Enterovirus Encephalitis Research Articles

Enteroviral encephalitis with neurological sequelae treated successfully with corticoids

Enteroviral infections are a common condition in childhood that may compromise the central nervous system. The primary concern is the absence of specific treatment for severe cases. Data report uses immunotherapy to reduce neurological sequelae, with limited studies evaluating its efficacy and safety. This case describes enteroviral encephalitis with neurological sequelae, treated successfully with corticosteroids.

Development of a translational inflammation panel for the quantification of cerebrospinal fluid Pterin, Tryptophan-Kynurenine and Nitric oxide pathway metabolites

SummaryBackgroundNeuroinflammatory diseases such as encephalitis, meningitis, multiple sclerosis and other neurological diseases with inflammatory components, have demonstrated a need for diagnostic biomarkers to define treatable and reversible neuroinflammation. The development and clinical validation of a targeted translational inflammation panel using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) could provide early diagnosis, rapid treatment and insights into neuroinflammatory mechanisms.MethodsAn inflammation panel of 13 metabolites (neopterin, tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, xanthurenic acid, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, picolinic acid, arginine, citrulline and methylhistamine) was measured based on a simple precipitation and filtration method using minimal CSF volume. The chromatographic separation was achieved using the Acquity UPLC BEH C18 column in combination with a gradient elution within a 12-min time frame. Acute encephalitis (n=10; myelin oligodendrocyte glycoprotein encephalitis n=3, anti-N-methyl-D-aspartate encephalitis n=2, acute disseminated encephalomyelitis n=2, herpes simplex encephalitis n=1, enteroviral encephalitis n=1) and frequency-matched non-inflammatory neurological disease controls (n=10) were examined.FindingsThe method exhibited good sensitivity as the limits of quantification ranged between 0.75 and 3.00 ng mL−1, good linearity (r2 > 0.99), acceptable matrix effects (<± 19.4%) and high recoveries (89.8-109.1 %). There were no interferences observed from common endogenous CSF metabolites, no carryover and concordance with well-established clinical methods. The accuracy and precision for all analytes were within tolerances, at <± 15 mean relative error and < 15 % coefficient of variation respectively. All analytes in matrix-matched pooled human CSF calibrators and human CSF extracts were stable for 24 h after extraction and two freeze-thaw cycles.InterpretationThe method was successfully applied to a pilot study investigating acute brain inflammation case-control groups. Statistical discrimination between encephalitis (n=10) and control groups (n=10) was achieved using orthogonal partial least squares discriminant analysis and heatmap cluster analysis. Statistical analysis of the measured metabolites identified significant alterations of seven metabolites in the tryptophan-kynurenine pathway (tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid), arginine and neopterin in presence of acute neuroinflammation. Furthermore, elevated ratios of CSF kynurenine/tryptophan ratio, quinolinic acid/kynurenic acid and anthranilic acid/3-hydroxyanthranilic acid provided strong discriminative power for neuroinflammatory conditions. Studies of large groups of neurological diseases are required to explore the sensitivity and specificity of the inflammation panel.FundingFinancial support for the study was granted by Dale NHMRC Investigator grant APP1193648, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead.

Epidemiological characteristics and cerebrospinal fluid cytokine profiles of enterovirus encephalitis in children in Hangzhou, China

