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• Protein chip tech screened 2 expressed Pr in VE group. CTSL up, Fractalkine down. • CSF cytokines like CTSL, MIF, etc. can be cand biomks for VE diag & prog. • These cytokines may involve in VE pathog via inflam response, BBB destruction, etc. • It shows potential in viral enceph research using protein chip and cytokines. • The findings provide insights into viral enceph through CSF cytokine analysis. To extensively identify cerebrospinal fluid (CSF) cytokine profiles related to the occurrence, development and prognosis of viral encephalitis (VE) patients by using a high-throughput proteomic approach. We measured 80 cytokines in the CSF of acute-phase VE patients (n = 11) using high-throughput protein chip technology, comparing them to controls (n = 6). ELISA validated these findings and assessed additional cytokines from prior literature in a larger cohort (15 VE patients, 15 controls). Correlations between biomarkers and clinical characteristics were also examined. In the initial stage, we identified two differentially expressed cytokines: cathepsin-L (CTSL), which was up-regulated, and Fractalkine, which was down-regulated. Functional enrichment analysis revealed that these proteins are linked to inflammation, apoptosis, autophagy, and blood-brain barrier disruption. In stage2, the elevations of cathepsin-L (CTSL), fractalkine, interleukin-6 (IL-6), IL-1β, macrophage migration inhibitory factor (MIF), tumor necrosis factor-α (TNF-α), insulin-like growth factor Ⅱ (IGF-2) and CXC chemokine ligand 10 (CXCL10) in VE were validated by ELISA. The results of linear regression indicated that these cytokines was positively correlated with CSF reactive lesions (p < 0.05). In this study, some biomarkers related with CSF level changes and prognosis were obtained. Although these cytokines are not specific, they may be related to the occurrence and development of VE. CTSL, MIF, IL-1β, TNF-α and CXCL10 can be used as VE potential biomarkers. These cytokines may participate in the pathogenesis of VE through inflammatory response, cell apoptosis, autophagy, blood-brain barrier disruption and cytokine-cytokine receptor interaction pathway. [ABSTRACT FROM AUTHOR]

The Japanese encephalitis virus (JEV), a zoonotic flavivirus, is Asia's primary cause of viral encephalitis. JEV induces apoptosis in a variety of cells; however, the precise mechanisms underlying this apoptosis resulting from JEV infection remain to be elucidated. Our previous studies showed that the proapoptosis gene BAX may have a role in JEV proliferation. In this study, we constructed a PK-15 cell line (BAX.KO) with a knockout of the BAX gene using CRISPR/Cas9. The knockout of the BAX gene effectively inhibited the proliferation of JEV, resulting in a 39.9% decrease in viral protein levels, while BAX overexpression produced the opposite effect. We confirmed that JEV induces apoptosis of PK-15 using 4′,6-diamidino-2-phenylindole (DAPI) staining and Annexin V-FITC/PI staining. Furthermore, we found that the phosphorylation of P53 and the expression levels of BAX, NOXA, PUMA, and cleaved-caspase-3/9 were significantly upregulated after JEV infection. Moreover, we found that JEV infection not only caused mitochondrial damage, the release of mitochondrial cytochrome C (Cyt C), and the downregulation of the apoptosis-inhibiting protein BCL-2 but also reduced the mitochondrial membrane potential (MOMP) and the accumulation of intracellular reactive oxygen species (ROS). These factors collectively encourage the activation of the mitochondrial apoptosis pathway. In contrast, BAX gene knockout significantly reduces the apoptotic changes caused by JEV infection. Treatment with the caspase3 inhibitor attenuated JEV-induced viral proliferation and release, leading to a decrease in viral protein levels of 46% in PK-15 cells and 30% in BAX.KO cells. In conclusion, this study clarified the molecular mechanisms of JEV-induced apoptosis and provided a theoretical basis for revealing the pathogenic mechanisms of JEV infection. [ABSTRACT FROM AUTHOR]

The editorial discusses the treatment of acute encephalitis, a severe condition characterized by brain inflammation leading to various symptoms. The most common causes are viral infections and autoimmune factors, with challenges in diagnosing the exact etiology in many cases. Treatment involves antimicrobial therapy, corticosteroids like dexamethasone, and antiseizure drugs, tailored to the specific needs of each patient. Diagnostic studies, including CSF analysis and advanced testing methods, are crucial for accurate diagnosis and management. Suspected autoimmune encephalitis is diagnosed based on clinical symptoms, imaging, and autoantibody detection, with treatment involving immunotherapy. A comprehensive and individualized approach is essential for optimizing patient outcomes in severe encephalitis cases. [Extracted from the article]

Objective: Kyasanur Forest Disease (KFD) is a viral zoonosis reported from Karnataka, India. We investigated cases in the Shivamogga district, Karnataka, to describe the epidemiology and identify risk factors in the affected block in 2022. Methods: A case was defined as a laboratory-confirmed KFD-positive resident of Shivamogga from 1 January-31 May 2022. We extracted the records of KFD cases from district surveillance. We conducted a 1:3 case-control study in the Thirthahalli block. We enrolled laboratory-confirmed KFD-positive Thirthahalli residents from January to May 2022 as cases, and residents without "fever with myalgia" as controls. We reported adjusted odds ratios (aOR) with 95% confidence intervals (CI). Results: Shivamogga reported 35 cases, with a median age of 46 (4-75) years, of which 51% were men, and one death. Among 25 cases and 90 controls, knowledge of avoiding recent monkey death sites was low (cases = 0%, controls = 11%). Monkey death sites within 500 m [aOR = 8.6 (1.8-41.9)] and household tick exposure [aOR = 3.7 (1.3-10.7)] were independent risk factors. Conclusion: This was a laboratory-confirmed cluster of KFD cases in Thirthahalli, with residence near a monkey death site and household tick exposure considered significant risk factors. We recommend evaluating monkey carcass disposal procedures and increasing awareness of tick protective measures. [ABSTRACT FROM AUTHOR]

Background: Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation that results in an uncontrolled hyperinflammatory state. HLH is classified into two main categories: primary (familial) HLH and secondary (acquired) HLH. Secondary HLH can result from various underlying, including infection-associated hemophagocytic syndrome (IAHS) and macrophage activation syndrome (MAS) associated with rheumatologic disorders, among others. Epstein–Barr virus (EBV) often causes IAHS, but central nervous system (CNS) involvement is rare among systemic lupus erythematosus (SLE) patients. We report a case of EBV encephalitis associated with HLH in a patient with childhood-onset SLE. Case presentation: A 12-year-old girl had received a diagnosis of SLE 2 months before presentation. After a period of inactive disease on treatment, fever and seizures, with altered mental status and hallucinations, developed over several weeks. A complete blood cell count (CBC) revealed pancytopenia, accompanied by elevated levels of inflammatory markers: 86 mm/hr erythrocyte sedimentation rate, 8.9 mg/dl c-reactive protein, and 3,966 ng/mL of ferritin. The differential diagnosis included active neuropsychiatric SLE, CNS infection and neurological manifestations in secondary HLH, which could have represented either IAHS or MAS. Meropenem and acyclovir were initially administered for clinical acute encephalitis, followed by pulse methylprednisolone; however, the fever persisted, and another CBC revealed progressive cytopenia. A bone marrow study showed hypocellularity and active hemophagocytic activity, and intravenous immunoglobulin was additionally given due to the diagnosis of HLH. Cerebrospinal fluid (CSF) analysis showed 60/mm3 white blood cells (N 55%, L 45%), 141 mg/dL glucose (0.7 blood-CSF glucose ratio), < 4 mg/dL protein; results of Gram stain and bacterial culture were negative. The viral encephalitis panel from the CSF confirmed EBV infection. Bone marrow immunohistochemistry examination revealed increasing levels of CD8 + T-cell and equivocal positive results for EBV-encoded RNA in situ hybridization; therefore, HLH potentially associated with EBV was diagnosed. After treatment with IVIg, cyclosporin A, and prednisolone, the patient's symptoms gradually improved and she was eventually able to return to school. Conclusions: Our case highlights the importance of a thorough differential diagnosis, including EBV encephalitis associated with HLH, in patients with childhood SLE, particularly in cases of clinical deterioration occurs after initial treatment. [ABSTRACT FROM AUTHOR]

Japanese encephalitis virus (JEV) is a neurotropic and neuroinvasive flavivirus causing viral encephalitis, which seriously threatens the development of animal husbandry and human health. DNA methylation is a major epigenetic modification involved in viral pathogenesis, yet how DNA methylation affects JEV infection remains unknown. Here, we show genome-wide DNA methylation profiles in the brains of JEV-infected mice compared to mock-infected mice. JEV can significantly increase the overall DNA methylation levels in JEV-infected mouse brains. A total of 14,781 differentially methylated regions associated genes (DMGs) have been identified. Subsequently, KEGG pathway analysis suggested that DNA methylation modulates the tight junction signaling pathway, which can potentially impact the permeability of the blood-brain barrier (BBB). We demonstrate that hypermethylation of the tight junction gene Afdn promoter inhibited AFDN expression and increased monolayer permeability of mouse brain microvascular endothelial (bEnd.3) cells in an in vitro transwell assay. Collectively, this study reveals that DNA methylation is increased in a murine Japanese encephalitis model and that modulation of Afdn expression promotes BBB permeability. [ABSTRACT FROM AUTHOR]

