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Background: Viral encephalitis (VE) is a common infectious disease of the central nervous system in children. Children with severe disease may have progressive neurological damage and even lead to death., Aims: To assess the serum miR-142-3p levels in children with VE and the correlation between miR-142-3p and the severity and prognosis of VE. Besides, its relationship with nerve injury and inflammatory response was assessed., Methods: Children with VE were regarded as a case group and healthy children served as control. The content of serum miR-142-3p was determined using real-time quantitative PCR. The risk factors associated with severity and prognosis of cases were evaluated using logistic analysis. The discrepancy in miR-142-3p levels, nerve injury-related indicators, and inflammatory cytokines were contrasted among groups. The ROC curve was conducted to assess the diagnostic performance of serum miR-142-3p in predicting prognosis of children with VE., Results: The altered expression of miR-142-3p in serum of children with VE was enhanced in contrast to healthy control. Serum nerve injury indicators MBP, β-EP, and NSE levels and serum inflammatory cytokines IL-6, IL-18, and IFN-γ were high in children with VE in contrast to healthy control, and had positive relevance with serum miR-142-3p. Besides, serum miR-142-3p was a risk factor associated with the severity and prognosis of children with VE. Serum miR-142-3p had diagnostic performance in predicting the prognosis of children with VE., Conclusion: Serum miR-142-3p content is high in children with VE and maybe a diagnosis marker for predicting prognosis. The specific miR-142-3p expression may be directly related to the severity of nerve injury and inflammatory response for VE., (© 2024. The Author(s) under exclusive licence to The Journal of NeuroVirology, Inc.)

Background and Objectives: Neurotropic viruses are suspected to play a role in the pathogenesis of autoimmune diseases of the CNS such as the association between the Epstein-Barr virus (EBV) and multiple sclerosis (MS). A group of autoimmune encephalitis (AE) is linked to antibodies against neuronal cell surface proteins. Because CNS infection with the herpes simplex virus can trigger anti-NMDA receptor (NMDAR) encephalitis, a similar mechanism for EBV and other neurotropic viruses could be postulated. To investigate for previous viral infections of the CNS, intrathecally produced virus-specific antibody synthesis was determined in patients with AE., Methods: Antibody-specific indices (AIs) against EBV and measles, rubella, varicella zoster, herpes simplex virus, and cytomegalovirus were determined in 27 patients having AE (anti-NMDAR encephalitis, n = 21, and LGI1 encephalitis, n = 6) and in 2 control groups comprising of 30 patients with MS and 21 patients with noninflammatory CNS diseases (NIND), which were sex and age matched., Results: An intrathecal synthesis of antibodies against EBV was found in 5/27 (19%) patients with AE and 2/30 (7%) of the patients with MS. All these patients had also at least 1 additional elevated virus-specific AI. In contrast, in none of the patients with NIND, an elevated virus-specific AI was detected., Discussion: Intrathecally produced antibodies against EBV can be found in patients with AE and MS but only together with antibodies against different neurotropic viruses. Evidence of these antibodies is the result of a polyspecific immune response similar yet distinct from MS response rather than an elapsed infection of the CNS., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To analyze the clinical efficacy of naloxone combined with acyclovir in the treatment of children viral encephalitis and the impacts on inflammatory factors IL-1 and IL-6., Patients and Methods: 96 children with viral encephalitis were retrospectively analyzed. They were treated from July 2013 to January 2014 in our hospital. They were divided into control group (45 cases treated with acyclovir) and observation group (51 cases treated with acyclovir combined with naloxone). Both groups were treated with comprehensive measures. Changes of the content of serum IL-1 and IL-6 in the two groups before and after treatment were monitored by enzyme-linked immunosorbent assay (ELISA). Signs, recovery time of clinical symptoms, total effective rate, occurrence of adverse reactions and adverse reactions after treatment of children in the two groups were compared., Results: Levels of serum IL-1 and IL-6 of children in the control group and the observation group decreased after treatment, and the decrease was greater in the observation group (p<0.05). Signs and recovery time of clinical symptoms of the observation group were significantly shorter than that of the control group (p<0.05). Indexes of serum in the observation group were significantly lower than those of the control group after treatment (p<0.05). The total effective rate of the observation group was significantly higher than that of the control group (p<0.05). The prevalence of adverse reactions and sequelae in the observation group were lower than those in the control group (p<0.05)., Conclusions: In the treatment of children, viral encephalitis has naloxone combined with ganciclovir had a more significant effect on the decrease of levels of serum IL-1 and IL-6; naloxone combined with acyclovir in the treatment of children viral encephalitis had better effects, lower adverse reactions and lower prevalence of sequelae compared with sole medication, which is worth clinical promotion.

Background: Human herpesvirus (HHV)-6B encephalitis has been recognized as a serious complication after allogeneic hematopoietic cell transplantation (allo-HCT). Little is known about the pathogenic mechanism for its progression., Study Design: We retrospectively evaluated the 16 kinds of cytokines and chemokines in cerebrospinal fluid (CSF) and plasma in patients who developed HHV-6B encephalitis. Among a total of 20 patients, 12 were categorized as the poor prognosis group (died of encephalitis; n = 8 and retained sequelae; n = 4), and other eight patients were categorized as the good prognosis group (complete recovery; n = 8)., Results: Concentrations of CSF IL-6 and IL-8 at the onset of encephalitis were significantly higher in the poor prognosis group than in the good prognosis group (median CSF IL-6, 28.27 pg/mL vs 14.32 pg/mL, P = .004; median CSF IL-8, 128.70 pg/mL vs 59.43 pg/mL, P = .043). Regarding plasma, the concentration of each cytokine at the onset of encephalitis was not significantly different between the two groups, except IL-5. However, higher levels of IL-6, IL-7, and MCP-1 and lower levels of IL-12 were observed 1 week before the development of encephalitis in patients with poor prognosis (median IL-6; 464.17 pg/mL vs 47.82 pg/mL, P = .02; median IL-12; 1.63 pg/mL vs 6.57 pg/mL, P = .03)., Conclusion: We found that one week before onset of HHV-6B encephalitis, poor prognosis patients had high plasma concentrations of IL-6, IL-7, and MCP-1 and low concentrations of IL-12. At the onset of encephalitis, high concentrations of IL-6 and IL-8 in CSF were more common in the poor prognosis group, consistent with other evidence that IL-6 can have a role in CNS disturbances. Our findings show that specific cytokine status is associated with severe brain damage in patients with HHV-6B encephalitis, demonstrate prognostic value of plasma IL-6 concentrations, and suggest evaluation of anti-cytokine therapeutics in patients with HHV-6B encephalitis., (© 2019 Wiley Periodicals, Inc.)

