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Naegleria fowleri ( N. fowleri ) infection via the upper respiratory tract causes a fatal CNS disease known as primary amoebic meningoencephalitis (PAM). The robust in vivo immune response to N. fowleri infection underlies the immunopathology that characterizes the disease. However, little is known about why this pathogen evades immune control. Infections occur in seemingly healthy individuals and effective clinical options are lacking, thus a nearly 98% fatality rate. It is unclear how or if host factors may contribute to susceptibility or disease exacerbation, yet mechanistic studies of the in vivo immune response and disease progression are hampered by a lack of tools. In this study, we have generated monoclonal antibodies to N. fowleri surface antigens and shown them to be excellent tools for studying the in vivo immune response. We also identified one monoclonal, 2B6, with potent inherent anti-amoebastatic activity in vitro . This antibody is also able to therapeutically prolong host survival in vivo and furthermore, recombinant antibodies with an isotype more capable of directing immune effector activity further improved survival when given therapeutically. Thus, we report the generation of a novel monoclonal antibody to N. fowleri that can enhance beneficial immune functions, even when given therapeutically during disease. We believe this provides evidence for the potential of therapeutic antibody treatments in PAM.IMPORTANCE Naegleria fowleri ( N. fowleri ) is a free-living amoeba that is found ubiquitously in warm freshwater. While human exposure is common, it rarely results in pathogenesis. However, when N. fowleri gains access to the upper airway, specifically the olfactory mucosa, infection leads to a lethal disease known as primary amoebic meningoencephalitis (PAM). As a free-living amoeba, N. fowleri does not need a mammalian host; indeed, it can be accurately described as an accidental opportunistic pathogen. While most opportunistic infections occur in humans who are immunocompromised, there are no reported immune dysfunctions associated with N. fowleri infection. Therefore, the basis for N. fowleri opportunism is not known, and the reasons why some humans develop PAM while others do not are simply not well understood. It is reasonable to speculate that local or acute immune failures, potentially even a lack of prior adaptive immunity, are related to disease susceptibility. Careful immune profiling and characterization of the in vivo immune response to N. fowleri in a mammalian host are desperately needed to understand which host factors are critical to defense, and how these responses might be compromised in a way that results in lethal infection. To identify genes and pathways that provide resistance against in vivo N. fowleri infection, we generated surface reactive monoclonal antibodies (Abs) that provide rapid amoeba detection and quantification in vivo . Interestingly, N. fowleri binding Abs have been readily detected in the serum and saliva of humans and animals suggesting that non-lethal exposure drives a humoral immune response against the amoeba. Yet, how Abs might interact with Naegleria in vivo or contribute to preventing lethal infection is not well understood. In this study, we have generated and characterized a monoclonal antibody (Ab), Clone 2B6, that recognizes a glycosylated surface antigen present in cultured in vitro N. fowleri as well as mouse passaged N. fowleri . When clone 2B6 binds to N. fowleri , it inhibits amoeba motility and feeding behavior, leading to strong growth inhibition. Mice treated systemically and intracerebrally with Ab displayed a delayed disease onset and prolonged survival. In addition, we found that enhancing immune-directed effector activity via antibody isotype could further enhance survival without obvious immunopathogenic side effects. These findings show the potential for antibody treatment as an additional therapeutic to those used currently in PAM., Competing Interests: The authors declare no conflict of interest.

Background: During the 2018-20 Ebola virus disease outbreak in the Democratic Republic of the Congo, thousands of patients received unprecedented vaccination, monoclonal antibody (mAb) therapy, or both, leading to a large number of survivors. We aimed to report the clinical, virological, viral genomic, and immunological features of two previously vaccinated and mAb-treated survivors of Ebola virus disease in the Democratic Republic of the Congo who developed second episodes of disease months after initial discharge, ultimately complicated by fatal meningoencephalitis associated with viral persistence., Methods: In this case report study, we describe the presentation, management, and subsequent investigations of two patients who developed recrudescent Ebola virus disease and subsequent fatal meningoencephalitis. We obtained data from epidemiological databases, Ebola treatment units, survivor programme databases, laboratory datasets, and hospital records. Following national protocols established during the 2018-20 outbreak in the Democratic Republic of the Congo, blood, plasma, and cerebrospinal fluid (CSF) samples were collected during the first and second episodes of Ebola virus disease from both individuals and were analysed by molecular (quantitative RT-PCR and next-generation sequencing) and serological (IgG and IgM ELISA and Luminex assays) techniques., Findings: The total time between the end of the first Ebola virus episode and the onset of the second episode was 342 days for patient 1 and 137 days for patient 2. In both patients, Ebola virus RNA was detected in blood and CSF samples during the second episode of disease. Complete genomes from CSF samples from this relapse episode showed phylogenetic relatedness to the genome sequenced from blood samples collected from the initial infection, confirming in-host persistence of Ebola virus. Serological analysis showed an antigen-specific humoral response with typical IgM and IgG kinetics in patient 1, but an absence of an endogenous adaptive immune response in patient 2., Interpretation: We report the first two cases of fatal meningoencephalitis associated with Ebola virus persistence in two survivors of Ebola virus disease who had received vaccination and mAb-based treatment in the Democratic Republic of the Congo. Our findings highlight the importance of long-term monitoring of survivors, including continued clinical, virological, and immunological profiling, as well as the urgent need for novel therapeutic strategies to prevent and mitigate the individual and public health consequences of Ebola virus persistence., Funding: Ministry of Health of the Democratic Republic of the Congo, Institut National de Recherche Biomédicale, Infectious Disease Rapid Response Reserve Fund, US Centers for Disease Control and Prevention, US National Cancer Institute (National Institutes of Health), French National Research Institute for Development, and WHO., Competing Interests: Declaration of interests We declare no competing interests., (Published by Elsevier Ltd.)

