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Purpose of Review: This article reviews the diagnosis and treatment of infectious meningitis, including updates on newer molecular diagnostic techniques for microbiological diagnosis., Recent Findings: New polymerase chain reaction (PCR)-based molecular diagnostic techniques have improved the timeliness of microbiological diagnosis in meningitis, but clinicians must be aware of the limitations of such tests. Next-generation sequencing can now be applied to CSF, allowing for diagnosis of infections not identifiable by conventional means., Summary: Infectious meningitis can be caused by a broad range of organisms. The clinician must be aware of the test characteristics of new molecular techniques for microbiological diagnosis as well as traditional techniques to tailor antimicrobial therapy appropriately in patients with meningitis., (Copyright © 2021 American Academy of Neurology.)

Viral encephalitis is difficult to treat. Herpes simplex encephalitis has been successfully treated with acyclovir, but is still a cause for significant morbidity even with that treatment. A rare form of autoimmune encephalitis related to NMDA receptor antibody after infection by herpes simplex can be treated with corticosteroid therapy. Arthropod-borne encephalitides, such as West Nile virus encephalitis and Eastern equine encephalitis, are primarily treated with supportive measures. Attempts have been made to use immunoglobulin therapy with limited effects. Progressive multifocal leukoencephalopathy has been treated with an emerging immune activation therapy in a limited number of patients with incomplete success., Competing Interests: Disclosure The author has nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: Tumor necrosis factor (TNF) inhibitors are common therapies for certain autoimmune diseases, such as rheumatoid arthritis. An association between TNF inhibitor exposure and inflammatory central nervous system (CNS) events has been postulated but is poorly understood., Objective: To evaluate whether TNF inhibitor exposure is associated with inflammatory demyelinating and nondemyelinating CNS events in patients with an indication for TNF inhibitor use and to describe the spectrum of those CNS events., Design, Setting, and Participants: A nested case-control study was conducted using the medical records of patients with autoimmune diseases treated at 3 Mayo Clinic locations (Rochester, Minnesota; Scottsdale, Arizona; and Jacksonville, Florida) between January 1, 2003, and February 20, 2019. Patients were included if their records reported International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnostic codes for US Food and Drug Administration-approved autoimmune disease indication for TNF inhibitor use (ie, rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, Crohn disease, and ulcerative colitis) and diagnostic codes for inflammatory CNS events of interest. Patients were matched 1:1 with control participants by year of birth, type of autoimmune disease, and sex., Exposures: TNF inhibitor exposure data were derived from the medical records along with type of TNF inhibitor, cumulative duration of exposure, and time of exposure., Main Outcomes and Measures: The main outcome was either inflammatory demyelinating (multiple sclerosis and other diseases such as optic neuritis) or nondemyelinating (meningitis, meningoencephalitis, encephalitis, neurosarcoidosis, and CNS vasculitis) CNS event. Association with TNF inhibitor was evaluated with conditional logistic regression and adjusted for disease duration to determine the odds ratios (ORs) and 95% CIs. Secondary analyses included stratification of outcome by inflammatory demyelinating and nondemyelinating CNS events and by autoimmune disease (rheumatoid arthritis and non-rheumatoid arthritis)., Results: A total of 212 individuals were included: 106 patients with inflammatory CNS events and 106 control participants without such events. Of this total, 136 were female (64%); the median (interquartile range) age at disease onset for patients was 52 (43-62) years. Exposure to TNF inhibitors occurred in 64 patients (60%) and 42 control participants (40%) and was associated with an increased risk of any inflammatory CNS event (adjusted OR, 3.01; 95% CI, 1.55-5.82; P = .001). These results were similar when the outcome was stratified by demyelinating and nondemyelinating CNS events. Secondary analyses found the association was predominantly observed in patients with rheumatoid arthritis (adjusted OR, 4.82; 95% CI, 1.62-14.36; P = .005)., Conclusions and Relevance: This study found that exposure to TNF inhibitors in patients with autoimmune diseases appeared to be associated with increased risk for inflammatory CNS events. Whether this association represents de novo or exacerbated inflammatory pathways requires further research.