Mutations of the CPT2 gene cause CPT2 deficiency and affect the β-oxidation of fatty acids. This study examined the consequence of a polymorphism of rs1799822 in the CPT2 gene with respect to EV71 encephalitis in Chinese children. The study included 406 cases of both mild and severe EV71 infection diagnosed by RT-PCR, together with controls (n = 348). We used an improved multiplex ligation detection reaction technique to detect the polymorphism of rs1799822 in the CPT2 gene. The frequency of the (AG+GG) genotype and G allele in the EV71 infection group and in the severe EV71 encephalitis group was significantly lower than in the control group (p = 0.012 vs. p = 0.005, and p = 0.022 vs. p = 0.006, respectively). The frequency of the (AG+GG) genotype and G allele in the severe EV71 encephalitis group was markedly lower than in the mild EV71 encephalitis group (p = 0.045, p = 0.033). The ATP levels in the blood of the (AG+GG) genotype were distinctly higher than in the AA genotype in mild and severe EV71 encephalitis patients (P = 0.037, P = 0.040). A polymorphism of rs1799822 in the CPT2 gene is associated with the severity of EV71 encephalitis and may be one of the protection factors of severe EV71 encephalitis.

Aim of the Study: Acute central nervous system viral infections are progressive and inflammatory diseases with inflammatory cells infiltrating into the central nervous system (CNS), and thyroid hormone (TH) level is associated with the oxidative and antioxidant status. Variations in oxidative stress and antioxidant status are related to the pathogenesis of inflammatory diseases. Our study aimed to investigate the possible correlation between viral infections in CNS and TH levels of thyroid stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3)., Materials and Methods: We measured serum concentrations of TSH, fT4, and fT3 in 206 individuals, including 59 viral meningitis (VM) patients, 60 viral encephalitis (VE) patients, and 87 healthy controls., Results: Our findings showed that VE and VM patients had lower levels of fT3 and higher levels of fT4 compared with healthy controls, whether male or female. Moreover, levels of TSH and fT3 in patients with viral infections in CNS were inversely correlated with disease prognosis measured by the Glasgow Outcome Scale., Conclusions: Variations in TH level may represent the oxidative status and are surrogate biomarkers for disease prognosis of acute central nervous system viral infections.

Encephalitis causes significant global morbidity and mortality. A large number of viruses cause encephalitis, and their geographic and temporal distributions vary. In many encephalitis cases, the virus cannot be detected, even after extensive testing. This is one challenge in management of the encephalitis patient. Since cytokines are pivotal in any form of inflammation and vary according to the nature of the inflammation, we hypothesized cytokine levels would allow us to discriminate between encephalitis caused by viruses and other aetiologies. This pilot study was conducted in a tertiary care hospital in Dhaka, Bangladesh. Viral detection was performed by polymerase chain reaction using patient cerebrospinal fluid. Acute phase reactants and cytokines were detected in patient serum. Of the 29 biomarkers assessed using the Wilcoxon rank-sum test, only vascular endothelial growth factor (VEGF) was significantly higher (P = 0.0015) in viral-positive compared with virus-negative encephalitis patients. The area under the curve (AUC) for VEGF was 0.82 (95% confidence interval: 0.66-0.98). Serum VEGF may discriminate between virus-positive and virus-negative encephalitis. Further study will be needed to confirm these findings.

This study aims to evaluate the effect of peripheral blood miR-125b expression on severity and prognosis in children with viral encephalitis (VE). Children with VE (severe and mild groups) were grouped into VE group, and 40 healthy children as control group. Plasma RNA was extracted, and real-time quantitative PCR was conducted to detect miR-125b relative expression. Associations of miR-125b expression with clinical characteristics and prognosis of VE children were analyzed. Area under ROC curve (AUC) was calculated to evaluate the accuracy of the prognostic value of miR-125b. Univariate analysis and logistic regression analysis were performed to analyze risk factors of the prognoses of VE children. The plasma miR-125b expression was higher in the VE group than in the control group and higher in the severe group than the mild group. MiR-125b expression was associated with status convulsion, hemiplegia, multiple organ injuries, and stress hyperglycemia in VE children. Patients with poor prognosis exhibited higher miR-125b expression than those with good prognosis, and the rate of high miR-125b expression of the patients with poor prognosis (64.10%, 25/39) was higher than that in those with good prognosis (28.92%, 24/83). The AUC of miR-125b expression to predict prognosis of VE children was 0.833. When the cutoff value was 1.715, the diagnostic sensitivity (87.2%), specificity (71.1%), and accuracy (76.2%) were the highest. Status convulsion, stress hyperglycemia, and miR-125b were considered as risk factors for poor prognosis in VE children. Peripheral blood miR-125b expression may be correlated with the severity and prognosis of VE in children.

Objective: To compare local and systemic profiles between different disease pathologies (pneumonia and encephalitis) induced by influenza A virus (IAV)., Methods: An IAV pneumonia model was created by intranasal inoculation of C57BL/6 mice with influenza A/WSN/33 (H1N1) virus. Lung lavage and blood collection were performed on day 3 after IAV inoculation. Similarly, an IAV encephalitis mouse model was created by direct intracranial IAV inoculation. Cerebrospinal fluid (CSF) and blood collection were conducted according to the same schedule. Cytokine/chemokine profiles were produced for each collected sample. Then the data were compared visually using radar charts., Results: Serum cytokine profiles were similar in pneumonia and encephalitis models, but local responses between the bronchoalveolar lavage fluid (BALF) in the pneumonia model and CSF in the encephalitis model differed. Moreover, to varying degrees, the profiles of local cytokines/chemokines differed from those of serum in both the pneumonia and encephalitis models., Conclusion: Investigating local samples such as BALF and CSF is important for evaluating local immune responses, providing insight into pathology at the primary loci of infection. Serum data alone might be insufficient to elucidate local immune responses and might not enable clinicians to devise the most appropriate treatment strategies.

