Molecular diagnostics in cerebrospinal fluid for the diagnosis of central nervous system infections.

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.

Human Listeriosis.

Listeria monocytogenes is a Gram-positive facultative intracellular pathogen that can cause severe invasive infections upon ingestion with contaminated food. Clinically, listerial disease, or listeriosis, most often presents as bacteremia, meningitis or meningoencephalitis, and pregnancy-associated infections manifesting as miscarriage or neonatal sepsis. Invasive listeriosis is life-threatening and a main cause of foodborne illness leading to hospital admissions in Western countries. Sources of contamination can be identified through international surveillance systems for foodborne bacteria and strains' genetic data sharing. Large-scale whole genome studies have increased our knowledge on the diversity and evolution of L. monocytogenes, while recent pathophysiological investigations have improved our mechanistic understanding of listeriosis. In this article, we present an overview of human listeriosis with particular focus on relevant features of the causative bacterium, epidemiology, risk groups, pathogenesis, clinical manifestations, and treatment and prevention.

Analysis of >3400 worldwide eggplant accessions reveals two independent domestication events and multiple migration-diversification routes.

Eggplant (Solanum melongena) is an important Solanaceous crop, widely cultivated and consumed in Asia, the Mediterranean basin, and Southeast Europe. Its domestication centers and migration and diversification routes are still a matter of debate. We report the largest georeferenced and genotyped collection to this date for eggplant and its wild relatives, consisting of 3499 accessions from seven worldwide genebanks, originating from 105 countries in five continents. The combination of genotypic and passport data points to the existence of at least two main centers of domestication, in Southeast Asia and the Indian subcontinent, with limited genetic exchange between them. The wild and weedy eggplant ancestor S. insanum shows admixture with domesticated S. melongena, similar to what was described for other fruit-bearing Solanaceous crops such as tomato and pepper and their wild ancestors. After domestication, migration and admixture of eggplant populations from different regions have been less conspicuous with respect to tomato and pepper, thus better preserving 'local' phenotypic characteristics. The data allowed the identification of misclassified and putatively duplicated accessions, facilitating genebank management. All the genetic, phenotypic, and passport data have been deposited in the Open Access G2P-SOL database, and constitute an invaluable resource for understanding the domestication, migration and diversification of this cosmopolitan vegetable.

Multi-environment association study highlights candidate genes for robust agronomic quantitative trait loci in a novel worldwide Capsicum core collection.

Investigating crop diversity through genome-wide association studies (GWAS) on core collections helps in deciphering the genetic determinants of complex quantitative traits. Using the G2P-SOL project world collection of 10 038 wild and cultivated Capsicum accessions from 10 major genebanks, we assembled a core collection of 423 accessions representing the known genetic diversity. Since complex traits are often highly dependent upon environmental variables and genotype-by-environment (G × E) interactions, multi-environment GWAS with a 10 195-marker genotypic matrix were conducted on a highly diverse subset of 350 Capsicum annuum accessions, extensively phenotyped in up to six independent trials from five climatically differing countries. Environment-specific and multi-environment quantitative trait loci (QTLs) were detected for 23 diverse agronomic traits. We identified 97 candidate genes potentially implicated in 53 of the most robust and high-confidence QTLs for fruit flavor, color, size, and shape traits, and for plant productivity, vigor, and earliness traits. Investigating the genetic architecture of agronomic traits in this way will assist the development of genetic markers and pave the way for marker-assisted selection. The G2P-SOL pepper core collection will be available upon request as a unique and universal resource for further exploitation in future gene discovery and marker-assisted breeding efforts by the pepper community.

Otitis in Patients With Community-Acquired Bacterial Meningitis: A Nationwide Prospective Cohort Study.

