Viral Encephalitis—Background, Arboviruses, and Enteroviruses

Background: Viral encephalitis is a rare condition affecting approximately 1.4 individuals per 100.000 annually worldwide. It is characterized by inflammation of the brain parenchyma due to common viral infections in Brazil, such as dengue, Zika, and chikungunya. Given the high mortality associated with viral encephalitis and the lack of studies focusing on the Brazilian Midwest and, more specifically, the pediatric population, conducting an epidemiological analysis of mortality cases in this region is crucial. Objective: To analyze the epidemiological profile of mortality cases due to viral encephalitis in the pediatric population of the Brazilian Midwest from 2008 to 2023. Methods: This is a descriptive, retrospective, and quantitative epidemiological study based on data from the Hospital Information System (SIH/SUS) provided by the Department of Information Technology of the Unified Health System (DATASUS), regarding the mortality from viral encephalitis in pediatric patients from 2008 to 2023 in Goiás, Mato Grosso, Mato Grosso do Sul, and Distrito Federal. Filters applied included: ICD-10 morbidity list (viral encephalitis), midwest region, race/ethnicity, gender, age group, available period (January 2008 to December 2023), and year of processing. Data were tabulated in Excel and subjected to descriptive statistical analysis using R 4.40 with RStudio 2024.04.1 + 748. Since this study utilizes publicly available anonymous data, it is exempt from the Ethics Committee’s approval. Results: During the study period, the average mortality rate was 2.85 %, with 2012 having the highest mortality rate (6.9%) followed by 2009 (6.45%). On the other hand, records from 2023 show the lowest mortality rate, 1.02%. Among the analyzed regions, Mato Grosso exhibited the highest mortality rate (4.12%), whereas Distrito Federal had the lowest (1.93%). Notably, individuals of indigenous ethnicity were most affected, with a mortality rate of 12.5%. Additionally, males showed a higher mortality rate compared to females, with rates of 3.49% and 1.95%, respectively. The most affected age group was 10-14 years, with a mortality rate of 4.62%. Conclusion: This study identified the indigenous population as vulnerable to viral encephalitis, likely due to geographical isolation and insufficient healthcare services available. Therefore, there is a clear need to invest in public health policies targeted at this social minority. It is also worth mentioning that Mato Grosso had the highest mortality rate, while the Federal District had the lowest. Furthermore, the highest mortality rates were concentrated about 10 years ago, notably in 2009 and 2012, while there is a decreasing trend in mortality rates, as demonstrated by the 2023 rate, the lowest recorded in the study. Given the data analysis, further studies are needed to investigate the factors influencing the correlation between mortality and viral encephalitis in the Brazilian Midwest regions.

Encephalitis is an inflammatory process involving the brain parenchyma associated with neurologic dysfunction. The main causes of infectious encephalitis are viruses, including Herpes simplex virus type 1 (HSV-1). As the mortality rate of HSV-1 encephalitis could be reduced with early acyclovir treatment, it is imperative to distinguish HSV-1 encephalitis from other type of viral encephalitis as early as possible. However, sophisticated methods for definitive diagnosis of HSV-1 encephalitis are not readily available. We aimed to explore distinctive clinical and laboratory features of HSV-1 encephalitis. All of the adult patients with viral encephalitis hospitalized between 2011-2017 were enrolled, including 16 patients with HSV-1 encephalitis and 51 patients non-HSV-1 viral encephalitis. Determination of viruses in cerebrospinal fluid was performed by PCR tests. Female sex, hyponatremia, and abnormalities in MRI were independently associated with HSV-1 encephalitis (p < 0.05 for each). In particular, hyponatremia (< 135 mEq/L) was found in nine patients with HSV-1 encephalitis (56.3%) and 10 patients with non-HSV-1 viral encephalitis (19.6%) (p = 0.005). As serum sodium is determined easily and quickly in clinical practice, the presence of hyponatremia among patients with viral encephalitis could be helpful for the early diagnosis of HSV-1 encephalitis before cerebrospinal fluid PCR results were available. Moreover, the presence of positive finding in MRI could further support the diagnosis. This is the first study that compared the serum sodium levels among patients between HSV-1 and non-HSV-1 viral encephalitis. We thus propose the diagnostic value of hyponatremia for HSV-1 encephalitis.