Background: Encephalitis is parenchymal brain inflammation due to infectious or immune-mediated processes. However, in 15-60% the cause remains unknown. This study aimed to determine if the cytokine/chemokine-mediated host response can distinguish infectious from immune-mediated cases, and whether this may give a clue to aetiology in those of unknown cause., Methods: We measured 38 mediators in serum and cerebrospinal fluid (CSF) of patients from the Health Protection Agency Encephalitis Study. Of serum from 78 patients, 38 had infectious, 20 immune-mediated, and 20 unknown aetiology. Of CSF from 37 patients, 20 had infectious, nine immune-mediated and eight unknown aetiology., Results: Heat-map analysis of CSF mediator interactions was different for infectious and immune-mediated cases, and that of the unknown aetiology group was similar to the infectious pattern. Higher myeloperoxidase (MPO) concentrations were found in infectious than immune-mediated cases, in serum and CSF (p = 0.01 and p = 0.006). Serum MPO was also higher in unknown than immune-mediated cases (p = 0.03). Multivariate analysis selected serum MPO; classifying 31 (91%) as infectious (p = 0.008) and 17 (85%) as unknown (p = 0.009) as opposed to immune-mediated. CSF data also selected MPO classifying 11 (85%) as infectious as opposed to immune-mediated (p = 0.036). CSF neutrophils were detected in eight (62%) infective and one (14%) immune-mediated cases (p = 0.004); CSF MPO correlated with neutrophils (p<0.0001)., Conclusions: Mediator profiles of infectious aetiology differed from immune-mediated encephalitis; and those of unknown cause were similar to infectious cases, raising the hypothesis of a possible undiagnosed infectious cause. Particularly, neutrophils and MPO merit further investigation.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) at onset manifests an early seizure (ES) usually lasting more than 30 min. Following ES, some patients exhibit almost clear consciousness with no neurological symptoms, and no MRI abnormality for a few days, which may lead to an initial misdiagnosis of prolonged febrile seizures (PFS). To allow an early diagnosis of AESD, we retrospectively analyzed clinical manifestations, laboratory data, and radiologic and EEG findings in patients with AESD (n=62) having ES of over 30 min, and ones with PFS (n=54), using logistic regression analyses. Multivariate logistic regression analysis revealed that an age below 1.5 years and a Glasgow Coma Scale score of 14 or less than 14 (Japan Coma Scale score of 1 or higher) were high risk factors of developing AESD. We proposed an AESD prediction score system consisting of consciousness level, age, duration of convulsions, enforcement of mechanical intubation, and aspartate aminotransferase, blood glucose and creatinine levels (full score: 9), the mean scores in AESD and PFS being 5.9 and 1.8, which were significantly different (p<0.001). We herein propose a scoring system for differentiating patients with AESD and PFS around the time of ES (score of 4 or more than 4 suggesting AESD), which may contribute to early therapeutic intervention and an improved neurologic outcome., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Human herpesvirus-6 (HHV-6) is the etiological agent of exanthema subitum-associated encephalopathy, which usually occurs in children younger than 3 years. Brain imaging shows various abnormalities., Patient: A previously healthy 4-year-old girl developed acute encephalopathy with clinical features consisting of fever, repetitive seizures, and a disturbance of consciousness. The patient did not show skin rash suggestive of exanthema subitum during the course of her illness. The primary HHV-6 infection was diagnosed based on the absence of IgG against HHV-6 and identification of the virus DNA in the acute phase serum and a significant increase of the anti-HHV-6 IgG titers in the convalescent phase sera. Diffusion-weighted images showed transient high signal intensity in the bilateral periventricular white matter and splenium of the corpus callosum and in the gray matter structures such as the bilateral basal ganglia and thalami. Upon therapy with steroid and γ-globulin, the patient recovered without any neurological deficits., Conclusion: Primary HHV-6 infection can cause acute encephalopathy without exanthema subitum. The etiological diagnosis is possible only by examining the blood and cerebrospinal fluid, when the patient shows no skin rash. This condition should be included in the differential diagnosis of acute encephalopathy even in patients older than 3 years., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: The sudden death of 10 children in a tribal village of Kandhamal district, Odisha in eastern India led to this investigation., Methods: We conducted a door-to-door survey to identify cases. Antibodies for Chandipura, Japanese encephalitis, dengue, chikungunya and West Nile viruses were tested by ELISA in probable cases. Chandipura virus RNA was tested from both human blood samples and sand flies by reverse transcriptase polymerase chain reaction. We conducted vector surveys in domestic and peridomestic areas, and collected sand flies., Results: Entomological investigations revealed the presence of Phlebotomus argentipes and Sergentomiya sp. Thirty-five patients presented with fever, 12 of them had altered sensorium including 4 who had convulsions. The blood samples of 21 patients were tested; four samples revealed Chandipura virusspecific IgM antibody., Conclusion: Chandipura virus infection causing encephalitis affected this tribal population in eastern India at 1212 m above sea level., (Copyright 2015, NMJI.)

Acute virus-associated encephalopathy induces seizures. Serum N-terminal pro-B-type natriuretic peptide (NTproBNP) levels are elevated following febrile and afebrile seizures. However, the role of NTproBNP in acute virus-associated encephalopathy pathology is unknown. We enrolled 10 patients with acute virus-associated encephalopathy and convulsions (E group: 7 boys, 3 girls; median age, 3.10 ± 1.92 years) and 130 patients with febrile seizure (FS group: 80 boys, 50 girls; median age, 3.23 ± 2.44 years). The E group had significantly higher NTproBNP levels (345 ± 141 pg/mL) compared with the FS group (166 ± 228 pg/mL) (P < .0005). Furthermore, subjects with prolonged seizure within the E group had significantly higher NTproBNP levels (303 ± 107 pg/mL) compared with subjects with prolonged seizure within the FS group (134 ± 100 pg/mL) (P < .005). Our findings suggest that serum NTproBNP levels are increased during the acute phase of acute virus-associated encephalopathy associated with convulsion., (© The Author(s) 2014.)

