Viral encephalitis (VE), is a life-threatening neurological disorder marked by inflammation of brain parenchyma, driven by direct viral cytotoxicity and host immune-mediated injury. Globally, its incidence ranges from 1.4 to 13.8 cases per 100,000 individuals annually, with significant morbidity and mortality in endemic regions such as India, among children. Neurotropic viruses including herpes simplex virus (HSV), Japanese encephalitis virus (JEV) and West Nile virus, enter central nervous system via hematogenous or neuronal routes, triggering viral replication, cytokine release and blood-brain barrier disruption, resulting in seizures, cerebral edema and long-term neurological deficits. Current management in neurological intensive care relies on immunity-oriented strategies: Acyclovir as first-line antiviral for HSV and varicella-zoster virus, antiepileptics to control seizures and limit secondary neuronal injury and corticosteroids to modulate harmful neuroinflammation and cerebral edema. Emerging therapies, including novel antivirals (favipiravir, remdesivir, brincidofovir), monoclonal antibodies, cytokine inhibitors (tocilizumab, anakinra) and B-cell/plasma cell-targeted agents (rituximab, daratumumab), offer promise by simultaneously addressing viral replication and immune dysregulation. Personalized biomarker-guided integrating pathogen-directed and host-targeted therapies may optimize outcomes, reduce neuronal injury and improve recovery. This review underscores the importance of a multidimensional, immunity-oriented treatment paradigm, highlighting both established and emerging strategies to enhance prognosis and long-term neurological functions in patients with viral encephalitis.

Zinc is an essential micronutrient with well-characterized immunomodulatory properties and has been widely investigated in viral infectious diseases, yet its specific functional role in neurotropic viral encephalitis remains poorly elucidated. In this study, we demonstrate that a zinc-supplemented (ZnS) dietary intervention confers protection against Japanese encephalitis virus (JEV) infection by suppressing macrophage-mediated inflammatory pathology in the central nervous system (CNS). Besides, zinc inhibited the phosphorylation of Bruton's tyrosine kinase (BTK) and NF-κB p65 in macrophages, thereby effectively curbing excessive neuroinflammation and alleviating JEV-induced neuronal damage in the murine brain. Our findings have identified a previously unrecognized mechanism by which zinc regulates immune responses in the central nervous system, and suggest zinc supplementation as a potential intervention for neurological complications arising from central nervous system infections.

Automating laboratory developed tests using the panther fusion open access: Analytical and clinical evaluation of assays for the detection of viral causes of meningitis and encephalitis.

Hypersarcosinemia, resulting from sarcosine dehydrogenase (SARDH) gene mutation, is a rare autosomal recessive disorder with variable, often nonspecific clinical presentations, leading to diagnostic difficulty and low clinical awareness. A 6-year-old boy presented with clinical features suggestive of viral encephalitis, including headache, vomiting, intermittent fever, and lethargy. Initial MRI revealed cytotoxic edema in the subcortical white matter and splenium of the corpus callosum. Although symptoms improved transiently with steroid therapy, persistent imaging abnormalities prompted metabolic and genetic evaluations. Metabolic and genetic investigations confirmed a diagnosis of hypersarcosinemia, with markedly elevating sarcosine levels and compounding heterozygous SARDH mutations. Genetic testing identified compound heterozygous mutations in the SARDH gene (c.293G > C and c.679C > T), confirming hypersarcosinemia. Following initiation of folic acid and mecobalamin, partial radiological improvement was observed, although a causal relationship could not be established. This case highlights the diagnostic challenge of hypersarcosinemia and its potential mimicry of acquired encephalitis. To our knowledge, this is the first report describing an acute encephalitis-like presentation accompanied by persistent cytotoxic edema on MRI, thereby suggesting a possible expansion of the known clinical and neuroimaging spectrum of this disorder, although this observation requires confirmation in additional cases. However, given the rarity of hypersarcosinemia and the possibility of underreporting, the absence of prior similar reports should be interpreted with caution. In this case, genetic testing was essential for establishing the diagnosis, although the necessity of genetic testing in all cases of unexplained white matter changes cannot be determined from a single report. The temporal association of partial radiological improvement with folic acid and mecobalamin supplementation is hypothesis-generating only and requires further investigation ; no causal or therapeutic conclusion can be drawn from this single case.