BACKGROUND: Otitis is commonly associated with community-acquired bacterial meningitis, but the role of ear surgery as treatment is debated. In this study, we investigated the impact of otitis and ear surgery on outcome of adults with community-acquired bacterial meningitis. METHODS: We analyzed episodes of adults with community-acquired bacterial meningitis from a nationwide prospective cohort study in the Netherlands, between March 2006 and July 2021. RESULTS: A total of 2548 episodes of community-acquired bacterial meningitis were evaluated. Otitis was present in 696 episodes (27%). In these patients the primary causative pathogen was Streptococcus pneumoniae (615 of 696 [88%]), followed by Streptococcus pyogenes (5%) and Haemophilus influenzae (4%). In 519 of 632 otitis episodes (82%) an ear-nose-throat specialist was consulted, and surgery was performed in 287 of 519 (55%). The types of surgery performed were myringotomy with ventilation tube insertion in 110 of 287 episodes (38%), mastoidectomy in 103 of 287 (36%), and myringotomy alone in 74 of 287 (26%). Unfavorable outcome occurred in 210 of 696 episodes (30%) and in 65 of 696 episodes was fatal (9%). Otitis was associated with a favorable outcome in a multivariable analysis (odds ratio 0.74; 95% confidence interval [CI] .59-.92; P = .008). There was no association between outcome and ear surgery. CONCLUSIONS: Otitis is a common focus of infection in community-acquired bacterial meningitis in adults, with S. pneumoniae being the most common causative pathogen. Presence of otitis is associated with a favorable outcome. Ear surgery's impact on the outcome of otogenic meningitis patients remains uncertain.

Allelic variation in the autotetraploid potato: genes involved in starch and steroidal glycoalkaloid metabolism as a case study.

BACKGROUND: Tuber starch and steroidal glycoalkaloid (SGA)-related traits have been consistently prioritized in potato breeding, while allelic variation pattern of genes that underlie these traits is less explored. RESULTS: Here, we focused on the genes involved in two important metabolic pathways in the potato: starch metabolism and SGA biosynthesis. We identified 119 genes consisting of 81 involved in starch metabolism and 38 in the biosynthesis of steroidal glycoalkaloids, and discovered 96,166 allelic variants among 2,169 gene haplotypes in six autotetraploid potato genomes. Comparative analyses revealed an uneven distribution of allelic variants among gene haplotypes and that the vast majority of deleterious mutations in these genes are retained in heterozygous state in the autotetraploid potato genomes. Leveraging full-length cDNA sequencing data, we find that approximately 70% of haplotypes of the 119 genes are transcribable. Population genetic analyses identify starch and SGA biosynthetic genes that are potentially conserved or diverged between potato varieties with varying starch or SGA content. CONCLUSIONS: These results deepen the understanding of haplotypic diversity within functionally important genes in autotetraploid genomes and may facilitate functional characterization of genes or haplotypes contributing to traits related to starch and SGA in potato.

Noncompressive myelopathy in acute community-acquired bacterial meningitis: Report of seven cases and review of literature.

BACKGROUND AND PURPOSE: Bacterial meningitis is a severe disease with high rates of complications and unfavorable outcome. Complications involving the spinal cord are rarely reported. METHODS: Cases of noncompressive myelopathy were identified from a nationwide cohort study of adults with community-acquired bacterial meningitis in the Netherlands. The American Spinal Injury Association Impairment Scale was used to classify the severity of spinal cord dysfunction. Subsequently, we reviewed the literature on noncompressive myelopathy as a complication of bacterial meningitis. RESULTS: Noncompressive myelopathy was reported in seven of 3047 episodes of community-acquired bacterial meningitis (0.2%). The median age of these patients was 51 years (range = 17-77). Causative pathogens were Streptococcus pneumoniae in three, Streptococcus agalactiae in two, and Neisseria meningitidis and Haemophilus influenzae both in one. Paresis of legs (n = 6) or arms and legs (n = 1) was the presenting symptom, occurring after a median duration of 9 days after admission (range = 2-28). Spinal magnetic resonance imaging showed T2-weighted abnormalities of the spinal cord in six of seven patients. Improvement of spinal cord function during admission was noted in four of seven patients. The literature review yielded 15 additional cases. Among patients from our cohort and the literature, there was no significant association between immunosuppressive therapy and subsequent improvement of spinal cord function (5/8 patients with immunosuppressive therapy [63%] vs. 5/14 without immunosuppressive therapy [36%], p = 0.44). CONCLUSIONS: Noncompressive myelopathy is an uncommon but severe complication of bacterial meningitis. Improvement after diagnosis is expected, but all patients had persistent neurological deficits.