Objective: The overlapping syndrome of anti-GFAP and anti-MOG antibodies is extremely rare. This retrospective study reports 8 adult cases of the GFAP-MOG overlapping syndrome., Methods: We reviewed the clinical characteristics of 8 adult patients with the GFAP-MOG overlapping syndrome from Jan 2019 and Sep 2023 at the Third Affiliated Hospital, Sun Yat-sen University. Moreover, we searched the literature and included all case reports with this overlapping syndrome since 2018 on PubMed., Results: The predominant clinical syndrome was meningoencephalomyelitis (5/8), followed by meningoencephalitis (2/8), and myelitis (1/8). Five patients had a flu-like prodromal symptom or diarrhea. No neoplasms were found in these patients. Regarding brain MRI, T2-weighted/fluid-attenuated inversion recovery hyperintensities were in 7 patients and leptomeningeal enhancement was in 4 patients. However, only one patient had periventricular radial linear enhancement. Besides, two patients had large space-occupying lesions. For spinal MRI, T2-hyperintensities were observed in 4 patients, in which 3 patients had longitudinally extensive lesions. All patients were treated with immunotherapy, the median follow-up period was 18 months (range, 3-36 months). Three patients presented relapses during the follow-up, but all cases recovered to mRS scores ≤ 2 at last follow-up. In addition, we also reviewed 14 cases (including 7 adults and 7 children) with this overlapping syndrome by literature review., Conclusion: Our findings provide data to understand the clinical features and prognosis of the GFAP-MOG overlapping syndrome. Recognizing this overlapping syndrome will expand our knowledge, allowing for better management of these patients., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Cryptococcosis, caused by fungi of the genus Cryptococcus , manifests in a broad range of clinical presentations, including severe pneumonia and disease of the central nervous system (CNS) and other tissues (bone and skin). Immune deficiency or development of overexuberant inflammatory responses can result in increased susceptibility or host damage, respectively, during fungal encounters. Leukotrienes help regulate inflammatory responses against fungal infections. Nevertheless, studies showed that Cryptococcus exploits host 5-lipoxygenase (5-LO), an enzyme central to the metabolism of arachidonic acid into leukotrienes, to facilitate transmigration across the brain-blood barrier. To investigate the impact of host 5-LO on the development of protective host immune responses and mortality during cryptococcosis, wild-type (C57BL/6) and 5-lipoxygenase-deficient (5-LO -/- ) mice were given experimental pulmonary and systemic Cryptococcus sp., infections. Our results showed that 5-LO -/- mice exhibited reduced pathology and better disease outcomes (i.e., no mortality or signs associated with cryptococcal meningoencephalitis) following pulmonary infection with C. deneoformans, despite having detectable yeast in the brain tissues. In contrast, C57BL/6 mice exhibited classical signs associated with cryptococcal meningoencephalitis. Additionally, brain tissues of 5-LO -/- mice exhibited lower levels of cytokines (CCL2 and CCL3) clinically associated with Cryptococcus -related immune reconstitution inflammatory syndrome (C-IRIS). In a systemic mouse model of cryptococcosis, 5-LO -/- mice and those treated with a Federal Drug Administration (FDA)-approved 5-LO synthesis inhibitor, zileuton, displayed significantly reduced mortality compared to C57BL/6 infected mice. These results suggest that therapeutics designed to inhibit host 5-LO signaling could reduce disease pathology and mortality associated with cryptococcal meningoencephalitis., Importance: Cryptococcosis is a mycosis with worldwide distribution and has a broad range of clinical manifestations, including diseases of the CNS. Globally, there is an estimated 179,000 cases of cryptococcal meningitis, resulting in approximately 112,000 fatalities per annum and 19% of AIDS-related deaths. Understanding how host immune responses are modulated during cryptococcosis is central to mitigating the morbidity and mortality associated with cryptococcosis. Leukotrienes (LTs) have been shown to modulate inflammatory responses during infection. In this study, we show that mice deficient in 5-lipoxygenase (5-LO), an enzyme central to the metabolism of arachidonic acid into leukotrienes, exhibit reduced pathology, disease, and neurological signs associated with cryptococcal meningitis. Additionally, mice given an experimental cryptococcal infection and subsequently treated with an FDA-approved 5-LO synthesis inhibitor exhibited significantly reduced mortality rates. These results suggest that therapeutics designed to inhibit host 5-LO activity could significantly reduce pathology and mortality rates associated with cryptococcal meningitis., Competing Interests: The authors declare no conflict of interest.

Background: Pugs commonly present with thoracolumbar myelopathy, also known as pug dog myelopathy (PDM), which is clinically characterised by progressive signs involving the pelvic limbs, no apparent signs of pain and, often, incontinence. In addition to meningeal fibrosis and focal spinal cord destruction, histopathology has confirmed lymphohistiocytic infiltrates in the central nervous system (CNS) in a considerable number of pugs with PDM. Lymphohistiocytic CNS inflammation also characterises necrotising meningoencephalitis (NME) in pugs. This study aimed to investigate the potential contribution of an immunological aetiology to the development of PDM., Methods: The concentrations of glial fibrillary acidic protein (GFAP) in serum and CSF and of anti-GFAP autoantibodies in CSF were measured with an ELISA. In addition, a commercial test was used for genetic characterisation of the dog leukocyte antigen class II haplotype, which is associated with NME susceptibility., Results: This study included 87 dogs: 52 PDM pugs, 14 control pugs, four NME pugs and 17 dogs of breeds other than pugs that were investigated for neurological disease (neuro controls). Anti-GFAP autoantibodies were present in 15 of 19 (79%) of the PDM pugs tested versus six of 16 (38%) of the neuro controls tested (p = 0.018). All 18 PDM pugs evaluated had detectable CSF GFAP. Serum GFAP was detected in two of three (67%) of the NME pugs and in two of 11 (18%) of the control pugs but not in any of the 40 tested PDM pugs. Male pugs heterozygous for the NME risk haplotype had an earlier onset of clinical signs (70 months) compared to male pugs without the risk haplotype (78 months) (p = 0.036)., Limitations: The study was limited by the lack of healthy dogs of breeds other than pugs and the small numbers of control pugs and pugs with NME., Conclusions: The high proportion of PDM pugs with anti-GFAP autoantibodies and high CSF GFAP concentrations provide support for a potential immunological contribution to the development of PDM., (© 2024 The Authors. Veterinary Record published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)

Objective: Patients with X linked agammaglobulinemia are susceptible to enterovirus (EV) infections. Similarly, severe EV infections have been described in patients with impaired B-cell response following treatment with anti-CD20 monoclonal antibodies (mAbs), mostly in those treated for haematological malignancies. We aimed to describe severe EV infections in patients receiving anti-CD20 mAbs for immune-mediated inflammatory diseases (IMIDs)., Methods: Patients were included following a screening of data collected through the routine surveillance of EV infections coordinated by the National Reference Center and a review of the literature. Additionally, neutralising antibodies were assessed in a patient with chronic EV-A71 meningoencephalitis., Results: Nine original and 17 previously published cases were retrieved. Meningoencephalitis (n=21/26, 81%) associated with EV-positive cerebrospinal fluid (n=20/22, 91%) was the most common manifestation. The mortality rate was high (27%). EV was the only causal agents in all reported cases. Patients received multiple anti-CD20 mAbs infusions (median 8 (5-10)), resulting in complete B-cell depletion and moderate hypogammaglobulinemia (median 4.9 g/L (4.3-6.7)), and had limited concomitant immunosuppressive treatments. Finally, in a patient with EV-A71 meningoencephalitis, a lack of B-cell response to EV was shown., Conclusion: EV infection should be evoked in patients with IMIDs presenting with atypical organ involvement, especially meningoencephalitis. Anti-CD20 mAbs may lead to impaired B-cell response against EV, although an underlying primary immunodeficiency should systematically be discussed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To analyze the clinical manifestations, imaging, electroencephalography, treatment, and prognosis of 35 cases of autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) in children., Methods: Children hospitalized in the Department of Neurology, Hunan Children's Hospital, China, between January 2015 and June 2021, owing to autoimmune diseases of the central nervous system were subjected to a cell-based assay (CBA). The assay identified 40 children positive for GFAP-immunoglobulin (Ig)G antibodies in the serum and/or the cerebrospinal fluid. Based on clinical manifestations and imaging characteristics, five children who were only positive for GFAP-IgG antibodies in serum were excluded, and the remaining 35 children were diagnosed with autoimmune GFAP-A. The clinical data derived from the 35 children were retrospectively analyzed., Results: A total of 35 children, including 23 males and 12 females with a mean age of 6.3 ± 0.6 years, manifested clinical symptoms of fever (62.9%), headache (42.9%), convulsions (42.9%), abnormal mental behavior (51.4%), disorders of consciousness (54.3%), visual disturbance (22.9%), ataxia (11.4%), paralysis (40%), and autonomic dysfunction (25.7%). One child exhibited only the clinical symptom of peripheral facial nerve palsy. Eleven out of 35 children were also positive for other antibodies. In addition to the common overlapping autoimmune syndromes, one case of autoimmune GFAP-A also manifested as Bickerstaff's brainstem encephalitis. Linear periventricular enhancement upon MRI was significantly less frequent in children (8.5%) than in adults. In pediatric patients, MRI contrast enhancement was principally seen in the meninges and brain lobes. Although repeated relapse (17.1%) and sequelae symptoms (20%) occurred in some cases, most children showed a favorable prognosis. Spearman's rank correlation showed that the antibody titer was not significantly associated with the severity of the initial disease conditions., Conclusions: The disease diagnosis in children seropositive for GFAP antibodies only should receive a comprehensive diagnosis based on their clinical symptoms, imaging, electroencephalographic characteristics, and treatment responses. Some patients with relapses should receive repeated gamma globulin and corticosteroid therapy or the addition of immunosuppressants to their therapeutic regimen, and slow-dose tapering of corticosteroids and extended treatment are recommended for patients with overlapping autoimmune syndromes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fang, Hu, Jiang, Yang, Liao, Yang and Wu.)

