Matthijs C. Brouwer

Background: Immune‐mediated inflammatory responses exacerbate brain injury and affect the prognosis in acute ischemic stroke. Methods: We characterized longitudinal complement activation after acute ischemic stroke using serial plasma samples from 10 patients and 8 controls. Initial markers of classical (C1q), lectin (mannose‐binding lectin), and alternative (complement factor Bb) pathways, as well as regulatory (complement factor H) and downstream markers (C3a, C5a, and C5b‐9) were measured by ELISA at 9 time points. Results: Patients with stroke showed broad complement activation, with increased C1q, mannose‐binding lectin, complement factor Bb, C3a, C5a, and C5b‐9, and reduced complement factor H compared with controls. Complement components showed distinct temporal patterns during follow‐up. Complement factor Bb levels were lower in patients with unfavorable functional outcome and in those with moderate‐to‐severe stroke. C1q and C3a trajectories differed according to functional outcome, whereas C3a trajectories also differed according to stroke severity. C1q trajectories differed according to age group and infarct volume. Conclusions: These findings suggest dynamic, pathway‐specific complement activation after acute ischemic stroke and highlight the need for larger studies to clarify its prognostic and therapeutic relevance.

Several scoring methods have been developed to identify critically ill patients with suspected sepsis who may benefit from intensive care treatment. We studied the prognostic value of the Systemic Inflammatory Response Syndrome (SIRS) criteria and the quick Sequential related Organ Failure Assessment (qSOFA) score in patients with (suspected) central nervous system (CNS) infections. We included adult patients from two prospective cohort studies consisting of (1) patients who underwent a lumbar puncture for the suspicion of a CNS infection and (2) patients with confirmed bacterial meningitis. The primary outcome was Intensive Care Unit (ICU) admission. We calculated sensitivity, specificity, and area under the curve (AUC) for the SIRS score of > 2 and a qSOFA of > 2. From April 2007 to May 2022, 629 patients with a suspected CNS infection, and 326 patients with a bacterial meningitis were evaluated. 78 of 629 (12%) episodes with a suspected CNS infection were admitted to the ICU, and 197 of 326 (60%) with bacterial meningitis. The SIRS criteria showed a sensitivity of 81% (95%CI 70–89%) with a specificity of 48% (95%CI 44–52%) in patients with suspected CNS infection. Sensitivity of the qSOFA score was 67% (95%CI 55–77%) with a specificity of 82% (95%CI 78–85%) in the same cohort. The SIRS criteria showed a sensitivity of 94% (95%CI 89–97%) and specificity of 9% (95%CI 5–15%) in patients with bacterial meningitis. The qSOFA score had a sensitivity of 59% (95%CI 52–66%) and specificity of 52% (95%CI 43–61%) in bacterial meningitis patients. In patients with a suspected CNS infection the qSOFA score was more accurate than the SIRS criteria as a risk stratification tool for ICU admission. SIRS criteria and qSOFA score showed a poor performance for the prediction of ICU admission in bacterial meningitis patients. The limited value of SIRS and qSOFA criteria in these patient populations should be acknowledged and use in clinical practice should be approached with caution.

Background and Objectives: Recognition of autoimmune encephalitis (AIE) can be difficult as typical radiological or cerebrospinal fluid abnormalities may be lacking. We investigated the yield of comprehensive diagnostic testing for anti‐neuronal antibodies in patients suspected of encephalitis in an acute setting. Methods: In a prospective multicenter cohort, we included patients suspected of encephalitis in whom a lumbar puncture was performed. We retrospectively selected patients from this cohort in whom no infectious cause was identified and an autoimmune CNS disease was considered. Immunohistochemistry was performed on the CSF samples as an index test to screen for anti‐neuronal antibodies, and confirmatory cell‐based assays were performed. Results: Between 2017 and 2021, 723 episodes were included in 707 patients. The median age was 55 years, and 347 (48%) of the episodes occurred in women. In 59 of 723 episodes (8%), a clinical diagnosis of autoimmune CNS disease was made. Twenty‐three (3%) of them fulfilled the diagnostic criteria for possible AIE, and 9 (1%) had antibody‐positive AIE (five anti‐NMDAR encephalitis, two anti‐LGi1 encephalitis, one anti‐Ma2 encephalitis and anti‐CV2 encephalitis). Extensive antibody testing identified no additional anti‐neuronal antibodies in the remaining 47 episodes. Discussion: In a cohort of patients with a suspected encephalitis presenting in an acute setting, the incidence of possible AIE was low, and in only one‐third of possible AIE episodes an anti‐neuronal antibody was detected. Anti‐neuronal antibody testing beyond what was done in the clinical setting did not yield additional cases of antibody‐positive AIE.