Secondary epilepsy is a common concomitant disease of viral encephalitis (VE) in children. However, the risk factors for secondary epilepsy after VE remain debated. The aim of this study was to perform a 10-year single-center retrospective analysis to investigate the incidence and risk factors of secondary epilepsy after VE in children. A total of 8691 patients suffered from VE in our hospital between December 2011 and February 2022 were included. The patients were divided into control group (Group C) and epilepsy group (Group E) according to whether they followed secondary epilepsy. Information about treatment process was collected from medical records to determine the incidence. Univariate analysis and multivariate logistic regression analysis were performed to identify the independent risk factors. In the current study, the occurrence of secondary epilepsy after VE in pediatric patients was 10.99% (385 of 3503). The results of univariate and multivariate analysis showed that unconsciousness, convulsions, times of epilepsy >2, epileptiform discharge of Electroencephalogram (EEG), and cortical and subcortical damage of magnetic resonance imaging/computer tomography were the significant risk factors for secondary epilepsy after VE. Nearly one tenth of pediatric patients suffered from secondary epilepsy after VE. Interventions for identified risk factors should be used to prevent the occurrence of secondary epilepsy.

Objective We detected the enterovirus in the CSF of patients with sporadic aseptic meningitis and viral encephalitis in to investigate the enterovirus infection in this area, and two methods were used in this study. Methods CSF samples of 36 patients with sporadic aseptic meningitis and viral encephalitis were collected during 2009-2013. All the samples were frozen and stored at -80℃ immediately before RNA extraction. Total viral RNA extraction was taken within 3 month after the sample was stored by using an RNA extraction kit according to the method described by the instruction of the kit.Then RNA was reversed into cDNA immediately after the extraction of RNA. cDNA was stored at -80℃. Finaly, we used a rapid and sensitive method for the detection of all members of the enterovirus genus by using real-time PCR. We also detected the IgM of 7enterovirus including Echo virus and Coxsackie virus 1-6 serotype by Enzyme-Linked Immunosorbent Assay(ELISA) method. Results Of all the 36 CSF samples, 9(25%) were positive for enterovirus by PCR method. For patients with aseptic meningitis, viral encephalitis and meningoencephalitis, the proportion were 42.86%, 12.50% and 11.11%. Only 2 samples were positive for Coxsackie virus by ELISA method, and both of them had aseptic meningitis. Conclusion Enterovirus infection is a common cause of sporadic CNS virus infection among patients with viral encephalitis, aseptic meningitis and aseptic meningoencephalitis in Beijing, especially for the patients with aseptic meningitis.Real-time PCR was more sensitive than ELISA, while the better way is to use both of them to detect the serotype of the enterovirus. Key words: Enterovirus; Meningitis; Encephalitis; Infection

To study the etiological profile of patients with acute febrile encephalopathy syndrome focusing chiefly on the viral etiology, and to correlate clinical and radiological features of patients with viral encephalitis. A prospective hospital based study conducted on the consecutive patients admitted in a pediatric unit during the period of 1(st) February 2004 to 31st January 2005 based on the following inclusion criteria: (1) Age more than 1 month and less than 18 years and (2) A diagnoses of acute febrile encephalopathy, based on the following criteria: (i) fever (ii) acute depression of consciousness or mental deterioration for more than 12 hours with or without motor or sensory deficit and (iii) Total duration of illness at the time of admission 1 week or less. The final study group comprised of 151 patients with mean age of 3.21 +/- 2.9 (range of mth-13 years) and male: female ratio of 1.71: 1. A diagnosis other than viral encephalitis was reached in 94 patients (62.3 %). Pyogenic meningitis was the most frequent diagnosis 51(33.8 %) followed by tubercular meningitis 12 (7.9 %), and cerebral malaria 8 (5.2 %) in the patient group of non-viral causes. Fifty-seven cases (37.3%) were suspected as viral encephalitis and mean age of the cases suspected as viral encephalitis was 2.8 +/- 2.9 (Range 1 mth-10 yrs) with male: female ratio of 1.28: 1. Etiological diagnosis was reached or considered probable in 41 (72%) cases out of the suspected patients. The most common etiological agent identified was enterovirus 71 in 20 patients (35.1 %). The other viruses identified were mumps in 6 (10.5%), Japanese encephalitis in 5 (8.7%), and measles in 4 (7%) cases. MRI brain was done in 39 patients and was abnormal in 14 patients. Out of 57 cases of suspected viral encephalitis 10 patients expired within 48 hours, 2 > 48 hours and 19 atients had significant neurological sequels at discharge. The etiology of acute febrile encephalopathy varies from infectious etiologies to noninfectious metabolic disorders. There are no distinguishing clinical or radiological features to differentiate the various causes of viral encephalitis. The clinical and the radiological findings in encephalitis should be interpreted in the geographical and other epidemiological background.