Viral encephalitis is characterized by a series of immunological reactions that can control virus infection in the brain, but dysregulated responses may cause excessive inflammation and brain damage. Microglia are brain-resident myeloid cells that are specialized in surveilling the local CNS environment and in case of viral brain infection they contribute to the control of the infection and to restriction of viral dissemination. Here, we report that after exposure to neurotropic vesicular stomatitis virus (VSV), murine in vitro microglia cultures showed rapid upregulation of a broad range of pro-inflammatory and antiviral genes, which were stably expressed over the entire 8 h infection period. Additionally, a set of immunomodulatory genes was upregulated between 6 and 8 h post infection. In microglia cultures, the induction of several immune response pathways including cytokine responses was dependent on mitochondrial antiviral-signaling protein (MAVS). Consequently, in Mavs-deficient microglia the control of virus propagation failed as indicated by augmented virus titers and the accumulation of viral transcripts. Thus, in the analyzed in vitro system, MAVS signaling is critically required to achieve full microglia activation and to mediate profound antiviral effects. In Mavs-deficient mice, intranasal VSV instillation caused higher disease severity than in WT mice and virus dissemination was noticed beyond the olfactory bulb. Virus spread to inner regions of the olfactory bulb, i.e., the granular cell layer, correlated with the recruitment of highly inflammatory non-microglia myeloid cells into the olfactory bulb in Mavs−/− mice. Furthermore, increased cytokine levels were detected in the nasal cavity, the olfactory bulb and in other brain regions. Thus, microglial MAVS signaling is critically needed for virus sensing, full microglia activation, and for orchestration of protective immunity in the virus-infected CNS. [ABSTRACT FROM AUTHOR]

(1) Background: Central nervous system (CNS) infections, including meningitis and encephalitis, are serious conditions which are associated with high morbidity and mortality. This study aims to identify the clinical manifestations, etiologies, and outcomes of meningitis and encephalitis in adult patients in Saudi Arabia, addressing the current gap in understanding these conditions within this population. (2) Methods: This is a single-center retrospective study which included all adult patients diagnosed with meningitis and encephalitis from March 2016 to May 2022. (3) Results: This study found that most cases of meningitis and encephalitis occurred due to unknown pathogens. Pretreatment with antibiotics prior to lumbar puncture (LP) was found in 71.2% of patients with meningitis. Altered mental status and seizures were common presenting symptoms among patients with encephalitis while altered mental status and fever were common among patients with meningitis. (4) Conclusions: Adherence to guidelines in treating meningitis and encephalitis and performing LPs in a timely manner are important. Establishing national biobanks with biological samples from patients suspected of having meningitis or encephalitis will significantly enhance our understanding of these conditions in Saudi Arabia. [ABSTRACT FROM AUTHOR]

Summary: The objective of this study was to identify independent prognostic factors of viral encephalitis (VE) after allogeneic haematopoietic stem cell transplantation (allo‐HSCT) and establish a prognostic model to identify post‐transplant VE patients with a greater likelihood of mortality. Among 5380 patients in our centre from 2014 to 2022, 211 patients who developed VE after allo‐HSCT were reviewed in this retrospective study. Prognostic factors were selected, and a prognostic model was constructed using Cox regression analysis. The model was subsequently validated and estimated using the area under the receiver operating characteristic curve (AUC), a calibration plot and decision curve analysis (DCA). Glasgow Coma Scale score <9, lesions >3 lobes on magnetic resonance imaging and severe thrombocytopenia were identified as independent prognostic risk factors for VE patients who underwent allo‐HSCT. The prognostic model GTM (GTM is an abbreviation for a model composed of three risk factors: GCS score <9, severe thrombocytopenia [platelet count <20 000 per microliter], and lesions >3 lobes on MRI) was established according to the regression coefficients. The validated internal AUC was 0.862 (95% confidence interval [CI], 0.773–0.950), and the external AUC was 0.815 (95% CI, 0.708–0.922), indicating strong discriminatory ability. Furthermore, we constructed calibration plots that demonstrated good consistency between the predicted outcomes and the observed outcomes. DCA exhibited high accuracy in this system, leading to potential benefits for patients. [ABSTRACT FROM AUTHOR]

Electroencephalography (EEG) has been used for almost a century in well-equipped medical centers to facilitate the diagnosis of epilepsy and other brain disorders. Lassa fever (LF) and other emerging viral infections (EVI) are known to cause neurological complications, including meningitis, seizures, and encephalopathy, though to date it remains unclear whether these are secondary to metabolic disturbances caused by the disease or by direct involvement of the central nervous system (CNS). To better characterize how Lassa virus (LASV) affects the CNS, we established an EEG diagnostic unit in the LF isolation ward at Irrua Specialist Teaching Hospital in Edo State, Nigeria. Here, we report on the specific difficulties to successful implementation of EEG in this highly challenging setting. Technical artefacts due to electrical interferences and interrupted power supply, artefacts deriving from a partly improvised EEG setup within a high consequence pathogen isolation ward, and environmental factors, such as heat in the endemic West African setting are among the main difficulties encountered when setting up this diagnostic facility. It takes experienced neurophysiologists to distinguish such artefacts from actual EEG abnormalities as many of them are not commonly encountered to this extent in well-equipped EEG laboratories and can easily be confused with pathologies. The EEG recording process is further complicated by biosafety considerations and the necessity of wearing extensive personal protective equipment. Nevertheless, with the help of experienced neurophysiologists, it is possible to correctly set up the facility and interpret recordings. Taking the above into consideration, EEG is valuable in identifying CNS involvement in emerging infections, particularly regarding assessment of encephalitis, differential diagnosis of impaired consciousness and treatment adjustment in patients with symptomatic seizures. Although highly challenging under these circumstances, EEG can be an important, noninvasive diagnostic tool for neurological complications in EVI where other more advanced imaging modalities are not available. Author summary: Lassa fever (LF) is an emerging viral infection which, in severe cases, may result in viral hemorrhagic fever with neurological complications like meningitis, confusion, and seizures. Electroencephalography (EEG), a well-established diagnostic tool for neurological diseases, measures the electric activity of the brain. It helps to differentiate between various causes of an altered level of consciousness and seizures and is essential to guide anti-convulsive therapy. We established an EEG unit at the LF isolation ward of Irrua Specialist Teaching Hospital in Nigeria, which is the worldwide largest LF treatment center. In emerging viral infections like LF, EEG can be a valuable diagnostic tool in the absence of neuroimaging to detect cerebral involvement. In viral encephalitis, EEGs typically show general slowing of the background activity, encephalopathic patterns and epileptic seizures. Establishing EEG in a resource-limited and high consequence pathogen isolation ward setting requires attention to unique technical pitfalls not commonly observed in well-equipped medical centers. To prevent misinterpretation due to technical artefacts, EEG setup and interpretation should be overseen by experienced neurophysiologists. With these challenges in mind, EEG presents a vital diagnostic tool for neurological complications in emerging viral infections. [ABSTRACT FROM AUTHOR]

Background: There are established associations between viral and autoimmune encephalitis as well as between autoimmune encephalitis and demyelinating central nervous system (CNS) diseases. Here, we report the evolution from varicella zoster virus (VZV) encephalitis to limbic autoimmune encephalitis (AIE) to multiple sclerosis (MS) in one patient. Case report: A woman in her mid-thirties presented with headache, aphasia, and a generalized tonic–clonic seizure. Cerebrospinal fluid (CSF) VZV polymerase chain reaction was positive and treatment with acyclovir was administered for VZV encephalitis. Five months later, the patient presented with cognitive deficits and MRI showed new bilateral hippocampal T2-hyperintensities. CSF analyses revealed pleocytosis and neuropil antibodies in tissue-staining. A diagnosis of limbic AIE was established and treatment with IV steroids and IV immunoglobulins initiated. One year later, the patient developed paresthesia of both legs and magnetic resonance imaging studies now showed new supratentorial and spinal demyelinating lesions. The patient was diagnosed with MS and treatment was changed to rituximab. Conclusions: This unique case report links three important neuroimmunological entities in characterizing the evolution from infectious to autoimmune encephalitis to multiple sclerosis in one patient. Identification of such rare clinical constellations is critical for correct treatment choice and provides important novel insights into the pathophysiology of neuroimmunological disorders including viral triggers and overlap manifestations of autoimmune CNS diseases. [ABSTRACT FROM AUTHOR]

