Central Nervous System Infection Research Articles

Metagenomic next-generation sequencing for diagnosis of infectious encephalitis and meningitis: a retrospective study of 90 patients

ABSTRACT Background Infections of the central nervous system (CNS) are potentially life-threatening and can cause serious morbidity. We evaluated the clinical value of metagenomic next-generation sequencing (mNGS) in the diagnosis of infectious encephalitis and meningitis and explored the factors affecting the results of mNGS. Methods Patients with suspected cases of encephalitis or meningitis who presented in Northern Jiangsu People’s Hospital from 1 March 2018 to 30 September 2022 were collected. Demographic, historical, and clinical information were obtained, and cerebrospinal fluid (CSF) samples were treated with mNGS. The pathogen was identified using National Center for Biotechnology Information (NCBI) GenBank sequence data. Results Ninety-six patients were screened and finally 90 subjects enrolled. Of the 90 enrolled cases, 67 (74.4%) were diagnosed with central nervous system infections, which included 48 cases (71.6%) of viral infection, 11 (12.2%) of bacterial infection, 5 (7.5%) of mycobacterium tuberculosis, 2 (3.0%) of fungal infection, and 1 (1.5%) of rickettsia infection. From these cases, mNGS identified 40 (44.4%) true-positive cases, 3 (3.3%) false-positive case, 22 (24.4%) true-negative cases, and 25 (27.8%) false-negative cases. The sensitivity and specificity of mNGS were 61.5% and 88%, respectively. mNGS of CSF could show a higher positive rate in patients with marked CSF abnormalities, including elevated protein concentrations and monocyte counts. Conclusion mNGS of CSF is an effective method for detecting infectious encephalitis and meningitis, and the results should be analyzed combined with conventional microbiological testing results.

Neither Conditioning Chemotherapy Nor GvHD-Prophylaxis: CD7 CAR-T Treatment Bridging to Haplo-HSCT

BACKGROUND: Relapsed/refractory (R/R) acute leukemia patients ineligible for allo-HSCT have poor prognosis. CAR-T therapy has shown promising therapeutic outcomes for these patients, but simultaneously confers the risk of pancytopenia and potential tumor relapse. Bridging CAR-T therapy with allo-HSCT has the potential to restore hematopoiesis and consolidate long-term efficacy. However, GvHD remains a major impediment, and the myeloablative conditioning regimen eradicates residual CAR-T cells and compromises CAR-mediated antitumor function. Furthermore, the implementation of conditioning regimen and GvHD-prophylaxis could lead to severe toxicities. Novel strategies are therefore warranted to preserve CAR-T cells, enhance antitumor potency and minimize complications. METHODS: In this study, we presented 10 patients (enrolled between November 2021 and June 2023) with R/R CD7-positive acute leukemia who proceeded directly to haploidentical HSCT (haplo-HSCT) after CAR-T therapy. All patients received allogeneic CD7 CAR-T therapy, manufactured from either haploidentical donors (n=8) in a phase I clinical trial of donor-derived CAR-T cells (NCT04599556) or (n=1) universal CD7 CAR-T cells (RD13-02) therapy (NCT05716113) or as a compassionate use program after the end of a phase I clinical trial of universal CD7 CAR-T cells (RD13-01) (NCT04538599). CAR-T cell doses were at 2´10 6(haploidentical donor, n=8), 4´10 6 (RD13-02, n=1) or 5´10 6 (RD13-01, n=1) cells/kg. After achieving complete remission with incomplete hematological recovery (CRi), all patients underwent haplo-HSCT without conditioning regimen or GvHD prophylaxis. The primary end point was efficacy, safety, hematopoiesis recovery, and donor chimerism. RESULTS: All patients relapsed from multiple lines of chemotherapy or immunotherapy (median, 7; range, 4-13), were ineligible for allo-HSCT and received palliative care. After CAR-T infusion, 9 patients achieved MRD-negative CRi, and 1 achieved MRD-positive CRi, on day 15 after CD7 CAR-T therapy. 9 patients developed grade 1-2 cytokine release syndrome, and no neurological toxicity was reported. All patients exhibited grade 4 pancytopenia and bone marrow hypocellularity and were directly bridging to haplo-HSCT. The median time from CAR-T infusion to haplo-HSCT was 19 (range, 15-89) days. One patient died of HHV6 infection in central nervous system on day 13 after haplo-HSCT and was not evaluable for the following safety and efficacy. 3 patients experienced short-term grade II acute GvHD, which was resolved completely after low dose steroid, anti-TNF-α or ruxolitinib therapy. One patient developed PTLD at 2.1 months post-HSCT. In 9 evaluable patients, 8 showed full donor chimerism at 1-month post-HSCT, and 1 showed autologous hematopoiesis recovery. At a median follow-up of 10.2 (range, 2.2-20.7) months after CAR-T therapy, 6 patients remained in MRD-negative CR with normal hematopoiesis (including the patient with autologous hematopoietic recovery), 1 had CD7-negative relapse at 5.6 months, 1 developed CD7-negative relapse at 4.3 months and died at 4.8 months, and 1 died from septic shocks at 3.7 months. OS, PFS, NRM, and CIR at 1 year were 64.3% (95% CI, 38.5%-100%), 51.4% (95% CI, 26.2%-100%), 22.9% and 25.7%, respectively. Peripheral normal T cells in 8/10 of patients remained CD7-negative at the last follow-up, illustrating a well-maintained CAR-T function post-HSCT. CONCLUSIONS: Our findings demonstrate a novel strategy to simultaneously achieve CAR-T persistence and complete HSC engraftment, while reducing the risks of GvHD, providing valuable insights into combining cellular therapy with allo-HSCT for the treatment of R/R acute leukemia patients ineligible for conventional allo-HSCT.

