Severity Of Encephalitis Research Articles

Automated diagnosis of encephalitis in pediatric patients using EEG rhythms and slow biphasic complexes.

Slow biphasic complexes (SBC) have been identified in the EEG of patients suffering for inflammatory brain diseases. Their amplitude, location and frequency of appearance were found to correlate with the severity of encephalitis. Other characteristics of SBCs and of EEG traces of patients could reflect the grade of pathology. Here, EEG rhythms are investigated together with SBCs for a better characterization of encephalitis. EEGs have been acquired from pediatric patients: ten controls and ten encephalitic patients. They were split by neurologists into five classes of different severity of the pathology. The relative power of EEG rhythms was found to change significantly in EEGs labeled with different severity scores. Moreover, a significant variation was found in the last seconds before the appearance of an SBC. This information and quantitative indexes characterizing the SBCs were used to build a binary classification decision tree able to identify the classes of severity. True classification rate of the best model was 76.1% (73.5% with leave-one-out test). Moreover, the classification errors were among classes with similar severity scores (precision higher than 80% was achieved considering three instead of five classes). Our classification method may be a promising supporting tool for clinicians to diagnose, assess and make the follow-up of patients with encephalitis.

A proline insertion-deletion in the spike glycoprotein fusion peptide of mouse hepatitis virus strongly alters neuropathology

Fusion peptides (FPs) in spike proteins are key players mediating early events in cell-to-cell fusion, vital for intercellular viral spread. A proline residue located at the central FP region has often been suggested to have a distinctive role in this fusion event. The spike glycoprotein from strain RSA59 (PP) of mouse hepatitis virus (MHV) contains two central, consecutive prolines in the FP. Here, we report that deletion of one of these proline residues, resulting in RSA59 (P), significantly affected neural cell syncytia formation and viral titers postinfection in vitro Transcranial inoculation of C57Bl/6 mice with RSA59 (PP) or RSA59 (P) yielded similar degrees of necrotizing hepatitis and meningitis, but only RSA59 (PP) produced widespread encephalitis that extended deeply into the brain parenchyma. By day 6 postinfection, both virus variants were mostly cleared from the brain. Interestingly, inoculation with the RSA59 (P)-carrying MHV significantly reduced demyelination at the chronic stage. We also found that the presence of two consecutive prolines in FP promotes a more ordered, compact, and rigid structure in the spike protein. These effects on FP structure were due to proline's unique stereochemical properties intrinsic to its secondary amino acid structure, revealed by molecular dynamics and NMR experiments. We therefore propose that the differences in the severity of encephalitis and demyelination between RSA59 (PP) and RSA59 (P) arise from the presence or absence, respectively, of the two consecutive prolines in FP. Our studies define a structural determinant of MHV entry in the brain parenchyma important for altered neuropathogenesis.

Changes of Caveolin-1, IL-1β, VEGF in cerebrospinal fluid of children with viral encephalitis and their clinical significance

Objective To detect the disparity of three biological molecules Caveolin-1,IL-1β,VEGF in cerebrospinal fluid of children with viral encephalitis at the different stages; to explore the role of Caveolin-1,IL-1β,VEGF in the pathogenesis of viral encephalitis;and to evaluate their clinical significance in assessing the severity and prognosis of viral encephalitis.Methods We recruited 65 inpatients children with viral encephalitis in the Second Neurology Department of Hunan Children's Hospital from July 2011 to July 2012.Subjects were divided into 2 groups:54 cases of acute phase and 11 cases of recovery phase.According to the clinical manifestations,they were re-divided into 40 patients with mild viral encephalitis and 25 cases of severe viral encephalitis.Twenty healthy age matched controls (10 cases of epilepsy and 10 cases of congenital abnormality) were also taken for the study.Cerebrospinal fluid exam,EEG,head MRI and other tests were performed in all patients.Caveolin-1,IL-1β and VEGF levels in cerebrospinal fluid of 65 children with viral encephalitis and 20 age-matched controls were measured using ELISA.Results Cerebrospinal fluid Caveolin-1,IL-1β,VEGF levels in the acute phase of viral encephalitis were (49.209 ± 22.320) pg/ml,(16.923 ± 6.823) ng/ml,(44.342 ± 19.264) ng/ml respectively,and (33.253 ± 20.349)pg/ml,(11.724 ± 3.009)ng/ml,(30.312 ± 18.147) ng/ml in recovery phase,which were significantly higher than those of controls (P ＜0.01).The difference was statistically significant between acute phase and recovery phase (P ＜ 0.05).Acute viral encephalitis patients had higher Caveolin-l,IL-1β,VEGF levels than the epilepsy group,and the difference was statistically significant (P ＜ 0.05).In viral encephalitis group,children with cerebrospinal fluid protein content (0.5 ～ 1.0 g / L) had higher of Caveolin-1,IL-1β and VEGF levels as compared with those with cerebrospinal fluid protein content ≤ 0.5 g/L,and the difference was statistically significant (P ＜ 0.01).Cerebrospinal fluid Caveolin-1,IL-1 β and VEGF showed no significant difference among children with different severity of encephalitis,different levels of frequent seizures,different degrees EEG changes (P ＞ 0.05).But in the patients with severe head MRI changes,cerebrospinal fluid Caveolin-1,IL-1β,VEGF levels increased significantly (P ＜ 0.05).Conclusions Caveolin-1,IL-1β and VEGF may participate in the pathogenesis of viral encephalitis.Detection of these parameters may be helpful to the evaluation of the severity and prognosis of viral encephalitis. Key words: Viral encephalitis; Caveolin-1 ; Interleukin-1β; Vascular endothelial growth factor