Objective: Herpes simplex virus encephalitis (HSVE) is associated with significant morbidity and mortality. Here, we present the occurrence of HSVE in a 36-year-old immunocompetent patient following craniotomy for a traumatic acute subdural hematoma (ASDH). Methods: Imaging after four days of progressive headache following a fall with head-strike demonstrated a 1 cm thick left holohemispheric ASDH with significant cerebral compression, edema, and 8 mm of left-to-right midline shift, and an emergent craniotomy and ASDH evacuation were performed, with additional treatment needed for reaccumulation. Postoperatively, the patient developed a worsening leukocytosis, became febrile, and was hypotensive requiring vasopressor support. Results: Despite empiric antibiotics, the patient remained persistently febrile with significant leukocytosis. Repeat head CT showed a new left insular hypodensity and a subsequent viral encephalitis panel was positive for HSV-1. The patient was then started on intravenous acyclovir, with progressive neurological exam improvement. Of note, the patient was noted to have a positive serum HSV-1 IgG antibody titer, indicative of prior infection. Conclusions: Given the known systemic immunosuppression in brain injury and the high prevalence of HSV seropositivity, clinicians should consider the possibility of HSVE from HSV reactivation in TBI patients with persistent fever, leukocytosis, and/or neurological deficits without an obvious etiology. [ABSTRACT FROM AUTHOR]

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Background: Herpes simplex encephalitis (HSE) is a disease with unfavorable vital and functional prognoses. There are no recent epidemiological data on HSE at a national level using real-life databases, especially in France. This study aimed to report the incidence, the clinical characteristics and outcomes of the patients with HSE. Methods: We conducted a comprehensive retrospective cohort study on all patients hospitalized for HSE in France between 2015 and 2022 using national hospital discharge databases. Incidence, socio-demographic and clinical characteristics (including comorbidities, seizure, stays' features, intensive care supports) were described. The short- (first stay) and long-term (6-month) outcomes were reported, in terms of mortality and rehospitalizations. Results: 1425 HSE patients were included (median age 67 [54–77] years old, M/F sex ratio 1.07), giving a mean yearly hospital incidence of 2.3 [2.1–2.5] per 1,000,000 inhabitants. 51.2% of the patients were admitted in ICU (n = 730), of whom 59.0% were mechanically ventilated. The overall mortality during the first stay was 14.3% (n = 204), up to 17.9% for ICU patients. Within 6 months, among the survivors, 10.1% had at least one rehospitalization related to HSE. At 6 months, 16.5% of all patients had died (n = 235), 20.8% for ICU patients. Conclusion: In France, the incidence of hospitalizations for HSE was 2.3 per 1,000,000 inhabitants with more than half of the patients admitted in ICU and a 6-month in-hospital mortality about 16.5%. This real-life update on the characteristics and severe outcomes of the disease raises awareness among care practitioners, of the serious nature of the disease, and thus can lead to higher vigilance. [ABSTRACT FROM AUTHOR]

The purpose of the rehabilitation program is to improve motor skills, coordination, sensory system, mobilization and other existing disorders to achieve activity of daily living (ADL). For a span of five months, beginning two months ago, the patient had been incapable of independent mobilization. Throughout this duration, he was confined to a bed and wheelchair, necessitating assistance from family members for movement, who would lift or carry him as necessary. Physical therapy as part of the multidisciplinary approach can provide core stability exercises, muscular facilitation and stimulation of motion of the upper and lower extremities, balance exercises and mobility exercises, as well as strengthening exercises with PNF facilitation and active stimulation techniques and using the patient's body weight as a training burden. Bobath approach and facilitation exercise can reduce spasticity by strengthening the antagonist muscles. This case report concludes that although physiotherapy is done late with strengthening exercise and core stability strengthening techniques, prone strengthening exercise, it can improve motor skills, coordination, which in turn will increase the patient's independence in carrying out functional activities and ADLs. [ABSTRACT FROM AUTHOR]

A diverse group of RNA viruses have the ability to gain access to the central nervous system (CNS) and cause severe neurological disease. Current treatment for people with this type of infection is generally limited to supportive care. To address the need for reliable antivirals, we utilized a strategy of lethal mutagenesis to limit virus replication. We evaluated ribavirin (RBV), favipiravir (FAV) and N4-hydroxycytidine (NHC) against La Crosse virus (LACV), which is one of the most common causes of pediatric arboviral encephalitis cases in North America and serves as a model for viral CNS invasion during acute infection. NHC was approximately 3 to 170 times more potent than RBV or FAV in neuronal cells. Oral administration of molnupiravir (MOV), the prodrug of NHC, decreased neurological disease development (assessed as limb paralysis, ataxia and weakness, repeated seizures, or death) by 31% (4 mice survived out of 13) when treatment was started on the day of infection. MOV also reduced disease by 23% when virus was administered intranasally (IN). NHC and MOV produced less fit viruses by incorporating predominantly G to A or C to U mutations. Furthermore, NHC also inhibited virus production of two other orthobunyaviruses, Jamestown Canyon virus and Cache Valley virus. Collectively, these studies indicate that NHC/MOV has therapeutic potential to inhibit viral replication and subsequent neurological disease caused by orthobunyaviruses and potentially as a generalizable strategy for treating acute viral encephalitis. Author summary: Mutagenic ribonucleosides can be viewed as broadly acting antivirals against RNA viruses. These viruses have small genomes of essential genes and thus are susceptible to enhanced mutation rates as an antiviral strategy. Here we show that the mutagenic ribonucleoside N4-hydroxycytidine (NHC) and its prodrug molnupiravir are active against the negative strand bunyavirus La Crosse Virus. Loss of viral infectivity was proportional to the density of mutations induced by NHC. Using a mouse model, we showed that oral administration of molnupiravir attenuated encephalitis caused by La Crosse virus and resulted in reduced virus titers and less fit virus in the brain. This treatment approach should be widely applicable to acute RNA virus diseases, especially those with high morbidity and an absence of other treatment options. [ABSTRACT FROM AUTHOR]

Viral encephalitis is characterized by inflammation of the brain parenchyma caused by a variety of viruses, among which the Japanese encephalitis (JE) virus (JEV) is a typical representative arbovirus. Neuronal death, neuroinflammation, and breakdown of the blood brain barrier (BBB) constitute vicious circles of JE progression. Currently, there is no effective therapy to prevent this damage. Growth arrest specific gene 6 (GAS6) is a secreted growth factor that binds to the TYRO3, AXL, and MERTK (TAM) family of receptor tyrosine kinases and has been demonstrated to participate in neuroprotection and suppression of inflammation in many central nervous system (CNS) diseases which has great potential for JE intervention. In this study, we found that GAS6 expression in the brain was decreased and was reversely correlated with viral load and neuronal loss. Mice with GAS6/TAM signalling deficiency showed higher mortality and accelerated neuroinflammation during peripheral JEV infection, accompanied by BBB breakdown. GAS6 directly promoted the expression of tight junction proteins in bEnd.3 cells and strengthened BBB integrity, partly via AXL. Mice administered GAS6 were more resistant to JEV infection due to increased BBB integrity, as well as decreased viral load and neuroinflammation. Thus, targeted GAS6 delivery may represent a strategy for the prevention and treatment of JE especially in patients with impaired BBB. [ABSTRACT FROM AUTHOR]

Objective: To analyze the expression of pediatric Critical Case scoring (PCIS) combined with serum microRNA-125b and granulocyte colony stimulating factor (G-CSF) in children with viral encephalitis and its correlation with prognosis. Methods: 105 children with viral encephalitis admitted to our hospital from January 2022 to June 2023 were selected to be included in the observation group, and another 105 healthy physical examination children in the same period were selected to be included in the control group. All enrollees were subjected to PCIS scoring, and serum microRNA-125b and G-CSF expression levels were detected to analyze the variability of PCIS scoring, serum microRNA-125b, and G-CSF expression levels in children with viral encephalitis of different severity and the relationship with indicators of cerebral damage in the cerebrospinal fluid; with a follow-up of 6 months, the poor prognosis was recorded, and a multifactorial logistic regression and a multifactor logistic regression were used to measure the prognosis. Factor logistic regression and subject work characteristics (ROC) curves were used to analyze the relationship between PCIS score, serum microRNA-125b, G-CSF and poor prognosis. Results: The PCIS score of observation group was lower than that of control group, and the expression levels of serum microRNA-125b and G-CSF were higher than those of control group (P<0.05). Of the 105 children with viral encephalitis, 40 were severe and 65 were non-severe cases. The PCIS score of the critical group was lower than that of the non-critical group, and the expression levels of serum microRNA-125b and G-CSF were higher than those of the non-critical group (P<0.05). By Pearson correlation analysis, the children with viral encephalitis PCIS score, serum microRNA-125b, the expression level of G-CSF and myelin basic protein (MBP) in cerebrospinal fluid, brain type of creatine kinase (CK-BB), neuron specific enolization enzyme (NSE) expression levels were positively correlated (P<0.05). The multi-factor Logistic regression, PCIS score, serum microRNA-125b and G-CSF is children with viral encephalitis is an independent predictor of poor prognosis (P<0.05). The ROC curve analysis, PCIS score, serum microRNA-125b joint G-CSF prediction of prognosis of children with viral encephalitis, AUC is 0.923. Conclusion: PCIS score, serum microRNA-125b, and G-CSF are all associated with severity of illness in children with viral encephalitis, and the combination improves the level of prediction of poor prognosis. [ABSTRACT FROM AUTHOR]

