Search

ImportanceCerebrospinal fluid (CSF) cytologic testing and flow cytometry are insensitive for diagnosing neoplasms of the central nervous system (CNS). Such clinical phenotypes can mimic infectious and autoimmune causes of meningoencephalitis.ObjectiveTo ascertain whether CSF metagenomic next-generation sequencing (mNGS) can identify aneuploidy, a hallmark of malignant neoplasms, in difficult-to-diagnose cases of CNS malignant neoplasm.Design, setting, and participantsTwo case-control studies were performed at the University of California, San Francisco (UCSF). The first study used CSF specimens collected at the UCSF Clinical Laboratories between July 1, 2017, and December 31, 2019, and evaluated test performance in specimens from patients with a CNS malignant neoplasm (positive controls) or without (negative controls). The results were compared with those from CSF cytologic testing and/or flow cytometry. The second study evaluated patients who were enrolled in an ongoing prospective study between April 1, 2014, and July 31, 2019, with presentations that were suggestive of neuroinflammatory disease but who were ultimately diagnosed with a CNS malignant neoplasm. Cases of individuals whose tumors could have been detected earlier without additional invasive testing are discussed.Main outcomes and measuresThe primary outcome measures were the sensitivity and specificity of aneuploidy detection by CSF mNGS. Secondary subset analyses included a comparison of CSF and tumor tissue chromosomal abnormalities and the identification of neuroimaging characteristics that were associated with test performance.ResultsAcross both studies, 130 participants were included (median [interquartile range] age, 57.5 [43.3-68.0] years; 72 men [55.4%]). The test performance study used 125 residual laboratory CSF specimens from 47 patients with a CNS malignant neoplasm and 56 patients with other neurological diseases. The neuroinflammatory disease study enrolled 12 patients and 17 matched control participants. The sensitivity of the CSF mNGS assay was 75% (95% CI, 63%-85%), and the specificity was 100% (95% CI, 96%-100%). Aneuploidy was detected in 64% (95% CI, 41%-83%) of the patients in the test performance study with nondiagnostic cytologic testing and/or flow cytometry, and in 55% (95% CI, 23%-83%) of patients in the neuroinflammatory disease study who were ultimately diagnosed with a CNS malignant neoplasm. Of the patients in whom aneuploidy was detected, 38 (90.5%) had multiple copy number variations with tumor fractions ranging from 31% to 49%.Conclusions and relevanceThis case-control study showed that CSF mNGS, which has low specimen volume requirements, does not require the preservation of cell integrity, and was orginally developed to diagnose neurologic infections, can also detect genetic evidence of a CNS malignant neoplasm in patients in whom CSF cytologic testing and/or flow cytometry yielded negative results with a low risk of false-positive results.

ImportanceCurrent attempts to gauge the acute care needs of patients with dementia have not effectively addressed the role of caregivers, despite their extensive involvement in decisions about acute care management.ObjectiveTo determine whether caregiver depression is associated with increased use of the emergency department (ED) among patients with dementia.Design, setting, and participantsThis longitudinal cohort study used data from the Care Ecosystem study, a randomized clinical trial examining telephone-based supportive care for patients with dementia and their caregivers. Patients were 45 years or older with any type of dementia. A total of 780 caregiver-patient dyads were enrolled from March 20, 2015, until February 28, 2017, and 663 dyads contributed baseline and 6-month data and were included in the analysis.ExposuresCaregiver depression (9-item Patient Health Questionnaire score of ≥10). Secondary analyses examined caregiver burden and self-efficacy.Main outcomes and measuresThe primary outcome was the number of ED visits in a 6-month period.ResultsAmong the 663 caregivers (467 women and 196 men; mean [SD] age, 64.9 [11.8] years), 84 caregivers (12.7%) had depression at baseline. The mean incidence rate of ED visits was 0.9 per person-year. Rates of ED presentation were higher among dyads whose caregiver did vs did not have depression (1.5 vs 0.8 ED visits per person-year). In a Poisson regression model adjusting for patient age, sex, severity of dementia, number of comorbidities, and baseline ED use, as well as caregiver age and sex, caregiver depression continued to be associated with ED use, with a 73% increase in rates of ED use among dyads with caregivers with depression (adjusted incident rate ratio, 1.73; 95% CI, 1.30-2.30). Caregiver burden was associated with higher ED use in the unadjusted model, but this association did not reach statistical significance after adjustment (incident rate ratio, 1.19; 95% CI, 0.93-1.52). Caregiver self-efficacy was inversely proportional to the number of ED visits in the unadjusted and adjusted models (adjusted incident rate ratio, 0.96; 95% CI, 0.92-0.99).Conclusions and relevanceAmong patients with dementia, caregiver depression appears to be significantly associated with increased ED use, revealing a key caregiver vulnerability, which, if addressed with patient- and caregiver-centered dementia care, could improve health outcomes and lower costs for this high-risk population.