Clinical and imaging features of acute encephalopathy with biphasic seizures and late reduced diffusion in children

Objective: To explore the clinical and imaging features of acute encephalopathy with biphasic seizures and late reduced diffusion(AESD) in children. Methods: For the case series study, 21 children with AESD from Peking University First Hospital, Provincial Children's Hospital Affiliated to Anhui Medical University, Children's Hospital of Fudan University, and Shanxi Children's Hospital who were diagnosed and treated from October 2021 to July 2023 were selected. Clinical data were collected to summarize their clinical information, imaging, and laboratory tests, as well as treatment and prognostic characteristics. Descriptive statistical analysis was applicated. Results: Of the 21 cases with AESD, 11 were males and 10 were females, with the age of onset of 2 years and 6 months (1 year and 7 months, 3 years and 6 months). Of the 21 cases, 18 were typical cases with biphasic seizures. All typical cases had early seizures within 24 hours before or after fever onset. Among them, 16 cases had generalized seizures, 2 cases had focal seizures, and 7 cases reached the status epilepticus. Of the 21 cases, 3 atypical cases had late seizures in biphasic only. The late seizures in the 21 cases occurred on days 3 to 9. The types of late seizures included focal seizures in 12 cases, generalized seizures in 6 cases, and both focal and generalized seizures in 3 cases. Diffusion-weighted imaging (DWI) test on days 3 to 11 showed reduced diffusion of subcortical white matter which was named "bright tree sign" in all cases. The diffuse cerebral atrophy predominantly presented in the front-parietal-temporal lobes was found in 19 cases between day 12 and 3 months after the onset of the disease. Among 21 cases, 20 had been misdiagnosed as autoimmune encephalitis, central nervous system infection, febrile convulsions, posterior reversible encephalopathy syndrome, acute disseminated encephalomyelitis, and hemiconvulsion-hemiplegia-epilepsy syndrome. All the cases received high-dose gammaglobulin and methylprednisolone pulse therapy with poor therapeutic effect. By July 2023, 18 cases were under follow-up. Among them, 17 cases were left with varying degrees of neurologic sequelae, including 11 cases with post-encephalopathic epilepsy; 1 recovered completely. Conclusions: AESD is characterized by biphasic seizures clinically and "bright tree sign" on DWI images. Symptomatic and supportive treatments are recommended. The immunotherapy is ineffective. The prognosis of AESD is poor, with a high incidence of neurological sequelae and a low mortality.

Elevated phospholipids and acylcarnitines C4 and C5 in cerebrospinal fluid distinguish viral CNS infections from autoimmune neuroinflammation

BackgroundViral and autoimmune encephalitis may present with similar symptoms, but require different treatments. Thus, there is a need for biomarkers to improve diagnosis and understanding of pathogenesis. We hypothesized that virus-host cell interactions lead to different changes in central nervous system (CNS) metabolism than autoimmune processes and searched for metabolite biomarkers in cerebrospinal fluid (CSF) to distinguish between the two conditions.MethodsWe applied a targeted metabolomic/lipidomic analysis to CSF samples from patients with viral CNS infections (n = 34; due to herpes simplex virus [n = 9], varicella zoster virus [n = 15], enteroviruses [n = 10]), autoimmune neuroinflammation (n = 25; autoimmune anti-NMDA-receptor encephalitis [n = 8], multiple sclerosis [n = 17), and non-inflamed controls (n = 31; Gilles de la Tourette syndrome [n = 20], Bell’s palsy with normal CSF cell count [n = 11]). 85 metabolites passed quality screening and were evaluated as biomarkers. Standard diagnostic CSF parameters were assessed for comparison.ResultsOf the standard CSF parameters, the best biomarkers were: CSF cell count for viral infections vs. controls (area under the ROC curve, AUC = 0.93), Q-albumin for viral infections vs. autoimmune neuroinflammation (AUC = 0.86), and IgG index for autoimmune neuroinflammation vs. controls (AUC = 0.90). Concentrations of 2 metabolites differed significantly (p < 0.05) between autoimmune neuroinflammation and controls, with proline being the best biomarker (AUC = 0.77). In contrast, concentrations of 67 metabolites were significantly higher in viral infections than controls, with SM.C16.0 being the best biomarker (AUC = 0.94). Concentrations of 68 metabolites were significantly higher in viral infections than in autoimmune neuroinflammation, and the 10 most accurate metabolite biomarkers (AUC = 0.89–0.93) were substantially better than Q-albumin (AUC = 0.86). These biomarkers comprised six phosphatidylcholines (AUC = 0.89–0.92), two sphingomyelins (AUC = 0.89, 0.91), and acylcarnitines isobutyrylcarnitine (C4, AUC = 0.92) and isovalerylcarnitine (C5, AUC = 0.93). Elevated C4 and C5 concentrations suggested dysfunctional mitochondrial β-oxidation and correlated only moderately with CSF cell count (Spearman ρ = 0.41 and 0.44), indicating that their increase is not primarily driven by inflammation.ConclusionsChanges in CNS metabolism differ substantially between viral CNS infections and autoimmune neuroinflammation and reveal CSF metabolites as pathophysiologically relevant diagnostic biomarkers for the differentiation between the two conditions. In viral CNS infections, the observed higher concentrations of free phospholipids are consistent with disruption of host cell membranes, whereas the elevated short-chain acylcarnitines likely reflect compromised mitochondrial homeostasis and energy generation.