This study aims to explore the clinical features, radiological findings, management and the factors influencing prognosis in PCR-confirmed herpes simplex virus encephalitis (HSE). This is a retrospective review of consecutive patients diagnosed with HSE at Mayo Clinic, Rochester, MN, between January 1995 and December 2013. Only HSE cases confirmed by PCR were included. Univariate and multivariate analysis was used to identify factors associated with good (modified Rankin Scale of 0-2) or poor outcome (mRS of 3-6) at hospital discharge and 1-year follow-up. We identified 45 patients with HSE. Median age was 66 (IQR 53.5-78) years. HSE was caused by HSV-1 in 33 cases and by HSV-2 in 9. Nearly half had seizures upon admission or during hospitalization. The most common regions involved on MRI were the temporal lobe in 35 (87.5%), insula in 28 (70.0%), frontal lobe in 27 (67.5%) and thalamus in 11 (27.5%) patients. MRI pattern was quite homogeneous with HSV-1 infection, but much more heterogeneous with HSV-2. Good outcome at discharge and at 6-12 months was seen in 16 (35.6%) and 27 (65.9%) patients, respectively. On multivariate analyses, older age (p = 0.001), coma (p = 0.008), restricted diffusion on MRI (p = 0.005) and acyclovir started after the first day of admission (p = 0.050) were associated with poor outcome at discharge. Older age, development of coma, presence of restricted diffusion on brain MRI and delay in the administration of acyclovir portend poor outcome in HSE. Conversely, presence of seizures, focal neurological deficits, EEG abnormalities and location or extension of FLAIR/T2 abnormalities did not influence functional outcome.

Herpes simplex virus 2 is a leading cause of viral meningitis and the most commonly recognized infectious cause of benign, recurrent meningitis. We report a retrospective, observational cohort study of patients with herpes simplex virus type 2 (HSV-2) meningitis, confirmed by polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF). The terms "herpes simplex," "meningitis," or "encephalitis" were searched in the medical records system of the Mayo Clinic in Rochester, Minnesota (1995-2008). Patients were included if they had a clinical diagnosis of meningitis and HSV-2 detected by PCR in the CSF. There were 28 patients with 33 episodes identified (83 % female; mean age at presentation of meningitis 36 years, range 17-53; mean time to HSV2 detection from symptom onset 3 days, range 0-6; history of genital herpes 23 %). No patient took oral antiviral treatment at the time of presentation. Episodes were most likely to include headache (100 %), photophobia (47 %), self-reported fever (45 %), meningismus (44 %), and nausea and/or vomiting (29 %). CSF at the time of meningitis was notable for elevated protein (mean 156 g/dL, range 60-258) and white cell count (mean 504 cells/μL, range 86-1,860) with normal glucose (mean 54 mg/dL, range 32-80). Mollaret cells were never detected. Neuroimaging was most often normal (83 %) when performed, although some cases showed nonspecific (14 %) or meningeal changes (3 %). There was no consistent relationship to genital herpes. The duration of treatment with intravenous acyclovir ranged from 3 to 14 days for the first meningitic episode (daily dose range from 500 to 1,000 mg and total dose range from 500 mg q8h for 3 days to 800 mg q8h for 14 days). For subsequent episodes, the duration of treatment of intravenous acyclovir ranged from less than 1 to 14 days (total dose range from 1,390 mg for 1 day to 900 mg q8h for 10 days). The dose of valacyclovir ranged from 500 mg once daily to 500 mg four times daily. The median duration of valacyclovir treatment following the first episode was 10 days (range 3 to 14 days, n = 13). The median duration of valacyclovir treatment following a subsequent meningitic episode was 9 days (range 7 days to indefinite period, n = 9). No patient was reported to have seizures, neurological disability, or death in extended follow-up (mean follow-up 3.4 years). Recurrence of meningitic symptoms was not universal.

Adult onset Still's disease (AOSD) is a systemic inflammatory disease characterized by high-fevers, articular involvement, maculopapular rash, hepatosplenomegaly, lymphadenopathy, and a neutrophilic leukocytosis. Though systemic complications of AOSD or its treatment are well described in the literature, CNS involvement in AOSD is exceedingly rare and can have protean manifestations. We present a patient with AOSD who developed chronic meningitis and sensorineural hearing loss on treatment, with a review of prior reported cases of aseptic meningitis, to highlight this rare complication of this uncommon illness.

Purpose of Review: Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the human CNS that has gained new importance because of AIDS and newer immunosuppressive therapies. It destroys oligodendrocytes, leading to neurologic deficits associated with demyelination., Recent Findings: PML most commonly occurs in patients who are HIV infected, but increasing numbers of patients are being recognized in the context of immunosuppressive therapies for autoimmune diseases. The precise pathogenesis of infection by JC virus, the etiologic human papovavirus, remains elusive, but much has been learned since the original description of the pathologic entity PML in 1958. Detection and diagnosis of this disorder have become more sophisticated with MRI of the brain and spinal fluid analysis using PCR detection. Immune reconstitution inflammatory syndrome complicates reversal of immunosuppression when PML has established a foothold in the brain., Summary: No effective therapy exists, but there is hope for better management of patients by withdrawing exogenous immunosuppression and reconstituting the immune system, with a projection of better long-term survival.