SIV/macaque model of HIV infection in cocaine users: minimal effects of cocaine on behavior, virus replication, and CNS inflammation.

Studies of the effects of drugs of abuse on HIV immune status, disease progression, and neuroAIDS have produced conflicting data and have not definitively shown whether this combination promotes cognitive impairment or disease progression. Using a consistent SIV-macaque model, we investigated the effects of cocaine on behavior, virologic parameters, and CNS inflammation. Macaques received either vehicle or chronic administration of behaviorally active doses of cocaine (1.7 or 3.2mg/kg/day). Chronic cocaine administration reduced CD8+ T cell counts during acute and late stage infection but had no effect on CD4+ T cell counts. Low-dose cocaine-treated animals had lower CSF vRNA levels late in infection, but cocaine did not alter plasma viral load or vRNA or protein in brain. There were no differences in CSF CCL-2 or interleukin (IL)-6 levels or severity of encephalitis in cocaine-treated as compared to vehicle-treated macaques. There were no differences in brain inflammation or neurodegeneration markers, as determined by interferon (IFN)-β, MxA, CCL2, IL-6, TNFα, IFNγ, and indolamine 2,3-deoxygenase mRNA levels. APP levels also were not altered. The executive function of inhibitory control was not impaired in cocaine-treated or control animals following SIV infection. However, animals receiving 3.2mg/kg/day cocaine performed more slowly in a bimanual motor test. Thus, chronic administration of cocaine produced only minor changes in behavior, encephalitis severity, CNS inflammation/neurodegeneration, and virus replication in SIV-infected pigtailed macaques, suggesting that cocaine would have only modest effects on the progression of neuroAIDS in HIV-infected individuals.

Eradication of HIV from the brain: reasons for pause

Recent advances in HIV research have made it possible to scientists to consider approaches to eradicate HIV infection from T cell reservoirs. These include either engineering cells that would be resistant to HIV infection of suppression of HIV replication with intensified antiretroviral therapy followed by activation of HIV reservoirs and elimination of these cells by cytotoxic immune responses. Several variations of this theme are being considered. Careful consideration needs to be given to the viral reservoirs in the brain, where it may infect cell types such as macrophages, microglia and astrocytes. The life cycle of the virus in these cells is distinct compared to that in T cells and thus the antiviral approaches may not be effective in fully suppressing viral replication. Even small amounts of viral proteins produced by these cells can be neurotoxic. And if T cells in the periphery are restored before impacting the brain reservoirs these cells may enter the brain causing a T cell mediated encephalitis. This articlediscusses thefundamentalquestionsthatneedto beaddressedwithregards tothe biology of the virus in the brain before successful attempts to eradicate the virus can be made. 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2011, 25:000‐000

Cytokines and chemokines in viral encephalitis: A clinicoradiological correlation