BackgroundFew cases concerning acute retinal necrosis with viral encephalitis in children have been reported, especially cases where the fundus cannot be identified due to severe vitreous opacity in the early stage that makes diagnosis difficult.MethodsWe conducted a retrospective review of an unusual case of herpes simplex virus-2 (HSV-2) acute retinal necrosis with viral encephalitis in an immunocompetent child, along with a review of relevant literature published up to September 2021.ResultAn 11-year-old girl presented with an approximate 20-day history of ocular redness and decreased visual acuity in the left eye. Examination revealed anterior uveitis and vitreous opacity in the left eye. An anterior chamber tap was performed because the fundus could not be observed clearly, and the aqueous humor was positive for HSV-2 DNA. Cerebrospinal fluid also tested positive for HSV-2. She was diagnosed with acute retinal necrosis syndrome and viral encephalitis. The condition was controlled with timely antiviral and steroid therapy. She was also treated with prophylactic laser therapy to prevent retinal detachment during subsequent follow-up. The pathogenesis, diagnosis, and treatment of HSV-2 acute retinal necrosis in children and the association between acute retinal necrosis and viral encephalitis are further discussed, based on published literature.ConclusionHSV-2-related pediatric acute retinal necrosis may be due to the acquisition of subclinical infection with HSV-2 during parturition, followed by reactivation of the virus latent in the body on account of certain factors. Moreover, it may be complicated with viral encephalitis. For suspected cases with invisible fundus, early intraocular fluid examination is especially helpful for differential diagnosis. Early diagnosis, early treatment, and timely prophylactic laser treatment to prevent retinal detachment are key to a better prognosis. Physicians need to pay attention to such suspected cases during diagnosis and treatment.

Objective To discuss the incidence rate and influencing factors of postencephalitic epilepsy (PE) in children with viral encephalitis at acute symptomatic seizure(ASS). Methods The data of 132 children with ASS in the First Affiliated Hospital of Zhengzhou University from September 2013 to July 2018 were retrospectively analyzed, and the patients were divided into PE group (62 cases) and non-PE group (70 cases) according to whether they had PE at final follow-up.The risk factors of PE in children with ASS were analyzed using the multivariate Logistic regre-ssion methods. Results The incidence of PE in children with ASS was 46.97% (62/132 cases). There were statistically significant differences in terms of psychological and behavioral abnormalities[19.4%(12/62 cases) vs.2.9%(2/70 cases)], repetitive seizures (more than 5 seizures) [67.7%(42/62 cases) vs.17.1%(12/70 cases)], status epilepticus (SE) [30.6%(19/62 cases) vs.11.4%(8/70 cases)], generalized seizures [72.6%(45/62 cases) vs.88.6%(62/70 cases)], endotracheal intubation [21.0%(13/62 cases) vs.2.9%(2/70 cases)], the duration of fever [5.5(3.0, 11.0) d vs.3.0(2.0, 6.0) d], the duration in the intensive care unit (ICU) [13(5, 21) d vs.6(3, 8) d], electroencephalography epileptiform discharges [49.1%(27/55 cases) vs.6.8%(4/59 cases)], presence of subcortical involvement on neuroimaging [37.3%(22/55 cases) vs.20.3%(14/59 cases)] in children with ASS between the PE group and the non-PE group(all P<0.05). The multivariate Logistic regression analysis showed that repetitive seizures (more than 5 seizures) (OR=5.256, 95%CI: 1.538-17.961, P=0.008), SE(OR=6.003, 95%CI: 1.411-25.539, P=0.015), electroencephalography epileptiform discharges (OR=36.693, 95%CI: 7.031-191.485, P<0.01) and the duration in ICU (OR=1.170, 95%CI: 1.058-1.298, P=0.002) were the risk factors for PE in children with ASS. Conclusions The incidence rate of PE in children with ASS is high.Children with ASS are more likely to develop into PE if they have repetitive seizures (more than 5 seizures), SE, electroencephalography epileptiform discharges, and the longer duration in ICU. Key words: Child; Viral encephalitis; Seizures; Postencephalitic epilepsy; Risk factor