Coma in adult cerebral venous thrombosis: The BEAST study.

BACKGROUND AND PURPOSE: Coma is an independent predictor of poor clinical outcomes in cerebral venous thrombosis (CVT). We aimed to describe the association of age, sex, and radiological characteristics of adult coma patients with CVT. METHODS: We used data from the international, multicentre prospective observational BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis) study. Only positively associated variables with coma with <10% missing data in univariate analysis were considered for the multivariate logistic regression model. RESULTS: Of the 596 adult patients with CVT (75.7% women), 53 (8.9%) patients suffered coma. Despite being a female-predominant disease, the prevalence of coma was higher among men than women (13.1% vs. 7.5%, p = 0.04). Transverse sinus thrombosis was least likely to be associated with coma (23.9% vs. 73.3%, p < 0.001). The prevalence of superior sagittal sinus thrombosis was higher among men than women in the coma sample (73.6% vs. 37.5%, p = 0.01). Men were significantly older than women, with a median (interquartile range) age of 51 (38.5-60) versus 40 (33-47) years in the coma (p = 0.04) and 44.5 (34-58) versus 37 (29-48) years in the non-coma sample (p < 0.001), respectively. Furthermore, an age- and superior sagittal sinus-adjusted multivariate logistic regression model found male sex (odds ratio = 1.8, 95% confidence interval [CI] = 1.0-3.4, p = 0.04) to be an independent predictor of coma in CVT, with an area under the receiver operating characteristic curve of 0.61 (95% CI = 0.52-0.68, p = 0.01). CONCLUSIONS: Although CVT is a female-predominant disease, men were older and nearly twice as likely to suffer from coma than women.

Effect of the COVID-19 pandemic on clinical characteristics and outcomes of adult pneumococcal meningitis patients - a Dutch prospective nationwide cohort study.

PURPOSE: To investigate clinical characteristics and outcomes of patients with pneumococcal meningitis during the COVID-19 pandemic. METHODS: In a Dutch prospective cohort, risk factors and clinical characteristics of pneumococcal meningitis episodes occurring during the COVID-19 pandemic (starting March 2020) were compared with those from baseline and the time afterwards. Outcomes were compared with an age-adjusted logistic regression model. RESULTS: We included 1,699 patients in 2006-2020, 50 patients in 2020-2021, and 182 patients in 2021-2023. After March 2020 relatively more alcoholism was reported (2006-2020, 6.1%; 2020-2021, 18%; 2021-2023, 9.7%; P = 0.002) and otitis-sinusitis was less frequently reported (2006-2020, 45%; 2020-2021, 22%; 2021-2023, 47%; P = 0.006). Other parameters, i.e. age, sex, symptom duration or initial C-reactive protein level, remained unaffected. Compared to baseline, lumbar punctures were more frequently delayed (on admission day, 2006-2020, 89%; 2020-2021, 74%; 2021-2022, 86%; P = 0.002) and outcomes were worse ('good recovery', 2020-2021, OR 0.5, 95% CI 0.3-0.8). CONCLUSION: During the COVID-19 pandemic, we observed worse outcomes in patients with pneumococcal meningitis. This may be explained by differing adherence to restrictions according to risk groups or by reduced health care quality.

Granulocytes in cerebrospinal fluid of adults suspected of a central nervous system infection: a prospective study of diagnostic accuracy.