Loss to Hospital Follow-Up in Pediatric Cerebral Malaria Survivors: A Case-Control Study.

Children surviving central nervous system (CNS) infections are at high risk of neurological, behavioral, and cognitive sequalae. Early identification, characterization, and treatment of these sequelae may improve child and family health. In Africa, it is unclear if there are demographic or clinical factors that increase the risk of post-hospital loss to follow-up in children with CNS infections. If these factors exist, targeted educational efforts to increase rates of post-hospital retention could be focused on families at highest risk. We performed a case-control study of Malawian children with cerebral malaria, a locally common CNS infection, previously admitted to a specialized research unit in Blantyre, Malawi. Routine survivor post-hospital follow-up was scheduled for 1 month, 6 months, and 12 months. We compared demographic and clinical characteristics between 84 children who missed one or more of these post-hospital visits with 120 children who attended all visits. There were no statistically significant differences in demographic or clinical characteristics between children whose families returned for all follow-up visits and those who did not. Specifically, when comparing these groups, we found no differences in age (P = 00.646), sex (P = 0.789), duration of hospitalization (P = 0.903), distance from home to hospital (P = 0.355), type or severity of neurological sequelae (P = 0.837), guardian literacy (P = 0.057), or number of discharge medications (P = 0.464). No factors assessed in this study were associated with higher risk of loss to follow-up in Malawian child survivors of CNS infections. During hospitalization, educational efforts to increase post-hospital retention should focus on all families.

Abstract 129: Endovascular Therapy in Cerebral Venous Thrombosis: Nationwide Insights and Implications for Mortality

Introduction Cerebral Venous Thrombosis (CVT) is a rare cerebrovascular condition causing death or functional dependency in 10‐15%. Although Endovascular Therapy (EVT) is deployed variably across centers for managing CVT, the determinants and consequences of such use remain under‐explored. We examined the demographic and clinical correlates of EVT use in CVT and assessed its impact on patient outcomes utilizing a national database. Methods We identified CVT cases from 2015 to 2020 in the National Inpatient Sample, with EVT as the primary exposure. CVT and other diagnoses, and EVT and other procedures, were identified using standard ICD 10 codes. A backward stepwise regression model (at p&lt;0.05) was used to explore patient demographics, hospital characteristics, and comorbidities significantly associated with EVT use. We examined the association between EVT use and in‐hospital mortality using survey weighted unadjusted and adjusted logistic regression models. Covariates in the model one assessing inpatient mortality included age, insurance status, hospital teaching status, hospital volume size, central nervous system (CNS) infections, CNS cancer, other types of cancer, hematological disorder, traumatic head injuries, seizure, intubation, and transfer from an outside hospital. Model two additionally adjusted for female sex, NIH Stroke Scale (NIHSS), and Elixhauser mortality index. Results We identified 48,835 individuals with CVT, of whom 1,275 (2.6%) underwent EVT. The stepwise regression analysis revealed a higher likelihood of receiving EVT with older age (OR per year: 1.01, 95% CI: 1.01‐1.02, p&lt;0.001), presence of a hematological disorder (OR: 2.06, 95% CI: 1.58‐2.67, p&lt;0.001), seizure (OR: 1.54, 95% CI: 1.09‐2.16, p=0.014), intubation (OR: 3.85, 95% CI: 2.78‐5.34, p&lt;0.001), higher NIHSS (10.5[4‐18] versus 3[1‐8], p&lt;0.001), or admission to a teaching hospital (OR: 4.15, 95% CI: 1.93‐8.92, p&lt;0.001), high‐volume center (OR: 6.30, 95% CI: 2.29‐17.33, p&lt;0.001), or transfer from an outside hospital (OR: 1.89, 95% CI: 1.42‐2.51, p&lt;0.001). Conversely, there was a lower likelihood of EVT in those with CNS infections (OR: 0.19, 95% CI: 0.07‐0.48, p=0.001), CNS cancer (OR: 0.24, 95% CI: 0.06‐0.93, p=0.039), other types of cancer (OR: 0.47, 95% CI: 0.32‐0.69, p&lt;0.001), and traumatic head injuries (OR: 0.41, 95% CI: 0.25‐0.68, p&lt;0.001). Individuals with Medicare (OR: 0.39, 95% CI: 0.26‐0.59, p&lt;0.001) or Medicaid insurance (OR: 0.70, 95% CI: 0.50‐0.99, p=0.041), were also less likely to undergo EVT. EVT was associated with an increased odds of in‐hospital mortality (OR: 4.01, 95% CI 2.82‐5.68, p&lt;0.001), a relationship that persisted even after multivariable adjustment with model one (adjusted OR: 2.37 95% CI 1.50‐3.74, p&lt;0.001) and model two (adjusted OR: 7.32 95% CI 2.62‐20.5, p&lt;0.001). Conclusion We identified specific demographic and clinical factors associated with EVT use in CVT and found EVT use linked to higher mortality. The directionality of this relation is uncertain but could suggest more frequent use of EVT in individuals with very severe clinical presentations. These findings underscore the need for further prospective work to assess which individuals may benefit from therapy, in addition to optimal timing and approaches.