We examined serum levels of various cytokines, chemokines, growth factors, and adhesion molecules in patients with uncomplicated influenza (n=20) and influenza virus-associated encephalopathy (IE) (n=18) to understand the underlying mechanism of IE. We found that IL-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, G-CSF, GM-CSF, TNF-α, TIMP-1, MMP-9, sE-selectin, and neutrophil elastase were elevated significantly in sera from patients with uncomplicated influenza and those with IE, compared with normal controls (n=20). Of note, neutrophil elastase, sE-selectin, IL-8, and IL-13 were elevated significantly in IE as compared with uncomplicated influenza. In the present study, for the first time, we found that serum levels of neutrophil elastase were increased in patients with IE compared with uncomplicated influenza, which suggested that cerebral endothelial damage in the development of IE was mediated by neutrophil elastase. The present study implied that anti-elastase agents are possibly an effective therapeutic protocol for IE, but this needs further elucidation., (Copyright © 2015 Elsevier B.V. All rights reserved.)

This study reports on vascular endothelial growth factor (VEGF) in dengue patients with neurological manifestations. Their bleeding diathesis, hypotension, edema, flushing, and hepatosplenomegaly were noted. Complete blood counts, serum chemistry, coagulation profile, liver and kidney function tests, creatine kinase (CK), and MRI in encephalopathic patients were carried out. Serum VEGF was estimated by ELISA in 21 dengue patients and 14 controls. Twelve patients had dengue fever (DF), eight dengue hemorrhagic fever (DHF), and one dengue shock syndrome (DSS). Fifteen patients had neurological manifestation, 12 had muscle involvement (raised CK with or without weakness), and 3 had encephalopathy. The VEGF level in dengue patients was 50.0 ± 56.1 pg/mL and in the controls, 60.6 ± 20.3 pg/mL. The VEGF level neither correlated with the severity nor with the neurological involvement. Thrombocytopenia, however, correlated with the severity of dengue and neurological manifestations. The VEGF level is not related to the severity of dengue and neurological syndrome.

We encountered a 3.5-year-old girl with acute encephalopathy associated with human metapneumovirus (hMPV) infection. She had pyrexia and status epilepticus, followed by a coma. Cerebrospinal fluid analysis showed no pleocytosis or elevation of protein levels. hMPV RNA was detected in tracheal aspirate. Acute encephalopathy in the patient was probably related to the hMPV infection. Serum levels of interleukin-6 and matrix metalloproteinase-9 were elevated on admission, and these factors were presumed to be related to acute encephalopathy, associated with her viral infection, or due to status epilepticus. She was treated with dexamethasone pulse therapy, intravenous immunoglobulin, and continuous thiopental infusion. She recovered without neurological sequelae.

Background: An epidemic of measles broke out in France in 2008. We designed a retrospective study focusing on adults hospitalized for measles in 2010/2011., Methods: A case was any patient aged more than 15 years, hospitalized (September 2010 to September 2011) with a typical rash or a biological diagnosis. Data was collected with standardized questionnaires in participating hospitals., Results: Four hundred and sixty cases were reported: sex-ratio (M/F) = 0.93, median age 26 years (σ = 8.8). Twenty-nine cases were severe (6.5%), 27 of which hospitalized in an ICU. Three hundred and twelve (68%) cases had elevated serum transaminases (EST), 155 (34%) cases had pneumonia, 34 (7%) cases had elevated serum creatinine (ESC), four (0.9%) cases had elevated serum amylase and lipase (ESAL), and three (0.7%) cases had neurological symptoms. One hundred and four (23%) patients presented simultaneously with EST and pneumonia. One patient presenting with severe pneumonia died (0.2%). One hundred and ten (24%) patients received antibiotics during a median seven days., Conclusion: Measles can present as various syndromes in adults and be responsible for a high burden during outbreaks. The immediate outcome is favorable in most patients. Long-term outcome needs further investigations to identify possible late complications., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Introduction: Acute bacterial meningitis (ABM) is a life-threatening infectious disease requiring prompt antimicrobial therapy. ABM must be differentiated from systemic disorders with CNS manifestations that may mimic ABM. ABM should also be differentiated from acute meningoencephalitis (AME) and acute viral encephalitis (AVE). Nonviral causes of AME are treatable. Among the causes of AVE, Herpes simplex encephalitis (HSE) is treatable. This article reviews the clinical diagnostic approach to ABM, AME and AVE., Areas Covered: The differential diagnostic (DDx) approach to ABM, AME and AVE is based on clinical and laboratory findings. A specific pathogen diagnosis is based on serum/cerebrospinal fluid (CSF) tests. This overview presents the diagnostic approach to ABM, AME and AVE in normal hosts (excluding brain abscesses and chronic CNS infections)., Expert Opinion: It is time critical to diagnose ABM and begin empiric antimicrobial therapy based on the known/most likely pathogen. The diagnosis of ABM depends on clinical features and the CSF profile. The CSF Gram stain and CSF lactic acid (LA) levels provide the most rapid, reliable and cost-effective tests to diagnose ABM. CSF LA levels are also the best way to diagnose partially treated acute bacterial meningitis (PTABM). In those cases of AME/AVE due to viruses with a CSF profile mimicking ABM, for example, HSE, unelevated CSF LA levels rapidly/reliably rule out ABM as a diagnostic possibility.