PURPOSE: Cerebrospinal fluid (CSF) granulocytes are associated with bacterial meningitis, but information on its diagnostic value is limited and primarily based on retrospective studies. Therefore, we assessed the diagnostic accuracy of CSF granulocytes. METHODS: We analyzed CSF granulocytes (index test) from all consecutive patients in two prospective cohort studies in the Netherlands. Both studies included patients ≥ 16 years, suspected of a central nervous system (CNS) infection, who underwent a diagnostic lumbar puncture. All episodes with elevated CSF leukocytes (≥ 5 cells per mm3) were selected and categorized by clinical diagnosis (reference standard). RESULTS: Of 1261 episodes, 625 (50%) had elevated CSF leukocytes and 541 (87%) were included. 117 of 541 (22%) were diagnosed with bacterial meningitis, 144 (27%) with viral meningoencephalitis, 49 (9%) with other CNS infections, 76 (14%) with CNS autoimmune disorders, 93 (17%) with other neurological diseases and 62 (11%) with systemic diseases. The area under the curve to discriminate bacterial meningitis from other diagnoses was 0.97 (95% confidence interval [CI] 0.95-0.98) for CSF granulocyte count and 0.93 (95% CI 0.91-0.96) for CSF granulocyte percentage. CSF granulocyte predominance occurred in all diagnostic categories. A cutoff at 50% CSF granulocytes gave a sensitivity of 94% (95% CI 90-98), specificity of 80% (95% CI 76-84), negative predictive value of 98% (95% CI 97-99) and positive predictive value of 57% (95% CI 52-62). CONCLUSION: CSF granulocytes have a high diagnostic accuracy for bacterial meningitis in patients suspected of a CNS infection. CSF granulocyte predominance occurred in all diagnostic categories, limiting its value in clinical practice.

Pericytes are protective in experimental pneumococcal meningitis through regulating leukocyte infiltration and blood-brain barrier function.

BACKGROUND: Brain pericytes participate in the regulation of cerebral blood flow and the maintenance of blood-brain barrier integrity. Because of their perivascular localization, their receptor repertoire, and their potential ability to respond to inflammatory and infectious stimuli by producing various cytokines and chemokines, these cells are also thought to play an active role in the immune response to brain infections. This assumption is mainly supported by in vitro studies, investigations in in vivo disease models are largely missing. Here, we analysed the role of brain pericytes in pneumococcal meningitis, in vitro and in vivo in two animal models of pneumococcal meningitis. METHODS: Primary murine and human pericytes were stimulated with increasing concentrations of different serotypes of Streptococcus pneumoniae in the presence or absence of Toll-like receptor inhibitors and their cell viability and cytokine production were monitored. To gain insight into the role of pericytes in brain infection in vivo, we performed studies in a zebrafish embryo model of pneumococcal meningitis in which pericytes were pharmacologically depleted. Furthermore, we analyzed the impact of genetically induced pericyte ablation on disease progression, intracranial complications, and brain inflammation in an adult mouse model of this disease. RESULTS: Both murine and human pericytes reacted to pneumococcal exposure with the release of selected cytokines. This cytokine release is pneumolysin-dependent, TLR-dependent in murine (but not human) pericytes and can be significantly increased by macrophage-derived IL-1b. Pharmacological depletion of pericytes in zebrafish embryos resulted in increased cerebral edema and mortality due to pneumococcal meningitis. Correspondingly, in an adult mouse meningitis model, a more pronounced blood-brain barrier disruption and leukocyte infiltration, resulting in an unfavorable disease course, was observed following genetic pericyte ablation. The degree of leukocyte infiltration positively correlated with an upregulation of chemokine expression in the brains of pericyte-depleted mice. CONCLUSIONS: Our findings show that pericytes play a protective role in pneumococcal meningitis by impeding leukocyte migration and preventing blood-brain barrier breaching. Thus, preserving the integrity of the pericyte population has the potential as a new therapeutic strategy in pneumococcal meningitis.

Sex and Gender Differences in Bacterial Infections.

There is a growing awareness of the importance of sex and gender in medicine and research. Women typically have stronger immune responses to self and foreign antigens than men, resulting in sex-based differences in autoimmunity and infectious diseases. In both animals and humans, males are generally more susceptible than females to bacterial infections. At the same time, gender differences in health-seeking behavior, quality of health care, and adherence to treatment recommendations have been reported. This review explores our current understanding of differences between males and females in bacterial diseases. We describe how genetic, immunological, hormonal, and anatomical factors interact to influence sex-based differences in pathophysiology, epidemiology, clinical presentation, disease severity, and prognosis, and how gender roles affect the behavior of patients and providers in the health care system.

Pneumococcal Meningitis in Adults: A Prospective Nationwide Cohort Study Over a 20-year Period.