48 A Case of an Extremely Rare CNS C. Bantiana Infection with Cognitive Sequela in an Immunocompetent Patient

Objective:Central nervous system (CNS) infections with the dematiaceous fungus Cladophialophora bantiana (C. bantiana) are extremely rare, with approximately 120 confirmed cases reported as of 2016. C. bantiana is a highly neurotropic and thermotolerant fungus found in soil worldwide. The mode of entry into the CNS remains unknown, but inhalation of fungal spores or subcutaneous trauma have been suggested. Entry of fungal spores can cause cerebral phaeohyphomycosis with the main clinical manifestation of a brain abscess. Symptoms are non-specific and can include headache, fever, hemiparesis, aphasia, visual disturbances, and confusion. C. bantiana cerebral phaeohyphomycosis occurs in both immunocompetent and immunocompromised individuals, with a slightly higher prevalence in immunocompetent males for unknown reasons. Diagnosis is often delayed due to its nonspecific presentation and prevalence in individuals without pre-existing immunological disease. Prognosis is poor, with mortality rates of approximately 70% despite aggressive treatment. Treatment is not standardized but may include several anti-fungal agents and surgical intervention. Case reports documenting the variability seen with cerebral phaeohyphomycosis by C. bantiana can provide valuable insight into this emerging disease. C. bantiana’s neurotropic propensity also warrants cognitive investigation of the disease; however, there are currently limited descriptions of cognitive findings in published case reports of C. bantiana CNS infections.Participants and Methods:Here, we describe a case of a 35-year-old immunocompetent, college educated male with a CNS C. bantiana infection, presumably following a fall while biking in Costa Rica. First symptoms included left sided facial palsy, headache, and hand weakness, prompting extensive diagnostic workup, with diagnosis of C. bantiana infection confirmed 8 months after symptom onset. Initial treatment included anti-fungal agents and steroids, but his course of infection was complicated by infectious vasculitis with posterior circulation infarcts and obstructive hydrocephalus requiring ventriculoperitoneal shunt placement two years following the fungal infection diagnosis. The most recent brain MRI revealed encephalomalacia in global periventricular areas, two small masses, likely representing small fungal phlegmons, and enhancing lesions in the upper cervical spinal canal.Results:The patient reported cognitive changes following the infarcts and shunt placement including difficulties with spatial navigation, following directions, and articulating thoughts. Memory concerns and lapses in judgment were also reported. Results from a neuropsychological evaluation revealed high average baseline intellectual abilities with decrements in visuospatial processing, processing speed, executive functioning, and aspects of memory stemming from his executive dysfunction. At the time, his cognitive profile suggested parietal and frontosubcortical systems disruption meeting criteria for mild cognitive impairment. Two years later, the patient reported continuing cognitive difficulties prompting a follow-up neuropsychological evaluation. Results were similar to his first evaluation, revealing deficits in aspects of visuospatial processing, decreased verbal and visual learning, bradyphrenia and processing speed deficits, and difficulties with visual planning and organization. Minimal anxiety and depression, but increased apathy and executive dysfunction were endorsed on self-report measures.Conclusions:This case report highlights neurological sequela resulting from CNS infection with C. bantiana, -with a course complicated by subsequent strokes, hydrocephalus, and cognitive impairment-, and contributes additional insight into the relatively limited existing reports of an extremely rare but emerging disease.

Evaluation of Central Nervous System Involvement in Patients undergoing Chimeric antigen receptor-engineered T-cell Therapy by Magnetic Resonance Imaging

Chimeric antigen receptor-engineered (CAR) T-cell therapy is an effective immunotherapy for aggressive hematologic cancers. However, it can lead to complications such as immune effector cell-associated neurotoxicity syndrome (ICANS), or complications related to the immunosuppressive status of these patients. The role of imaging in this context is essential to help in ICANS diagnosis and to rule out other potential diagnosis, such as central nervous system infections. Two cases are presented to illustrate this clinical problem. Case 1describes a 38-year-old patient with diffuse large B-cell lymphoma who developed ICANS after CAR T-cell therapy. MRI revealed signs of leukoencephalopathy. Case 2 involves a 57-year-old patient with mantle-cell lymphoma who presented neurologic symptoms -clinically suggestive of ICANS- after CAR-T therapy. MRI showed signs indicative of limbic encephalitis.These two cases highlight the importance of MRI in clinical practice after CAR T-Cell Therapy underscoring the role of MRI in the diagnosis of complications in patients with neuropsychiatric symptoms.