Background: Enterovirus 71 (EV71) causes large outbreaks of hand, foot, and mouth disease (HFMD), with severe neurological complications and cardio-respiratory compromise, but the pathogenesis is poorly understood., Methods: We measured levels of 30 chemokines and cytokines in serum and cerebrospinal fluid (CSF) samples from Malaysian children hospitalized with EV71 infection (n = 88), comprising uncomplicated HFMD (n = 47), meningitis (n = 8), acute flaccid paralysis (n = 1), encephalitis (n = 21), and encephalitis with cardiorespiratory compromise (n = 11). Four of the latter patients died., Results: Both pro-inflammatory and anti-inflammatory mediator levels were elevated, with different patterns of mediator abundance in the CSF and vascular compartments. Serum concentrations of interleukin 1β (IL-1β), interleukin 1 receptor antagonist (IL-1Ra), and granulocyte colony-stimulating factor (G-CSF) were raised significantly in patients who developed cardio-respiratory compromise (P = .013, P = .004, and P < .001, respectively). Serum IL-1Ra and G-CSF levels were also significantly elevated in patients who died, with a serum G-CSF to interleukin 5 ratio of >100 at admission being the most accurate prognostic marker for death (P < .001; accuracy, 85.5%; sensitivity, 100%; specificity, 84.7%)., Conclusions: Given that IL-1β has a negative inotropic action on the heart, and that both its natural antagonist, IL-1Ra, and G-CSF are being assessed as treatments for acute cardiac impairment, the findings suggest we have identified functional markers of EV71-related cardiac dysfunction and potential treatment options.

Objective: To study serum ferritin and neuron-specific enolase (NSE) levels in children with hand-foot-mouth disease (HFMD) complicated by acute viral encephalitis and their clinical significance., Methods: Serum levels of ferritin and NSE were measured using ELISA and electrochemical luminescence in 20 children with HFMD complicated by viral encephalitis (encephalitis group), 20 children with HFMD only (simple HFMD group) and 20 healthy children (control group)., Results: Serum levels of ferritin in the encephalitis group (212 ± 71 μg/L) were significantly higher than in the simple HFMD group (85 ± 18 μg/L) and control group (70 ± 15 μg/L) (P<0.01). Serum levels of NSE in the encephalitis group (8.6 ± 2.6 μg/L) were also significantly higher than in the simple HFMD group (6.0 ± 1.3 μg/L) and control group (5.6 ± 1.8 μg/L) (P<0.01). Significantly decreased serum ferritin (126 ± 37 μg/L) and NSE levels (6.8 ± 1.9 μg/L) were found in the encephalitis group (P<0.01) after treatment., Conclusions: Serum levels of ferritin and NSE in children with HFMD complicated by acute viral encephalitis increase, suggesting that serum ferritin and NSE measurement is useful in the early diagnosis of HFMD complicated by acute viral encephalitis.

Aims: The pathogenesis of human/simian immunodeficiency virus encephalitis (HIVE/SIVE) remains incompletely understood, but is associated with alterations in the blood-brain barrier. At present, it is not possible to easily determine if an individual has HIVE/SIVE before post mortem examination., Methods: We have examined serum levels of the astroglial protein S100β in SIV-infected macaques and show that it can be used to determine which animals have SIVE. We also checked for correlations with inflammatory markers such as CCL2/MCP-1, IL-6 and C-reactive protein., Results: We found that increased S100β protein in serum correlated with decreased expression of the tight junction protein zonula occludens-1 on brain microvessels. Furthermore, the decrease in zonula occludens-1 expression was spatially related to SIVE lesions and perivascular deposition of plasma fibrinogen. There was no correlation between encephalitis and plasma levels of IL-6, MCP-1/CCL2 or C-reactive protein., Conclusions: Together, these data indicate that SIVE lesions are associated with vascular leakage that can be determined by S100β protein in the periphery. The ability to simply monitor the presence of SIVE will greatly facilitate studies of the neuropathogenesis of AIDS., (© 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.)

Despite the decrease in Reye syndrome after the discontinuation of aspirin, acute encephalopathy (non-Reye syndrome type) has been continually reported in Japan. Recent studies suggested that the thermolabile phenotype of carnitine palmitoyltransferase II (CPT II) variation [F352C] was closely related to the pathomechanism of influenza-associated encephalopathy (IAE) in Japanese, causing mitochondrial ATP utilization failure during periods of high fever, resulting in brain edema. So, we analyzed CPT II polymorphism and peripheral blood ATP levels as a signal of "energy crisis" in 12 and 10 patients with acute encephalopathy, respectively. Out of the 12 patients with acute encephalopathy, six showed thermolabile CPT II variants [F352C], and of these six, two patients died in spite of intensive care. In contrast, the remaining six patients with no thermolabile CPT II variant [F352C] showed a relatively mild clinical course. Blood ATP levels of the 10 patients in the acute phase of encephalopathy were significantly lower than those during the convalescent phase and also those of patients with febrile seizure status. Our data suggest that the thermolabile F352C CPT II variant, found only in Japanese, might be one of the predisposing factors to trigger the pathomechanism of acute encephalopathy in the Japanese population, and that it is causally related to the severity of disease. The decreased blood ATP level seems to reflect systemic mitochondrial dysfunction including the blood brain barrier during the acute phase of encephalopathy., (Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Three children developed severe encephalopathy associated with human herpesvirus 6 infection. Magnetic resonance imaging of the brain showed either basal ganglia involvement or diffusion abnormalities in the cerebral white matter. Coagulopathy with hypercytokinemia was observed in 2 patients. One demonstrated thermolabile variation in carnitine palmitoyltransferase 2. These results suggest a heterogeneous pathogenic mechanism in encephalopathy associated with human herpesvirus 6 infection.

Pandemic H1N1 influenza (pH1N1) has been associated with encephalopathy, but the role of adaptive immunity in disease pathogenesis remains unclear. A child presented with seizures 5 days after onset of respiratory symptoms with pH1N1, with no detectable virus in cerebrospinal fluid. The authors compared her serum cytokines and pH1N1 antibody titers to those of 22 children with pH1N1, seasonal influenza, or other respiratory viral infections. They also compared her cerebrospinal fluid biomarkers to those of 20 children with confirmed or probable central nervous system infection or viral infection without central nervous system involvement. Her serum antibody titers were several-fold higher, and levels of proinflammatory cytokines in cerebrospinal fluid and serum were lower than those of controls. Antibody titers in cerebrospinal fluid were undetectable. The delayed onset of neurologic manifestations, normal cytokine levels in serum and cerebrospinal fluid, markedly elevated hemagglutinating and neutralizing antibody titers, and absence of virus and antibodies in cerebrospinal fluid raise the possibility of a post-infectious autoimmune-mediated process.