Toll-like receptors (TLRs) are a family of pattern recognition receptors that recognise both pathogen-associated and damage-associated molecular patterns. While their expression was initially believed to be restricted to immune cells, accumulating evidence now demonstrates their presence across multiple neural cell types. Due to their significant involvement in neuroinflammatory and neurodegenerative processes, TLRs have garnered growing attention for their potential contributions to neurocognitive disorders, including Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and other forms of dementia. Potential treatment targets for lowering neuroinflammation and slowing the evolution of neurocognitive diseases include TLR signalling pathways, namely the MYD88-dependent and TRIF-dependent cascades. To initiate signalling, Toll-like receptors (TLRs) recruit specific adaptor molecules that activate the transcription factors NF-κB and IRFs, which regulate the induction of innate immune responses. Over the past decade, a combination of genetic, biochemical, structural, cellular, and bioinformatics approaches has been utilised to elucidate the detailed molecular mechanisms underlying TLR signalling. These studies have clarified how TLRs interact with cytosolic innate immune sensors to orchestrate effective immunological reactions. The function of different TLRs expressed in various brain immune cells and their contribution to the pathophysiology of neuroinflammation are described. This paper discusses the involvement of TLRs in autoimmune and neuroinflammatory circumstances like multiple sclerosis (MS), bacterial meningitis, viral encephalitis, stroke, Alzheimer's disease, and Parkinson's disease. It is intended for TLR biologists and immunologists studying neuroinflammation, as well as neuroscientists delving into central nervous system processes mediated by TLRs.

Brain [18F]FDG PET in Encephalitis and Postinfectious Neurocognitive Syndromes.

Central nervous system (CNS) infections remain a leading cause of morbidity, mortality, and disability among children in low-income and middle-income countries. In India, regional variations in etiology and outcomes are influenced by vaccination uptake, environmental conditions, and healthcare access. Data from rural western India remains limited. To evaluate the epidemiological trends, clinical spectrum, etiological distribution, and short-term outcomes of pediatric CNS infections, and to identify factors associated with adverse neurological outcomes. This retrospective study included 278 children (1 month to 12 years) admitted with CNS infections between January 2021 and April 2025. Cases were classified as bacterial meningitis, viral encephalitis, tuberculous meningitis (TBM), brain abscess, or undetermined etiology, based on clinical, laboratory, and neuroimaging criteria. Outcomes were categorized as recovery, neurological sequelae, or death. Data were analyzed for demographic distribution, seasonal patterns, and temporal trends. The mean age was 5.8 years; 51.1% were < 5 years old, and males accounted for 58.3%. Viral encephalitis was the leading etiology (39.9%), followed by bacterial meningitis (30.9%), TBM (15.1%), brain abscess (2.2%), and undetermined (11.9%). Seasonal clustering occurred during monsoon/post-monsoon months (41.7%). Mortality was 9.4% overall, highest in TBM (21.4%) and bacterial meningitis (12.8%), while viral encephalitis had the lowest (2.7%). Neurological sequelae affected 14.0% of children, predominantly after TBM and bacterial meningitis. Over time, bacterial meningitis declined (31%-21%), while viral encephalitis increased (34%-42%). Children aged < 5 years were more likely to have poor outcomes (P = 0.03). Mortality was highest in TBM (21.4%, P = 0.01), followed by bacterial meningitis (11.4%). Pediatric CNS infections in rural India show shifting trends, with viral encephalitis surpassing bacterial meningitis. Strengthening vaccination coverage, early diagnosis, and hospital preparedness can reduce morbidity and mortality associated with pediatric CNS infection.