Abstract 17 — Overall Infection Risks of Tofacitinib in Patient with Rheumatoid Arthritis: A Meta-Analysis of Randomized Clinical Trials

Background There is an ongoing controversy surrounding whether tofacitinib increases the risk of infections in patients with rheumatoid arthritis (RA). To address this issue, we conducted a meta-analysis using data from randomized clinical trials (RCTs) to assess the overall risk of infection in these patients. Methods We conducted a comprehensive systematic search in EMBASE, MEDLINE, and CENTRAL from their inception until December 2022 to identify relevant RCTs reporting the occurrence of infections in patients with RA who were treated with the standard clinical therapeutic dosage of tofacitinib (5mg twice daily orally). The primary outcomes of the included studies in this review focused on the incidence of total infections, serious infections, non-serious infections, and opportunistic infections (including herpes zoster and tuberculosis). Additionally, we examined secondary outcomes related to the incidence of various sites of infections, including the upper respiratory tract, lower respiratory tract, gastrointestinal tract, hepatobiliary system, urinary tract, skin and soft tissue, blood, dental and oral soft tissue, genital, reproductive tract, bone and joint, and central nervous system infections. Due to the expected anticipation of clinical and methodological heterogeneity across studies, the effect estimate was pooled with a random-effects model, to obtain the RRs and 95% CIs, using Mantel-Haenszel statistical method. Results Twelve eligible RCTs, involving a total of 6,056 patients, were included in the analysis. In comparison to the control group (placebo and other active treatments), tofacitinib exhibited a significant increase in the risk of total infections (RR, 1.21; 95% CI, 1.07-1.37; I2, 28%), serious infections (RR, 1.23; 95% CI, 1.02-1.48; I2, 0%), non-serious infections (RR, 1.20; 95% CI, 1.05-1.36; I2, 29%), and opportunistic infections (RR, 1.66; 95% CI, 1.40-1.97; I2, 0%). Secondary outcomes analyses revealed a significant increase in the risk of lower respiratory infections with tofacitinib (RR, 1.27; 95% CI, 1.10–1.47; I2, 0%). Conclusion Compared with placebo and other active treatments, tofacitinib significantly increased the overall risk of infections (total infections, serious infections, non-serious infections, and opportunistic infections). These findings can help clinicians assess the risk of infections in RA patients treated with tofacitinib.

Posterior reversible encephalopathy syndrome in children with acute lymphoblastic leukemia during remission induction chemotherapy: a single-center retrospective study.

This study investigated the clinical characteristics, cranial magnetic resonance imaging (MRI) features, MRI follow-up, and prognosis of children with acute lymphoblastic leukemia (ALL) who developed posterior reversible encephalopathy syndrome (PRES) during remission induction chemotherapy. We analyzed the age, gender, PRES symptoms and signs, cranial MRI findings, therapeutic effect, and prognosis of children with ALL who developed PRES during chemotherapy from January 2010 to December 2013 at the Hematology Oncology Center of Beijing Children's Hospital. Changes in cranial MRI findings were analyzed, and intelligence (IQ) and cognitive function were evaluated using the Wechsler Scale and the Wisconsin Card Score Test after the children completed chemotherapy. There were 850 children with newly diagnosed ALL in this period; 13 (1.5%), 6 boys and 7 girls, developed PRES. All were diagnosed as B-cell ALL. The median age at PRES onset was 7 years (2-11 years). The median day of PRES onset was day 28 (day 17-34) of remission induction chemotherapy. Of the 13 children with PRES onset and seizures, 4 had visual disturbances and 2 had consciousness disturbances. Cranial MRI showed hyperintensity in the subcortical white matter on T2-weighted axial and fluid-attenuated inversion recovery (FLAIR) images. The lesion locations were as follows: occipital lobe, 12 (92.3%) patients; frontal lobe, 7 (53.8%) patients; temporal lobe, 5 (38.4%) patients; parietal lobe, 3 (23.1%) patients; and cerebellum, 1 (7.7%) patient. There were 8 (61.5%) patients with vasogenic edema and 5 (38.5%) with cytotoxic edema. After treatment, all children recovered within one month, when their PRES symptoms were relieved, they continued to receive chemotherapy. However, 1 child (1.07%) died of severe central nervous system infection one year after PRES treatment, and 3 (25%) had recurrent seizures and were diagnosed with epilepsy after three months of PRES treatment. Their cranial MRIs showed cytotoxic edema, which was acute stage on day 15, with aggravated lesions on cranial MRI. The cranial MRI lesions returned to normal at one month in 3 (23.1%) patients, at three months in 6 (46.1%) patients, at one year in 8 (61.5%) patients, and at two years in 12 (92.3%) patients. The 12 surviving children all returned to school, and their full-scale, verbal, and performance IQs were normal, with no significant differences in intelligence or cognitive function compared with children with ALL without PRES during the same period. PRES can occur during remission induction chemotherapy treatment of children with ALL, but the incidence is low. Cranial MRI can be used for diagnosis and to characterize lesions. The children recover about a month after treatment, and cranial MRI lesions return to normal within two years. The time for complete resolution of MRI lesions differs, and children with cytotoxic edema have worse prognosis with sequelae, such as epilepsy, which requires close monitoring. PRES does not affect intelligence or cognitive development.

Analysis of Vacuum-Assisted Closure-Assisted Antibiotic Irrigation in Treatment of Severe Neurosurgical Central Nervous System Infections.

