, but this outcome is less common than death, and the CI for the relative effect includes possible harm. However, this small possible harm is unlikely to be quantitatively important when compared to the reduction in mortality.The number of HIV-positive people included in the review is small, so we are not sure if the benefits in terms of reduced mortality are preserved in this group of patients.
Topics: Adult; Antitubercular Agents; Chemotherapy, Adjuvant; Child; Dexamethasone; Glucocorticoids; Humans; Hydrocortisone; Intention to Treat Analysis; Prednisolone; Randomized Controlled Trials as Topic; Tuberculosis, Meningeal
PubMed: 27121755
DOI: 10.1002/14651858.CD002244.pub4 -
The New England Journal of Medicine Jun 2019Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test.
BACKGROUND
Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test.
METHODS
In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review.
RESULTS
We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment.
CONCLUSIONS
Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.).
Topics: Adolescent; Adult; Cerebrospinal Fluid; Child; Child, Preschool; Encephalitis; Female; Genome, Microbial; High-Throughput Nucleotide Sequencing; Humans; Infant; Infections; Length of Stay; Male; Meningitis; Meningoencephalitis; Metagenomics; Middle Aged; Myelitis; Prospective Studies; Sequence Analysis, DNA; Sequence Analysis, RNA; Young Adult
PubMed: 31189036
DOI: 10.1056/NEJMoa1803396