ImportanceIdentifying infectious causes of subacute or chronic meningitis can be challenging. Enhanced, unbiased diagnostic approaches are needed.ObjectiveTo present a case series of patients with diagnostically challenging subacute or chronic meningitis using metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) supported by a statistical framework generated from mNGS of control samples from the environment and from patients who were noninfectious.Design, setting, and participantsIn this case series, mNGS data obtained from the CSF of 94 patients with noninfectious neuroinflammatory disorders and from 24 water and reagent control samples were used to develop and implement a weighted scoring metric based on z scores at the species and genus levels for both nucleotide and protein alignments to prioritize and rank the mNGS results. Total RNA was extracted for mNGS from the CSF of 7 participants with subacute or chronic meningitis who were recruited between September 2013 and March 2017 as part of a multicenter study of mNGS pathogen discovery among patients with suspected neuroinflammatory conditions. The neurologic infections identified by mNGS in these 7 participants represented a diverse array of pathogens. The patients were referred from the University of California, San Francisco Medical Center (n = 2), Zuckerberg San Francisco General Hospital and Trauma Center (n = 2), Cleveland Clinic (n = 1), University of Washington (n = 1), and Kaiser Permanente (n = 1). A weighted z score was used to filter out environmental contaminants and facilitate efficient data triage and analysis.Main outcomes and measuresPathogens identified by mNGS and the ability of a statistical model to prioritize, rank, and simplify mNGS results.ResultsThe 7 participants ranged in age from 10 to 55 years, and 3 (43%) were female. A parasitic worm (Taenia solium, in 2 participants), a virus (HIV-1), and 4 fungi (Cryptococcus neoformans, Aspergillus oryzae, Histoplasma capsulatum, and Candida dubliniensis) were identified among the 7 participants by using mNGS. Evaluating mNGS data with a weighted z score-based scoring algorithm reduced the reported microbial taxa by a mean of 87% (range, 41%-99%) when taxa with a combined score of 0 or less were removed, effectively separating bona fide pathogen sequences from spurious environmental sequences so that, in each case, the causative pathogen was found within the top 2 scoring microbes identified using the algorithm.Conclusions and relevanceDiverse microbial pathogens were identified by mNGS in the CSF of patients with diagnostically challenging subacute or chronic meningitis, including a case of subarachnoid neurocysticercosis that defied diagnosis for 1 year, the first reported case of CNS vasculitis caused by Aspergillus oryzae, and the fourth reported case of C dubliniensis meningitis. Prioritizing metagenomic data with a scoring algorithm greatly clarified data interpretation and highlighted the problem of attributing biological significance to organisms present in control samples used for metagenomic sequencing studies.

Central nervous system (CNS) lymphoma can present a diagnostic challenge. Currently, there is no consensus regarding what presurgical evaluation is warranted or how to proceed when lesions are not surgically accessible. We conducted a review of the literature on CNS lymphoma diagnosis (1966 to October 2011) to determine whether a common diagnostic algorithm can be generated. We extracted data regarding the usefulness of brain and body imaging, serum and cerebrospinal fluid (CSF) studies, ophthalmologic examination, and tissue biopsy in the diagnosis of CNS lymphoma. Contrast enhancement on imaging is highly sensitive at the time of diagnosis: 98.9% in immunocompetent lymphoma and 96.1% in human immunodeficiency virus-related CNS lymphoma. The sensitivity of CSF cytology is low (2%-32%) but increases when combined with flow cytometry. Cerebrospinal fluid lactate dehydrogenase isozyme 5, β2-microglobulin, and immunoglobulin heavy chain rearrangement studies have improved sensitivity over CSF cytology (58%-85%) but have only moderate specificity (85%). New techniques of proteomics and microRNA analysis have more than 95% specificity in the diagnosis of CNS lymphoma. Positive CSF cytology, vitreous biopsy, or brain/leptomeningeal biopsy remain the current standard for diagnosis. A combined stepwise systematic approach outlined here may facilitate an expeditious, comprehensive presurgical evaluation for cases of suspected CNS lymphoma.