Japanese encephalitis (JE) is the commonest encephalitis in South East Asia associated with high morbidity and mortality. Neuronal injury is attributed to a number of proinflammatory cytokines. This study evaluates cerebrospinal fluid (CSF) cytokines and chemokines in encephalitis and correlates these with clinical and magnetic resonance imaging (MRI) findings. We examined 14 patients with encephalitis (8 JE, 1 dengue, 5 nonspecific encephalitis) and 10 healthy controls. CSF cytokines (IL-1β, IL-6, IL-10, IL-12p70, TNF-α, IL-8) and chemokines (IP-10, MCP-1, MIG, IL-8 and RANTES) were estimated using Cytometric Bead Array, compared with controls and were correlated with severity of encephalitis, radiological findings and presence of movement disorders. Median age of the patients was 25.5 (range 6–55 years); 6 had seizures, 10 movement disorders and 6 out of 11 had MRI abnormalities. The MRI abnormalities included thalamic involvement in 5, basal ganglia and mid brain in 3 each and cortical involvement in 2 patients. Both the patients with cortical involvement had seizures and 5 of the 10 patients with movement disorders had thalamic, basal ganglia and/or mid brain involvement. There was significant increase in IL-6 ( p = 0.01), RANTES ( p = 0.02) and IL-8 ( p = 0.02) in encephalitis compared to controls but there was no difference in IL12p70, TNF-α, IL-10, IL-1β and MCP-1. Cytokines and chemokines did not correlate with severity of encephalitis, radiological changes and presence of movement disorders. CSF IL-6, IL-8 and RANTES were significantly higher in encephalitis patients compared to controls.

Extracellular matrix degradation in SIV encephalitis induces IRF‐1 signaling in astrocytes

The neuropathological changes associated with HIV encephalitis (HIVE) include activated and infected macrophages, astrocytosis and loss of perineuronal nets (PNNs) indicating of extracellular matrix (ECM) disruption. The aim of this study was to explore the kinetics of ECM degradation, identify the ECM degrading enzymes involved, study whether IRF‐1 and its target genes are induced by ECM degradation and whether they play a role in nerurodegeneration. Longitudinal analysis of SIV‐infected pigtailed macaques showed an increase in CSF ECM degradation products. Consistent with these findings, the ECM degrading enzyme hyaluronidase and heparinase were upregulated in brain homogenates commensurate with the severity of encephalitis. Microarray analysis showed induction of the transcription factor IRF‐1 in encephalitic animals that was confirmed by semi‐quantitative RT‐PCR. In situ hybridization combined with immunohistochemistry showed that IRF‐1 was induced in astrocytes. Primary human astrocyte cultures exposed to hyaluronidase and heparitinase showed induction of IRF‐1 as well as toll‐like receptor 4 (TLR4) mRNA. Initial screening of the target genes that are induced by ECM degrading enzymes include ADAM8, caspase 1 & 3. We conclude that ECM degradation in SIVE results in the formation of HA and HS fragments that can activate TLR signaling and subsequent IRF‐1 induction in astrocytes.

Reduced Expression of Excitatory Amino Acid Transporter 2 and Diffuse Microglial Activation in the Cerebral Cortex in AIDS Cases With or Without HIV Encephalitis

To determine the relationship between the human immunodeficiency virus type 1 (HIV-1) encephalitis (HIVE) and diffuse poliodystrophy in the acquired immunodeficiency syndrome dementia complex, we examined the neuropathologic features in brain autopsy tissue specimens of HIV-1-infected patients with (n = 11) or without HIVE (n = 9). The brains were free of opportunistic diseases and major cerebrovascular lesions. In both groups, there was diffuse microglial activation, astrocytic gliosis, and decreased excitatory amino acid transporter 2 (EAAT-2) immunoreactivity. These changes did not correlate either with the severity of encephalitis or local HIV-1 infection as detected by p24 immunostaining. Some activated microglia expressed EAAT-2; interleukin-1beta and tumor necrosis factor were detected only in microglial nodules of HIVE cases but not in areas with diffusely activated microglia. There was a significant negative correlation between the areas of EAAT-2 expression and numbers of activated microglia (p < 0.01) in cases with decreased EAAT-2. These data indicate that diffuse cortical changes may occur independently of HIVE in acquired immunodeficiency syndrome patients. The expression of EAAT-2 by activated microglia suggests that they might exert a compensatory effect that protects neurons from glutamate neurotoxicity.

Encephalitozoonosis in pet rabbits (Oryctolagus cuniculus): pathohistological findings in animals with latent infection versus clinical manifestation

Encephalitozoon cuniculi is a common infectious agent of rabbits. The aim of this study was to determine the distribution and extent of histological lesions in the brain and in the kidney of naturally infected pet rabbits with or without clinical encephalitozoonosis. In 71 animals (33 with symptoms) which died or were euthanised, histopathological examination including staining of spores (Ziehl-Neelsen, acid-fast trichrome) was performed and changes were described quantitatively. The cerebrum was the most frequently affected brain region (97.5%), whilst the cerebellum (55%) and the vestibular cores (37.5%) were less commonly concerned. Granulomas were found in 77.5% of animals with encephalitis and in 12.5% of rabbits with interstitial nephritis. Although cerebral granulomas were found irrespective of the grade of histological changes, they were significantly correlated with changes at higher grades. There was no correlation between the severity of encephalitis and neurological symptoms. Since severe lesions were also found in clinically inconspicuous animals, histological findings of inflammatory lesions are not indicative of overt encephalitozoonosis as the causative agent for neurological signs. Other diseases causing neurological symptoms, such as suppurative encephalitis, otitis media as well as malignant lymphoma were also detected in the rabbit population that was examined in the present study.