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a recently defined autoimmune meningoencephalomyelitis, associated with GFAP-IgG antibody. A pooled analysis of 324 cases from published literature and a retrospective single-center study were performed, firstly reveals the possibility that patients with myelitic lesions respond better to initial immunotherapy, but are prone to relapse, suggesting a more aggressive and long-term immunosuppressive medication for them. Moreover, our results showed using tacrolimus at maintenance stage exhibited a less tendency to relapse, providing a possibly new choice to future clinical treatments., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Objectives: To describe the autopsy findings and neuropathologic evaluation of autoimmune meningoencephalomyelitis associated with glial fibrillary acidic protein (GFAP) antibody., Methods: We reviewed the clinical course, imaging, laboratory, and autopsy findings of a patient with autoimmune meningoencephalomyelitis associated with GFAP antibody who had a refractory course to multiple immunosuppressive therapies., Results: The patient was a 70-year-old man who was diagnosed as GFAP antibody-associated autoimmune meningoencephalomyelitis. MRI of the head showed linear perivascular enhancement in the midbrain and the basal ganglia. Despite treatment with high-dose corticosteroids, plasma exchange, IV immunoglobulins, and cyclophosphamide, he died with devastating neurologic complications. Autopsy revealed a coexistent neuroendocrine tumor in the small intestine and diffuse inflammation in the brain parenchyma, perivascular spaces, and leptomeninges, with predominant T-cells, macrophages, and activated microglia. B-cells and plasma cells were absent. There was no astrocyte involvement with change in GFAP immunostaining., Discussion: This case illustrates autoimmune meningoencephalomyelitis associated with GFAP antibody in the CSF and coexistent neuroendocrine tumor. The autopsy findings were nonspecific and did not demonstrate astrocyte involvement. Further accumulation of cases is warranted to delineate the utility and pathogenic significance of the GFAP autoantibody., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Cryptococcal meningoencephalitis (CM) is a leading cause of central nervous system (CNS) infection-related mortality worldwide, with surviving patients often developing neurological deficiencies. While CNS inflammation has been implicated in the pathogenesis of CM, little is known about the relative contribution of the specific inflammatory/immune pathways to CNS pathology versus fungal clearance. Increased cerebrospinal fluid level of C-C chemokine receptor 2 (CCR2) ligand CCL2 is associated with disease deterioration in patients with CM. Using a murine model, we investigated the role of the CCR2 pathway in the development of CNS inflammation and pathology during CM. We found that CCR2-deficient mice exhibited improved 28-day survival and alleviated neurological disease scores despite a brain fungal burden higher than that of the WT mice. Reduced CM pathology in CCR2-deficient mice was accompanied by markedly decreased neuronal cell death around cryptococcal microcysts and restored expression of genes involved in neurotransmission, connectivity, and neuronal cell structure in the brains. Results show that CCR2 axis is the major pathway recruiting CD45 hi CD11b + Ly6C + inflammatory monocyte to the brain and indirectly modulates the accumulation of CD4 + T cells and CD8 + T cells. In particular, CCR2 axis promotes recruitment of interferon gamma (IFN-γ)-producing CD4 + T cells and classical activation of myeloid cells. In this context, CCR2 deletion limits the immune network dysregulation we see in CM and attenuates neuropathology. Thus, the CCR2 axis is a potential target for interventions aimed to limit inflammatory CNS pathology in CM patients. IMPORTANCE Cryptococcal meningoencephalitis (CM) causes nearly 200,000 deaths worldwide each year, and survivors frequently develop long-lasting neurological sequelae. The high rate of mortality and neurologic sequelae in CM patients indicate that antifungal therapies alone are often insufficient to control disease progression. Here, we reveal that CM disease progression in mice is accompanied by inflammatory monocytes infiltration at the periphery of the infected foci that overlap locally perturbed neuronal function and death. Importantly, we identified that CCR2 signaling is a critical pathway driving neuroinflammation, especially inflammatory monocyte recruitment, as well as CNS pathology and mortality in CM mice. Our results imply that targeting the CCR2 pathway may be beneficial as a therapy complementary to antifungal drug treatment, helping to reduce CNS damage and mortality in CM patients.

Myelin oligodendrocyte glycoprotein (MOG) antibodies have been found in a broad range of demyelination diseases. In the present study, we reported three cases of patients with anti-MOG antibodies associated disorders (MOG-ADs) who initially presented as intracranial infection like encephalomeningitis with no evidence of demyelination injury, but were subsequently found the expression of MOG antibodies and other demyelination presentations. Our findings suggested that MOG-ADs can start as an intracranial infection like prodromal symptoms prior to the lesions of optic nerve, spinal cord, and white matter. Therefore, clinicians should be cautious of MOG-ADs in cases of encephalomeningitis even without demyelination injury., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Data on the immune response to West Nile virus (WNV) are limited. We analyzed the antiviral cytokine response in serum and cerebrospinal fluid (CSF) samples of patients with WNV fever and WNV neuroinvasive disease using a multiplex bead-based assay for the simultaneous quantification of 13 human cytokines. The panel included cytokines associated with innate and early pro-inflammatory immune responses (TNF-α/IL-6), Th1 (IL-2/IFN-γ), Th2 (IL-4/IL-5/IL-9/IL-13), Th17 immune response (IL-17A/IL-17F/IL-21/IL-22) and the key anti-inflammatory cytokine IL-10. Elevated levels of IFN-γ were detected in 71.7% of CSF and 22.7% of serum samples ( p = 0.003). Expression of IL-2/IL-4/TNF-α and Th1 17 cytokines (IL-17A/IL-17F/IL-21) was detected in the serum but not in the CSF (except one positive CSF sample for IL-17F/IL-4). While IL-6 levels were markedly higher in the CSF compared to serum (CSF median 2036.71, IQR 213.82-6190.50; serum median 24.48, IQR 11.93-49.81; p < 0.001), no difference in the IL-13/IL-9/IL-10/IFN-γ/IL-22 levels in serum/CSF was found. In conclusion, increased concentrations of the key cytokines associated with innate and early acute phase responses (IL-6) and Th1 type immune responses (IFN-γ) were found in the CNS of patients with WNV infection. In contrast, expression of the key T-cell growth factor IL-2, Th17 cytokines, a Th2 cytokine IL-4 and the proinflammatory cytokine TNF-α appear to be concentrated mainly in the periphery.

Background: Manifestations of intractable hyponatremia and hypokalemia in autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy have been rarely reported., Case Presentation: A 75-year-old male patient presented as the case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) and intractable hypokalemia, showed fever, fatigue, and mental disorders. Signs and symptoms of meningoencephalitis, ataxia, and cognitive abnormalities. Magnetic resonance imaging (MRI) revealed multiple white matter lesions of the central nervous system. He had GFAP-IgG in the cerebrospinal fluid (CSF). After treatment with corticosteroids, his symptoms were alleviated gradually, and the level of electrolytes was normal. However, head contrast-enhanced MRI + susceptibility-weighted imaging (SWI) showed a wide afflicted region, and the serum GFAP-IgG turned positive. Considering the relapse of the disease, ha was treated with immunoglobulin and mycophenolate mofetil (MMF) to stabilize his condition., Conclusion: This case showed a rare disease with uncommon manifestations, suggesting that careful examination and timely diagnosis are essential for disease management and satisfactory prognosis.