Enteroviruses (EVs) are common causes of viral encephalitis in children. To better understand the epidemiological and pathological characteristics of EV encephalitis, we enrolled suspected encephalitis patients younger than 15 years old in Hangzhou, China, from October 2016 to September 2019 for cerebrospinal fluid (CSF) collection and analyses. A total of 7735 CSF samples were collected, among which 330 (4.27%) were positive for the EV genome. The positivity rate was significantly higher in boys than girls (χ2 = 5.68, p = 0.02). The monthly case numbers peaked from June to August (80.30%). Among the different age groups, the 0-2 months age group showed the highest number of cases (28.48% of all cases). The 6-7 years (10.82%) and 9-10 years (9.29%) age groups showed the highest EV-positivity rates among suspected encephalitis cases. Sixty-two EV-positive and 53 control CSF samples were collected for Bio-Plex Pro human cytokine assays that simultaneously tested 48 cytokines. Principle component analyses showed significant separation between EV-positive and control samples, but insignificant separation between children and newborns. The levels of 28 cytokines and chemokines were significantly elevated in the EV-positive group including many proinflammatory and a few anti-inflammatory cytokines, as well as chemokines belonging to the CC and CXC subfamilies. Only one cytokine, stem cell growth factor-β, showed a decrease in the EV-positive group. Thus, this study revealed age, sex, and seasonal preferences for EV encephalitis incidences in children and identified many cytokines dysregulated during EV encephalitis.

Case of GFAP astropathy associated with enterovirus encephalitis or COVID-19 Infection? (2468)

Case of GFAP astropathy associated with enterovirus encephalitis or COVID-19 Infection? (2468)

Progression of enteroviral encephalitis in children

The article presents analysis of the results of a dynamic follow-up of 35 children with enteroviral encephalitis. The average age of these children suffering enteroviral encephalitis was 6.04±0.84 years old. Maximal morbidity rate of enteroviral encephalitis was observed in August and September and corresponded to the common morbidity rate of all enteroviral infections.

X-Linked Agammaglobulinemia With Chronic Meningoencephalitis: A Diagnostic Challenge

X-linked agammaglobulinemia (XLA) is a primary disorder of humoral immunity characterized by Bruton tyrosine kinase gene mutations resulting in a primary antibody deficiency. While an intact T-cell function largely protects against majority of viral infections, enteroviruses are notorious for infecting these patients due to impaired mucosal immunity. Although the incidence of enteroviral meningoencephalitis in XLA is only 1-5%, yet the mortality is quite high. A typical presentation of enteroviral encephalitis in XLA is a subacute to chronic nervous system infection. A progressive loss of motor and cognitive milestones, spastic quadriplegia, coma, and death are common presentations. The histopathological features reflect gliosis, gradual neuronal loss, neuronophagia, and microglial proliferation. We describe the clinical and brain histopathological findings in a 2-year-old boy with XLA and progressive encephalitis, possibly due to an enteroviral infection.

Cerebrospinal fluid metabolites in tryptophan-kynurenine and nitric oxide pathways: biomarkers for acute neuroinflammation.

To explore the cerebrospinal fluid (CSF) metabolite features in acute neuroinflammatory diseases and identify potential biomarkers to diagnose and monitor neuroinflammation. A cohort of 14 patients (five females, nine males; mean [median] age 7y 9mo [9y], range 6mo-13y) with acute encephalitis (acute disseminated encephalomyelitis n=6, unknown suspected viral encephalitis n=3, enteroviral encephalitis n=2, seronegative autoimmune encephalitis n=2, herpes simplex encephalitis n=1) and age-matched non-inflammatory neurological disease controls (n=14) were investigated using an untargeted metabolomics approach. CSF metabolites were analyzed with liquid chromatography coupled to high resolution mass spectrometry, followed by subsequent multivariate and univariate statistical methods. A total of 35 metabolites could be discriminated statistically between the groups using supervised orthogonal partial least squares discriminant analysis and analysis of variance. The tryptophan-kynurenine pathway contributed nine key metabolites. There was a statistical increase of kynurenine, quinolinic acid, and anthranilic acid in patients with encephalitis, whereas tryptophan, 3-hydroxyanthrnailic acid, and kynurenic acid were decreased. The nitric oxide pathway contributed four metabolites, with elevated asymmetric dimethylarginine and argininosuccinic acid, and decreased arginine and citrulline in patients with encephalitis. An increase in the CSF kynurenine/tryptophan ratio (p<0.001), anthranilic acid/3-hydroxyanthranilic acid ratio (p<0.001), asymmetric dimethylarginine/arginine ratio (p<0.001), and neopterin (p<0.001) strongly predicted neuroinflammation. The combination of alterations in the tryptophan-kynurenine pathway, nitric oxide pathway, and neopterin represent a useful potential panel for neuroinflammation and holds potential for clinical translation practice. The kynurenine/tryptophan and anthranilic acid/3-hydroxyanthranilic acid ratios hold great potential as biomarkers of neuroinflammation. Elevation of the asymmetric dimethylarginine/arginine ratio in acute brain inflammation shows dysregulation of the nitric oxide pathway.

