Central nervous system infections in patients with systemic lupus erythematosus: a systematic review and meta-analysis

We aimed to conduct a systematic review and meta-analysis of studies on central nervous system (CNS) infections in patients with SLE, in order to describe their clinical and microbiological characteristics, and outcomes. A systematic search of PubMed/Medline and Embase electronic databases was performed (March 2021) to identify all published studies on CNS infections and their characteristics in patients with SLE. A random-effects model was adopted and findings were reported with 95% CI. Overall, 6 studies involving 17 751 patients with SLE and 209 SLE cases with CNS infection were included in our meta-analysis. The frequency rate of CNS infections in patients with SLE was 0.012 (95% CI: 0.008 to 0.018). Meningitis was the most common clinical syndrome (93.5%, n=109/114, 95% CI: 82.6% to 97.8%) and Cryptococcus neoformans (35.9%, n=55, 95% CI: 27.2% to 45.7%) and Mycobacterium tuberculosis (27.1%, n=43, 95% CI: 14.6% to 44.8%) were the most common causative pathogens. Our patient-pool showed a mean SLE Disease Activity Index (SLEDAI) score of 7.9 (95% CI: 6.1 to 9.6), while 92.4% (n=72/76, 95% CI: 83.0% to 96.8%) of cases were on oral systemic corticosteroids, with a prednisone equivalent mean daily dose of 30.9 mg/day (95% CI: 18.0 to 43.7). Our meta-analysis revealed a mortality rate of 29.0% (95% CI: 15.0% to 48.6%). Clinicians should maintain a high index of suspicion for cryptococcal and tuberculosis (TB) meningitis in patients with SLE with suspected CNS infection, particularly in those with higher SLEDAI and on higher doses of systemic corticosteroids. In conclusion, initiation of empiric antituberculous treatment for patients with SLE who are highly suspected to have CNS TB is warranted while awaiting the results of diagnostic tests. Antifungals might also be potentially useful empirically in patients with SLE who are suspected to have fungal CNS infections. However, with respect to side effects such as toxicity and high cost of antifungals, decision regarding early antifungal therapy should be guided by early and less time-consuming fungal diagnostic tests.

Development of a Multiplex Droplet Digital PCR Assay for Detection of Enterovirus, Parechovirus, Herpes Simplex Virus 1 and 2 Simultaneously for Diagnosis of Viral CNS Infections

Background: Enterovirus (EV), parechovirus (HPeV), herpes simplex virus 1 and 2 (HSV1/2) are common viruses leading to viral central nervous system (CNS) infections which are increasingly predominant but exhibit deficiency in definite pathogen diagnosis with gold-standard quantitative PCR method. Previous studies have shown that droplet digital PCR (ddPCR) has great potential in pathogen detection and quantification especially in low concentration samples.Methods: Targeting four common viruses of EV, HPeV, HSV1, and HSV2 in cerebrospinal fluid (CSF), we developed a multiplex ddPCR assay using probe ratio-based multiplexing strategy, analyzed the performance, and evaluated it in 97 CSF samples collected from patients with suspected viral CNS infections on a two-channel ddPCR detection system.Results: The four viruses were clearly distinguished by their corresponding fluorescence amplitude. The limits of detection for EV, HPeV, HSV1, and HSV2 were 5, 10, 5, and 10 copies per reaction, respectively. The dynamic range was at least four orders of magnitude spanned from 2000 to 2 copies per reaction. The results of 97 tested clinical CSF specimens were identical to those deduced from qPCR/qRT-PCR assays using commercial kits.Conclusion: The multiplex ddPCR assay was demonstrated to be an accurate and robust method which could detect EV, HPeV, HSV1, and HSV2 simultaneously. It provides a useful tool for clinical diagnosis and disease monitoring of viral CNS infections.

