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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.

ImportanceIn multiple sclerosis (MS), upper cervical cord gray matter (GM) atrophy correlates more strongly with disability than does brain or cord white matter (WM) atrophy. The corresponding relationships in the thoracic cord are unknown owing to technical difficulties in assessing GM and WM compartments by conventional magnetic resonance imaging techniques.ObjectivesTo investigate the associations between MS disability and disease type with lower thoracic cord GM and WM areas using phase-sensitive inversion recovery magnetic resonance imaging at 3 T, as well as to compare these relationships with those obtained at upper cervical levels.Design, setting, and participantsBetween July 2013 and March 2014, a total of 142 patients with MS (aged 25-75 years; 86 women) and 20 healthy control individuals were included in this cross-sectional observational study conducted at an academic university hospital.Main outcomes and measuresTotal cord areas (TCAs), GM areas, and WM areas at the disc levels C2/C3, C3/C4, T8/9, and T9/10. Area differences between groups were assessed, with age and sex as covariates.ResultsPatients with relapsing MS (RMS) had smaller thoracic cord GM areas than did age- and sex-matched control individuals (mean differences [coefficient of variation (COV)]: 0.98 mm2 [9.2%]; P = .003 at T8/T9 and 0.93 mm2 [8.0%]; P = .01 at T9/T10); however, there were no significant differences in either the WM area or TCA. Patients with progressive MS showed smaller GM areas (mean differences [COV]: 1.02 mm2 [10.6%]; P

ImportanceBrain biopsy specimens that exhibit encephalitis without specific histopathologic features pose a diagnostic challenge to neuropathologists and neurologists. Such cases are generally referred to pathologically as encephalitis, not otherwise specified (ENOS). A systematic approach to diagnostic evaluation in such patients is challenging, and currently there is no generally accepted algorithm.ObjectiveTo examine ultimate diagnostic outcomes in patients with ENOS diagnosed by brain biopsy.Design, setting, and participantsThis retrospective case series at the University of California, San Francisco, Medical Center, a tertiary care urban neurosciences center, studied patients with encephalitis diagnosed by brain biopsy from January 1, 1983, through December 31, 2011.ExposuresBrain biopsy.Main outcomes and measuresClinical and neuropathologic diagnosis.ResultsAmong 58 patients who met the inclusion criteria for the study, the original pathologic diagnosis was ENOS in 49 patients (84%). The median age was 40 years (interquartile range, 27-53 years), 35 patients were male, and 13 had known human immunodeficiency virus or AIDS. Median time from onset of symptoms to brain biopsy was 66 days (interquartile range, 18-135 days). For the 29 patients in whom material for pathologic analysis was still available, additional neuropathologic review led to a more specific categorization in 10 (34%). Clinical detail and follow-up information was available for 42 patients, and a specific diagnosis was reached with the help of ancillary testing and/or clinical follow-up in 12 patients. Despite a comprehensive neuropathologic review with additional studies and information, 27 patients still had to be classified in the ENOS category at the end of the study.Conclusions and relevanceENOS is the most common initial type of encephalitis diagnosed by brain biopsy. In such patients, it may be worth having the biopsy materials reviewed again in a comprehensive fashion by a neuropathologist because additional review led to a more specific categorization in one-third of our cases. Ancillary testing, clinical correlation, and clinical follow-up establish more specific diagnoses in some patients. ENOS still remains a diagnostic challenge after all these efforts in many cases. Current algorithms are of limited value. More advanced methods and better diagnostic algorithms are needed to characterize these patients.