Introduction: The last few decades have increased our understanding of autoimmune encephalitis (AE). In both the pediatric and adult populations, it proves to be a disease of dramatic acute onset of heterogeneous clinical manifestations, notably encephalopathy with neuropsychiatric symptoms, seizures, and extrapyramidal symptoms. More often, it is triggered by a viral infection in the pediatric age groups, as suggested by the preceding febrile symptoms in over half of cases, and more ostensibly, NMDAR encephalitis post herpes encephalitis. An underlying neoplasm may be present in certain types (i.e., NMDAR encephalitis). The rising rate of antibody detection and subsequent confirmation has been boosted by improved live cellular assay detection methods. The corresponding clinical phenotypes, common underlying malignancies, and histopathological findings have helped improve our management regarding intervention and choice of immunotherapy. New assessment tools such as the Clinical Assessment Scale in Autoimmune Encephalitis (CASE score) have helped improve the objective assessment of impact on cognitive functions (1). Early intervention with immunotherapy (and tumor removal in proven underlying neoplasms) has improved overall outcomes in most presenting patients. But nearly 40% of cases fail to respond to the first tier of treatment (2). The complex interplay between pathogenic autoantibodies, T-cells, B-cells, and cytokines has led to the emergence of additional immunotherapy agents (i.e., tocilizumab and bortezomib). Methods: In this retrospective observational study of pediatric AE conducted at two tertiary care centers, we observed the clinical characteristics, autoantibody yield, treatment modalities used, and disability scores during presentation and follow-up. Our secondary aim was to delineate prognostic factors for poor outcomes. Results: Neuropsychiatric symptoms, encephalopathy, and seizures were the predominant manifestations in most of our patients. Younger age groups, refractory seizures, profound encephalopathy, and refractory disease harbored higher disability scores. The group that received combined immunotherapy has shown mitigation of disability score from severe to mild during long-term follow-up, signifying the role of multifaceted immunotherapy in pediatric refractory AE. Conclusion: Early implementation of combined immunotherapy in refractory cases significantly improved longterm disability scores, in spite of lingering residual effects on neurologic functions, notably cognition, behavior, and speech. [ABSTRACT FROM AUTHOR]

Background: Herpes simplex virus type 1 (HSV-1) is a major cause of viral encephalitis, genital mucosal infections, and neonatal infections. Lactococcus lactis (L. lactis) has been proven to be an effective vehicle for delivering protein antigens and stimulating both mucosal and systemic immune responses. In this study, we constructed a recombinant L. lactis system expressing the protective antigen glycoprotein D (gD) of HSV-1. Results: To improve the stability and persistence of antigen stimulation of the local mucosa, we inserted the immunologic adjuvant interleukin (IL)-2 and the Fc fragment of IgG into the expression system, and a recombinant L. lactis named NZ3900-gD-IL-2-Fc was constructed. By utilizing this recombinant L. lactis strain to elicit an immune response and evaluate the protective effect in mice, the recombinant L. lactis vaccine induced a significant increase in specific neutralizing antibodies, IgG, IgA, interferon-γ, and IL-4 levels in the serum of mice. Furthermore, in comparison to the mice in the control group, the vaccine also enhanced the proliferation levels of lymphocytes in response to gD. Moreover, recombinant L. lactis expressing gD significantly boosted nonspecific immune reactions in mice through the activation of immune-related genes. Furthermore, following the HSV-1 challenge of the murine lung mucosa, mice inoculated with the experimental vaccine exhibited less lung damage than control mice. Conclusion: Our study presents a novel method for constructing a recombinant vaccine using the food-grade, non-pathogenic, and non-commercial bacterium L. lactis. The findings indicate that this recombinant vaccine shows promise in preventing HSV-1 infection in mice. [ABSTRACT FROM AUTHOR]

Objectives: The incidence of autoimmune encephalitis (AIE) has risen in the last decade, yet recent studies are lacking. We compared the epidemiology of autoimmune and infectious encephalitis cases in Tel‐Aviv Sourasky Medical Center (TASMC) between 2010 and 2020. Methods: All encephalitis cases, aged 18 and above, admitted to TASMC between the years 2010 and 2020 were reviewed for demographic, clinical, laboratory, and imaging data and categorized based on etiology. Results: Two hundred and twenty‐five patients with encephalitis were identified. The most common identifiable cause was viral (42%), followed by autoimmune encephalitis (35%), bacterial (18%), and fungal/parasitic (5%). The incidence of AIE cases out of the yearly admitted cases increased substantially, from 3.8/100 K in 2010 to 18.8/100 K in 2020. The incidence of viral cases also increased while those of bacterial and fungal/parasitic infections remained stable. Patients with AIE were younger compared to infectious patients (p‐value <0.001) and had lower markers of systemic and cerebrospinal fluid inflammation (p‐value for all <0.001). Seizures were more common among AIE patients (p‐value <0.001), yet one‐year mortality rates were higher among infectious patients (p‐value <0.001). Interpretation: AIE incidence has risen significantly in our institution during the past decade, with current rates comparable to those of all infectious causes combined. Based on this cohort, clinical clues for an autoimmune etiology include a non‐inflammatory cerebrospinal fluid profile, the presence of seizures, and temporal lobe imaging abnormalities (also common in herpetic encephalitis). In light of its rising incidence and the importance of early treatment, AIE should be considered in the differential diagnosis of all encephalitis cases. [ABSTRACT FROM AUTHOR]

Oropouche Virus (OROV; genus of Orthobunyavirus) is the causal agent of Oropouche Fever (OF). Due to the lack of specific signs and symptoms and the limited availability of diagnostic tests, the actual epidemiology of OROV infections and OF has been extensively disputed. In this systematic review with meta-analysis, a literature search was carried out in PubMed, Scopus, EMBASE, and MedRxiv in order to retrieve relevant articles on the documented occurrence of OROV infections. Pooled detection rates were then calculated for anti-OROV antibodies and virus detection (i.e., viral RNA detected by viral cultures and/or real-time polymerase chain reaction [RT-qPCR]). Where available, detection rates for other arboviruses (i.e., Dengue [DENV], Chikungunya [CHKV], and Zika Virus [ZIKV]) were calculated and compared to those for OROV. A total of 47 studies from South America and the Caribbean were retrieved. In individuals affected by febrile illness during OROV outbreaks, a documented prevalence of 0.45% (95% confidence interval [95%CI] 0.16 to 1.12) for virus isolation, 12.21% (95%CI 4.96 to 27.09) for seroprevalence (including both IgM and IgG class antibodies), and 12.45% (95%CI 3.28 to 37.39) for the detection of OROV-targeting IgM class antibodies were eventually documented. In the general population, seroprevalence was estimated to be 24.45% (95%CI 7.83 to 55.21) for IgG class antibodies. The OROV detection rate from the cerebrospinal fluids of suspected cases of viral encephalitis was estimated to be 2.40% (95%CI 1.17 to 5.03). The occurrence of OROV infections was consistently lower than that of DENV, CHKV, and ZIKV during outbreaks (Risk Ratio [RR] 24.82, 95%CI 21.12 to 29.16; RR 2.207, 95%CI 1.427 to 3.412; and RR 7.900, 95%CI 5.386 to 11.578, respectively) and in the general population (RR 23.614, 95%CI 20.584 to 27.129; RR 3.103, 95%CI 2.056 to 4.685; and RR 49.500, 95%CI 12.256 to 199.921, respectively). In conclusion, our study stresses the possibly high underestimation of OROV prevalence in the general population of South America, the potential global threat represented by this arbovirus infection, and the potential preventive role of a comprehensive "One Health approach". [ABSTRACT FROM AUTHOR]