Long-term cognitive impairment is observed in 14%-32% of patients surviving community-acquired bacterial meningitis. We hypothesized that the impairment might be linked to secondary immune activation due to the development of neuronal autoantibodies, similar to postinfectious autoimmune encephalitis after viral encephalitis. In this cross-sectional observational study, we included adult patients from a prospective, nationwide cohort study of community-acquired bacterial meningitis in the Netherlands, the MeninGene study. The presence of neuronal autoantibodies was evaluated in follow-up serum samples at 7 days, at 3 months, or over a year. Immunohistochemistry on complete rat brain slices was performed for the initial screening. If positive or ambiguous, immunocytochemistry using live primary rat hippocampal neurons and cell-based assays expressing extracellular targets were performed; immunoblots were used for intracellular targets. In total, 118 patients were included, of whom 24 of 100 (24%) had cognitive impairment and 14 of 109 (13%) had focal neurologic deficits at discharge. Causative pathogens were Streptococcus pneumoniae in 98 patients (83%), Neisseria meningitidis in 4 (3%), and other pathogens in 6 (5%); in 10 patients (9%), no causative pathogen was identified. Two of 118 patients (2%) had neuronal autoantibodies in follow-up serum: 1 had leucine-rich glioma inactivated 1 antibodies, and 1 had unspecified antibodies. None of the patients was positive for NMDA receptor antibodies. There was no clear evidence of postinfectious autoimmune encephalitis after bacterial meningitis. Therefore, acute brain damage caused by the infection itself seems to be the most plausible explanation for long-term cognitive impairment and neurologic disabilities.

Objective: To assess the diagnostic accuracy of metabolites in cerebrospinal fluid (CSF) for central nervous system (CNS) infections. Methods: Patients were derived from three prospective cohort studies in the Netherlands. All studies included adults suspected of a CNS infection who underwent a diagnostic lumbar puncture. Metabolomics was performed on CSF using ultra‐high‐performance liquid chromatography with tandem mass spectrometry on a discovery and validation cohort. Metabolite quantification was the index test; a microbiologically confirmed diagnosis was the reference standard. Results: In total, 343 episodes were included, of whom 170 (50%) had a CNS infections and 173 (50%) episodes had other diagnoses. CNS infections included bacterial meningitis in 88 (26%), viral meningoencephalitis in 50 (15%), and other CNS infections in 32 (9%) episodes. Other diagnoses consisted of CNS autoimmune disorders in 21 (6%), other neurological diseases in 84 (24%), and systemic infections in 68 (20%) episodes. A distinct metabolomic profile was observed in CSF of CNS infections, particularly bacterial meningitis. Glucose, glycerate, 1.3‐diphosphoglyceric acid, pyruvate, lactate, taurine, and alpha‐ketoglutarate had the highest diagnostic accuracy (area under the curve 0.87 to 0.95). Combinations further improved diagnostic accuracy, resulting in models that outperformed both individual metabolites and CSF leukocytes. Episodes with CSF leukocytes between 5 and 1,000 cells per mm ³ showed similar results. Interpretation: CSF metabolites demonstrate high diagnostic accuracy for CNS infections, particularly bacterial meningitis. Combinations further improve the diagnostic performance, exceeding that of CSF leukocytes alone. These findings highlight the potential of cerebrospinal fluid metabolites to improve diagnostic accuracy in clinical practice. ANN NEUROL 2025;98:851–863