Daytime Hypersomnolence in COVID-19: A Case Report and Literature Review

Coronavirus infectious disease 2019 (COVID-19) is confirmed to develop neurocognitive complications. In the present paper, we describe two patients with laboratory-confirmed COVID-19 and excessive daytime sleepiness. In the present study, we reported two laboratory-confirmed cases of COVID-19 with excessive daytime sleepiness. Patients had drowsiness and mild confusion on presentation. In both cases, CNS infections, including meningitis and encephalitis, were ruled out. Both patients’ symptoms remarkably improved following the therapeutic course indicating the direct effect of SARS-CoV2 in sleep modulating centers on the brain. COVID-19 should be considered in patients with excessive daytime sleepiness and drowsiness in the current outbreak.

Clinical Features and Predictors for Mortality in Neurolisteriosis: An Administrative Data-Based Study

Listeriosis is an uncommon and potentially severe zoonotic bacterial infection that usually occurs in outbreaks instead of isolated cases. In recent years, there has been an increase in the incidence of this disease. One of the most severe of its complications involves the central nervous system (CNS) in a condition known as neurolisteriosis. Here, we describe the demographic and clinical features of patients presenting with neurolisteriosis between 2001 and 2015 using administrative data and attempt to identify potential predictors for mortality. We used the Spanish Minimum Basic Data Set at Hospitalization, a compulsory registry that collects data from clinical discharge reports. Up to 2015, data were coded based on the International Classification of Diseases, 9th Revision, so we used diagnoses and clinical conditions based on these codes. Age, sex, clinical presentation, mortality, and involvement of the CNS were identified. Using algorithms to aggregate data, variables such as immunosuppression and malignant disease were obtained. We analyzed correlations among clinical features and identified risk factors for morbidity and mortality. Between 2001 and 2015 we identified 5180 individuals, with a hospitalization rate of 0.76 per 100,000 population. Most (94%) were adults, and only 5.4% were pregnant women. The average age was 66 years. Neurological involvement was present in 2313 patients (44.7%), mostly meningitis (90.4%). Global mortality was 17%, but mortality in CNS infections was 19.2%. Age, severe sepsis, chronic liver disease, chronic kidney disease, and malignancy were the main risk factors for mortality in patients with CNS infections by Listeria monocytogenes. Although it is uncommon, neurolisteriosis can be a severe condition, associated with a high rate of mortality. Health care providers should be aware of potential sources of infection so that appropriate measures can be taken to prevent it.

A clinical, aetiological, and public health perspective on central nervous system infections in Bolivia, 2017–2018

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

Factors affecting prognosis of status epilepticus among patients presenting to a tertiary care hospital

Objectives: This study aimed to evaluate the etiology, outcomes and prognostic factors associated with status epilepticus (SE) admissions in Neurology Department of a tertiary care hospital. Methods: A retrospective review was performed on all SE admissions at Dr. Ruth K.M. Pfau Civil Hospital Karachi over a five-year period from July 2015 to June 2020. Demographic, clinical, and etiological factors were investigated for prognostic value. Statistical tests were applied to determine significant prognostic factors. A five percent significance level was used. Results: A total of 176 patients were included in the study. Mortality was reported in 22 cases (12.5%) and morbidity at six months was observed in 44 cases (25.0%). Male gender, previous history of SE, prolonged seizure duration, and late presentation to hospital were significantly associated with mortality (p<0.05). De novo cases of SE tended to be older (p=0.048) and were associated with morbidity at follow-up (p=0.000). The most common causes of epilepsy in our patients with SE were CNS infections (n=54) and Idiopathic epilepsy (n=34). Non-compliance to medicines/under-dosing was the most common provocative factor (n=68). Acute symptomatic causes of SE were more likely to be associated with greater morbidity (p=0.000). Refractory and super-refractory SE were strongly associated with higher mortality (p=0.000). A longer duration of hospital stay was associated with higher morbidity (p=0.000). Conclusion: Male gender, poor control of seizures, CNS infections, prolonged seizures, delayed hospital arrival and refractory/super-refractory status epilepticus were key determinants of mortality in our setting. Previous history of status epilepticus, and acute and symptomatic etiologies were associated with higher morbidity. doi: https://doi.org/10.12669/pjms.38.1.5195 How to cite this:Jawaid W, Irfan M, Shafee SM, Barry SJ, Shah SMM, Shahbaz N. Factors affecting prognosis of status epilepticus among patients presenting to a tertiary care hospital. Pak J Med Sci. 2022;38(1):---------. doi: https://doi.org/10.12669/pjms.38.1.5195 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Clinical Application and Drug-Use-Guidance Value of Metagenomic Next-Generation Sequencing in Central Nervous System Infection