Objective: To study the value of serum Cystatin C (Cyst C) in the evaluation of glomerular filtration function in children with viral encephalitis., Methods: Serum levels of Cyst C, urea nitrogen (BUN) and creatinine (Cr) were measured in 92 children with viral encephalitis and in 50 healthy children as a control group. According to glomerular filtration rate (GFR), the encephalitis group was subdivided into normal renal function, renal insufficiency in the compensatory or decompensatory stage, and renal failure /end-stage groups., Results: Serum levels of Cyst C, BUN and Cr in the encephalitis group increased and GFR decreased significantly compared with those in the control group (P<0.01). With the decline of renal function, GFR decreased and serum levels of Cyst C, BUN and Cr increased gradually. Serum levels of Cyst C and GFR were significantly different among the encephaitis subgroups (P<0.01). For serum levels of BUN and Cr, there were significant differences among the subgroups except between the normal renal function and the compensatory renal insufficiency groups. Serum Cyst C level was positively correlated with serum BUN and Cr levels, and negatively correlated with GFR., Conclusions: The children with viral encephalitis have different degrees of renal impairments. Cyst C appears to be superior to BUN and Cr as a marker for the evaluation of glomerular filtration function. Measurement of serum Cyst C levels is very valuable in renal function monitoring in children with viral encephalitis.

Norovirus causes acute gastroenteritis in all age groups. Afebrile convulsion is an occasional neurologic complication in norovirus infection, but encephalitis is rare. We report the case of a previously healthy 15-month-old girl with norovirus encephalopathy who had a poor neurologic outcome. Norovirus (genogroup II) was detected in plasma and stool by real-time reverse transcription polymerase chain reaction, but the cerebrospinal fluid showed negative result for genome. Elevated concentrations of cerebrospinal fluid interleukin-6, interleukin-10, interferon-γ, and tumor necrosis factor-α were observed on the third day of illness. The encephalopathy in our patient may be related to hypercytokinemia rather than to direct viral invasion.

Objective: To understand the impact of surveillance system of viral encephalitis during 2005-2007 in Baoji city of Shaanxi province, to find epidemiological characteristic, control strategies and measurement to Japanese Encephalitis (JE)., Methods: Establishing the monitoring system of viral encephalitis, special monitoring of viral encephalitis cases was analyzed statistically by Epi data and Excel software., Results: The seasonal trend of viral encephalitis was identical with that of JE, but the age of the incidence was different. Rate of missed diagnosis was 23.76%, squcalac cases was 5.5 times of the regular reported cases. The actual mortality was 7 times of the reported cases after 90 days and 180 days follow-up visit., Conclusions: Viral encephalitis monitoring and JE follow-up should be conducted in epidemic season so as to improve the accuracy of report and diagnosis of JE.

Investigating, predicting, diagnosing, and treating HIV-1-associated neurocognitive disorder (HAND) has been hindered by the lack of disease-related molecular markers. In this study, plasma from rhesus monkeys (n = 6), before and after infection with simian immunodeficiency virus (SIV), was profiled to obtain differential fingerprints in protein expression during SIV-induced central nervous system (CNS) disease. A quantitative proteomic analysis was performed by means of isobaric tag for relative and absolute quantification (iTRAQ) labeling, using multidimensional liquid chromatography tandem mass spectrometry (LC-MS/MS) run on a linear ion trap mass spectrometer in an integrated mode comprising pulsed-Q-dissociation (PQD) and CID. Among a panel of proteins showing differential expression following SIV infection, we identified afamin, a member of the albumin superfamily, to be significantly down regulated after infection. Validation by Western blot confirmed this observation and, given its potential implication in neuroprotection by transport of alpha-tocopherol (alphaTocH), provides new avenues into further understanding HIV induced CNS disease. iTRAQ-based LC-MS/MS provides a valuable platform for plasma protein profiling and has important implications in identifying molecular markers relevant for the pathogenesis of neurodegenerative diseases. Using such an approach, we show its successful application in identifying differential fingerprints in SIV/HIV induced CNS disease.

Objective: To investigate the infection of Borna disease virus (BDV) in unidentified viral encephalitis patients in Ningxia in order to explore if the nucleotide sequence and amino acid sequence in BDV p24 were homophylic with the overseas standard strain. We also intended to investigate the correlation between BDV infection and the unidentified viral encephalitis patients from Ningxia to lay an experimental basis for etiological diagnosis, prevention and treatment on certain human neuropsychiatric disorders., Methods: BDV p24 gene fragment was detected by nested reverse transcriptase polymerase chain reaction with fluorescence quantitative PCR (FQ-nRT-PCR) in peripheral blood mononuclear cells (PBMCs). Samples were from 59 unidentified viral encephalitis patients and 60 normal controls. For those positive products, gene sequence and amino acid sequence were then analyzed by BLAST and DNAsist 5.0., Results: The positive rate of the BDV p24 gene fragment in PBMCs from the unidentified viral encephalitis (10.17%) was significantly higher than from the controls (0%) (P < 0.05). Data from the gene sequence on those positive products showed BDV p24 fragment in the patients with unidentified viral encephalitis from Ningxia was homophylic with strain H3915 detected from ill horses (97.67%), as well as with the strain H1766 (96.51%) and strain V (95.35%). However, their amino acid sequences remained the same., Conclusion: BDV infection might probably have existed in the unidentified viral encephalitis patients of Ningxia. The gene sequence seemed to be homophylic with that of standard strain H1766 and strain V, especially with strain H3915.