Next-generation sequencing in the diagnosis of viral encephalitis: sensitivity and clinical limitations

Identification of pathogens causing viral encephalitis remains challenging, and in over 50% of cases the etiologic factor remains undetermined. Next-generation sequencing (NGS) based metagenomics has been successfully used to detect novel and rare infections, but its value for routine diagnosis of encephalitis remains unclear. The aim of the present study was to determine the sensitivity of shotgun metagenomic sequencing protocols, which include preamplification, and testing it against cerebrospinal fluid (CSF) samples from encephalitis patients. For sensitivity testing HIV and HBV positive sera were serially diluted in CSF from an uninfected patient. NGS repeatedly detected HIV and HBV sequences present at concentrations from 105 to 102 and from 105 to 10 viral copies/reaction, respectively. However, when the same protocols were applied to RT-PCR/PCR positive CSF samples from 6 patients with enteroviral encephalitis (median viral load 47 copies/ml) and 15 patients with HSV, CMV or VZV encephalitis (median viral load 148 copies/ml), only 7 (28.6%) were identified as positive. In conclusions, while NGS has the advantage of being able to identify a wide range of potential pathogens it seems to be less sensitive compared to the standard amplification-based assays in the diagnosis of encephalitis, where low viral loads are common.

Enterovirus Encephalitis in Newborns: Not-Periventricular Brain Involvement and Vascular Pathogenesis in a Novel Case

AbstractNeonatal encephalitis by either enteroviruses (EVs) or parechoviruses (PeVs) is often complicated by hemispheric periventricular white matter lesions. Although showing many similarities, the two types of encephalitis differ in some clinical and laboratory aspects, mostly because PeV encephalitis does not show any change of protein and white cell content in the cerebrospinal fluid, and clinically, the onset of PeV encephalitis is often marked by early seizures accompanying a fever of sepsis-like disease. Instead, no difference exists relative to the white matter lesions, which are constantly described as periventricular, even in rare detailed neuropathological studies. Herein, taking a cue from a neonate with EV encephalitis who showed occipital white matter lesions involving the overlying cortex, but completely sparing the periventricular area, we demonstrate that the brain lesions in EV encephalitis in newborns can be more extended than known. To our knowledge, the not-periventricular involvement of the white matter with EV encephalitis has never been described so far, as well as the potential of EV to injure the cortex. We confirm the pathogenetic role of a vascular mechanism for the tissue injury, but other proposed mechanisms are also discussed. It is noteworthy that the neurological outcome of this newborn remained favorable, and no epileptic seizures occurred in the first few days nor afterward.

Enteroviral encephalitis with neurological impairment: a successful recovery after corticosteroid therapy

Enteroviral encephalitis with neurological impairment: a successful recovery after corticosteroid therapy

Enterovirus and Encephalitis.

Enterovirus-induced infection of the central nervous system (CNS) results in acute inflammation of the brain (encephalitis) and constitutes a significant global burden to human health. These viruses are thought to be highly cytolytic, therefore normal brain function could be greatly compromised following enteroviral infection of the CNS. A further layer of complexity is added by evidence showing that some enteroviruses may establish a persistent infection within the CNS and eventually lead to pathogenesis of certain neurodegenerative disorders. Interestingly, enterovirus encephalitis is particularly common among young children, suggesting a potential causal link between the development of the neuroimmune system and enteroviral neuroinvasion. Although the CNS involvement in enterovirus infections is a relatively rare complication, it represents a serious underlying cause of mortality. Here we review a selection of enteroviruses that infect the CNS and discuss recent advances in the characterization of these enteroviruses with regard to their routes of CNS infection, tropism, virulence, and immune responses.