Background Timely and precise etiology diagnosis is crucial for optimized medication regimens and better prognosis in central nervous system infections (CNS infections). We aimed to analyze the impact of mNGS tests on the management of patients with CNS infections. Methods We conducted a single-center retrospective cohort study to analyze the value of mNGS in clinical application. Three hundred sixty-nine patients with a specific CNS infection diagnosis were enrolled, and their clinical data were collected. CDI and DDI were defined in our study to describe the intensity of drug use in different groups. We also used LOH and mRS to evaluate whether the application of mNGS could benefit CNS infection patients. Results mNGS reported a 91.67% sensitivity in culture-positive patients and an 88.24% specificity compared with the final diagnoses. Patients performed with the mNGS test had less drug use, both total (58.77 vs. 81.18) and daily (22.6 vs. 28.12, p <0.1, McNemar) intensity of drug use, as well as the length of hospitalization (23.14 vs. 24.29). Patients with consciousness grading 1 and 3 had a decrease in CDI (Grade1, 86.49 vs. 173.37; Grade 3, 48.18 vs. 68.21), DDI (Grade1, 1.52 vs. 2.72; Grade 3, 2.3 vs. 2.45) and LOH (Grade1, 32 vs. 40; Grade 3, 21 vs. 23) with the application of mNGS. Patients infected with bacteria in CNS had a reduced CDI, DDI, and LOH in the mNGS Group, in contrast with the TraE Group. 49% of patients altered medication plans, and 24.7% of patients reduced drug intensity four days after mNGS reports, mostly due to the reduction of drug types. Conclusion mNGS showed its high sensitivity and specificity characteristics. mNGS may assist clinicians with more rational medication regimens and reduce the drug intensity of patients, of which the primary way was to reduce the variety of drugs, especially for severe patients and bacterial infections. mNGS has the potential value of improving the prognosis of CNS infectious patients.

66. Utilizing ceftazidime/avibactam therapeutic drug monitoring in the treatment of neurosurgical meningitis caused by Difficult-to-treat resistant (DTR)-Pseudomonas aeruginosa and KPC-producing Enterobacterales

Background Central nervous system (CNS) infections caused by carbapenem-resistant Enterobacterales (CRE) and Difficult-to-treat resistant (DTR)-Pseudomonas aeruginosa (PA) are a therapeutic challenge. Data demonstrating the pharmacokinetic/pharmacodynamic (PK/PD) properties of newer beta-lactamase inhibitors remains scarce. A clinical challenge lies in selecting an antimicrobial regimen that diffuses across the blood brain barrier and maintains concentrations to achieve PD targets associated with bacterial killing. These complexities compelled us to quantify the pharmacological properties of ceftazidime/avibactam (CZA). Utilizing therapeutic drug monitoring (TDM), we evaluated the adequacy of therapy and aimed to guide precise CNS dosing in the treatment of three patients with neurosurgical meningitis. Methods Bacterial identification and susceptibility testing were performed using MicroScan. TDM of CZA was implemented using a dose of 2.5 g infused intravenously over 2-hours, every 8 hours. The concentrations of ceftazidime and avibactam were determined by liquid chromatography/mass spectrometry. For patients 2 and 3, four unique CSF and plasma samples spanning the dosing interval were obtained; including trough values. (See table) Results Bacterial identification and CZA MICs for patients 1, 2, and 3 revealed blaKPCKp (0.25μg/mL), DTR PA (4 μg/mL), and blaKPCE. cloacae (0.25 μg/mL), respectively. Measured plasma and CSF concentrations of avibactam (AVI) and ceftazidime (CAZ) are shown in Table 1. Table 1a. Therapeutic Drug Monitoring of CAZ-AVI depicting dosing, time of samples, and measured concentrations in CSF and Human Plasma (HP) Table 1b. Therapeutic Drug Monitoring of CAZ-AVI concentrations in CSF and Human Plasma (HP) pertaining to patient 2 and 3 Conclusion Measuring CZA concentration levels in CSF was achieved in 3 patients with complicated CNS infections. Post-infusion concentrations indicated that adequate CAZ and AVI exposures were attained in the CSF. Notably, avibactam was shown to achieve concentrations ≥1 µg/ml in the CSF throughout the dosing interval. For avibactam and ceftazidime, the PK/PD target correlated with bacterial killing is ~50% fT &gt;MIC. In 2 out of 3 patients, concentrations were determined to be above the respective MICs throughout the entire dosing interval in the CSF. All patients attained clinical and microbiological cure. A novel CZA TDM method was successfully employed to establish that CZA maintains therapeutic CSF concentrations that exceed the MIC throughout the dosing interval. Disclosures Robert A. Bonomo, MD, entasis (Research Grant or Support)Merck (Grant/Research Support)NIH (Grant/Research Support)VA Merit Award (Grant/Research Support)VenatoRx (Grant/Research Support)