Timely administration of IV aciclovir reduces mortality in herpes simplex virus (HSV) encephalitis (Sköldenberg in Lancet, 1984), (Whitley in N Engl J Med, 1986). Early diagnosis, however, is challenging due to non-specific symptoms and delays in obtaining key investigation results. Empiric treatment with intravenous (IV) aciclovir in cases of suspected meningitis to cover for possible concurrent viral encephalitis is an approach not supported by the National Institute for Clinical Excellence (NICE) ( https://www.nice.org.uk/guidance/ng240 , 2024). Such practice exposes patients to the risk of iatrogenic nephrotoxicity and neurotoxicity. Our objectives were to evaluate the diagnostic approach to suspected viral encephalitis and appropriateness of aciclovir prescription. This was a retrospective cohort study of 410 patients over 16years old prescribed IV aciclovir for suspected central nervous system infection at Royal Free London NHS Foundation Trust between December 2021 and February 2024. 29% of patients fulfilled diagnostic criteria for possible or probable encephalitis while 5% did not fulfil any of the criteria. 38% had no microbiological or serological testing for HSV or varicella zoster virus.Discharge diagnoses included 5% with viral encephalitis (2% confirmed on cerebrospinal fluid testing) and 6% with meningitis, while the commonest diagnosis was delirium (11% of patients). While acknowledging clinical uncertainty and attendant risks of missing a diagnosis of true viral encephalitis, in line with NICE guidelines we suggest a review of routine prescription of IV aciclovir in suspected meningitis and emphasise the importance of altered mental status as a useful distinguishing feature between viral encephalitis and meningitis in immunocompetent patients.

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. To describe speech and language pathology and the occurrence of comorbid disorders in children with perisylvian syndrome induced by viral encephalitis. 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. 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. 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.

Viral encephalitis is still very prominent around the world, and traditional antiviral therapies still have shortcomings. Some patients cannot get effective relief or suffer from serious sequelae. At present, people are studying the role of the innate immune system in viral encephalitis. Microglia, as resident cells of the central nervous system (CNS), can respond quickly to various CNS injuries including trauma, ischemia, and infection and maintain the homeostasis of CNS, but this response is not always good; sometimes, it will exacerbate damage. Studies have shown that microglia also act as a double-edged sword during viral encephalitis. On the one hand, microglia can sense ATP signals through the purinergic receptor P2Y12 and are recruited around infected neurons to exert phagocytic activity. Microglia can exert a direct antiviral effect by producing type 1 interferon (IFN-1) to induce IFN-stimulated gene (ISG) expression of themselves or indirect antiviral effects by IFN-1 acting on other cells to activate corresponding signaling pathways. In addition, microglia can also exert an antiviral effect by inducing autophagy or secreting cytokines. On the other hand, microglia mediate presynaptic membrane damage in the hippocampus through complement, resulting in long-term memory impairment and cognitive dysfunction in patients with encephalitis. Microglia mediate fetal congenital malformations caused by Zika virus (ZIKV) infection. The gene expression profile of microglia in HIV encephalitis changes, and they tend to be a pro-inflammatory type. Microglia inhibited neuronal autophagy and aggravated the damage of CNS in HIV encephalitis; E3 ubiquitin ligase Pellino (pelia) expressed by microglia promotes the replication of virus in neurons. The interaction between amyloid-β peptide (Aβ) produced by neurons and activated microglia during viral infection is uncertain. Although neurons can mediate antiviral effects by activating receptor-interacting protein kinases 3 (RIPK3) in a death-independent pathway, the RIPK3 pathway of microglia is unknown. Different brain regions have different susceptibility to viruses, and the gene expression of microglia in different brain regions is specific. The relationship between the two needs to be further confirmed. How to properly regulate the function of microglia and make it exert more anti-inflammatory effects is our next research direction.