113 A case of suspected autoimmune encephalitis secondary to nivolumab

ObjectiveTo describe a case of suspected immune encephalitis following nivolumab for metastatic melanoma.MethodsRetrospective review of clinical records and diagnostic tests.ResultsA 78-year-old man with cerebral and lung melanoma metastases was treated with nivolumab, the newly developed monoclonal antibody which inhibits PD-1 deactivation of T-cells. He showed good radiological response.Three months after ceasing nivolumab, he presented to ED with acute confusion, aphasia, left-sided weakness and neglect as a stroke call. MRI demonstrated no evidence of stroke or acute encephalitis. EEG showed diffuse slowing. Lumbar puncture was not performed as he was therapeutically anticoagulated and had begun to improve on empirical antibiotics and acyclovir. One week later, he suddenly deteriorated with fevers and reduced level of consciousness. Acyclovir was restarted. Repeat EEG revealed periodic epileptic discharges over the right hemisphere and MRI demonstrated hyperintense signal and diffusion restriction of the right mesial temporal lobe suggestive of encephalitis. Subsequent lumbar puncture was negative for HSV, VZV, enterovirus, and autoimmune encephalitis antibodies.The patient’s oncology team had been in support of a course of methylprednisone on suspicion of autoimmune encephalitis, but by the time the lumbar puncture results returned he was again improving. A diagnosis of suspected nivolumab-induced encephalitis was made based on exclusion of other possible diagnoses.ConclusionsThe rising use of immune checkpoint inhibitors heralds an array of new and unexpected neurological complications including autoimmune encephalitis. A nationwide registry of possible cases may be helpful in improving our currently limited understanding of these emerging complications.

Balancing immunosuppression and infection: recurrent enterovirus encephalitis in SLE

A young woman with systemic lupus erythematosus (SLE) developed recurrent enterovirus meningoencephalitis while taking prednisolone, azathioprine and rituximab. After reducing the immunosuppression, she developed a central nervous system (CNS) flare...

Epilepsy and Neurodevelopmental Outcomes in Children With Etiologically Diagnosed Central Nervous System Infections: A Retrospective Cohort Study.

Background: Central nervous system (CNS) infection in childhood can lead to neurological sequelae, including epilepsy, and neurodevelopmental disorders, such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). This study investigated the association of etiologically diagnosed childhood brain infections with the subsequent risks of epilepsy and neurodevelopmental disorders.Objectives: We retrospectively analyzed the data of children aged <18 years who had definite brain infections with positive cerebrospinal fluid cultures from January 1, 2005, to December 31, 2017. These patients were followed to evaluate the risks of epilepsy and neurodevelopmental disease (ADHD and ASD) after brain infections (group 1) in comparison with the risks in those without brain infections (group 2).Results: A total of 145 patients with an average age of 41.2 months were included in group 1. Enterovirus accounted for the majority of infections, followed by group B Streptococcus, S. pneumoniae, and herpes simplex virus. A total of 292 patients with an average age of 44.8 months were included in group 2. The 12-year risk of epilepsy in group 1 was 10.7 (95% confidence interval [CI], 2.30–49; p < 0.01). Compared with group 2 (reference), the risk of ASD in the age interval of 2–5 years in group 1 was 21.3 (95% CI, 1.33–341.4; p = 0.03). The incidence of ADHD in group 1 was not significantly higher than that in group 2.Conclusions: This study identified the common etiological causes of brain infections in Taiwanese children. The highest-risk neurodevelopmental sequelae associated with brain infections was epilepsy. Children who had a diagnosis of brain infection (specially Enterovirus) should be followed since they are at greater risk of developing epilepsy and ASD.