BackgroundAutoimmune encephalitis (AE) is a major cause of acute and subacute neuropsychiatric syndromes.PurposeWhile neuronal autoantibody testing aids diagnosis, results are often delayed or negative in seronegative cases. Cerebrospinal fluid (CSF) cytokine profiling may provide a rapid diagnostic adjunct.MethodsIn this cross-sectional study, we analysed CSF from 43 AE patients (29 seronegative, 9 N-methyl-d-aspartate receptor antibody-positive, 3 leucine-rich glioma-inactivated 1 (LGI1)-positive, and 2 with rare antibodies) and 34 controls (33 idiopathic intracranial hypertension and 1 viral encephalitis). Cytokine levels (IL-6, IL-7, IL-13, IL-21, CXCL10 and CXCL13) were quantified using a multiplex immunoassay.ResultsAll measured cytokines were significantly elevated in AE compared with controls (p < .001). CXCL10 and CXCL13 showed the largest differences between AE and controls, with CXCL13 particularly high in LGI1-positive cases. IL-6 correlated positively with IL-13 (r = 0.47, p = .0013) and CXCL13 (r = 0.41, p = .0064), while IL-7 correlated with IL-21 (r = 0.33, p = .029). Cytokine profiles in seronegative AE were comparable to antibody-positive AE, with no statistically significant differences.ConclusionsCSF cytokines—particularly CXCL10, CXCL13, IL-6 and IL-13—are consistently elevated in AE and reflect shared intrathecal immune activation across antibody-positive and seronegative cases. These findings are exploratory, and cytokines are proposed as adjunctive immunological markers rather than standalone diagnostic tools.

This case involves a 28-year-old Black man who presented with new-onset seizures and bilateral medial temporal lobe hyperintensities on brain MRI, initially raising concern for viral encephalitis. CSF analysis revealed mild lymphocytic pleocytosis, but extensive infectious testing was negative. One year later, he developed acute right-sided weakness, and an MRI showed an enhancing FLAIR/T2 hyperintense mass-like lesion in the left thalamus. Stereotactic biopsy demonstrated reactive changes and Periodic acid-Schiff diastase (PASD)-positive macrophages, prompting consideration of atypical infectious or inflammatory etiologies. Despite empiric antibiotic treatment, his symptoms recurred 8 months later with new T2/FLAIR hyperintense lesions in the bilateral thalami and internal capsule, accompanied by mucocutaneous findings. He responded well to immunosuppressive therapy, with significant clinical and radiographic improvement. This case highlights the challenges of diagnosing relapsing neurologic syndromes with overlapping infectious, inflammatory, and neoplastic features and underscores the importance of integrating imaging, histopathology, and clinical evolution to reach a definitive diagnosis.

Rabies is a fatal acute viral encephalitis that remains a public health problem in Iraq. There is continuous reported transmission nationwide. To describe the epidemiology of reported rabies cases from 1997 to 2024 among humans in Iraq. We collected data on all reported probable cases of rabies among humans for 1997-2024, from the Iraq national rabies surveillance database. We analysed the data using SPSS version 27 and Microsoft Excel 2019, and calculated the incidence rates per 10 million population. A total of 437 rabies cases were reported during the period, with an annual mean of 15.6 ± 6.6 cases. Cases occurred throughout the year, with a relative peak between May and October. The highest number of cases was reported in 1999 (30 cases; 6.9%) and the lowest was in 2015 (6 cases; 1.4%). Most cases occurred among children aged <15 years (60.2%), and males accounted for 82.2% of cases. The highest incidence rates per 10 million population were reported in the central and southern governorates, particularly Babylon (11.18) and Diyala (10.99). Iraq continues to report a high number of rabies cases among humans annually. To achieve the WHO target of eliminating rabies among humans by 2030, there is a need for more effective rabies control measures, including better stray dog population management, expanded animal vaccinations, improved public awareness, and continuous access to rabies vaccines and immunoglobulin.