It is well known that N-methyl-D-aspartate receptor encephalitis (NMDARE) can be triggered by infectious encephalitis such as herpes simplex virus 1 encephalitis (HSE). However, the incidence of post-HSE NMDARE in Denmark is unknown. We reviewed literature cases and compared these to retrospectively identified cases of post-HSE NMDARE in Denmark, using a national cohort database of autoimmune encephalitis (AE) and two regional databases of infectious encephalitis patients. We identified 80 post-HSE NMDARE cases in the literature, 66% being children, who more often presented movement disorders, decreased consciousness, and sleep disturbances compared to adults. Eight patients with post-HSE NMDARE were identified from the national cohort database of AE, none being children. Forty-four HSE patients were identified from the regional infectious encephalitis databases. Of these, 16 (36%) fulfilled the Graus criteria for probable/definite NMDARE, and eight (18%) presented a prolonged/relapsing disease course. Ten (23%) were tested for AE during hospitalization. Six (14%) had leftover cerebrospinal fluid available for retrospective autoantibody testing. One out of these six patients (17%) harbored NMDARE antibodies. Thus, in total, nine post-HSE NMDARE patients have been identified in Denmark from 2009 to 2021. Comparing the adult Danish patients to the literature, Danish patients were older, but the clinical phenotype and paraclinical findings were similar. Overall, the incidence of adult post-HSE NMDARE in the Region of Southern Denmark was 0.17 per million people per year and only 7% of adult HSE patients in the region were diagnosed with post-HSE NMDARE. Our findings suggest that adult patients are still underdiagnosed and the absence of pediatric cases diagnosed with post-HSE NMDARE in Denmark is highly concerning. [ABSTRACT FROM AUTHOR]

Importance: Viral encephalitis is one of the main causes of the perisylvian syndrome, which can cause damage to children's language‐speech, feeding, and swallowing functions. Comprehensive assessment of language‐speech and swallowing function and comorbidity research on these children will help children's rehabilitation workers to better understand the disease and strengthen the systematic management of comorbid disorders. Objective: To describe speech and language pathology and the occurrence of comorbid disorders in children with perisylvian syndrome induced by viral encephalitis. Methods: Twenty‐two children with acquired perisylvian syndrome were recruited in this study. Language and speech functions, including oral motor function, swallowing function, language ability, and dysarthria were assessed in these patients. Craniocerebral magnetic resonance imaging (MRI), electroencephalogram examination, and intelligence evaluation were performed to determine brain lesions and comorbid disorders. Results: All children exhibited different degrees of oral movement, dysphagia, and speech and language disorders. There was a significant difference between expressive and receptive language ability (P < 0.05). There were 10, 8, and 12 children who had an intellectual disability, limb disability, and epilepsy, respectively. In addition to the damage of the peri‐tegmental cortex found in MRI, thalamus lesions occurred in 19 cases and white matter involvement in six cases. Interpretation: Children with acquired perisylvian syndrome caused by viral encephalitis are characterized by persistent pseudobulbar dysfunction, speech and language impairment, and orofacial diplegia. They have a high probability of secondary epilepsy and are prone to motor and cognitive impairment, which need systematic management. [ABSTRACT FROM AUTHOR]

(1) Background: Central nervous system (CNS) infections, including meningitis and encephalitis, are serious conditions which are associated with high morbidity and mortality. This study aims to identify the clinical manifestations, etiologies, and outcomes of meningitis and encephalitis in adult patients in Saudi Arabia, addressing the current gap in understanding these conditions within this population. (2) Methods: This is a single-center retrospective study which included all adult patients diagnosed with meningitis and encephalitis from March 2016 to May 2022. (3) Results: This study found that most cases of meningitis and encephalitis occurred due to unknown pathogens. Pretreatment with antibiotics prior to lumbar puncture (LP) was found in 71.2% of patients with meningitis. Altered mental status and seizures were common presenting symptoms among patients with encephalitis while altered mental status and fever were common among patients with meningitis. (4) Conclusions: Adherence to guidelines in treating meningitis and encephalitis and performing LPs in a timely manner are important. Establishing national biobanks with biological samples from patients suspected of having meningitis or encephalitis will significantly enhance our understanding of these conditions in Saudi Arabia.

ABSTRACT Importance Viral encephalitis is one of the main causes of the perisylvian syndrome, which can cause damage to children's language‐speech, feeding, and swallowing functions. Comprehensive assessment of language‐speech and swallowing function and comorbidity research on these children will help children's rehabilitation workers to better understand the disease and strengthen the systematic management of comorbid disorders. Objective To describe speech and language pathology and the occurrence of comorbid disorders in children with perisylvian syndrome induced by viral encephalitis. Methods Twenty‐two children with acquired perisylvian syndrome were recruited in this study. Language and speech functions, including oral motor function, swallowing function, language ability, and dysarthria were assessed in these patients. Craniocerebral magnetic resonance imaging (MRI), electroencephalogram examination, and intelligence evaluation were performed to determine brain lesions and comorbid disorders. Results All children exhibited different degrees of oral movement, dysphagia, and speech and language disorders. There was a significant difference between expressive and receptive language ability (P

The article in the journal "Current Allergy & Clinical Immunology" discusses a case of a 54-year-old man with herpes simplex virus (HSV) type-1 encephalitis and raises the question of whether inborn errors of immunity could be associated with severe viral infections like HSV-1 encephalitis. It highlights the role of genetic factors in severe viral infections and the importance of considering underlying inborn errors of immunity in patients with severe, persistent, unusual, or recurrent viral infections. The article emphasizes the need for a high level of clinical suspicion and appropriate laboratory workup to identify potential genetic susceptibilities to viral infections. [Extracted from the article]

Japanese encephalitis virus (JEV) is a zoonotic mosquito-transmitted Flavivirus circulating in birds and pigs. In humans, JEV can cause severe viral encephalitis with high mortality. Considering that vector-free direct virus transmission was observed in experimentally infected pigs, JEV introduction into an immunologically naïve pig population could result in a series of direct transmissions disrupting the alternating host cycling between vertebrates and mosquitoes. To assess the potential consequences of such a realistic scenario, we passaged JEV ten times in pigs. This resulted in higher in vivo viral replication, increased shedding, and stronger innate immune responses in pigs. Nevertheless, the viral tissue tropism remained similar, and frequency of direct transmission was not enhanced. Next generation sequencing showed single nucleotide deviations in 10% of the genome during passaging. In total, 25 point mutations were selected to reach a frequency of at least 35% in one of the passages. From these, six mutations resulted in amino acid changes located in the precursor of membrane, the envelope, the non-structural 3 and the non-structural 5 proteins. In a competition experiment with two lines of passaging, the mutation M374L in the envelope protein and N275D in the non-structural protein 5 showed a fitness advantage in pigs. Altogether, the interruption of the alternating host cycle of JEV caused a prominent selection of viral quasispecies as well as selection of de novo mutations associated with fitness gains in pigs, albeit without enhancing direct transmission frequency. Author summary: Japanese encephalitis virus (JEV) represents a major health threat in parts of Asia and Oceania. Primary vertebrate hosts are birds and pigs, but human infection also occurs and can cause severe encephalitis with high mortality. Like other Flaviviruses transmitted by insect bites, JEV requires replication in alternating cycles between mosquitoes on one side and birds or pigs on the other side. However, we previously reported that direct transmissions between pigs in absence of mosquitos can occur. Considering the increased risks for such events after the spread of JEV to a new region with immunologically naïve pigs, the present study was performed to understand if and how a series of direct transmissions would promote JEV adaptations to pigs and change virus-host interactions. Pigs infected with JEV passaged ten times showed enhanced clinical symptoms and stronger antiviral immune response, but luckily no increase in direct transmission was observed. Nevertheless, genomic analysis demonstrated a complete change in dominant virus variants, as well as selection of six viral amino acid changes. This indicates that interruptions of the alternating lifestyle of JEV causes a strong evolutionary pressure, which through fitness adaptations can change the viral characteristics. [ABSTRACT FROM AUTHOR]

This article discusses a case of Powassan virus encephalitis in a 9-year-old boy in Canada. Powassan virus is a tick-borne flavivirus that can cause encephalitis and has a high mortality rate. The boy presented with fever, neck stiffness, and headache after attending a summer camping trip. He experienced neurological symptoms and was eventually diagnosed with Powassan virus encephalitis. The article emphasizes the importance of considering arthropod-borne infections in patients with encephalitis, increasing awareness among clinicians, and reporting cases to public health authorities. [Extracted from the article]

Microglia serve as a front-line defense against neuroinvasive viral infection, however, determination of their actual transcriptional profiles under conditions of health and disease is challenging. Here, we used various experimental approaches to delineate the transcriptional landscape of microglia during viral infection. Intriguingly, multiple activation genes were found to be artificially induced in sorted microglia and we demonstrated that shear stress encountered during cell sorting was one of the key inducers. Post-hoc analysis revealed that publicly available large-scale single-cell RNA sequencing datasets were significantly tainted by aberrant signatures that are associated with cell sorting. By exploiting the ribosomal tagging approach, we developed a strategy to enrich microglia-specific transcripts by comparing immunoprecipitated RNA with total RNA. Such enriched transcripts were instrumental in defining bona fide signatures of microglia under conditions of health and virus infection. These unified microglial signatures may serve as a benchmark to retrospectively assess ex vivo artefacts from available atlases. Leveraging the microglial translatome, we found enrichment of genes implicated in T-cell activation and cytokine production during the course of VSV infection. These data linked microglia with T-cell re-stimulation and further underscored that microglia are involved in shaping antiviral T-cell responses in the brain. Collectively, our study defines the transcriptional landscape of microglia under steady state and during viral encephalitis and highlights cellular interactions between microglia and T cells that contribute to the control of virus dissemination. [ABSTRACT FROM AUTHOR]