BACKGROUND: The epidemiology and treatment of pneumococcal meningitis has changed with the implementation of conjugate vaccines and the introduction of adjunctive dexamethasone therapy. METHODS: We analyzed episodes of community-acquired pneumococcal meningitis in adults (≥16 years) in the Netherlands, identified by the National Reference Laboratory for Bacterial Meningitis or treating physician between October 1, 1998, and April 1, 2002, and between January 1, 2006, and July 1, 2018. We studied incidence, pneumococcal serotypes, and clinical features. Predictors for unfavorable outcome (Glasgow Outcome Scale score 1-4) were identified in a multivariable logistic regression model. Two physicians independently categorized causes of death as neurological or systemic. RESULTS: There were 1816 episodes in 1783 patients. The incidence of 7- and 10-7-valent pneumococcal conjugate vaccine serotypes decreased (from 0.42 to 0.06, P = .001; from 0.12 to 0.03 episodes per 100 000 population per year, P = .014). Incidence of nonvaccine serotypes increased (from 0.45 to 0.68, P = .005). The use of adjunctive treatment with dexamethasone increased and was administered in 85% of patients in 2018. In-hospital death occurred in 363 episodes (20%) and unfavorable outcome in 772 episodes (43%). Delayed cerebral thrombosis occurred in 29 patients (2%), of whom 15 patients (52%) died. Adjunctive dexamethasone therapy was associated with favorable outcome (adjusted odds ratio 2.27, P < .001), individual pneumococcal serotypes were not. CONCLUSION: Implementation of conjugate vaccines and adjunctive dexamethasone therapy have changed the incidence and outcome of pneumococcal meningitis in adults over the last two decades. Despite recent advances pneumococcal meningitis remains associated with a residual high rate of mortality and morbidity.

Community-acquired bacterial meningitis.

Progress has been made in the prevention and treatment of community-acquired bacterial meningitis during the past three decades but the burden of the disease remains high globally. Conjugate vaccines against the three most common causative pathogens (Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae) have reduced the incidence of disease, but with the replacement by non-vaccine pneumococcal serotypes and the emergence of bacterial strains with reduced susceptibility to antimicrobial treatment, meningitis continues to pose a major health challenge worldwide. In patients presenting with bacterial meningitis, typical clinical characteristics (such as the classic triad of neck stiffness, fever, and an altered mental status) might be absent and cerebrospinal fluid examination for biochemistry, microscopy, culture, and PCR to identify bacterial DNA are essential for the diagnosis. Multiplex PCR point-of-care panels in cerebrospinal fluid show promise in accelerating the diagnosis, but diagnostic accuracy studies to justify routine implementation are scarce and randomised, controlled studies are absent. Early administration of antimicrobial treatment (within 1 hour of presentation) improves outcomes and needs to be adjusted according to local emergence of drug resistance. Adjunctive dexamethasone treatment has proven efficacy beyond the neonatal age but only in patients from high-income countries. Further progress can be expected from implementing preventive measures, especially the development of new vaccines, implementation of hospital protocols aimed at early treatment, and new treatments targeting checkpoints of the inflammatory cascade.

Genome-Wide Association Study Identifies First Locus Associated with Susceptibility to Cerebral Venous Thrombosis.

OBJECTIVE: Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood. METHODS: A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets. RESULTS: In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 × 10-24 ; odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 × 10-16 ). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 × 10-16 ) increased risk of CVT compared with individuals with blood group O. INTERPRETATION: We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021;90:777-788.

Anti-C5a antibody vilobelimab treatment and the effect on biomarkers of inflammation and coagulation in patients with severe COVID-19: a substudy of the phase 2 PANAMO trial.