PANoptosis is a newly described type of cell death that can be triggered upon microbial infection, autoinflammatory diseases, and cytokine storms, and involves the coordinated activation of pyroptosis, apoptosis, and necroptosis. Pseudorabies virus (PRV) infection has been reported to trigger excessive inflammatory responses in mice, swine, and in rare cases in humans, leading to acute viral encephalitis. However, the precise mechanisms by which PRV exacerbates host inflammation responses remain incompletely understood, and the potential role of PANoptosis in this pathogenic process has yet to be elucidated. Here, we demonstrate that PRV infection in different cell lines, murine primary macrophages and mice all results in activation of the PANoptotic signaling pathway and drives the formation of the core scaffold (caspase-8/ASC/RIPK3) within the PANoptosome. We observe that innate sensor proteins AIM2, Pyrin, and ZBP1 interact with the core scaffold protein ASC in PRV-infected THP-1 Mφ and co-localize with ASC. We further identify that IRF1 serves as the key transcription factor that is upregulated during PRV infection. Increased IRF1 translocates to the nucleus and binds directly to the promoter regions of innate sensor genes ZBP1 and AIM2, thereby elevating their gene expression. Ultimately, we discover that the genetic suppression of IRF1 expression and pharmacological blockade of PANoptosis markedly attenuate the extracellular release of pro-inflammatory mediators HMGB1 and IL-1β during PRV infection in vitro. Moreover, pharmacological inhibition of PANoptosis in vivo substantially reduces levels of HMGB1 and IL-1β in cerebral tissue of PRV-infected mice and effectively confers significant protection against PRV challenge, supporting an important role for PANoptosis in PRV pathogenesis. Collectively, our study not only provides a novel perspective on the pro-inflammatory mechanisms of PRV but also highlights that PANoptosis may be therapeutically targeted to improve viral infection outcomes.

Enteroviruses (EVs) are the major pathogens causing viral encephalitis and meningitis and frequently drive outbreaks in high-risk settings such as schools and healthcare facilities. We analyzed outbreaks reported from 1960-2025 to map epidemiology, clinical manifestations, and serotypes, informing prevention and control. We systematically searched Web of Science, PubMed, CNKI, and Wanfang from 1960 to July 1, 2025 using the keywords of enterovirus, encephalitis, meningitis and outbreak to assemble a global dataset of enterovirus encephalitis and meningitis outbreaks. Eligible studies must report outbreaks of laboratory-confirmed enterovirus meningitis or encephalitis, while those with unclear outbreak definitions or no laboratory confirmation were excluded. Standardized forms were used to extract information on outbreak characteristics, case demographics, and etiology data. A random-effects model was employed to derive combined estimates of attack rates, hospitalization rates, clinical manifestations and serotype distribution, with subgroup analyzes by geographic region, temporal period, and age group. This research was registered in PROSPERO (CRD420251140412). A total of 56 outbreaks (28,622 cases) across 20 countries were included. Outbreaks were most prevalent in the Western Pacific and Europe, exhibiting seasonal peaks in June-July (Northern Hemisphere) and April-May (Southern Hemisphere), with a median size of 90 cases. Schools and medical institutions were the major outbreak settings. EV-B was the dominant species (94.6%, 53/56), with E30 being the most prevalent serotype. Two decades, 2000-2009 and 2010-2019, saw the highest number of reported outbreaks. The overall attack rate was estimated at 13.2% (95% CI 6.1-22.3). Notably, the pooled hospitalization rate was exceptionally high at 94.0% (95% CI 85.9-99.2). The most frequently reported symptoms were fever, headache, and vomiting. Enterovirus encephalitis and meningitis outbreaks remain a persistent global concern, marked by high hospitalization rates, summer-autumn peaks and regional patterns. They primarily affect children under 15 years old, with multiple serotypes in circulation. Shifting toward active syndromic and genomic surveillance, alongside targeted prevention in high-risk settings, is urgently needed. This work was supported by the Beijing Natural Science Foundation (L242052) and National Key R&D Program of China (2024YFC2310403); Jiangsu Province 333 Project.

From sensing to shaping: microglial responses in the pathogenesis of viral encephalitis.

Mycoplasma hominis (M. hominis) is a rare cause of intracranial infection with diagnostic challenges due to its fastidious nature, nonspecific symptoms mimicking common nervous system infection (e.g., viral encephalitis), and absence of characteristic neuroimaging. Traditional methods (culture/ serology) often yield false negatives, delaying appropriate therapy. Metagenomic Next-Generation Sequencing (mNGS) provides an unbiased solution for such pathogens. We report a 50-year-old male presented with recurrent fever and coma after hematoma evacuation and external ventricular drainage for cerebral hemorrhage. Empirical antimicrobial therapy (ceftriaxone → piperacillin-tazobactam → vancomycin) was ineffective. Cerebrospinal fluid (CSF) analysis confirmed intracranial infection, leading to escalation to meropenem plus intravenous/intrathecal vancomycin, yet clinical and CSF parameters showed no improvement. Although traditional culture of pathogens and serological testing yielded negative results, M. hominis was detected in CSF by mNGS mNGS on postoperative day 19. Targeted therapy with moxifloxacin and doxycycline resulted in marked clinical improvement: fever resolved and CSF abnormalities normalized. Conclusion: This case highlights mNGS as pivotal for diagnosing fastidious pathogens like M. hominis in culture-negative intracranial infections, enabling a critical shift from failed empirical therapy to successful pathogen-directed treatment. It further underscores the indispensable role of the clinical pharmacist in optimizing antimicrobial selection and monitoring based on mNGS findings. When empirical therapy fails and pathogen identification remains elusive in CNS infections, mNGS emerges as a valuable diagnostic option to guide targeted treatment.