Background: Glial fibrillary acidic protein (GFAP) autoimmune astrocytopathy is characterized by GFAP autoantibody positive encephalitis, meningoencephalitis or meningoencephalomyelitis. The initial clinical presentation may be similar to central nervous system infections making early diagnosis challenging., Case Presentation: A Chinese female patient presented with subacute meningitis with symptoms of headache, vomiting, and fever. Cerebrospinal fluid (CSF) analysis showed monocytic pleocytosis, elevated protein level, low glucose level, and negative basic microbiological studies including Xpert MTB/RIF. Brain magnetic resonance imaging (MRI) showed bilateral cerebral cortical and white matter hyperintensities on FLAIR sequences. The patient was diagnosed with possible tuberculous meningitis and started on anti-tuberculosis therapy (ATT). Three months later, the patient developed cervical myelopathy and encephalopathy with persistent CSF pleocytosis. Five months later, tissue-based and cell-based assays demonstrated GFAP antibodies in blood and CSF. Her symptoms improved with repeated administration of intravenous immunoglobulin (IVIG) and corticosteroids. One-and-a-half -year follow-up showed neither clinical progression nor relapses., Conclusions: Anti-GFAP astrocytopathy should be included in the differential diagnosis of patients who present with subacute meningitis with negative microbiological studies and a progressive clinical course including encephalitis and/or myelitis.

Angiostrongylus cantonensis is the main causative agent of eosinophilic meningoencephalitis (EoM) in humans. Molecular diagnostic methods are essential since the identification of larvae in cerebrospinal fluid (CSF) is extremely rare. To date, the detection of a 31 kDa antigen by Western blotting has been the primary immunodiagnostic method for EoM caused by A. cantonensis. However, cross-reactivity with other parasites has been observed. Therefore, we conducted a comparative analysis using sera from individuals with angiostrongyliasis. We also characterized proteins isolated from different cellular sources of A. cantonensis, Toxocara canis, Schistosoma mansoni, and Strongyloides stercoralis with mass spectrometry. A total of 115 cross-reactive proteins were identified. Three of these proteins, heat shock protein, an intermediate filament protein, and galectin 1, represent potential markers for cross-reactivity. In addition, synthetic peptides were generated from previously identified diagnostic targets and tested against sera from individuals infected with several other parasites. As a result, two other markers of cross-reactivity were identified: peptide #4 derived from the 14-3-3 protein and peptide #12 derived from the Lec-5 protein. In contrast, 34 proteins were exclusively present in the Angiostrongylus extracts and represent promising diagnostic molecules for specific identification of A. cantonensis infection. In particular, cytochrome oxidase subunit I is of great interest as a possible immunodiagnostic target for angiostrongyliasis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Angiostrongylus cantonensis is a metastrongyloid nematode that causes eosinophilic meningoencephalitis in humans. A high infestation of A. cantonensis can cause permanent brain damage or even death. The inflammasome is an oligomeric molecular platform that can detect microbial pathogens and activate inflammatory cytokines. The recognition of larval surface antigens by pattern recognition receptors (PRRs) can cause oligomerization of the NOD-like receptor (NLR) or absent in melanoma 2 (AIM2) with the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) to form a caspase-1-activating scaffold. Activated caspase-1 converts pro-inflammatory cytokines into their mature, active forms. Helminths infection has been shown to activate NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasomes. In this study, we aimed to investigate the mechanism of inflammasome activation upon A. cantonensis infection in a mouse model. This study provides evidence that A. cantonensis infection can activate NLRP1B and NLRC4 inflammasomes and promote pyroptosis to cause meningoencephalitis., Competing Interests: Declaration of Competing Interest The authors confirm that they have no conflicts of interest in relation to this work., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Many pathogenicity factors are involved in the development of primary amoebic meningoencephalitis (PAM) caused by N fowleri. However, most of them are not exclusive for N fowleri and they have not even been described in other nonpathogenic Naegleria species. Therefore, the objective of this work was to identify differential proteins and protein pattern recognition between Naegleria fowleri and Naegleria lovaniensis using antibodies anti-N fowleri as strategy to find vaccine candidates against meningoencephalitis. Electrophoresis and Western blots conventional and 2-DE were performed for the identification of antigenic proteins, and these were analysed by the mass spectrometry technique. The results obtained in 2-DE gels and Western blot showed very notable differences in spot intensity between these two species, specifically those with relative molecular weight of 100, 75, 50 and 19 kDa. Some spots corresponding to these molecular weights were identified as actin fragment, myosin II, heat shock protein, membrane protein Mp2CL5 among others, with differences in theoretical post-translational modifications. In this work, we found differences in antigenic proteins between both species, proteins that could be used for a further development of vaccines against N fowleri infection., (© 2020 John Wiley & Sons Ltd.)

Objectives: Recent studies suggest that the clinical presentation of tick-borne encephalitis (TBE) is determined by the host immune responses to the tick-borne encephalitis virus (TBEV). The aim of the study was to characterize immune responses in TBE to give a better insight into the immunopathogenesis of this disease., Methods: Anti-TBEV antibody levels, cerebrospinal fluid (CSF) and blood lymphoid populations, and concentrations of CXCL13 (a potent B-cell and T-cell chemoattractant), were analyzed in 35 patients with TBE (20 adults and 15 children)., Results: When compared with the blood, the CSF lymphoid population was significantly enriched in CD4+ T-cells and relatively depleted in natural killer (NK) cells and B lymphocytes. In comparison with TBE meningitis, patients suffering from TBE meningoencephalitis (n = 11, 31%) had a 3.5-fold higher median CSF CXCL13 concentration, 1.8-fold higher CSF/serum ratio of anti-TBEV IgG antibodies, and 1.8-fold higher median CSF cell count. CSF CXCL13 levels did not change significantly in children with TBE meningitis receiving supportive treatment, but decreased in children with TBE meningoencephalitis who received intravenous steroids., Conclusions: CD4+ cells are abundant in the CSF of patients with TBE. CXCL13 may be involved in the neuropathology of TBE by attracting different subsets of lymphocytes to the CSF., (Copyright © 2020. Published by Elsevier Ltd.)