Background: Dengue infection is caused by a flavivirus, with 4 virus serotypes (types 1 to 4). The serotypes 2 and 3 represent the principal agents related to nervous system involvement. Neurologic involvement occurs in 4%-5% of dengue infection cases. The major mechanisms of the disease may be related to direct viral infection or postinfectious autoimmune process. The detection of intrathecal synthesis of specific antibodies has been used to support neurologic diagnosis as a proof of local reaction. It may be quantitatively calculated by the specific antibody index., Objectives: To determine if patients with neurologic manifestations associated with dengue produce specific antibodies in the CNS and to determine the antibodies' clinical and pathophysiologic relevance., Methods: CSF and serum were evaluated for dengue immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies by ELISA and for intrathecal synthesis of IgG antibodies to the dengue virus. Subjects included 10 patients IgM seropositive for dengue virus diagnosed with myelitis, encephalitis, optic neuromyelitis, or Guillain-Barré syndrome., Results: All patients had IgG and IgM antibodies to dengue virus in their sera; 7 were IgM positive and 9 were IgG positive for dengue virus in CSF. Only the 3 patients with myelitis had intrathecal synthesis of specific IgG antibodies., Conclusions: Intrathecal synthesis of antibodies to dengue virus occurs in the CNS. It may be used as a marker of myelitis associated with dengue, and it seems to be related to the pathogenesis of spinal cord disease due to direct viral invasion.

Objective: To understand the viral etiology of viral encephalitis in China by detecting IgM antibody and viral RNA in the clinical samples of patients from some provinces of China by enzyme-linked immunosorbent assay and polymerase chain reaction., Method: Serum and cerebrospinal fluid samples of 771 patients with viral encephalitis or meningitis were collected from six provinces of China and were stored at -20 degrees C or -70 degrees C. Enzyme-linked immunosorbent assays were used for detection of IgM antibody to Japanese encephalitis virus, coxsackievirus, echovirus, herpes simplex virus, measles virus, varicella-zoster virus, mumps virus, cytomegalovirus and Epstein-Barr virus. Polymerase chain reaction was applied for the detection of viral RNA of enteroviruses and seadornavirus., Results: IgM antibody was detected in 567 of 771 (73.5%) cases. The most common pathogen was Japanese encephalitis virus (47.0%, 362/771), followed by mumps virus (10.6%, 82/771), enteroviruses (8.8%, 68/771), herpes simplex virus (5.7%, 44/771), measles virus (0.4%, 3/771), varicella-zoster virus (0.4%, 3/771), Epstein-Barr virus (0.4%, 3/771), and cytomegalovirus (0.3%, 2/771). Enterovirus was positive in 8 cases, seadornavirus was negative in all the cases by PCR., Conclusion: According to the study, Japanese encephalitis was the most important encephalitis in China. Mumps virus was another important pathogen. Enteroviruses and herpes simplex virus were also important pathogens.

Background: A hospital-based prospective cross-sectional study was conducted in children aged 1 month-14 years to identify the proportion of viral encephalitis due to Japanese encephalitis (JE) and compare the clinico-laboratory profile and outcome of JE with that of other viral encephalitis (non-JE)., Methods: All probable cases of viral encephalitis on clinical and laboratory evaluation were confirmed as JE on anti-JE IgM in cerebrospinal fluid (CSF) and/or serum. Patients not having anti-JE IgM in CSF and/or serum were diagnosed as having non-JE., Results: Of 94 cases, 58 were JE and 36 non-JE. Although practice of rearing pigs at home was associated with JE (P = 0.0001), significantly higher serum creatinine, protein, aspartate aminotransferase and CSF protein levels were observed in non-JE. Longer duration of fever was associated with complete recovery in JE whereas shorter duration of fever was associated with recovery in non-JE. Risk of neurological sequelae (P = 0.01), especially hemiparesis (P = 0.03) was significantly more in JE. Sequelae were observed at 6 weeks follow up in 18.8% of JE and 13.9% of non-JE., Conclusion: JE was the most common cause of viral encephalitis in eastern Nepal and should be suspected in encephalitic patients having pig rearing at home and neurological sequelae. Although duration of hospitalization and complication were higher in JE, final outcome was similar to non-JE. Longer duration of fever in JE and shorter duration of fever in non-JE correlated with recovery, while altered sensorium and focal neurological deficit were independent predictors of sequelae at 6 weeks only in JE and not in non-JE.

Changes in the permeability of the blood-brain barrier (BBB) were evaluated in two mouse models of viral encephalitis. The ability of sodium fluorescein (NaFl) to cross the BBB from the serum into the central nervous system was assayed in animals inoculated with virulent strains of either Banzi or Semliki Forest viruses. To test the hypothesis that increases in BBB permeability were associated with poor disease outcome subsequent experiments measured BBB permeability in conjunction with treatment with the interferon inducer Ampligen (poly I:poly C(12)U). A single intraperitoneal injection of Ampligen (1 mg/kg) administered either 24 h or 4-6 h before, but not 24 h after, virus inoculation with Banzi virus provided significant improvements in survival, viral brain titers, weight change and BBB permeability. In comparison, a similar treatment with Ampligen administered either 24 h or 4-6 h before inoculation with Semliki Forest virus was able to significantly improve weight change, and BBB permeability, but only animals receiving Ampligen 4-6 h pre-virus showed a significantly improved mortality. In general, it was found that evaluation of BBB permeability was a more sensitive indicator of disease outcome and the antiviral efficacy Ampligen than either weight change or brain viral titers.

Cells of the monocyte/macrophage lineage have been shown to be the principal targets for productive HIV-1 replication within the CNS. In addition, HIV-1-associated dementia (HAD) has been shown to correlate with macrophage abundance in the brain. Although increased entry of monocytes into the brain is thought to initiate this process, mechanisms that prevent macrophage egress from the brain and means that prevent macrophage death may also contribute to cell accumulation. We hypothesized that osteopontin (OPN) was involved in the accumulation of macrophages in the brain in neuroAIDS. Using in vitro model systems, we have demonstrated the role of OPN in two distinct aspects of macrophage accumulation: prevention from recirculation and protection from apoptosis. In these unique mechanisms, OPN would aid in macrophage survival and accumulation in the brain, the pathological substrate of HAD.