Objective: Severe neurosurgical central nervous system infections (sNCNSIs) are among the most serious complications of neurosurgical disease. Conventional methods have shown a poor prognosis. This study aims to analyze the clinical characteristics of vacuum-assisted closure (VAC) in sNCNSIs with the help of antibiotic irrigation treatment. Patients and Methods: A retrospective study was performed for patients diagnosed with sNCNSIs. A VAC device was placed on the incision after debridement and the surgical cavity was rinsed with antibiotic agents in the VAC group. Meanwhile the surgical cavity was drained after debridement in the control group. Medical data were reviewed and analyzed. Results: Twenty-eight patients met the inclusion criteria, including 18 cases in the VAC group and 10 cases in the control group. The basic medical data showed no differences. Bacteria was isolated from 24 (85.7%) patients. The cure rate was significantly higher in the VAC group (p < 0.05). The cure rate in patients with multi-drug-resistant (MDR) infections was significantly higher in patients treated with VAC therapy (p < 0.05). The prognosis evaluated by Glasgow Outcome Score (GOS) between the two groups showed significant difference (p < 0.05). No re-infection in the VAC group occurred in the follow-up period. Conclusions: It is suggested that VAC-assisted antibiotic irrigation is safe and effective for patients with severe NCNSIs and can improve the prognosis dramatically. The results can provide a new effective and reasonable therapeutic strategy for patients with sNCNSIs.

Successful Treatment of Carbapenem-Resistant Klebsiella pneumoniae Meningitis with Combination Therapy of Meropenem and Amikacin

Introduction: The widespread use of carbapenems increased the prevalence of Carbapenem-resistant Enterobacteriaceae with subsequent increases in mortality due to extremely limited treatment options. Following neurosurgical procedures, carbapenem-resistant Klebsiella pneumoniae (CRKP) is the main cause of central nervous system (CNS) infections. The optimal antimicrobial treatment of such infections has not yet been defined. Case Presentation: We present a 4-month-old boy with an extra-ventricular drain-related central nervous system (CNS) infection with CRKP. Although meropenem minimum inhibitory concentration (MIC) for the bacterial isolate was ≥ 16 mg/L and it harbored blaNDM, blaVIM, and blaOXA-48-like Carbapenemase genes, this infection was effectively treated with a combination therapy of intravenous (IV) double dose extended infusion of meropenem in addition to amikacin. Conclusions: This successful treatment regimen for CRKP-causing meningitis may pave the way to manage severe CNS infections with extensive-drug-resistant bacteria in infants and children without inserting an external drain or intra-thecal antibiotic administration.

Demographic and Clinical Evaluation of Patients with Meningitis in a Hospital of Bangladesh

Background: Meningitis is an inflammatory disease of the leptomeninges, the tissues surrounding the brain and spinal cord. It is a life threatening central nervous system infection that is prevalent worldwide. The lack of rapid and sensitive tests remains a key issue in diagnosing meningitis and affordability impedes accessing molecular techniques in diagnosing. The challenge of this disease is the emergency identification and prompt treatment required to enable survival, reduce mortality and prevent long-term sequelae.&#x0D; Objectives: The aim of this study was to evaluate the demographic and clinical profile of meningitis in a tertiary care hospital in Bangladesh. &#x0D; Methods: This was a cross-sectional observational study conducted in the Department of Neurology at Comilla Medical College Hospital, Cumilla, Bangladesh, during the period from July 2018 to June 2019. A total of 159 patients were enrolled in this study. All cases were diagnosed based on clinical or laboratory criteria. Detailed demographic data were collected and recorded in a structured case report form. &#x0D; Results: Among the159 patient, 69 were male and 90 were female. The mean ages are 31±20.03 years. The highest number of patients were presented with fever (100%), headache (90%), vomiting (47%) and altered mental status (37%). Among all 159 case of meningitis 62(39%) were bacterial meningitis, 55 (35%) were viral meningitis and 42 (26%) were tubercular meningitis. Diagnosis was made on the besis of clinical findings and radiological, biochemical and CSF study. Regarding seasonal variations, there are 2 peaks: summer and winter, which are responsible for viral and bacterial meningitis, respectively.&#x0D; Conclusion: Meningitis is a deadly infection that can spread rapidly if not taken early management. So, proper and rapid detection and other investigational facilities reduce the disability. &#x0D; J Com Med Col Teachers Asso Jan 2023; 27(1): 19-26

Type VI Secretion System Accessory Protein TagAB-5 Promotes Burkholderia pseudomallei Pathogenicity in Human Microglia.