A 32-year-old female with advanced human immunodeficiency virus infection presented to an Australian hospital with subacute, worsening symptoms of encephalitis. Metagenomic sequencing and Dengue NS3 antigen staining of brain tissue confirmed active dengue virus (DENV) encephalitis. The most recent possible DENV exposure was months prior in West Africa, indicating chronicity. [ABSTRACT FROM AUTHOR]

Herpes simplex virus-2 encephalitis (HSV2E) in immunocompetent adults is exceptionally rare, and the subsequent onset of autoimmune encephalitis after HSV2E is even less common. This report presents the inaugural Chinese case of anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) induced by HSV2E, confirmed via metagenomic next-generation sequencing (mNGS). The patient demonstrated a favorable response to intravenous immunoglobulin (IVIG) monotherapy. This case emphasizes the importance of considering autoimmune encephalitis in patients exhibiting new or recurrent neurological symptoms after HSV2E recovery. Comprehensive mNGS and neuronal antibody testing are essential for timely diagnosis. Moreover, IVIG monotherapy can serve as an effective treatment for NMDARE induced by HSV2, providing a viable alternative, particularly when steroid therapy is contraindicated. [ABSTRACT FROM AUTHOR]

Neonatal herpes simplex virus (HSV) infection (HSV infection in infants less than 6 weeks of age) is rare but mortality and morbidity rates are high after disseminated disease and encephalitis. In France, the epidemiology is poorly described, and two decades ago, incidence was estimated to be 3 per 100,000 live births a year. We describe determinants, epidemiologic and clinical characteristics of neonatal HSV infection in a managed-care population attending in two major obstetric and paediatric centres, Paris, France, over a 10-year period. This retrospective case series study was conducted from 2013 to 2023, in infants less than 42 days of age who had virologically confirmed HSV infection. We report an overall rate of neonatal herpes of 5.5 per 100,000 live births a year and an incidence of symptomatic cases of 1.2 per 100,000 live births a year. HSV-1 was the major serotype involved (84.2%) and post-natal acquisition through the orolabial route reached 63.2%. All neonates who had neonatal HSV PCR screening (owing to clinical signs in parents) and who received prompt acyclovir treatment remained asymptomatic. Symptomatic forms accounted for 21.1% cases of the total and mortality was high (62.5% of symptomatic forms). Conclusion: This case series confirms that neonates at risk for HSV disease and poor outcome are those born to HSV-seronegative mothers, preterm infants, and those who received acyclovir after onset of symptoms (mainly because mothers did not present evidence of acute HSV infection). Our study confirms the major role of HSV-1 and the frequency of its early post-natal acquisition. What is known: • Neonatal herpes simplex virus infection is rare but motality and morbidity rates are high after disseminted disease and encephalitis. National recommendations exist worldwide but mangement of this disease is not always easy. What is new: • As in France epidemiology of neonatal herpes is poorly described, our report is potentially an important addition to the existing literature. Moreover, we describe local practice that may be useful to physicians. [ABSTRACT FROM AUTHOR]

Introduction: Identifying coronavirus disease 2019 (COVID-19)-related encephalitis without clear etiological evidence is clinically challenging. The distinctions between this condition and other prevalent encephalitis types remain unknown. Therefore, we aimed to explore the similarities and differences in the clinical characteristics of COVID-19-related encephalitis and other encephalitis types. Methods: Adult patients with encephalitis admitted to the neurology department at Xuanwu Hospital were enrolled and categorized into the following six groups based on the results of metagenomic next-generation sequencing and autoimmune antibody detection in cerebrospinal fluid (CSF): COVID-19-related encephalitis (n = 36), herpes simplex virus type 1 encephalitis (HSV-1 encephalitis; n = 28), human herpesvirus 3 encephalitis (HHV-3 encephalitis; n = 10), NMDAR-antibody encephalitis (n = 18), LGI1-antibody encephalitis (n = 12), and GABAB-antibody encephalitis (n = 8). Results: The predominant characteristics of COVID-19-related encephalitis include a low incidence of seizures (38.9%), cognitive defects (30.6%), and meningeal irritation signs (8.3%). Compared with HSV-1 and HHV-3 encephalitis, COVID-19-related encephalitis exhibited lower white blood cell count (2.5 count/mm3), protein (32.2 mg/dL), and immunoglobulin M, G, and A levels (0.09, 3.2, and 0.46 mg/dL, respectively) in the CSF tests. Abnormal imaging findings were present in only 36.1% of COVID-19-related encephalitis cases, mostly showing diffuse inflammation scattered in various parts, which differed from HSV-1 encephalitis. Additionally, COVID-19-related encephalitis exhibited significant differences in clinical symptoms and CSF white blood cell counts compared with NMDAR-antibody encephalitis; however, it showed limited differences compared with LGI1-antibody and GABAB-antibody encephalitis. Discussion: COVID-19-related encephalitis and herpes virus or autoimmune encephalitis differ clinically. Symptoms and auxiliary examinations can be used as distinguishing tools. [ABSTRACT FROM AUTHOR]

Background: Distinguishing between viral encephalitis (VE) and autoimmune limbic encephalitis (ALE) presents a clinical challenge due to the overlap in symptoms. We aimed to develop and validate a diagnostic prediction model to differentiate VE and ALE. Methods: A prospective observational multicentre cohort study, which continuously enrolled patients diagnosed with either ALE or VE from October 2011 to April 2023. The demographic data, clinical features, and laboratory test results were collected and subjected to logistic regression analyses. The model was displayed as a web-based nomogram and then modified into a scored prediction tool. Model performance was assessed in both derivation and external validation cohorts. Results: A total of 2423 individuals were recruited, and 1001 (496 VE, 505 ALE) patients were included. Based on the derivation cohort (389 VE, 388 ALE), the model was developed with eight variables including age at onset, acuity, fever, headache, nausea/vomiting, psychiatric or memory complaints, status epilepticus, and CSF white blood cell count. The model showed good discrimination and calibration in both derivation (AUC 0.890; 0.868–0.913) and external validation (107 VE, 117 ALE, AUC 0.872; 0.827–0.917) cohorts. The scored prediction tool had a total point that ranged from − 4 to 10 also showing good discrimination and calibration in both derivation (AUC 0.885, 0.863–0.908) and external validation (AUC 0.868, 0.823–0.913) cohorts. Conclusions: The prediction model provides a reliable and user-friendly tool for differentiating between the VE and ALE, which would benefit early diagnosis and appropriate treatment and alleviate economic burdens on both patients and society. [ABSTRACT FROM AUTHOR]

Background: A score to differentiate autoimmune (AE) and viral encephalitis (VE) early upon admission has recently been developed but needed external validation. The objective of this study was to evaluate the performance of the score in a larger and more diagnostically diverse patient cohort. Methods: We conducted a retrospective nationwide and population-based cohort study including all adults with encephalitis of definite viral (2015–2022) or autoimmune aetiology (2009–2022) in Denmark. Variables included in the score-model were extracted from patient records and individual risk scores were assessed. The performance of the score was assessed by receiver-operating characteristics (ROC) curve analyses and calculation of the area under the curve (AUC). Results: A total of 496 patients with encephalitis [AE n = 90, VE n = 287 and presumed infectious encephalitis (PIE) n = 119] were included in the study. The score was highly accurate in predicting cases of AE reaching an AUC of 0.94 (95% CI 0.92–0.97). Having a score ≥ 3 predicted AE with a PPV of 87% and an NPV of 91%. The risk score was found to perform well across aetiological subgroups and applied to the PIE cohort resulted in an AUC of 0.88 (95% CI 0.84–0.93). Conclusion: The excellent performance of the score as reported in the development study was confirmed in this significantly larger and more diverse cohort of patients with encephalitis in Denmark. These results should prompt further prospective testing with wider inclusion criteria. [ABSTRACT FROM AUTHOR]

Infectious encephalitis in children is fairly uncommon, but unfavorable outcomes are seen in many survivors. The aim of this study was to prospectively describe the long-term neurocognitive consequences following infectious encephalitis in childhood. Children admitted to a primary and tertiary hospital in Sweden between 2011 and 2016 were asked to participate. Fifty-nine children were assessed at a median time of 18 months (IQR 18–20) after hospitalization. Follow-up included measures of intellectual functioning, attention, working memory, and executive functions. Caregiver ratings of executive functioning and behavioral – emotional symptoms were assessed with standardized questionnaires. Neurocognitive outcome and measures of executive functions and behavioral–emotional symptoms varied greatly among participants. Basic auditory attention, working memory, and mental processing speed were affected and significantly lower compared to a standardized mean. Other domains identified as areas of vulnerability included executive functions, sustained attention, and the exert of self-control. Behavioral–emotional symptoms were less common; however, somatic complaints and behaviors related to conduct problems were seen in about one-third of individuals. This study highlights the importance of a comprehensive neurocognitive examination to identify children with unfavorable outcomes. [ABSTRACT FROM AUTHOR]