Using electron microscopy to observe ultrastructural changes occurring in BHK-21 cells during cellular infection by Japanese encephalitis virus.

Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD) are multifactorial neurodegenerative disorders driven by complex interactions among genetic susceptibility, aging, and environmental exposures. Growing epidemiological and mechanistic evidence implicates neurotropic viral exposomes, defined as cumulative lifetime viral infections, as significant contributors to AD risk. Viral encephalitis and common viral infections, including herpes simplex virus type 1 (HSV-1), human immunodeficiency virus (HIV), cytomegalovirus (CMV), SARS-CoV-2, and influenza, have been associated with an increased incidence of AD/ADRD; however, the molecular mechanisms underlying these associations remain incompletely understood. A systematic literature review was conducted using PubMed, Web of Science, Scopus, and Google Scholar (1990-2025) to identify epidemiological, experimental, and mechanistic studies linking viral infections to AD-related pathology. Systems biology approaches were applied using Cytoscape, STRING, KEGG, WikiPathways, and Ingenuity Pathway Analysis to construct protein-protein interaction networks and identify convergent biological processes shared between AD and viral host-response pathways. Functional enrichment analyses focused on neuroinflammation, amyloid-β (Aβ) metabolism, tau pathology, autophagy, and blood-brain barrier (BBB) integrity. Across diverse viral infections, strong convergence was observed in innate immune activation pathways, including microglial priming and NLRP3 inflammasome signaling, accompanied by chronic production of proinflammatory cytokines (IL-1β, TNF-α, IFN-γ). Multiple viruses modulated amyloidogenic APP processing, impaired Aβ clearance, promoted tau hyperphosphorylation, disrupted autophagy-lysosomal systems, and compromised BBB integrity. Systems-level analyses revealed overlapping signaling hubs, including NF-κB, MAPK, PI3K-Akt, and cGAS-STING that amplify neurodegenerative cascades, with effects most pronounced in genetically susceptible populations such as APOE4 carriers. Collectively, current evidence supports a mechanistic link between viral exposomes and AD/ADRD mediated through convergent neuroinflammatory, and proteostatic pathways. Although viral infections alone are unlikely to be sufficient to cause AD, recurrent or persistent viral exposures may act as potent disease modifiers that accelerate neurodegenerative processes. Integrating viral biomarkers, genetic risk stratification, and systems biology approaches offers promising opportunities for early diagnosis, prevention, and development of mechanism-guided therapeutic strategies.

Tick-borne encephalitis (TBE) is an emerging vector-borne disease in Europe, but its epidemiology remains poorly defined in Serbia. In orthoflavivirus-endemic settings, diagnostic challenges may contribute to underrecognition of TBE, particularly among patients with suspected West Nile virus (WNV) infection. We conducted a multicenter retrospective study including patients hospitalized between 2018 and 2023 with suspected WNV neuroinvasive disease or viral encephalitis of unknown etiology. Serum samples were tested for TBEV-neutralizing antibodies using a microneutralization assay. Among 79 patients, TBEV-neutralizing antibodies were detected in four (5.1%). Most reactive cases occurred in patients initially classified as having suspected WNV-associated meningoencephalitis, while TBE had not been considered in the differential diagnosis at admission. These findings suggest that TBE may be underrecognized in Serbia and highlight the importance of confirmatory testing in orthoflavivirus-endemic settings. Strengthening clinical awareness and surveillance will be essential to better define the burden of TBE and inform prevention strategies.