We investigated an outbreak of encephalitis in Tangail District, Bangladesh. We defined case-patients as persons from the outbreak area in whom fever developed with new onset of seizures or altered mental status from December 15, 2004, through January 31, 2005. Twelve persons met the definition; 11 (92%) died. Serum specimens were available from 3; 2 had immunoglobulin M antibodies against Nipah virus by capture enzyme immunoassay. We enrolled 11 case-patients and 33 neighborhood controls in a case-control study. The only exposure significantly associated with illness was drinking raw date palm sap (64% among case-patients vs. 18% among controls, odds ratio [OR] 7.9, p = 0.01). Fruit bats (Pteropus giganteus) are a nuisance to date palm sap collectors because the bats drink from the clay pots used to collect the sap at night. This investigation suggests that Nipah virus was transmitted from P. giganteus to persons through drinking fresh date palm sap.

Human Cytomegalovirus (HCVM) encodes several G-protein coupled receptors, such as US28 protein. We determined the US28 gene sequence from clinical isolates obtained from 17 Human Immunodeficiency Virus (HIV)-infected patients with HCMV infection. Two types of clinical specimens were collected: peripheral blood leucocytes (PBLs) from 12 patients with HCMV-positive viremia and cerebro-spinal fluids (CSF) from five patients with HCMV-encephalitis. Comparison of US28 nucleotide sequences between clinical specimens and several HCMV reference strains showed that mutations were clustered at both ends of the gene. The mutations observed at the C-terminus were observed at some sequences whereas the mutations observed at the N-terminus lead us to define five patterns of mutations. These patterns were equally distributed among isolates obtained from CSF or PBLs of HIV-infected patients. For each clinical isolate, the gB genotype was determined. There was no genetic association between gB genotype and US28 patterns. The comparison of the results of the present study and those published from sequences obtained from children with HCMV congenital disease (Arav-Boger, 2002) demonstrates that two motifs appear especifically either in US28 protein sequences obtained from HIV-positive patients (motif 4) or in US28 protein sequences obtained from patients with congenital HCMV infection (motif 5/genotype B). The appearance of these patterns of mutations in other clinical context needs to be studied.

Norovirus is a common cause of gastroenteritis. We describe the case of a 23-month-old girl with encephalopathy possibly associated with norovirus infection. The viral genome was detected in stool, serum and cerebrospinal fluid (CSF) by reverse transcription polymerase chain reaction. This is the first report of encephalopathy potentially caused by norovirus as indicated by the presence of the virus genome in CSF.

Many neurologic manifestations of Epstein-Barr virus (EBV) infection have been documented, including encephalitis, aseptic meningitis, transverse myelitis, and Guillain-Barré syndrome. These manifestations can occur alone or coincidentally with the clinical picture of infectious mononucleosis. Since 1994, The Hospital for Sick Children has maintained a prospective registry of all children admitted with acute encephalitis. This report summarizes all cases of Epstein-Barr virus-associated encephalitis compiled from 1994 to 2003. Twenty-one (6%) of 216 children, median age 13 years (range 3-17 years), in the Encephalitis Registry were identified as having evidence of Epstein-Barr virus infection. This evidence consisted of convincing Epstein-Barr virus serology and/or positive cerebrospinal fluid polymerase chain reaction (PCR). One patient had symptoms of classic infectious mononucleosis; all others had a nonspecific prodrome, including fever (n = 17; 81%) and headache (n = 14; 66%). Slightly less than half (n = 10; 48%) had seizures and often had electroencephalograms showing a slow background (n = 12; 57%). Many demonstrated cerebrospinal fluid pleocytosis (n = 17; 81%), and 71% (n = 15) had abnormal magnetic resonance imaging findings. Two patients died, 2 suffered mild deficits, and 16 were neurologically normal at follow-up. Most patients with Epstein-Barr virus encephalitis do not show typical symptoms of infectious mononucleosis. Establishing a diagnosis of Epstein-Barr virus encephalitis can be difficult, and, consequently, a combination of serologic and molecular techniques should be used when investigating a child with acute encephalitis. Most children make full recoveries, but residual neurologic sequelae and even death can and do occur.

The aim of this study was to assess the validity of serum and CSF oxidative status of patients with IE in their initial stage through the d-ROM (Diacron-Reactive Oxygen Metabolites, Italy) test, compared to those with other neurological diseases. The study was conducted on the following four groups: (1) influenza virus-associated encephalopathy (IE, n = 8), including four patients showing neurological sequelae or mortal; (2) influenza virus-associated febrile seizures (IFS, n = 11); (3) febrile convulsion (FC, n = 10): (4) enterovirus-associated encephalopathy (EE, n = 4), including one patient with neurological sequelae. The CSF d-ROM levels in the IE group were significantly higher than those in the IFS and the FC groups but not in the EE group. In addition, general laboratory findings such as leukocytes, platelets, C-reactive protein, aspartate aminotransferase, creatinine, creatinine kinase and LDH, including interleukin-6 (IL-6), were analyzed in each group. The CSF d-ROM levels in the IE group were significantly higher than those in the IFS and FC groups but not in the EE group. As for the serum d-ROM levels and general laboratory findings, with the exception of CSF IL-6 levels in IE, no significant differences were detected compared with the other groups. In patients with IE, the CSF d-ROM levels could be a valid predictive biomarker of the severity, and oxidative stress may be related to the pathogenesis of IE.

Cytomegalovirus encephalitis occurs rarely in transplant recipients. We describe a patient with cytomegalovirus ventriculoencephalitis who had a very high CSF viral load but a low peripheral blood viral load. No resistance mutations were present in cerebrospinal fluid viral DNA, whereas DNA from blood showed a resistance mutation in the UL54 gene but not in the UL97 gene. Viral replication was intense in the brain ependyma and periventricular areas without evidence of peripheral cytomegalovirus disease. The data provide evidence for compartmentalization of cytomegalovirus infection. Levels of ganciclovir and foscarnet in the cerebrospinal fluid may be inadequate for treatment, even for some drug-susceptible strains, and, together with periventricular replication, may explain the disparity between cerebrospinal fluid viral load and peripheral blood viral load.