Central nervous system (CNS) melioidosis caused by Burkholderia pseudomallei is being increasingly reported. Because of the high mortality associated with CNS melioidosis, understanding the underlying mechanism of B. pseudomallei pathogenesis in the CNS needs to be intensively investigated to develop better therapeutic strategies against this deadly disease. The type VI secretion system (T6SS) is a multiprotein machine that uses a spring-like mechanism to inject effectors into target cells to benefit the infection process. In this study, the role of the T6SS accessory protein TagAB-5 in B. pseudomallei pathogenicity was examined using the human microglial cell line HCM3, a unique resident immune cell of the CNS acting as a primary mediator of inflammation. We constructed B. pseudomallei tagAB-5 mutant and complementary strains by the markerless allele replacement method. The effects of tagAB-5 deletion on the pathogenicity of B. pseudomallei were studied by bacterial infection assays of HCM3 cells. Compared with the wild type, the tagAB-5 mutant exhibited defective pathogenic abilities in intracellular replication, multinucleated giant cell formation, and induction of cell damage. Additionally, infection by the tagAB-5 mutant elicited a decreased production of interleukin 8 (IL-8) in HCM3, suggesting that efficient pathogenicity of B. pseudomallei is required for IL-8 production in microglia. However, no significant differences in virulence in the Galleria mellonella model were observed between the tagAB-5 mutant and the wild type. Taken together, this study indicated that microglia might be an important intracellular niche for B. pseudomallei, particularly in CNS infection, and TagAB-5 confers B. pseudomallei pathogenicity in these cells.

Clinical and Metagenomic Characterization of Neurological Infections of People With Human Immunodeficiency Virus in the Peruvian Amazon.

Neurological opportunistic infections cause significant morbidity and mortality in people with human immunodeficiency virus (HIV) but are difficult to diagnose. One hundred forty people with HIV with acute neurological symptoms from Iquitos, Peru, were evaluated for cerebral toxoplasmosis with quantitative polymerase chain reaction (qPCR) of cerebrospinal fluid (CSF) and for cryptococcal meningitis with cryptococcal antigen test (CrAg) in serum or CSF. Differences between groups were assessed with standard statistical methods. A subset of samples was evaluated by metagenomic next-generation sequencing (mNGS) of CSF to compare standard diagnostics and identify additional diagnoses. Twenty-seven participants were diagnosed with cerebral toxoplasmosis by qPCR and 13 with cryptococcal meningitis by CrAg. Compared to participants without cerebral toxoplasmosis, abnormal Glasgow Coma Scale score (P = .05), unilateral focal motor signs (P = .01), positive Babinski reflex (P = .01), and multiple lesions on head computed tomography (CT) (P = .002) were associated with cerebral toxoplasmosis. Photophobia (P = .03) and absence of lesions on head CT (P = .02) were associated with cryptococcal meningitis. mNGS of 42 samples identified 8 cases of cerebral toxoplasmosis, 7 cases of cryptococcal meningitis, 5 possible cases of tuberculous meningitis, and incidental detections of hepatitis B virus (n = 1) and pegivirus (n = 1). mNGS had a positive percentage agreement of 71% and a negative percentage agreement of 91% with qPCR for T gondii. mNGS had a sensitivity of 78% and specificity of 100% for Cryptococcus diagnosis. An infection was diagnosed by any method in only 34% of participants, demonstrating the challenges of diagnosing neurological opportunistic infections in this population and highlighting the need for broader, more sensitive diagnostic tests for central nervous system infections.

COVID-19 Recovery: Consistent Absence of Cerebrospinal Fluid Biomarker Abnormalities in Patients With Neurocognitive Post-COVID Complications.

To investigate evidence of residual viral infection, intrathecal immune activation, central nervous system (CNS) injury, and humoral responses in cerebrospinal fluid (CSF) and plasma in patients recovering from coronavirus disease 2019 (COVID-19), with or without neurocognitive post-COVID condition (PCC). Thirty-one participants (25 with neurocognitive PCC) underwent clinical examination, lumbar puncture, and venipuncture ≥3 months after COVID-19 symptom onset. Healthy volunteers were included. CSF and plasma severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid and spike antigen (N-Ag, S-Ag), and CSF biomarkers of immune activation and neuronal injury were analyzed. SARS-CoV-2 N-Ag or S-Ag were undetectable in all samples and no participant had pleocytosis. We detected no significant differences in CSF and plasma cytokine concentrations, albumin ratio, IgG index, neopterin, β2M, or in CSF biomarkers of neuronal injury and astrocytic damage. Furthermore, principal component analysis (PCA1) analysis did not indicate any significant differences between the study groups in the marker sets cytokines, neuronal markers, or anti-cytokine autoantibodies. We found no evidence of ongoing viral replication, immune activation, or CNS injury in plasma or CSF in patients with neurocognitive PCC compared with COVID-19 controls or healthy volunteers, suggesting that neurocognitive PCC is a consequence of events suffered during acute COVID-19 rather than persistent viral CNS infection or residual CNS inflammation.

Nomogram for Predicting Central Nervous System Infection Following Traumatic Brain Injury in the Elderly

This study aims to identify risk factors for central nervous system (CNS) infection in elderly patients hospitalized with traumatic brain injury (TBI) and to develop a reliable predictive tool for assessing the likelihood of CNS infection in this population. We conducted a retrospective study on 742 elderly TBI patients treated at Tangdu Hospital, China. Clinical data was randomly split into training and validation sets (7:3 ratio). By conducting univariate and multivariate logistic regression analysis in the training set, we identified a list of variables to develop a nomogram for predicting the risk of CNS infection. We evaluated the performance of the predictive model in both cohorts respectively, using receiver operating characteristics curves, calibration curves, and decision curve analysis. Results of the logistic analysis in the training set indicated that surgical intervention (P= 0.007), red blood cell count (P= 0.019), C-reactive protein concentration (P < 0.001), and cerebrospinal fluid leakage (P < 0.001) significantly predicted the occurrence of CNS infection in elderly TBI patients. The model constructed based on these variables had high predictive capability (area under the curve-training= 0.832; area under the curve-validation= 0.824) as well as clinical utility. A nomogram constructed based on several key predictors reasonably predicts the risk of CNS infection in elderly TBI patients upon hospital admission. The model of the nanogram may contribute to timely interventions and improve health outcomes among affected individuals.