To evaluate occurrence and extent of CSF CXCL13 elevations beyond Lyme neuroborreliosis, we investigated CXCL13 in an unselected patient cohort with neuroinflammatory disease. From March 2016 to March 2017, 180 in-patients with CSF pleocytosis were categorized into following groups: pyogenic CNS infections, aseptic meningoencephalitis, neuroimmunological diseases, and reactive pleocytosis. We provide evidence that CXCL13 elevation occurs at variable extent in the majority of neuroinflammatory diseases. The exact role of CXCL13 in CSF is elusive, but the broad occurrence in neuroinflammation points at CNS immune activation, which is not exclusive for LNB., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A young woman with systemic lupus erythematosus (SLE) developed recurrent enterovirus meningoencephalitis while taking prednisolone, azathioprine and rituximab. After reducing the immunosuppression, she developed a central nervous system (CNS) flare of SLE, with enterovirus still present in the cerebrospinal fluid (CSF). There are no evidence-based specific treatments for enterovirus encephalitis, but she responded well to intravenous immunoglobulin alongside pulsed methylprednisolone and rituximab. This case highlights the difficulties in managing people with co-existing infective and autoimmune conditions, especially if each affects the CNS. A viral infection and SLE flare can resemble one another clinically, although here the radiological differentiation of CNS lupus versus enterovirus encephalitis helped to guide the diagnosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Presumed autoimmune diseases affecting the central nervous system (CNS) of dogs are common. In people, antibodies against neuronal cell surface antigens that are associated with a wide variety of neurological syndromes have been identified. The presence of cerebrospinal fluid (CSF) autoantibodies that target neuronal cell surface proteins has not been reported in dogs with neurologic disorders., Objectives: Autoantibodies to neuronal cell surface antigens can be found in the CSF of dogs with inflammatory CNS disease. Our aim was to determine whether 6 neuronal cell surface autoantibodies were present in the CSF of dogs diagnosed with inflammatory and noninflammatory CNS disease., Animals: Client-owned dogs with CNS disease and complete diagnostic evaluation including magnetic resonance imaging and CSF analysis were included. One healthy dog was included as a negative control., Methods: Cerebrospinal fluid was tested for 6 antigenic targets with a commercially available indirect immunofluorescence assay test kit., Results: There were 32 dogs with neurological disease, 19 diagnosed with inflammatory disease (encephalitis and meningitis), 10 with noninflammatory disease (neoplasia, intervertebral disk disease, degenerative myelopathy, and epilepsy), 2 with no diagnosis, and 1 with neoplasia and meningoencephalitis. Anti-N-methyl-d-aspartate receptor 1 (NMDAR1) antibodies were detected in 3 dogs (3/32; 9.38%). All 3 dogs responded to treatment of meningoencephalomyelitis of unknown etiology (MUE)., Conclusions and Clinical Importance: Further evaluation of the prevalence and clinical relevance of CSF and serum antibodies to neuronal cell surface antigens is warranted. Defining antigenic targets associated with encephalitis in dogs might allow diagnostic categorization of MUE antemortem., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: We document a case of central nervous system infection with Trypanosoma cruzi., Case Description: An 88-year-old woman presented with altered mental status, right-sided weakness, and slurred speech. Her medical history was significant for methotrexate intake for rheumatoid arthritis, and she tested negative for human immunodeficiency virus. Magnetic resonance imaging of the brain showed bilateral thick and peripherally enhancing white matter lesions in the frontoparietal region with extensive surrounding vasogenic edema. A lumbar puncture revealed increased protein and lymphocytic pleocytosis, and needle biopsy highlighted brain necrosis, chronic inflammation, and numerous intracellular organisms suggestive of T. cruzi amastigotes. Despite treatment with benznidazole, the patient expired soon after presentation., Conclusion: Chagas disease should be included in the differential diagnosis of an immunocompromised patient presenting with a central nervous system mass, meningoencephalitis, or focal neurologic signs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In the healthy brain, microglia and other CNS macrophages are the most abundant immune cell type. Thus, they form the natural immune cell interface with streptococci, which are the leading cause of bacterial meningitis and encephalitis in infants and young children. In homeostasis, the blood-brain barrier allows for very limited access of immune cells circulating in the periphery. During bacterial meningoencephalitis, however, origin and fate of CNS macrophages are massively altered. This review summarizes the emerging knowledge on the sequence of reciprocal events between streptococci and CNS macrophages leading to host resistance, acute inflammation, changes in resident innate immune cells of the brain, and long-term neuronal damage., (©2019 Society for Leukocyte Biology.)

The majority of invasive human fungal pathogens gain access to their human hosts via the inhalation of spores from the environment into the lung, but relatively little is known about this infectious process. Among human fungal pathogens the most frequent cause of inhaled fatal fungal disease is Cryptococcus, which can disseminate from the lungs to other tissues, including the brain, where it causes meningoencephalitis. To determine the mechanisms by which distinct infectious particles of Cryptococcus cause disseminated disease, we evaluated two developmental cell types (spores and yeast) in mouse models of infection. We discovered that while both yeast and spores from several strains cause fatal disease, there was a consistently higher fungal burden in the brains of spore-infected mice. To determine the basis for this difference, we compared the pathogenesis of avirulent yeast strains with their spore progeny derived from sexual crosses. Strikingly, we discovered that spores produced by avirulent yeast caused uniformly fatal disease in the murine inhalation model of infection. We determined that this difference in outcome is associated with the preferential dissemination of spores to the lymph system. Specifically, mice infected with spores harbored Cryptococcus in their lung draining lymph nodes as early as one day after infection, whereas mice infected with yeast did not. Furthermore, phagocyte depletion experiments revealed this dissemination to the lymph nodes to be dependent on CD11c+ phagocytes, indicating a critical role for host immune cells in preferential spore trafficking. Taken together, these data support a model in which spores capitalize on phagocytosis by immune cells to escape the lung and gain access to other tissues, such as the central nervous system, to cause fatal disease. These previously unrealized insights into early interactions between pathogenic fungal spores and lung phagocytes provide new opportunities for understanding cryptococcosis and other spore-mediated fungal diseases., Competing Interests: The authors have declared that no competing interests exist.

Background: Recurrent optic neuritis (ON) was previously thought to be associated with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). Meningoencephalitis has recently been suggested to be a clinical finding typical of myelin oligodendrocyte glycoprotein (MOG) encephalomyelitis. We report a Chinese patient with recurrent ON at disease initiation, who had a delayed diagnosis of MOG-IgG syndrome, until recurrent meningoencephalitis appeared and serum MOG-IgG was detected., Case Presentation: From the age of 7 years, an AQP4-IgG negative female patient had 10 disease recurrences, including 4 episodes of recurrent ON, 4 episodes of fever and meningoencephalitis, and 2 episodes of ON as well as meningoencephalitis. She was initially diagnosed as recurrent ON and treated with glucocorticoids followed by gradual tapering when ON reoccurred. Later, she was diagnosed as central nervous system infection when fever and meningoencephalitis appeared, and antiviral drugs and glucocorticoids were used. However, when she returned to our department for follow-up on July 2017, the results of serum demyelinating autoimmune antibody revealed positive MOG-IgG (titer 1:320 by an in-house, cell-based assay using live cells transfected with full-length human MOG). A diagnosis of MOG-IgG syndrome was established., Conclusions: Testing for MOG-IgG in atypical MS and NMOSD patients, and patients with meningoencephalitis with a history of relapsing demyelinating symptoms is warranted.

The case was a 29-year-old male with no previous history of serious disease. He developed headache and fever, which then worsened and he was admitted to our hospital. His temperature was 38.3°C and he had a stiff neck. In cerebrospinal fluid (CSF) tests, the opening pressure was high, the cell count was increased, and the CSF/serum glucose ratio was decreased. In addition, he was positive for cryptococcal antigen. According to these findings, he was diagnosed with cryptococcal meningoencephalitis and antifungal treatment was initiated. His symptoms then improved, but on day 18 after admission, he developed convulsions, and on day 28, right visual field defects appeared. Brain MRI showed disseminated lesions in the bilateral cerebral cortex. Despite a decrease of the cryptococcal antigenic value in the CSF, the IgG index was elevated. IL-6, 8 and 10 in CSF were high levels on Day 1, then gradually reduced as the symptoms improved. But on Day 28, worsening of symptoms, IL-10 was significantly increased dispite IL-6 and 8 reducing. Therefore, the exacerbation of his symptoms and expansion of the lesions were not caused by the Cryptococcus itself, and it was considered that they were due to the late deterioration of cryptococcosis, which responded to steroid treatment.

A novel autoantibody, glial fibrillary acidic protein (GFAP)-IgG, has recently been associated with cases of meningoencephalomyelitis. This entity is still being unraveled. Very few pediatric patients have been identified; thus, the clinical, biological and imaging phenotype remains to be defined. Herein we describe the clinical course of a 6-year-old patient initially suspected to have a demyelinating disease but ultimately diagnosed with GFAP-IgG positive autoimmune meningoencephalomyelitis. We also provide a review of the literature regarding this novel entity., (Published by Elsevier B.V.)