The diagnosis and treatment of autoantibody-negative autoimmune encephalitis (AbNAE) remain challenging due to the absence of definitive serological markers and established treatment strategies. We present a case of a 54-year-old male with acute memory impairment. Cerebrospinal fluid (CSF) analysis and cranial magnetic resonance imaging (MRI) revealed features consistent with neuroinflammation. However, the autoimmune encephalitis (AE) antibody panel in both CSF and serum returned negative results. Initially misdiagnosed as viral encephalitis (VE), the patient received a three-week antiviral regimen. Subsequently, the patient developed seizures and neuropsychiatric symptoms, with concurrent deterioration on serial electroencephalography (EEG) and MRI. Repeat AE antibody testing remained negative. The diagnosis of autoantibody-negative but probable autoimmune encephalitis (ANPRA), a subtype of AbNAE, was established. Despite prompt initiation of first-line immunotherapies, including high-dose corticosteroids and intravenous immunoglobulin (IVIg), the patient's neurological status continued to decline. Therefore, subcutaneous telitacicept (160mg weekly) was administered for four consecutive weeks. This intervention led to progressive neurological improvement without clinically significant adverse events. This case highlights the aggressive nature and suboptimal response to conventional immunotherapy in ANPRA, and suggests that telitacicept may represent a viable therapeutic alternative for this challenging condition.

Purpose:To describe the clinical profile of a large cohort of patients with acute retinal necrosis (ARN) in a tertiary eyecare institute from India.Methods:Retrospective analysis of all patients with ARN, visiting the uveitis clinic of a tertiary eye institute between 2010 and 2022.Result:The study included 144 eyes of 119 patients with ARN (mean age 37.6 ± 15.8 years); 68.6% were males. A history of chickenpox was present in 12.6% and viral encephalitis in 9.2%. The common presenting symptom was blurred vision (94.9%), followed by redness (28.8%), pain (24.6%), and floaters (15.3%). Misdiagnosis occurred in 36.9% of cases. At presentation, 79.0% had unilateral disease, while 21.0% were bilateral, with many showing sequential involvement after a mean interval of 5.9 years. Anterior uveitis was documented in 30.5% of eyes, vitritis grade ≥ II in 70.8%, and all four quadrants of retinitis in 47.8%. Retinal vasculitis and optic nerve involvement were noted in 84.0% and 39.6%, respectively. Polymerase chain reaction detected herpes simplex virus and varicella-zoster virus with equal frequency (28.6% each); dual infection was found in 5.0%. Most patients received intravenous acyclovir induction followed by oral antivirals, with valacyclovir used in 80.7%. The mean treatment duration was 5 months. Follow-up averaged 2 years, during which the visual acuity declined from 1.58 to 1.89 logMAR. Major complications included cataract (79.2%), retinal detachment (72.5%), hypotony (48.6%), and optic atrophy (25%).Conclusion:ARN remains a devastating viral retinitis which is frequently underrecognized in its early stages.

In China, there were few studies about the etiology, outcome and disease burden of severe viral encephalitis (VE) in recent years. The aims of this study were to characterize the etiology, prognosis and identify the factors predicting severe VE in Chinese children. A multicenter retrospective cohort study was conducted at six hospitals from 2015 to 2021 in China. The clinical and outcome data were collected during patients' hospitalization. We analyzed the epidemiologic characteristics and disease burden of hospitalized children (≤ 14 years old) with VE in China. Univariate and multivariate logistic regression analyses were used to identify the factors predicting severe VE. In total, 801 episodes of VE were included. There were 272 females and 529 males among the included patients, with a mean age of 4.81 ± 3.46 years. There were 29 cases diagnosed severe VE, with an incidence of 3.6% (29/801). Among the severe cases, Enterovirus (EV) 55.2% (16/29) was the main pathogen. A total of 11 (1.4%) in-hospital deaths occurred, and 32 (4.0%) patients had the sequelae. The incidence of sequelae, the number of patients receiving treatment in the ICU, and the number of deceased patients were all higher in the severe VE group. After accounting for circularity between severity definition and predictors, significant factors for severe VE were abnormal brain imaging and EV infection. Coma was a defining criterion and not considered an independent predictor. This study will help understand the clinical epidemiology, prognosis and disease burden of hospitalized children with severe VE in China and offer useful information for identifying high-risk patients who are susceptible to poor prognosis.