CSF 14-3-3 and neuron-specific enolase (NSE) proteins were quantitated from patients who had Creutzfeldt-Jakob disease (CJD) or other rapidly dementing disorders initially considered to be CJD. Thirty-one patients were diagnosed as having CJD among 152 studied. CSF 14-3-3 values more than 8 ng/mL correlated with CJD. CSF NSE values less than 30 ng/mL and 14-3-3 values less than 8 ng/mL made a diagnosis of CJD unlikely, but did not exclude it.

Progressive multifocal leukoencephalopathy is an important viral opportunistic infection of oligodendrocytes leading to direct demyelination. Virus is likely disseminated to the brain via the blood. However, the timing of that dissemination with relationship to clinical disease is unknown. Important clues about viral pathogenesis have been learned by applying molecular in situ techniques to diseased brain. The oligodendrocyte is the primary target for JC virus infection, and its death is the primary reason for demyelination. Bizarre astrocytes show limited viral DNA replication but are abortively infected. Although lymphoid organs can be infected by JC virus, there is no definitive evidence that lymphoid cells carry virus into the brain at the time of immunosuppression. JC virus may be reactivated from a latent state in both the brain and in non-central nervous system (CNS) organs at the time of immunosuppression, leading to clinical disease. Future sensitive in situ studies will likely resolve controversies about pathogenesis.

Objective: To record long-term follow-up data on patients with chronic idiopathic meningitis., Design: We retrospectively reviewed the outcome of 49 patients who were examined at the Mayo Clinic between 1978 and 1990., Material and Methods: For all patients, symptoms, signs, laboratory values, results of imaging studies, findings on biopsies, results of any empiric treatment, and results of autopsy, if applicable, were assessed. Some of these findings were stratified on the basis of good versus poor outcome of the patients and were analyzed statistically., Results: Of the 49 patients who fulfilled the criteria for chronic idiopathic meningitis, 10 had a cause identified after repeated studies, brain biopsy, or autopsy (8 of these had a neoplasm). Of 21 brain biopsies, 5(24%) yielded a diagnosis. Follow-up of the 39 undiagnosed cases showed that 33 (85%) had a good outcome despite an often prolonged illness. Two patients (5%) died of the meningeal process. Of the eight patients treated empirically with antituberculous medications, none responded. Corticosteroid therapy was effective in 52% of the patients thus treated, but it did not influence the outcome., Conclusion: In this study, 85% of undiagnosed cases of chronic meningitis were benign. No clinical or laboratory findings predicted those patients who had a fatal outcome. In our study population, the most useful empiric therapy was corticosteroids rather than antituberculous medications.

Biotinylated DNA:DNA in situ hybridization was used for determining the presence of JC virus in brain tissues of 67 patients thought to have progressive multifocal leukoencephalopathy. Sixty patients had acquired immunodeficiency syndrome (AIDS) or other illnesses that decreased the cell-mediated immunity. Two patients had no underlying disease, and five others had chronic illnesses not typically associated with reduced cell-mediated immunity. In situ hybridization with biotinylated probe provides specificity and ease of interpretation. The presence of virus can be correlated at the single-cell level with attendant pathologic changes in oligodendrocytes and astrocytes. Not only archival tissue but also tiny fragments of brain biopsy material can be evaluated successfully. Quantifying the technique suggests that the nucleus of a cell labeling for JC virus DNA averages 1,000 copies of replicating genome. Identification of an infected cell is pathologically significant even when only a few such cells are present in a biopsy specimen. Biotinylated DNA or RNA probes are equally effective in identifying infected cells. In situ hybridization will likely continue to be a useful adjunctive procedure for the evaluation of brain tissue from patients suspected of having progressive multifocal leukoencephalopathy.

Polymerase chain reaction (PCR) was used in the detection of JC virus (JCV) DNA in formalin-fixed, paraffin-embedded brain tissue sections from 24 patients with progressive multifocal leukoencephalopathy. Brain sections from normal autopsies (n = 17) and other neurologic conditions (n = 4) were used as controls. Specific amplified products were detected in 20 (83%) of 24 patients with progressive multifocal leukoencephalopathy. PCR did not amplify JCV or human beta-globin gene sequences in four patients with characteristic demyelinating lesions of progressive multifocal leukoencephalopathy that were positive for JCV by in situ hybridization or immunocytochemistry. PCR from biopsy sections resulted in more intense amplification signals than PCR from autopsy tissue. Normal brain sections from 17 autopsies were negative by PCR. Low-grade amplification of JCV was observed in one patient with herpes simplex virus encephalitis. PCR served as a more rapid test for confirmation of progressive multifocal leukoencephalopathy than in situ hybridization. However, PCR performance was altered by prolonged formalin fixation of tissue and undetermined inhibitors of the amplification reaction. Laboratories and clinicians should be aware of the difficulties encountered when using paraffin-embedded tissue for PCR.