Background: In this study, we describe clinical findings in a patient with autoimmune inflammatory meningoencephalitis who was negative for antibodies against glial fibrillary acidic protein (GFAP-IgG)., Methods: Serum and cerebral spinal fluid (CSF) samples were collected from the patient as part of a study of 520 patients with neurological syndromes. Antibodies against GFAP and other proteins associated with neurological disorders were measured by rat brain- and cell-based indirect immunofluorescence assays., Results: A 42-year-old female was diagnosed with autoimmune inflammatory meningoencephalitis. She experienced a subacute and relapsing course with decreased vision, fever, headache, ataxia, hemiplegia, and disturbance of consciousness. Brain magnetic resonance imaging showed extensive lesions in the white matter along the ventricle, brainstem, right internal capsule, and meninges. The patient responded well to steroid treatment. Examination of CSF revealed a normal white blood cell count and protein level. Serum and CSF were negative for GFAP-specific antibodies and all other autoantibodies tested. Immunohistochemical staining of a brain biopsy collected during relapse revealed chronic inflammation and severe edema. Extensive and strong staining of CD163+ macrophages were evident throughout the lesions; however, CD3+ cells were rare and CD138+ and CD20+ cells were absent., Conclusion: We describe a case of subacute corticosteroid-responsive nonvasculitic autoimmune inflammatory meningoencephalitis in the absence of GFAP-IgG. The pathological features were distinct from those of patients with GFAP-IgG-positive meningoencephalitis, suggesting that nonvasculitic autoimmune inflammatory meningoencephalitis is a heterogeneous neurological syndrome., (Copyright © 2018. Published by Elsevier B.V.)

Vibrio vulnificus usually causes wound infection, gastroenteritis, and septicemia. However, it is a rare conditional pathogen causing meningoencephalitis. We report a case of a young, immunocompromised man presenting with severe sepsis after exposure to sea water and consumption of seafood. The patient subsequently developed meningoencephalitis, and Vibrio vulnificus was isolated from his blood culture. The sequence was confirmed by Next-generation sequencing of a sample of cerebrospinal fluid, as well as from a bacteria culture. After the pathogen was detected, the patient was treated with ceftriaxone, doxycycline, and moxifloxacin for 6 weeks, which controlled his infection. In this case, we acquired his clinical and dynamic MRI presentations, which were never reported. Physicians should consider Vibrio vulnificus infections when they see a similar clinical course, brain CT and MRI findings, susceptibility factors and recent seafood ingestion or exposure to seawater. Due to high mortality, the early diagnosis and treatment of Vibrio vulnificus infections are crucial. Next-generation sequencing was found to be useful for diagnosis.

Objective: To describe 2 atypical cases with Anti-MOG antibody related demyelinating syndrome., Methodology: Case series., Results: We present two cases. Case 1 is an 18-year-old woman who presented with headache, blurred vision, and papilledema and was initially diagnosed with pseudotumor cerebri syndrome. CSF showed mildly elevated opening pressure and lymphocytic pleocytosis and a diagnosis of aseptic meningitis was considered. MRI brain and spinal cord revealed longitudinally extensive bilateral simultaneous optic neuritis and multiple spinal cord lesions. Case 2 is a 28-year old man who presented initially with unilateral optic neuritis followed by aseptic meningitis three weeks later and subsequently acute disseminated encephalomyelitis (ADEM). Serology was positive for Anti-MOG antibody on a cell-based assay in both these cases., Discussion: Although bilateral optic neuritis has been well described in MOG related disorders, aseptic meningitis and pseudotumor cerebri-like syndromes are notable alternate presentations. The presence of eosinophils in the CSF (in the first patient) is a unique finding in our case series., Conclusion: In a patient with an aseptic meningitis like presentation, the presence of optic neuritis, brain and/or spinal cord lesions should raise suspicion for an MOG-Ab related syndrome., (Copyright © 2018. Published by Elsevier B.V.)

Purpose : The purpose of the article is to describe a novel case of idiopathic central nervous system inflammatory disease with bilateral human leukocyte antigen (HLA)-B27-positive anterior uveitis. Methods/Results : A 15-year-old African American boy with bilateral HLA-B27-positive anterior uveitis controlled with topical and oral steroids for 8 months acutely developed headaches, left eyelid ptosis, and binocular diplopia. Imaging showed lesions in the right midbrain, superior colliculus, cerebellar peduncles, and cerebellar vermis and leptomeningeal enhancement along the vermian foliae. Cerebral spinal fluid tests showed mild lymphohistiocytic pleocytosis with negative cytology; inflammatory and infectious workup were negative. He received intravenous methylprednisolone without initial symptomatic improvement; repeat magnetic resonance imaging (MRI) showed reduced lesion burden. Oral steroids were continued; his symptoms resolved in 1 month. Repeat MRI 2 months after presentation showed almost complete lesion resolution. Conclusions : Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) was diagnosed. HLA-B27 positivity may represent a novel association with CLIPPERS.

We report a case of a progressive supranuclear palsy-like phenotype with rapidly progressive dementia and prominent language and executive dysfunction. Pathological examination revealed no midbrain or white matter tauopathy, but rather chronic meningoencephalitis and other mixed pathology. The cerebrospinal fluid (CSF) in this case showed a novel antibody against central nervous system and renal tissue., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

After a 34-year-old female developed a headache and high fever, she was diagnosed with aseptic meningitis. On admission, neurological examinations revealed cerebellar limb ataxia, horizontal gaze paretic nystagmus, and pyramidal tract signs. Laboratory tests showed hyponatremia (129 mEq/l). Five days after admission, convulsions in the upper limbs due to the severe hyponatremia (108 mEq/l) were noted. In addition, serum antidiuretic hormone levels were markedly increased to 18.5 pg/ml. Brain MRI showed multiple small inflammatory lesions in the subcortical cerebral white matter, thalamus, and around the third ventricular diencephalic regions. Pulse corticosteroid treatment promptly improved her symptoms. Although tests for serum anti-aquaporin 4, anti-myelin oligodendrocyte glycoprotein, and anti-voltage-gated potassium channel antibodies were negative, cerebrospinal fluid samples tested positive for anti-N-methyl-D-aspartate (NMDA) receptor antibodies. Oral prednisolone administration was continued, but she developed paresthesia in her upper and lower extremities and gaze-evoked nystagmus three months after the first attack. MRI showed that the previously observed high-intensity regions were decreased, but a new area of high intensity was observed in ventral regions through the lower midbrain to the pons. Because pulse corticosteroid treatment was again effective, we continued the oral prednisolone treatment. This case presented none of the characteristic symptoms of anti-NMDA receptor antibody encephalitis during the clinical course other than repeated demyelinating encephalitis and severe syndrome of inappropriate antidiuretic hormone secretion (SIADH). Additional clinical observations are needed to better understand the underlying pathology of the NMDA receptor antibodies in the cerebrospinal fluid in this case.

Background: Glial fibrillary acidic protein (GFAP) autoantibody-positive meningoencephalitis is a newly described entity characterized by a corticosteroid-responsive meningoencephalomyelitis. Some patients with GFAP autoantibody-positive meningoencephalitis have been found to have optic disc edema, which has previously not been well characterized., Methods: We performed a retrospective, observational case series of Mayo Clinic patients found to have GFAP-IgG and optic disc edema from January 1, 2000, to December 31, 2016. We identified 40 patients with GFAP-IgG seropositivity by tissue-based immunofluorescence and cell-based assay. Patients were screened for the following inclusion criteria: 1) serum, cerebrospinal fluid, or both that yielded a characteristic astrocytic pattern of mouse tissue immunostaining with confirmation of IgG reactive with specific GFAPα isoform by cell-based assay; 2) meningoencephalitis or encephalitis; and 3) optic disc edema. We excluded those with coexisting aquaporin-4-IgG or insufficient clinical information., Results: Ten patients had optic disc edema and met inclusion criteria. The median age was 39.5 years and 60% were men. Visual acuity was unaffected and disc edema was bilateral in all cases. Mild vitreous cell was noted in 3 patients. The optic disc edema resolved with corticosteroid treatment but resulted in mild optic atrophy in 2 patients. The median lumbar puncture opening pressure was 144 mm H2O (range, 84-298 mm H2O). Brain MRI revealed radial perivascular enhancement in all except 1 patient. Fluorescein angiography was available for 1 patient with optic disc edema, which showed leakage from the venules., Conclusions: Patients with GFAP autoantibody-positive meningoencephalitis can have optic disc edema that can mimic papilledema. The cause of the optic disc edema remains uncertain, but most patients did not have raised intracranial pressure.