We recently reported in the phase 3 PANAMO trial that selectively blocking complement 5a (C5a) with vilobelimab led to improved survival in critically ill COVID-19 patients. C5a is an important contributor to the innate immune system and can also activate the coagulation system. High C5a levels have been reported in severely ill COVID-19 patients and correlate with disease severity and mortality. Previously, we assessed the potential benefit and safety of vilobelimab in severe COVID-19 patients. In the current substudy of the phase 2 PANAMO trial, we aim to explore the effects of vilobelimab on various biomarkers of inflammation and coagulation. Between March 31 and April 24, 2020, 17 patients with severe COVID-19 pneumonia were enrolled in an exploratory, open-label, randomised phase 2 trial. Blood markers of complement, endothelial activation, epithelial barrier disruption, inflammation, neutrophil activation, neutrophil extracellular trap (NET) formation and coagulopathy were measured using enzyme-linked immunosorbent assay (ELISA) or utilizing the Luminex platform. During the first 15 days after inclusion, change in biomarker concentrations between the two groups were modelled with linear mixed-effects models with spatial splines and compared. Eight patients were randomized to vilobelimab treatment plus best supportive care (BSC) and nine patients were randomized to BSC only. A significant decrease over time was seen in the vilobelimab plus BSC group for C5a compared to the BSC only group (p < 0.001). ADAMTS13 levels decreased over time in the BSC only group compared to the vilobelimab plus BSC group (p < 0.01) and interleukin-8 (IL-8) levels were statistically more suppressed in the vilobelimab plus BSC group compared to the BSC group (p = 0.03). Our preliminary results show that C5a inhibition decreases the inflammatory response and hypercoagulability, which likely explains the beneficial effect of vilobelimab in severe COVID-19 patients. Validation of these results in a larger sample size is warranted.

Clinical characteristics and outcome of neurosarcoidosis-associated myelitis: A retrospective cohort study and review of the literature.

BACKGROUND AND PURPOSE: Neurosarcoidosis can affect all parts of the nervous system of which myelitis is relatively frequent. The aim of this study was to describe clinical characteristics, treatment and prognosis of patients with myelitis attributable to neurosarcoidosis. METHODS: We performed a retrospective cohort study and a systematic review and meta-analysis of neurosarcoidosis-associated myelitis. RESULTS: Myelitis was identified in 41 of 153 (27%) neurosarcoidosis patients seen at our clinic from 2015 to 2020. Classification of neurosarcoidosis was definite in three (7%), probable in 29 (71%) and possible in nine patients (22%). The median (interquartile range) age at onset was 49 (41-53) years and 20 of the patients were female (49%). The presenting symptoms included muscle weakness in 31 of 41 patients (78%), sensory loss in 35 (88%) and micturition abnormalities in 30 (75%). Spinal magnetic resonance imaging showed longitudinally extensive myelitis in 27 of 36 patients (75%) and cerebrospinal fluid examination showed an elevated leukocyte count in 21 patients (81%). Initial treatment consisted of glucocorticoids in 38 of 41 patients (93%), with additional methotrexate or azathioprine in 21 of 41 patients (51%) and infliximab in 10 of 41 patients (24%). Treatment led to remission, improvement or stabilization of disease in 37 of 39 patients (95%). Despite treatment, 18 of 30 patients (60%) could not walk independently at the end of follow-up (median 36 months). A review of the literature published between 2000 and 2020 identified 215 patients with comparable clinical characteristics and results of ancillary investigations. CONCLUSION: Sarcoidosis-associated myelitis is observed in 27% of neurosarcoidosis patients. Although treatment often led to a decrease in disease activity, residual neurological deficits leading to loss of ambulation occurred frequently.

Subarachnoid Hemorrhage in Bacterial Meningitis Patients.