P.029 Case report: pediatric enterovirus encephalitis - a rare complication of rituximab therapy

Background: Opportunistic infection should be considered when seeing neurological complications in the setting of immunosuppression. Accumulating evidence that enteroviral meningoencephalitis can occur after rituximab administration exists but differentiating it from non-infectious conditions can be challenging. Methods: Case report Results: We describe a 4 year-old-boy with a history of pulmonary capillaritis, treated with immunosuppressive therapy -including steroids, rituximab, and azathioprine. He developed mutism and ataxia after 18 months on rituximab. MRI Brain/Spine revealed extensive T2/FLAIR hyperintensities in the deep subcortical white matter, temporal lobes, globus pallidi, thalami, brainstem, and cerebellum; and swelling of the dorsal cervical cord, showing primarily grey matter involvement. IgG levels had a decreasing trend over the course of Rituximab. CSF, and subsequent brain biopsy, were both positive for enterovirus RNA by RT-PCR. He was thought to have enterovirus encephalitis secondary to rituximab therapy, and was treated with IVIG and fluoxetine. Conclusions: One should consider chronic opportunistic CNS infections in children treated with immunosuppressive therapy, and to consider chronic enterovirus infection when B-cell suppression has occurred. As rituximab is being increasingly used in the pediatric population, and is generally thought to be safe, attention should be paid to any child with chronic neurological signs, particularly younger children who may be at higher risk for chronic enterovirus infection.

ICARES: a real-time automated detection tool for clusters of infectious diseases in the Netherlands

BackgroundClusters of infectious diseases are frequently detected late. Real-time, detailed information about an evolving cluster and possible associated conditions is essential for local policy makers, travelers planning to visit the area, and the local population. This is currently illustrated in the Zika virus outbreak.MethodsIn the Netherlands, ICARES (Integrated Crisis Alert and Response System) has been developed and tested on three syndromes as an automated, real-time tool for early detection of clusters of infectious diseases. From local general practices, General Practice Out-of-Hours services and a hospital, the numbers of routinely used syndrome codes for three piloted tracts i.e., respiratory tract infection, hepatitis and encephalitis/meningitis, are sent on a daily basis to a central unit of infectious disease control. Historic data combined with information about patients’ syndromes, age cohort, gender and postal code area have been used to detect clusters of cases.ResultsDuring the first 2 years, two out of eight alerts appeared to be a real cluster. The first was part of the seasonal increase in Enterovirus encephalitis and the second was a remarkably long lasting influenza season with high peak incidence.ConclusionsThis tool is believed to be the first flexible automated, real-time cluster detection system for infectious diseases, based on physician information from both general practitioners and hospitals. ICARES is able to detect and follow small regional clusters in real time and can handle any diseases entity that is regularly registered by first line physicians. Its value will be improved when more health care institutions agree to link up with ICARES thus improving further the signal-to-noise ratio.

Fifteen-minute consultation: enterovirus meningitis and encephalitis—when can we stop the antibiotics?

Enterovirus (EV) is the most common cause of aseptic meningitis and has a benign course, unlike EV encephalitis, which can result in long-term neurological sequelae. There are no active treatments...

Molecular epidemiological study of enteroviruses associated with encephalitis in children from Hangzhou, China.

Enterovirus (EV) has over 100 serotypes of species A–D, which can cause various symptoms in infants. Enterovirus encephalitis (EVE) is serve disease with high morbidity and mortality in children. To well define the epidemiology of EVE, we wanted to know more about EV and EV molecular typing by conducting this study in Hangzhou.Cerebrospinal fluid samples were collected from children with diagnosis of encephalitis. Meanwhile, one-step real-time RT-PCR was used for the detection of EV, and we also identified the serotypes of EV by using gene sequencing of VP1 or 5′UTR region.A total of 126 CSF specimens were tested and EV was detected in 26 specimens (20.6%). The molecular typing results showed different types of EV strains including Coxsackievirus B2, Coxsackievirus B3, Echovirus 5, Echovirus 16, Echovirus 18, Echovirus 30, and all EV isolates belonging to the human EV species B.According to the sequence of VP1 and 5′UTR region, E30 may be major cause of children's EVE in Hangzhou, China.