Rabies is a viral encephalitis that affects mammals, including humans. Rapid and effective laboratory diagnosis of the rabies virus is critical for public health. This study evaluated the operational, technical, and financial viability of the RT-qPCR in replacement of inoculation in mice for diagnosing rabies in the laboratory routine. A total of 316 samples of mammalian brains were analyzed, 121 positives and 195 negatives, previously diagnosed by direct immunofluorescence (DIF) and mouse inoculation test (MIT). The samples were submitted to the duplex TaqMan RT-qPCR technique. The accuracy, sensitivity, and specificity of RT-qPCR were analyzed. We analyzed the costs for performing the RT-qPCR technique and compared it with the cost of MIT. The results showed 99.37% accuracy, 99.17% sensitivity, and 99.49% specificity by RT-qPCR when related to DIF and MIT results, which proved to be a robust and repeatable technique. The minimum time for a positive diagnosis was reduced in RT-qPCR (1 day) if compared to MIT (9.64 days), with a 17.7% reduction in the cost of the molecular technique. The present study demonstrated that the molecular biology technique is an efficient tool to diagnose rabies in the laboratory routine, being able to replace MIT. [ABSTRACT FROM AUTHOR]

Introduction: An increasing number of studies demonstrate that viral meningitis and meningoencephalitis, even those with a mild course of meningitis, can result in residual sequelae. Methods: We aimed to investigate the long-term outcome in both viral meningitis and meningoencephalitis/encephalitis patients and impact of longterm sequelae on patients' social and professional daily lives in a prospective observational study with a follow-up period of 20 months. Results: A total of 50 patients (12% encephalitis, 58% meningoencephalitis and 30% meningitis) and 21 control persons participated in the study. The most common cause was the tick-borne encephalitis (TBE) virus. The most important persistent signs and symptoms after 2 years were subjective cognitive impairment (36%), fatigue and/or excessive daytime sleepiness (31%), disturbed nighttime sleep (31%) and headaches (13%), as well as feeling more rapidly exhausted after cognitive effort (53%). Independent of disease severity in the acute phase, almost one third of patients still reported mildly impaired social and/or professional life due to the long-term sequelae, with scores in the health status assessment still significantly lower compared to healthy controls. Discussion: Regardless of the severity of the acute illness and despite constant improvement within 2 years, 67% of patients still had persistent signs and symptoms, but these were only relevant to everyday social or professional life in about 30% of these patients. [ABSTRACT FROM AUTHOR]

Central nervous system Infections (CNSIs) is a disease characterized by complex pathogens, rapid disease progression, high mortality rate and high disability rate. Here, we evaluated the clinical value of metagenomic next generation sequencing (mNGS) in the diagnosis of central nervous system infections and explored the factors affecting the results of mNGS. We conducted a retrospective study to compare mNGS with conventional methods including culture, smear and etc. 111 suspected CNS infectious patients were enrolled in this study, and clinical data were recorded. Chi-square test were used to evaluate independent binomial variables, taking p < 0.05 as statistically significant threshold. Of the 111 enrolled cases, 57.7% (64/111) were diagnosed with central nervous system infections. From these cases, mNGS identified 39.6% (44/111) true-positive cases, 7.2% (8/111) false-positive case, 35.1% (39/111) true-negative cases, and 18.0% (20/111) false-negative cases. The sensitivity and specificity of mNGS were 68.7% (44/64) and 82.9% (39/47), respectively. Compared with culture, mNGS provided a higher pathogen detection rate in CNSIs patients (68.7% (44/64) vs. 26.5% (17/64), p < 0.0001). Compared to conventional methods, positive percent agreement and negative percent agreement was 84.60% (44/52) and 66.1% (39/59) separately. At a species-specific read number (SSRN) ≥ 2, mNGS performance in the diagnosis of definite viral encephalitis and/or meningitis was optimal (area under the curve [AUC] 0.758, 95% confidence interval [CI] 0.663–0.854). In bacterial CNSIs patients with significant CSF abnormalities (CSF WBC > 300*106/L), the positive rate of CSF mNGS is higher. To sum up, conventional microbiologic testing is insufficient to detect all neuroinvasive pathogens, and mNGS exhibited satisfactory diagnostic performance in CNSIs and with an overall detection rate higher than culture (p < 0.0001). [ABSTRACT FROM AUTHOR]

Background: COVID-19 is primarily considered a respiratory tract infection, but it can also affect the central nervous system (CNS), which can result in long-term sequelae. In contrast to CNS infections by classic neurotropic viruses, SARS-CoV-2 is usually not detected in cerebrospinal fluid (CSF) from patients with COVID-19 with neurological involvement (neuro-COVID), suggesting fundamental differences in pathogenesis. Methods: To assess differences in CNS metabolism in neuro-COVID compared to CNS infections with classic neurotropic viruses, we applied a targeted metabolomic analysis of 630 metabolites to CSF from patients with (i) COVID-19 with neurological involvement [n = 16, comprising acute (n = 13) and post-COVID-19 (n = 3)], (ii) viral meningitis, encephalitis, or myelitis (n = 10) due to herpes simplex virus (n = 2), varicella zoster virus (n = 6), enterovirus (n = 1) and tick-borne encephalitis virus (n = 1), and (iii) aseptic neuroinflammation (meningitis, encephalitis, or myelitis) of unknown etiology (n = 21) as additional disease controls. Results: Standard CSF parameters indicated absent or low neuroinflammation in neuro-COVID. Indeed, CSF cell count was low in neuro-COVID (median 1 cell/µL, range 0–12) and discriminated it accurately from viral CNS infections (AUC = 0.99) and aseptic neuroinflammation (AUC = 0.98). 32 CSF metabolites passed quality assessment and were included in the analysis. Concentrations of differentially abundant (fold change ≥|1.5|, FDR ≤ 0.05) metabolites were both higher (9 and 5 metabolites) and lower (2 metabolites) in neuro-COVID than in the other two groups. Concentrations of citrulline, ceramide (d18:1/18:0), and methionine were most significantly elevated in neuro-COVID. Remarkably, triglyceride TG(20:1_32:3) was much lower (mean fold change = 0.09 and 0.11) in neuro-COVID than in all viral CNS infections and most aseptic neuroinflammation samples, identifying it as highly accurate biomarker with AUC = 1 and 0.93, respectively. Across all samples, TG(20:1_32:3) concentration correlated only moderately with CSF cell count (ρ = 0.65), protein concentration (ρ = 0.64), and Q-albumin (ρ = 0.48), suggesting that its low levels in neuro-COVID CSF are only partially explained by less pronounced neuroinflammation. Conclusions: The results suggest that CNS metabolite responses in neuro-COVID differ fundamentally from viral CNS infections and aseptic neuroinflammation and may be used to discover accurate diagnostic biomarkers in CSF and to gain insights into differences in pathophysiology between neuro-COVID, viral CNS infections and aseptic neuroinflammation. [ABSTRACT FROM AUTHOR]

Omsk hemorrhagic fever virus (OHFV) is a member of the tick-borne encephalitis virus (TBEV) complex of the Flaviviridae family. Currently, there are no data on the cross-reactivity of antibodies to the NS1 proteins of OHFV and TBEV. Such data are of major interest for monitoring viral encephalitis of unknown etiology due to the increasing geographical distribution of OHFV. In this study, a recombinant OHFV NS1 protein was produced using the Escherichia coli expression system and purified. The recombinant OHFV NS1 protein was recognized by specific mice immune ascetic fluids to the native OHFV NS1 protein. A Western blot analysis and ELISA of the recombinant NS1 proteins of OHFV and TBEV were used to study the cross-reactivity of antibodies from immune ascites fluid obtained from OHFV-infected mice and mAbs against TBEV NS1. Anti-TBEV NS1 mouse monoclonal antibodies (mAbs) have been shown to not be cross-reactive to the OHFV NS1 protein. Sera from patients with confirmed tick-borne encephalitis (TBE) were examined by ELISA using recombinant OHFV NS1 and TBEV NS1 proteins as antigens. It was shown for the first time that cross-reactive antibodies to the OHFV NS1 protein were not detected in the sera of TBE patients, whereas the sera contained antibodies to the TBEV NS1 protein. [ABSTRACT FROM AUTHOR]

The article focuses on investigating the correlation between autoimmune diseases, immunosuppressive medications, and the onset of herpes simplex virus encephalitis (HSVE), highlighting associations found in a large U.S. Medicaid database study.