INTRODUCTION: Subarachnoid hemorrhage (SAH) has been described as an uncommon complication of community-acquired bacterial meningitis. However, the incidence, clinical course, and outcome are unclear. METHODS: We assessed the clinical characteristics, incidence, and clinical outcome of patients with SAH complicating bacterial meningitis in a prospective nationwide cohort study from 2006 to 2018 in the Netherlands. Patients were identified through the Netherlands Reference Laboratory for Bacterial Meningitis, which receives around 90% of CSF isolates of all Dutch patients with bacterial meningitis, or after direct report by the treating physician. RESULTS: SAH was diagnosed in 22 of 2,306 episodes (0.9%), of which 7 (32%) were diagnosed upon admission and 15 (68%) during admission. All patients showed clinical deterioration before SAH was diagnosed: altered mental status in 18 of 22 patients (82%), focal neurological symptoms in 2 (9%) and, new-onset fever with severe tachycardia in 1 (5%). Acute onset of headache was not reported in any of the patients. Distribution of blood was diffuse in the subarachnoid space in 7 patients (32%), multifocal in 8 patients (36%), and focal in 7 patients (32%) of 22 patients. In 6 patients (27%), CT angiography, MR angiography, or digital subtraction angiography was performed, showing a mycotic aneurysm in 1 patient (5%) and vasculitis in 1 patient (5%). Presence of SAH in bacterial meningitis patients was associated with a poor prognosis assessed at discharge: 12 of 22 patients with SAH died (54%) compared to 361 of 2,257 (16%, p < 0.001) without SAH, and 19 of 22 had an unfavorable outcome (86%) compared to 831 of 2,257 (37%, p < 0.001). CONCLUSION: SAH is an uncommon complication in bacterial meningitis and is associated with high case fatality and morbidity.

Seizures in adults with suspected central nervous system infection.

BACKGROUND: Seizures can be part of the clinical presentation of central nervous system (CNS) infections. We describe patients suspected of a neurological infection who present with a seizure and study diagnostic accuracy of clinical and laboratory features predictive of CNS infection in this population. METHODS: We analyzed all consecutive patients presenting with a seizure from two prospective Dutch cohort studies, in which patients were included who underwent cerebrospinal fluid (CSF) examination because of the suspicion of a CNS infection. RESULTS: Of 900 episodes of suspected CNS infection, 124 (14%) presented with a seizure. The median age in these 124 episodes was 60 years (IQR 45-71) and 53% of patients was female. CSF examination showed a leukocyte count ≥ 5/mm3 in 41% of episodes. A CNS infection was diagnosed in 27 of 124 episodes (22%), a CNS inflammatory disorder in 8 (6%) episodes, a systemic infection in 10 (8%), other neurological disease in 77 (62%) and in 2 (2%) episodes another systemic disease was diagnosed. Diagnostic accuracy of clinical and laboratory characteristics for the diagnosis of CNS infection in this population was low. CSF leukocyte count was the best predictor for CNS infection in patients with suspected CNS infection presenting with a seizure (area under the curve 0.94, [95% CI 0.88 - 1.00]). CONCLUSIONS: Clinical and laboratory features fail to distinguish CNS infections from other causes of seizures in patients with a suspected CNS infection. CSF leukocyte count is the best predictor for the diagnosis of CNS infection in this population.

Recurrent Community-Acquired Bacterial Meningitis in Adults.

BACKGROUND: Recurrent bacterial meningitis has been found to occur in about 5% of meningitis cases. METHODS: We analyzed adults with recurrent episodes in a prospective nationwide cohort study of community-acquired bacterial meningitis. RESULTS: Of 2264 episodes of community-acquired bacterial meningitis between 2006 and 2018, 143 (6%) were identified as recurrent episodes in 123 patients. The median age was 57 years (interquartile range [IQR], 43-66), and 57 episodes (46%) occurred in men. The median duration between the first and the current episode was 5 years (IQR, 1-15). For 82 of 123 patients (67%), it was the first recurrent episode, 31 patients had 2-5 previous episodes (25%), 2 had 6-10 episodes (2%), and 2 had >10 episodes (2%). Predisposing factors were identified in 87 of 118 patients (74%) and most commonly consisted of ear or sinus infections (43 of 120, 36%) and cerebrospinal fluid leakage (37 of 116, 32%). The most common pathogens were Streptococcus pneumoniae (93 of 143, 65%) and Haemophilus influenzae (19 of 143, 13%). The outcome was unfavorable (Glasgow outcome scale score, <5) in 24 episodes with recurrent meningitis (17%) vs 810 for nonrecurrent meningitis patients (39%, P < .001). Six of 143 died (4%) vs 362 of 2095 patients (17%, P < .001). CONCLUSIONS: Recurrent meningitis occurs mainly in patients with ear or sinus infections and cerebrospinal fluid leakage. Predominant causative pathogens are S. pneumoniae and H. influenzae. The disease course is less severe, resulting in lower case fatality compared with nonrecurrent meningitis patients.