Molecular Epidemiology of Echovirus 18 Circulating in Mainland China from 2015 to 2016.

Encephalitis is an acute inflammatory process of the brain parenchyma, which is often caused by viral infection. It is an vital cause of acute symptomatic seizures and subsequent epilepsy. The incidence of unprovoked and recurrent seizures after previous infections of the central nervous system is high and accounts for 1%~5% of the cases of epilepsy. Viral encephalitis (VE) is directly caused by viral infection. The occurrence of seizures after VE is associated with poor prognosis. In survivors of VE, among other neurological sequelae, the risk of developing epilepsy is increased 10-fold. The risk of severe neurological sequelae after VE is particularly high in very young children. Studies on seizure occurrence, possible underlying mechanisms, clinical characteristics, and clinical treatment (especially surgical treatment) of VE have yielded only limited detailed data. We reviewed the most recent literature on the clinical features and surgical treatment of post-VE epilepsy.

Encephalitis is an acute inflammatory process of the brain parenchyma, which is often caused by viral infection. It is an vital cause of acute symptomatic seizures and subsequent epilepsy. The incidence of unprovoked and recurrent seizures after previous infections of the central nervous system is high and accounts for 1%~5% of the cases of epilepsy. Viral encephalitis (VE) is directly caused by viral infection. The occurrence of seizures after VE is associated with poor prognosis. In survivors of VE, among other neurological sequelae, the risk of developing epilepsy is increased 10-fold. The risk of severe neurological sequelae after VE is particularly high in very young children. Studies on seizure occurrence, possible underlying mechanisms, clinical characteristics, and clinical treatment (especially surgical treatment) of VE have yielded only limited detailed data. We reviewed the most recent literature on the clinical features and surgical treatment of post-VE epilepsy.

BackgroundNowadays, few surgery analysis has been reported in cases of epilepsy after viral encephalitis(VE). Herein, this study was to evaluate the efficacy of surgery and capability of stereoelectroencephalography (SEEG) in the definition of the epileptogenic zone (EZ) after VE, and also to explore the relationship between the SEEG features and the surgical outcomes.MethodsWe retrospectively analyzed 10 surgically treated patients that identified to suffer from epilepsy secondary to VE using SEEG, and investigated the SEEG features associated with surgical outcomes in these patients. Besides visual analysis, we used the epileptogenicity index (EI), a semi-quantitative and supplementary tool to evaluate the validity of SEEG in the context of VE.ResultsAmong the 10 operated patients, 3 of them became completely seizure-free. The patients who got totally seizure free or significant improvement, the seizure onset was located either in the antero-mesial temporal structures or focal gyrus; patients who got worthwhile improvement or no improvement, the seizure started from multiple brain lobes. The number of electrodes classified as epileptogenic visually involved were closely correlated with EI positive onses.Anatomic areas defined and shown as EZ on MRI by visual assessment were also defined as epileptogenic by the EI in these cases.ConclusionApart from exploring the surgical outcome related to epilepsy after VE, we also bring insight into the relationship between the SEEG features and surgical outcome with the application of the supplementary methods.

While systemic viral infections are exceptionally common, symptomatic viral infections of the brain parenchyma itself are very rare, but a serious neurologic condition. It is estimated that viral encephalitis occurs at a rate of 1.4 cases per 100.000 inhabitants. Geography is a major determinant of encephalitis caused by vector-borne pathogens. A diagnosis of viral encephalitis could be a challenge to the clinician, since almost 70% of viral encephalitis cases are left without an etiologic agent identified. In this review, the most common viral encephalitis will be discussed, with focus on ecology, diagnosis, and clinical management.