1111. Therapeutic Drug Monitoring of Colistin in Cerebrospinal Fluid in the Treatment of Neurosurgical Meningitis caused by Pseudomonas aeruginosa and KPC-producing Enterobacterales

Background Central nervous system (CNS) infections caused by carbapenem-resistant Enterobacterales (CRE) and Difficult-to-treat resistant (DTR)-P. aeruginosa (PA) present a therapeutic dilemma. Therapies are limited due to antibiotic resistance and inadequate CNS diffusion. Intraventricular polymyxins are utilized in this setting despite a lack in pharmacokinetic data after CNS injection. We describe the utilization of intravenous and intrathecal polymyxin E [colistimethate (CMS)] therapeutic drug monitoring (TDM) in 3 cases of post-neurosurgical meningitis. Methods Bacterial identification and susceptibility testing were performed using MicroScan. TDM was employed by dosing CMS at 125,000 IU (i.e., 4.1 mg CBA or 10 mg) administered via external ventricular drain twice daily and 4.5 MIU (133.2 CBA or 360 mg) CMS administered over 30 minutes IV twice daily. Four pairs of CSF and blood samples were collected for each patient (Table 1). Samples were placed on ice to minimize in-vitro conversion of CMS to Colistin. Colistin binding in plasma and CSF was measured using ultracentrifugation. Concentrations of CMS and Colistin in CSF and human plasma were determined by liquid chromatography/mass spectrometry. Patients A, B and C received 20, 15, and 12 doses of CMS, respectively, prior to TDM. Results Bacterial cultures revealed DTR PA, blaKPCE. cloacae and blaOXA-48K. pneumoniae for patients A, B and C, respectively. Colistin minimum inhibitory concentrations (MIC) were 0.5 µg/ml, 0.125 µg/ml, and 0.125 µg/ml, respectively. The measured CSF and plasma concentrations of CMS, Colistin, and binding are shown in Table 1. Clinical resolution and microbiological cure were attained in all patients. Therapeutic Drug Monitoring of Unchanged CMS and Formed Colistin in CSF samples for patient A, B, and C Therapeutic Drug Monitoring of Unchanged CMS and Formed Colistin in Plasma Samples for patient A, B, and C Conclusion Favorable concentrations of formed Colistin and CMS in CSF were achieved in 3 patients with complicated CNS infection. To the best of our knowledge, this is the first study to report the binding of Colistin in CSF in humans. A TDM method was effectively applied to demonstrate that Colistin achieves and maintains the PK/PD target (fAUC/MIC) [ratio of area under the plasma concentration curve of unbound drug to MIC] that best correlates with killing activity. Overall, our results support intraventricular polymyxins for treating DTR Gram-negative CNS infections. Disclosures Robert A. Bonomo, MD, entasis (Research Grant or Support)Merck (Grant/Research Support)NIH (Grant/Research Support)VA Merit Award (Grant/Research Support)VenatoRx (Grant/Research Support)