Tick-borne encephalitis virus (TBEV) is a leading cause of viral meningoencephalitis in many parts of Europe and eastwards in Asia, with high morbidity and often long-term neurologic sequelae. With no treatment available, studies of the immune response to TBEV are essential for the understanding of the immunopathogenesis of tick-borne encephalitis and for the development of therapeutics. We have previously demonstrated that CD8 + T cell responses in peripheral blood in patients with acute TBEV peak at around 7 d after hospitalization in the neuroinvasive phase of the disease. In this study, we identified six novel TBEV HLA-A2- and HLA-B7-restricted epitopes, all derived from the nonstructural proteins of TBEV. This identification allowed for a comprehensive phenotypic and temporal analysis of the HLA-A2- and HLA-B7-restricted Ag-specific CD8 + T cell response during the acute stages of human TBEV infection. HLA-A2- and HLA-B7-restricted TBEV epitope-specific effector cells predominantly displayed a CD45RA - CCR7 - CD27 + CD57 - phenotype at day 7, which transitioned into separate distinct phenotypes for HLA-A2- and HLA-B7-restricted TBEV-specific CD8 + T cells, respectively. At day 21, the most prevalent phenotype in the HLA-A2-restricted CD8 + T cell populations was CD45RA - CCR7 - CD27 + CD57 + , whereas the HLA-B7-restricted CD8 + T cell population was predominantly CD45RA + CCR7 - CD27 + CD57 + Almost all TBEV epitope-specific CD8 + T cells expressed α4 and β1 integrins at days 7 and 21, whereas the bulk CD8 + T cells expressed lower integrin levels. Taken together, human TBEV infection elicits broad responses to multiple epitopes, predominantly derived from the nonstructural part of the virus, establishing distinct maturation patterns for HLA-A2- and HLA-B7-restricted TBEV epitope-specific CD8 + T cells., (Copyright © 2018 The Authors.)

In 2016, the live attenuated zoster vaccine (Zostavax, Merck and Co, USA) was introduced into the Australian National Immunisation Program for people aged 70 years who are not significantly immunocompromised. We report the administration of Zostavax in an immunocompromised patient with chronic lymphocytic leukaemia and no evidence of primary varicella zoster virus (VZV) infection. The patient presented with a bilateral vesicular facial rash 22 days after receiving Zostavax and was initially managed as an outpatient with oral acyclovir. He re-presented three days later and was diagnosed with disseminated VZV infection complicated by meningoencephalitis. The patient died following cardiac arrest on day 10 of hospitalisation. This unfortunate case highlights the challenge of safely implementing a high titre live vaccine in a population where contraindications are prevalent. The non-live recombinant herpes zoster subunit vaccine (Shingrix, GSK) may provide a safe and effective option to protect immunocompromised patients from shingles and post-herpetic neuralgia., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Encephalitis is an uncommon but severe disease characterized by neurologic dysfunction with central nervous system inflammation. Children with encephalitis should receive supportive care and empiric therapies for common and treatable causes while prioritizing diagnostic evaluation for common, treatable, and high-risk conditions. Even with an extensive diagnostic workup, an infectious cause is identified in less than half of cases, suggesting a role for postinfectious or noninfectious processes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To report the clinical and immunological characteristics of 22 new patients with glial fibrillar acidic protein (GFAP) autoantibodies., Methods: From January 2012 to March 2017, we recruited 451 patients with suspected neurological autoimmune disease at the Catholic University of Rome. Patients' serum and cerebrospinal fluid (CSF) samples were tested for neural autoantibodies by immunohistochemistry on mouse and rat brain sections, by cell-based assays (CBA) and immunoblot. GFAP autoantibodies were detected by immunohistochemistry and their specificity confirmed by CBA using cells expressing human GFAPα and GFAPδ proteins, by immunoblot and immunohistochemistry on GFAP-/- mouse brain sections., Results: Serum and/or CSF IgG of 22/451 (5%) patients bound to human GFAP, of which 22/22 bound to GFAPα, 14/22 to both GFAPα and GFAPδ and none to the GFAPδ isoform only. The neurological presentation was: meningoencephalomyelitis or encephalitis in 10, movement disorder (choreoathetosis or myoclonus) in 3, anti-epileptic drugs (AED)-resistant epilepsy in 3, cerebellar ataxia in 3, myelitis in 2, optic neuritis in 1 patient. Coexisting neural autoantibodies were detected in five patients. Six patients had other autoimmune diseases. Tumours were found in 3/22 patients (breast carcinoma, 1; ovarian carcinoma, 1; thymoma, 1). Nineteen patients were treated with immunotherapy and 16 patients (84%) improved. Histopathology analysis of the leptomeningeal biopsy specimen from one patient revealed a mononuclear infiltrate with macrophages and CD8+ T cells., Conclusions: GFAP autoimmunity is not rare. The clinical spectrum encompasses meningoencephalitis, myelitis, movement disorders, epilepsy and cerebellar ataxia. Coexisting neurological and systemic autoimmunity are relatively common. Immunotherapy is beneficial in most cases., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Rift Valley Fever (RVF) is an emerging arboviral disease of livestock and humans. Although the disease is caused by a mosquito-borne virus, humans are infected through contact with, or inhalation of, virus-laden particles from contaminated animal carcasses. Some individuals infected with RVF virus (RVFV) develop meningoencephalitis, resulting in morbidity and mortality. Little is known about the pathogenic mechanisms that lead to neurologic sequelae, and thus, animal models that represent human disease are needed. African green monkeys (AGM) exposed to aerosols containing RVFV develop a reproducibly lethal neurological disease that resembles human illness. To understand the disease process and identify biomarkers of lethality, two groups of 5 AGM were infected by inhalation with either a lethal or a sublethal dose of RVFV. Divergence between lethal and sublethal infections occurred as early as 2 days postinfection (dpi), at which point CD8 + T cells from lethally infected AGM expressed activated caspase-3 and simultaneously failed to increase levels of major histocompatibility complex (MHC) class II molecules, in contrast to surviving animals. At 4 dpi, lethally infected animals failed to demonstrate proliferation of total CD4 + and CD8 + T cells, in contrast to survivors. These marked changes in peripheral blood cells occur much earlier than more-established indicators of severe RVF disease, such as granulocytosis and fever. In addition, an early proinflammatory (gamma interferon [IFN-γ], interleukin 6 [IL-6], IL-8, monocyte chemoattractant protein 1 [MCP-1]) and antiviral (IFN-α) response was seen in survivors, while very late cytokine expression was found in animals with lethal infections. By characterizing immunological markers of lethal disease, this study furthers our understanding of RVF pathogenesis and will allow the testing of therapeutics and vaccines in the AGM model. IMPORTANCE Rift Valley Fever (RVF) is an important emerging viral disease for which we lack both an effective human vaccine and treatment. Encephalitis and neurological disease resulting from RVF lead to death or significant long-term disability for infected people. African green monkeys (AGM) develop lethal neurological disease when infected with RVF virus by inhalation. Here we report the similarities in disease course between infected AGM and humans. For the first time, we examine the peripheral immune response during the course of infection in AGM and show that there are very early differences in the immune response between animals that survive infection and those that succumb. We conclude that AGM are a novel and suitable monkey model for studying the neuropathogenesis of RVF and for testing vaccines and therapeutics against this emerging viral pathogen., (Copyright © 2018 American Society for Microbiology.)