Progressive selection for neurovirulent genotypes in the brain of SIV-infected macaques

To compare the viral genotypes present in RNA from brain and peripheral blood mononuclear cells (PBMC) and DNA from brain during acute, asymptomatic and late stages of SIV infection of macaques. Eighteen pigtailed macaques were intravenously inoculated with SIV. At 10, 21 and 56 days postinoculation, six were euthanized and the severity of encephalitis was assessed by microscopic examination. DNA and RNA were isolated from brain and PBMC, and the V1 region of env was amplified by the polymerase chain reaction and sequenced from over 800 different clones. Similar genotypes were detected in RNA from brain and PBMC at 10 days postinoculation, suggesting an unrestricted exchange of virus between the periphery and the brain during acute infection. There was a progressive increase in the percentage of neurovirulent genotypes in brain RNA from acute (14% of all genotypes detected in brain RNA) to early asymptomatic (45%), to late asymptomatic (52%) and to terminal (95%) infection. Fewer different genotypes were found in brain RNA than in PBMC RNA from macaques euthanized during early asymptomatic (2.5 and 5 different genotypes, respectively; P = 0.007), late asymptomatic (2 and 5 different genotypes, respectively; P = 0.003) and terminal (2 and 4 different genotypes, respectively; P < 0.001) infection. These data demonstrate that the almost exclusive replication of neurovirulent genotypes in the brain seen at late-stage infection is a progressive process that begins early in infection and continues to late stage disease.

Development of Neuronal Sensitivity to Toxins in Cerebrospinal Fluid from HIV-Type 1-Infected Individuals

HIV infection of the immature nervous system generally results in a rapid progression of neurological disease that cannot easily be explained by the severity of encephalitis, viral burden, systemic immune deficiency, or developmental changes in utero. Rather than the viral infection dictating disease progression, we explored the possibility that immature neurons might be particularly sensitive to toxins secreted in response to HIV. Primary cultures of rat cortical neurons were exposed to toxic cerebrospinal fluid (CSF) from HIV-infected individuals (CSF(tox)) and evaluated for changes in intracellular calcium and cell death. CSF(tox) had no detectable effect on early neurite outgrowth, calcium regulation, or cell death during the first few days in culture. Starting at Day 4, delayed increases in intracellular calcium appeared in response to CSF(tox). The magnitude of the delayed calcium rise and cell death increased with the age of the culture and correlated with the appearance of synaptophysin immunoreactive varicosities. A similar gradual development of sensitivity was seen during exposure of feline neurons to toxins generated by choroid plexus macrophages after exposure to feline immunodeficiency virus. The possibility that toxin sensitivity is dependent on the presence of synaptic activity is consistent with the rapid pathogenesis in the CNS seen during the first postnatal year. Emerging synaptic activity coupled with other factors such as high metabolic demand in the young nervous system may combine to increase the likelihood of calcium overload and neuronal dysfunction in response to HIV-associated toxins.

Epstein-Barr Virus Causing Encephalitis in an Elderly Woman

Although infectious mononucleosis commonly afflicts young persons, it is now being described more frequently in the elderly. Neurologic manifestations are uncommon, and encephalitis is rare, especially in elderly patients. We have reported a case of acute Epstein-Barr virus infection causing acute encephalitis in a 64-year-old woman. Despite the severity of encephalitis, the patient recovered fully after several weeks.

Experimental encephalitis following peripheral inoculation of West Nile virus in mice of different ages.

Experimental arbovirus infections of mice provide a convenient model to study factors which determine the occurrence or severity of encephalitis following extraneural infection with certain neurotropic viruses. Varying doses of West Nile or Powassan viruses were inoculated by intraperitoneal or intramuscular routes into mice of varing ages; individual variables were manipulated to influence the outcome of infection. Three patterns of pathogenesis were delineated: (1) Fatal encephalitis, preceded by early viraemia, and invasion of the central nervous system. (2) Inapparent infection, with no detectable viraemia and no evidence of central nervous system invasion. (3) Subclinical encephalitis, usually preceded by trace viraemia, with minimal transient levels of virus in the brain. In this latter type of subclinical infection with a potentially lethal virus, the immune response probably plays an important role in recovery.