BACKGROUND Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test. METHODS In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review. RESULTS We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment. CONCLUSIONS Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, .)

Identifying infectious causes of subacute or chronic meningitis can be challenging. Enhanced, unbiased diagnostic approaches are needed. OBJECTIVE To 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 PARTICIPANTS In 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 MEASURES Pathogens identified by mNGS and the ability of a statistical model to prioritize, rank, and simplify mNGS results. RESULTS The 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 RELEVANCE Diverse 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 contr...

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The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has emerged as an unprecedented worldwide crisis in the early months of 2020, overwhelming health systems and challenging societies as we seek to contain its spread. In the tremendous flood of viral pneumonia cases and resultant life-threatening respiratory complications, the extent of potential neurologic manifestations of coronavirus disease 2019 (COVID-19) has remained unclear. In this issue of JAMA Neurology, a retrospective consecutive case series 1 of 214 patients from Wuhan, China, with either moderate or severe COVID-19 reports an early view of the incidence and types of neurologic complications and sets the stage for future longitudinal work in the area.

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Objective: To describe the rate and predictors of central nervous system (CNS) disease in emergency department (ED) patients with dizziness in the modern era of neuroimaging. Patients and Methods: We retrospectively reviewed the medical records of all adults presenting between January 1, 2007, and December 31, 2009, to an academic ED for a primary triage complaint of dizziness, vertigo, or imbalance. The final diagnosis for the cause of dizziness was independently assigned by 2 neurologists, with a third neurologist resolving any disagreements. The primary outcome was a composite of ischemic stroke, intracranial hemorrhage, transient ischemic attack, seizure, brain tumor, demyelinating disease, and CNS infection. Univariate and multivariate logistic regression were used to assess the association between clinical variables and serious CNS causes of dizziness. Results: Of 907 patients experiencing dizziness (mean age, 59 years; 58% women [nϭ529]), 49 (5%) had a serious neurologic diagnosis, including 37 cerebrovascular events. Dizziness was often caused by benign conditions, such as peripheral vertigo (294 patients [32%]) or orthostatic hypotension (121 patients [13%]). Age 60 years or older (odds ratio [OR], 5.7; 95% confidence interval [CI], 2.5-11.2), a chief complaint of imbalance (OR, 5.9; 95% CI, 2.3-15.2), and any focal examination abnormality (OR, 5.9; 95% CI, 3.1-11.2) were independently associated with serious neurologic diagnoses, whereas isolated dizziness symptoms were inversely associated (OR, 0.2; 95% CI, 0.0-0.7). Conclusion: Dizziness in the ED is generally benign, although a substantial fraction of patients harbor serious neurologic disease. Clinical suspicion should be heightened for patients with advanced age, imbalance, or focal deficits.

Methamphetamine use is associated with ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage, especially among young patients. We showed no evidence that the ischemic stroke associated with methamphetamine use is due to an inflammatory etiology but may be due to a process of accelerated atherosclerosis.

Objective: Transient ischemic attacks are common and important harbingers of subsequent stroke. Management varies widely, and most published guidelines have not been updated in several years. We sought to create comprehensive, unbiased, evidencebased guidelines for the management of patients with transient ischemic attacks. Methods: Fifteen expert panelists were selected based on objective criteria, using publication metrics that predicted nomination by practitioners in the field. Prior published guidelines were identified through systematic review, and recommendations derived from them were rated independently for quality by the experts. Highest quality recommendations were selected and subsequently edited by the panelists using a modified Delphi approach with multiple iterations of questionnaires to reach consensus on new changes. Experts were provided systematic reviews of recent clinical studies and were asked to justify wording changes based on new evidence and to rate the final recommendations based on level of evidence and quality. No expert was allowed to contribute to recommendations on a topic for which there could be any perception of a conflict of interest. Results: Of 257 guidelines documents identified by systematic review, 13 documents containing 137 recommendations met all entry criteria. Six iterations of questionnaires were required to reach consensus on wording of 53 final recommendations. Final recommendations covered initial management, evaluation, medical treatment, surgical treatment, and risk factor management. Interpretation: The final recommendations on the care of patients with transient ischemic attacks emphasize the importance of urgent evaluation and treatment. The novel approach used to develop these guidelines is feasible, allows for rapid updating, and may reduce bias. Neurol 2006;60:301-313 A transient ischemic attack (TIA) has been defined classically as "rapidly developed clinical signs of focal or global disturbance of cerebral function lasting fewer than 24 hours, with no apparent non-vascular cause," 1 with a more recent proposal to alter the definition to "a brief episode of neurological dysfunction caused by a focal brain or retinal ischemia, with clinical symptoms typically lasting less than an hour, and without Ann