Background: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a novel meningoencephalomyelitis. However, the pathogenesis of this disease is unclear. We therefore examined a brain biopsy from a patient with autoimmune GFAP astrocytopathy by immunohistopathology., Methods: We examined brain biopsy sections from a patient with autoimmune GFAP astrocytopathy using hematoxylin and eosin (HE) and Luxol fast blue (LFB) staining, and immunostaining with antibodies for CD4, CD8, CD3, CD20, CD68, CD138, Neu-N, GFAP, myelin oligodendrocyte glycoprotein (MOG), and aquaporin-4 (AQP4)., Results: HE staining revealed extensive inflammatory cells (marked lymphocytes) around brain vessels, and LFB showed no signs of demyelination or axon loss. Immunohistochemical analysis showed CD3+ and CD4+ T cells cuffing around brain vessels, accompanied by CD8+ T cells, CD20+ B cells, and CD138+ plasma cells, while some macrophages (CD68+) were scattered throughout the brain parenchyma. There was no loss of AQP4 or MOG expression in this patient, while GFAP was abundantly expressed., Conclusions: These findings suggest that inflammatory cells, including T cells, B cells, plasma cells, and macrophages, are involved in autoimmune GFAP astrocytopathy. Demyelination and astrocyte loss may not necessarily occur in this disease., (© 2018 S. Karger AG, Basel.)

Cerebrospinal fluid/serum albumin ratio is one of the most informative parameters for blood-brain barrier (BBB) integrity in cases of central nervous system (CNS) infectious diseases. Normally, CNS albumin concentration is a function of diffusion processes along with CSF drainage and resorption. In pathological processes CSF albumin levels are dependent only on the rate of CSF drainage resulting in non-linear reciprocal changes of albumin quotient (Qalb). IgG, IgA and IgM concentrations both in CSF and serum can be compared to Qalb, thus determining the intrathecal immune response. The aim of the study was to detect BBB permeability impairment and the intrathecal immune response in patients with CNS infections with various etiologies. CSF/serum ratios were calculated and related to IgG IgA and IgM concentrations in CSF and blood serum. The results were integrated and presented by Reibergrams. The results demonstrated typical patterns which prove albumin to be the main modulator of protein dynamics and at the same time explicates the complex pathophysiological mechanisms involved in BBB disruption and intrathecal immune response in CNS infections. The diagnostic model presented in our study seeks to explain the observations of meningitis and meningoencephalitis pathophysiology and points out the mandatory cooperation between clinicians and laboratory for accurate diagnosis and proper treatment.

Cryptococcus neoformans is a major fungal pathogen that disseminates to the central nervous system (CNS) to cause fatal meningoencephalitis, but little is known about immune responses within this immune-privileged site. CD4 + T cells have demonstrated roles in anticryptococcal defenses, but increasing evidence suggests that they may contribute to clinical deterioration and pathology in both HIV-positive (HIV+) and non-HIV patients who develop immune reconstitution inflammatory syndrome (IRIS) and post-infectious inflammatory response syndrome (PIIRS), respectively. Here we report a novel murine model of cryptococcal meningoencephalitis and a potential damaging role of T cells in disseminated cryptococcal CNS infection. In this model, fungal burdens plateaued in the infected brain by day 7 postinfection, but activation of microglia and accumulation of CD45 hi leukocytes was significantly delayed relative to fungal growth and did not peak until day 21. The inflammatory leukocyte infiltrate consisted predominantly of gamma interferon (IFN-γ)-producing CD4 + T cells, conventionally believed to promote fungal clearance and recovery. However, more than 50% of mice succumbed to infection and neurological dysfunction between days 21 and 35 despite a 100-fold reduction in fungal burdens. Depletion of CD4 + cells significantly impaired IFN-γ production, CD8 + T cell and myeloid cell accumulation, and fungal clearance from the CNS but prevented the development of clinical symptoms and mortality. These findings conclusively demonstrate that although CD4 + T cells are necessary to control fungal growth, they can also promote significant immunopathology and mortality during CNS infection. The results from this model may provide important guidance for development and use of anti-inflammatory therapies to minimize CNS injury in patients with severe cryptococcal infections. IMPORTANCE CNS infection with the fungal pathogen Cryptococcus neoformans often results in debilitating brain injury and has a high mortality rate despite antifungal treatment. Treatment is complicated by the fact that immune responses needed to eliminate infection are also thought to drive CNS damage in a subset of both HIV+ and non-HIV patients. Thus, physicians need to balance efforts to enhance patients' immune responses and promote microbiological control with anti-inflammatory therapy to protect the CNS. Here we report a novel model of cryptococcal meningoencephalitis demonstrating that fungal growth within the CNS does not immediately cause symptomatic disease. Rather, accumulation of antifungal immune cells critically mediates CNS injury and mortality. This model demonstrates that antifungal immune responses in the CNS can cause detrimental pathology and addresses the urgent need for animal models to investigate the specific cellular and molecular mechanisms underlying cryptococcal disease in order to better treat treat patients with CNS infections.

Background: The aetiological spectrum of acute encephalitis shows inter- and intra-geographical variations. We aimed to identify the viruses that cause infectious encephalitis in Sri Lanka, which represents a South Asian population., Methods: A cross-sectional study was conducted among 99 patients with encephalitis/meningoencephalitis admitted to two tertiary-care hospitals in Colombo. Cerebrospinal fluid and serum were tested for conventional and emerging encephalitogenic viruses. Specific nucleic acid amplification and antibody assays were used to identify viruses. Plaque reduction neutralization test was done to confirm the diagnosis of West Nile virus (WNV)., Results: Patients' age ranged from 1 month to 73 years (mean = 24.91; SD = 21.33) with a male:female ratio of 1.75:1. A viral aetiology was identified in only 27.3%. These included dengue virus (40.7%), Japanese encephalitis virus (25.9%), varicella zoster virus, WNV and probable Epstein Barr virus (11.1% each). None were positive for herpes simplex viruses or cytomegalovirus. Screening for bacterial aetiologies was negative for all patients. There were no distinguishable clinical or laboratory findings between the different viral aetiologies. The case fatality rate was 7%, which was higher among patients with an identified viral aetiology., Conclusions: A viral aetiology was identified in only about a quarter of patients with encephalitis. Dengue virus accounted for the majority.

The World Health Organization considers the Zika virus (ZIKV) outbreak in the Americas a global public health emergency. The neurologic complications due to ZIKV infection comprise microcephaly, meningoencephalitis, and Guillain-Barré syndrome. We describe a fatal case of an adult patient receiving an immunosuppressive regimen following heart transplant. The patient was admitted with acute neurologic impairment and experienced progressive hemodynamic instability and mental deterioration that finally culminated in death. At autopsy, a pseudotumoral form of ZIKV meningoencephalitis was confirmed. Zika virus infection was documented by reverse trancriptase-polymerase chain reaction, immunohistochemistry, and immunofluorescence and electron microscopy of the brain parenchyma and cerebral spinal fluid. The sequencing of the viral genome in this patient confirmed a Brazilian ZIKV strain. In this case, central nervous system involvement and ZIKV propagation to other organs in a disseminated pattern is quite similar to that observed in other fatal Flaviviridae viral infections., (Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)