Utility of CSF Cytokine/Chemokines as Markers of Active Intrathecal Inflammation: Comparison of Demyelinating, Anti-NMDAR and Enteroviral Encephalitis

BackgroundDespite the discovery of CSF and serum diagnostic autoantibodies in autoimmune encephalitis, there are still very limited CSF biomarkers for diagnostic and monitoring purposes in children with inflammatory or autoimmune brain disease. The cause of encephalitis is unknown in up to a third of encephalitis cohorts, and it is important to differentiate infective from autoimmune encephalitis given the therapeutic implications.AimTo study CSF cytokines and chemokines as diagnostic biomarkers of active neuroinflammation, and assess their role in differentiating demyelinating, autoimmune, and viral encephalitis.MethodsWe measured and compared 32 cytokine/chemokines using multiplex immunoassay and APRIL and BAFF using ELISA in CSF collected prior to commencing treatment from paediatric patients with confirmed acute disseminated encephalomyelitis (ADEM, n = 16), anti-NMDAR encephalitis (anti-NMDAR E, n = 11), and enteroviral encephalitis (EVE, n = 16). We generated normative data using CSF from 20 non-inflammatory neurological controls. The sensitivity of CSF cytokine/chemokines to diagnose encephalitis cases was calculated using 95th centile of control values as cut off. We correlated CSF cytokine/chemokines with disease severity and follow up outcome based on modified Rankin scale. One-way hierarchical correlational cluster analysis of molecules was performed in different encephalitis and outcome groups.ResultsIn descending order, CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 had the best sensitivity (>79.1%) when all encephalitis patients were included. The combination of IL-6 and IFN-α was most predictive of inflammation on multiple logistic regression with area under the ROC curve 0.99 (CI 0.97–1.00). There were no differences in CSF cytokine concentrations between EVE and anti-NMDAR E, whereas ADEM showed more pronounced elevation of Th17 related (IL-17, IL-21) and Th2 (IL-4, CCL17) related cytokine/chemokines. Unlike EVE, heat map analysis showed similar clustering of cytokine/chemokine molecules in immune mediated encephalitis (ADEM and anti-NMDAR E). Th1 and B cell (CXCL13 and CXCL10) molecules clustered together in patients with severe encephalopathy at admission and worse disability at follow up in all encephalitis. There was no correlation between CSF neopterin and IFN-γ or IFN-α.ConclusionA combination panel of cytokine/chemokines consisting of CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 measured using multiplex immunoassay may be used to diagnose and monitor intrathecal inflammation in the brain. Given their association with worse outcome, certain key chemokines (CXCL13, CXCL10) could represent potential therapeutic targets in encephalitis.

Changing Nature of Health Crisis from Infectious Diseases and Responses Over Three Decades in Malaysia

The author relates his 35 years experiences serving the public health sector in various capacities at district, state and country levels in Malaysia. He described several important outbreaks encountered such as malaria, dengue, cholera, enterovirus encephalitis, Nipah virus encephalitis, avian influenza, SARS and leptospirosis. He discussed the determinants of infectious diseases outbreak such as the pathogenicity of the organism, the environmental factors, human and animal factors. The impact of these outbreaks affected the economy, psychosocial, political and international relations. The responses to these outbreaks had improved along with the development of new technologies in diagnosis, surveillance, information technology and human resource development. The author also identified the importance of networking, appropriate risk and crisis communication and the management of the after effect of the outbreak. Apart from outbreak preparedness plan, research remains an important tool in discovering new diseases and appropriate ways of responding to the crisis.