Case report: isolated prevotella intermedia causing intracranial infection detected using metagenomic next generation sequencing

BackgroundIsolated Prevotella intermedia, a rare gram-negative, rod-shaped, anaerobic bacterium, is rarely detected in clinical practice. It has been associated with infections of the oral cavity and female genital tract, but has never been detected in cerebrospinal fluid (CSF) of patients in China. Accurate detection of causative pathogens is still an arduous task owing to the difficult conditions of anaerobic bacterial culture. Isolated Prevotella intermedia can be detected by metagenomic next generation sequencing (mNGS) of the CSF. Correct diagnosis and antibiotic treatment can help patients avoid life-threatening events.Case presentationHerein, we describe the case of a 64-year-old Chinese woman who presented with typical features of meningoencephalitis. Routine CSF culture failed to identify the causative pathogen. Isolated Prevotella intermedia was detected by mNGS, and the patient was treated with antibacterial agents including ceftriaxone, vancomycin, moxifloxacin, meropenem, metronidazole, and linezolid. The patient underwent surgical treatment for abscess of left frontal parietal lobe, which was observed on magnetic resonance imaging (MRI) and was suspected to be caused by Prevotella intermedia. It was further confirmed that it was a secondary infection from the oral cavity, and the possible etiology might have been dental surgery. Treatment was rendered to the patient based on metagenomic test result, and her condition improved after two months.ConclusionsThis case highlights the role of mNGS in accurate diagnosis of patients with central nervous system infection. In particular, mNGS can be used to identify rare pathogens and confirm the diagnosis in patients with unknown etiology.

A Liquid Chromatography-Tandem Mass Spectrometry Method for Simultaneously Determining Meropenem and Linezolid in Blood and Cerebrospinal Fluid.

Antibiotic therapy requires appropriate dosage of drugs for effective treatment. Too low antibiotic concentrations may lead to treatment failure and the development of resistant pathogens, whereas overdosing may cause neurological side effects or hemolytic diseases. Meropenem and linezolid are used only in the treatment of serious infections or when other antibiotics are no longer effective as well as for treating central nervous system infections. It is difficult or sometimes even impossible to predict the relation between dosing of antibiotics and its cerebrospinal fluid (CSF) concentration; thus, a method of determining antibiotics not only in the blood but also in the CSF is needed. Analytical method validation is an integral part of good laboratory practice and ensures high accuracy of the results. We performed complete validation process according to the Food and Drug Administration and European Medicine Agency, covering the aspects precision, specificity, accuracy, recovery, limit of detection, limit of quantification, stability, carry-over, and matrix effects. Our liquid chromatography-tandem mass spectrometry method for the simultaneous measurement of meropenem and linezolid in different matrix meets all the acceptance criteria. The method was successfully applied to determine meropenem and linezolid concentrations in serum and CSF samples obtained from children treated with these antibiotics.

Clinical features, etiologies, and outcomes of central nervous system infections in intensive care: A multicentric retrospective study in a large Brazilian metropolitan area

PurposeThe goal of this study was to investigate severe central nervous system infections (CNSI) in adults admitted to the intensive care unit (ICU). We analyzed the clinical presentation, causes, and outcomes of these infections, while also identifying factors linked to higher in-hospital mortality rates. Materials and methodsWe conducted a retrospective multicenter study in Rio de Janeiro, Brazil, from 2012 to 2019. Using a prediction tool, we selected ICU patients suspected of having CNSI and reviewed their medical records. Multivariate analyses identified variables associated with in-hospital mortality. ResultsIn a cohort of 451 CNSI patients, 69 (15.3%) died after a median 11-day hospitalization (5–25 IQR). The distribution of cases was as follows: 29 (6.4%) had brain abscess, 161 (35.7%) had encephalitis, and 261 (57.8%) had meningitis. Characteristics: median age 41 years (27–53 IQR), 260 (58%) male, and 77 (17%) HIV positive. The independent mortality predictors for encephalitis were AIDS (OR = 4.3, p = 0.01), ECOG functional capacity limitation (OR = 4.0, p < 0.01), ICU admission from ward (OR = 4.0, p < 0.01), mechanical ventilation ≥10 days (OR = 6.1, p = 0.04), SAPS 3 ≥ 55 points (OR = 3.2, p = 0.02). Meningitis: Age > 60 years (OR = 234.2, p = 0.04), delay >3 days for treatment (OR = 2.9, p = 0.04), mechanical ventilation ≥10 days (OR = 254.3, p = 0.04), SOFA >3 points (OR = 2.7, p = 0.03). Brain abscess: No associated factors found in multivariate regression. ConclusionsPatients' overall health, prompt treatment, infection severity, and prolonged respiratory support in the ICU all significantly affect in-hospital mortality rates. Additionally, the implementation of CNSI surveillance with the used prediction tool could enhance public health policies.