Objective: This study was undertaken to provide a comprehensive review of neuroimaging characteristics and corresponding clinical phenotypes of autoimmune glial fibrillary acidic protein astrocytopathy (GFAP‐A), a rare but severe neuroinflammatory disorder, to facilitate early diagnosis and appropriate treatment. Methods: A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analysis)‐conforming systematic review and meta‐analysis was performed on all available data from January 2016 to June 2023. Clinical and neuroimaging phenotypes were extracted for both adult and paediatric forms. Results: A total of 93 studies with 681 cases (55% males; median age = 46, range = 1–103 years) were included. Of these, 13 studies with a total of 535 cases were eligible for the meta‐analysis. Clinically, GFAP‐A was often preceded by a viral prodromal state (45% of cases) and manifested as meningitis, encephalitis, and/or myelitis. The most common symptoms were headache, fever, and movement disturbances. Coexisting autoantibodies (45%) and neoplasms (18%) were relatively frequent. Corticosteroid treatment resulted in partial/complete remission in a majority of cases (83%). Neuroimaging often revealed T2/fluid‐attenuated inversion recovery (FLAIR) hyperintensities (74%) as well as perivascular (45%) and/or leptomeningeal (30%) enhancement. Spinal cord abnormalities were also frequent (49%), most commonly manifesting as longitudinally extensive myelitis. There were 88 paediatric cases; they had less prominent neuroimaging findings with lower frequencies of both T2/FLAIR hyperintensities (38%) and contrast enhancement (19%). Conclusions: This systematic review and meta‐analysis provide high‐level evidence for clinical and imaging phenotypes of GFAP‐A, which will benefit the identification and clinical workup of suspected cases. Differential diagnostic cues to distinguish GFAP‐A from common clinical and imaging mimics are provided as well as suitable magnetic resonance imaging protocol recommendations. [ABSTRACT FROM AUTHOR]

Objective: To summarize the clinical characteristics and prognosis of febrile infection-related epilepsy syndrome with claustrum lesions (FIRES-C). Method: Clinical data of FIRES-C patients were collected retrospectively. The study reviewed and analyzed their clinical manifestations, treatment strategies, and prognosis. Result: Twenty patients were enrolled, including 13 females and 7 males, with a median onset age of 20.5 years. All patients developed seizures after fever, with a median interval of 5 days. Brain MRI showed symmetric lesions in the claustrum in all patients. The median interval from seizure onset to abnormal MRI signals detection was 12.5 days. All patients had negative results for comprehensive tests of neurotropic viruses and antineuronal autoantibodies. Seventy percent of cases had been previously empirically diagnosed with autoimmune encephalitis or viral encephalitis before. All patients received anti-seizure medicine. Eleven patients (55%) received antiviral therapy. All patients received immunotherapy, including glucocorticoids (100%), intravenous immunoglobulin (IVIg) (65%), plasma exchange (PLEX) (10%), tocilizumab (10%), rituximab (5%), and cyclophosphamide (5%). Sixty percent of patients received long-term immunotherapy (≥ 3 months). The median follow-up was 11.5 months;60% of patients were diagnosed with refractory epilepsy. Conclusion: Bilateral claustrum lesion on MRI is a distinctive neuroimage feature for FIRES, which may serve as an indication for the initial clinical assessments. FIRES-C should be classified as a type of inflammatory encephalopathy characterized by a monophasic nature. Some FIRES-C patients respond to immunotherapy and antiseizure treatments but most experience refractory epilepsy as a long-term outcome. [ABSTRACT FROM AUTHOR]

Key Clinical Message: This case underscores the critical importance of timely recognition and management of NMDAR encephalitis in adolescents to mitigate potential long‐term sequelae. If a pediatric patient presents with suspected viral encephalitis, autoimmune etiology must be excluded via cerebrospinal fluid antibody assay to guide appropriate immunosuppressive therapy, and improve patient outcomes. Autoimmune encephalitis particularly involving the n‐methyl‐d‐aspartate receptor (NMDAR) is recognized as a rare cause of acute encephalopathy in pediatric patients. The following case is of a 14‐year‐old female diagnosed with anti‐NMDAR encephalitis who initially presented with fever, episodic convulsions, and loss of consciousness. She subsequently developed right‐sided body weakness, expressive aphasia, and visual hallucinations. Clinical examination revealed prominent neuropsychiatric manifestations such as altered sensorium, motor deficits, hallucinations, and visual disturbances. Cerebello‐bulbar signs were not appreciable in this particular case. She was treated for viral encephalitis but showed no improvement. Laboratory investigations revealed the presence of NMDAR antibodies in the cerebrospinal fluid confirming the diagnosis of autoimmune etiology. The patient demonstrated notable improvement following immunosuppressive treatment. [ABSTRACT FROM AUTHOR]

Viral retinitis composes a group of infectious ocular diseases with poor prognoses. With the advent of antivirals and HAART, the treatment of these diseases has evolved and ocular outcomes have improved. However, even with prompt medical treatment, a significant number of patients will experience complications that require surgical intervention. While there has been an abundance of research examining the medical treatment of CMV retinitis and acute retinal necrosis, the research examining surgical outcomes of complications such as retinitis-associated retinal detachment is comparatively limited. Literature review. In this review, we discuss the current literature examining treatment of CMV retinitis and acute retinal necrosis, with a focus on surgical management of complications such as retinal detachment. Despite significant improvements in the medical treatment of CMV retinitis and ARN over the last three decades, vision-threatening complications such as retinal detachment are relatively common and require surgical management via PPV, laser photocoagulation, and intraocular gas or silicone oil tamponade. [ABSTRACT FROM AUTHOR]

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The Varicella‐zoster virus (VZV), classified as a neurotropic member of the Herpesviridae family, exhibits a characteristic pathogenicity, predominantly inducing varicella, commonly known as chickenpox, during the initial infectious phase, and triggering the reactivation of herpes zoster, more commonly recognized as shingles, following its emergence from a latent state. The pathogenesis of VZV‐associated neuroinflammation involves a complex interplay between viral replication within sensory ganglia and immune‐mediated responses that contribute to tissue damage and dysfunction. Upon primary infection, VZV gains access to sensory ganglia, establishing latent infection within neurons. During reactivation, the virus can spread along sensory nerves, triggering a cascade of inflammatory mediators, chemokines, and immune cell infiltration in the affected neural tissues. The role of both adaptive and innate immune reactions, including the contributions of T and B cells, macrophages, and dendritic cells, in orchestrating the immune‐mediated damage in the central nervous system is elucidated. Furthermore, the aberrant activation of the natural defence mechanism, characterised by the dysregulated production of immunomodulatory proteins and chemokines, has been implicated in the pathogenesis of VZV‐induced neurological disorders, such as encephalitis, myelitis, and vasculopathy. The intricate balance between protective and detrimental immune responses in the context of VZV infection emphasises the necessity for an exhaustive comprehension of the immunopathogenic mechanisms propelling neuroinflammatory processes. Despite the availability of vaccines and antiviral therapies, VZV‐related neurological complications remain a significant concern, particularly in immunocompromised individuals and the elderly. Elucidating these mechanisms might facilitate the emergence of innovative immunomodulatory strategies and targeted therapies aimed at mitigating VZV‐induced neuroinflammatory damage and improving clinical outcomes. This comprehensive understanding enhances our grasp of viral pathogenesis and holds promise for pioneering therapeutic strategies designed to mitigate the neurological ramifications of VZV infections. [ABSTRACT FROM AUTHOR]

Background: Infectious meningitis/encephalitis (IM) is a severe neurological disease that can be caused by bacterial, viral, and fungal pathogens. IM suffers high morbidity, mortality, and sequelae in childhood. Metagenomic next-generation sequencing (mNGS) can potentially improve IM outcomes by sequencing both pathogen and host responses and increasing the diagnosis accuracy. Methods: Here we developed an optimized mNGS pipeline named comprehensive mNGS (c-mNGS) to monitor DNA/RNA pathogens and host responses simultaneously and applied it to 142 cerebrospinal fluid samples. According to retrospective diagnosis, these samples were classified into three categories: confirmed infectious meningitis/encephalitis (CIM), suspected infectious meningitis/encephalitis (SIM), and noninfectious controls (CTRL). Results: Our pipeline outperformed conventional methods and identified RNA viruses such as Echovirus E30 and etiologic pathogens such as HHV-7, which would not be clinically identified via conventional methods. Based on the results of the c-mNGS pipeline, we successfully detected antibiotic resistance genes related to common antibiotics for treating Escherichia coli, Acinetobacter baumannii, and Group B Streptococcus. Further, we identified differentially expressed genes in hosts of bacterial meningitis (BM) and viral meningitis/encephalitis (VM). We used these genes to build a machine-learning model to pinpoint sample contaminations. Similarly, we also built a model to predict poor prognosis in BM. Conclusions: This study developed an mNGS-based pipeline for IM which measures both DNA/RNA pathogens and host gene expression in a single assay. The pipeline allows detecting more viruses, predicting antibiotic resistance, pinpointing contaminations, and evaluating prognosis. Given the comparable cost to conventional mNGS, our pipeline can become a routine test for IM. [ABSTRACT FROM AUTHOR]