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Cerebrospinal fluid alterations in herpes simplex virus encephalitis.

Cellular and humoral alterations in the cerebrospinal fluid (CSF) of patients with herpes simplex virus (HSV) encephalitis are summarized. At the onset of signs of HSV encephalitis. CSF parameters may appear normal. Lymphoid pleocytosis is usual, and in some cases polymorphonuclear cells may dominate initially. The lymphoid reaction in CSF is prominent for months or even years after infection. Damage to the blood-brain barrier is variable. Total protein level and concentrations of IgG, IgM, and IgA increase in the early phase of the disease. The IgG content usually remains abnormal. Levels of HSV-specific IgG in the CSF increase in correspondence with total IgG content and remain high. A fairly consistent finding is the increased local IgG production in the central nervous system during HSV encephalitis. The ratio of the concentration of HSV antibody in serum to that in CSF is abnormal, usually from the second week of illness. In many cases a fourfold or greater increase in CSF antibody level is observed. The use of enzyme or radioimmunoassay in antibody determinations does not essentially hasten the diagnosis, and isolation of HSV or demonstration of its antigen in brain-biopsy specimens is the only way to achieve a conclusive diagnosis. The persistence of the CSF alterations suggests that HSV encephalitis is a chronic disease.

Albumins↗

Synergistic antiviral effects of adenine arabinoside and humoral antibodies in experimental encephalitis due to Herpesvirus hominis.

The antiviral effects of humoral antibodies and adenine arabinoside on encephalitis due to Herpesvirus hominis were studied in three-week-old mice. Exogenously administered antibodies to H. hominis, of rabbit or human origin, significantly reduced morbidity and mortality rates from H. hominis encephalitis if enough antibodies were given during the early phase of infection. Adenine arabinoside could also modulate the pathogenesis and reduce the mortality rate in mice with H. hominis encephalitis. Simultaneous administration of adenine arabinoside and human immune globulin resulted in an enhanced protection against H. hominis encephalitis. This increased protection was manifested by a significant reduction of mortality rate, a decrease in concentration of virus, and a lessening of histopathologic damage in the brain tissues. Mechanisms involved in the enhanced protective effects were not well defined. The use of adenine arabinoside plus human immune globulin did not completely suppress viral replication. Therefore, host recovery was probably mediated through (1) partial suppression of viral replication by adenine arabinoside, (2) neutralization of cell-free virus by antibodies, and (3) collaboration of antibodies with other host resistance factors (e.g., complement, leukocytes, nonimmune effector cells, etc.). Our data suggest that control of severe H. hominis infection may require the combined use of an antiviral agent and humoral factor and, perhaps, enhancement of host responses by other means.

Animals↗

Chronic granulomatous herpes simplex encephalitis in children.

Herpes simplex encephalitis is usually a monophasic acute illness but can cause chronic disease, particularly in children. Little information is available as to the histological substrate. We report the findings in 3 children. In 2 children, herpes encephalitis had occurred during the first 2 years, but both later developed intractable epilepsy that led to neurosurgery. The biopsies showed chronic granulomatous inflammation with foci of mineralization. One child made a good post-operative recovery. The other was found post-operatively to have herpes simplex virus type 1 (HSV-1) DNA and elevated titers of HSV IgM antibodies in the CSE He was given acyclovir but after initial improvement developed hemiparesis, with extensive signal change on MRI. Repeat biopsy revealed florid granulomatous inflammation with necrosis. The third patient was an infant who had had a cutaneous facial HSV-2 eruption soon after birth. This was treated with topical acyclovir, after which she remained well until 2 months, when she presented with a relatively non-specific illness, developed blisters of the right hand and foot, and died a few days later. Necropsy revealed severe granulomatous encephalitis, most extensive in the temporal lobe and insula, and associated with mineralization. Our findings indicate that herpes simplex encephalitis in children can be complicated by chronic granulomatous inflammation with mineralization. This pattern of disease may be an under-recognized complication of herpes simplex infection during the first few years of life.

Adolescent↗

Viral meningitis and encephalitis in Saudi Arabia.

The laboratory confirmation of twelve clinically diagnosed cases of aseptic meningitis and encephalitis is described. Among three cases of aseptic meningitis one was due to mumps in a 14-month infant and the other two attributable to Cocksackie B-1. Herpes virus encephalitis due to HSV-1 was conclusively identified by IF monoclonal test from brain biopsy in tissue culture, and a further four cases also of HSV-1 encephalitis by virus isolation from CSF and presence of significant levels of herpes virus antibody in CSF and serum. Measles encephalitis was identified in four pediatric patients with one based on the isolation of measles virus from the CSF and in the other three with significant CSF/serum ratios to measles virus.

Adolescent↗

Parkinsonism following encephalitis of unknown etiology.

The patient, a clinical case of parkinsonism, was a 32-year-old man, born in 1942, long after the prevalence of von Economo's lethargic encephalitis in Japan. Anatomically, the neurons in the substantia nigra of the mid-brain were extensively degenerated, and presented Alzheimer's neurofibrillary tangles. At the same time, melanin pigment was scattered in the tissue and was phagocytized by glia cells. Perivascular cuffing was observed in the frontal lobe, parietal lobe, temporal lobe, hippocampus, and thalamus as well as in the substantia nigra. Neuronophagia was noted in the thalamic nuclei. The present case was believed to have parkinsonism not clinically or pathologically related to von Economo's encephalitis or to Japanese encephalitis, but following a mild encephalitis of unknown etiology.

Adult↗

Severe amnesia associated with human herpesvirus 6 encephalitis after bone marrow transplantation.

BACKGROUND: Human herpesvirus 6 (HHV-6) appears to have a predilection for immunocompromised patients and has been implicated as a cause of posttransplant encephalitis. However, the pathogenesis, as well as the appropriate means of diagnosis and treatment of HHV-6 encephalitis is unclear. METHOD: We describe a case of a 20-year-old male university student with anemia who presented with an acute, severe amnesia 1 month after bone marrow transplantation. His illness was subsequently attributed to HHV-6 encephalitis. RESULTS: Cerebrospinal fluid analysis was consistent with encephalitis and polymerase chain reaction confirmed the presence of HHV-6 DNA in both cerebrospinal fluid and serum. No other herpes virus particles were detected. MRI showed bilateral hippocampal involvement. Treatment with acyclovir resulted in a decrease in serum HHV-6 DNA to undetectable levels, coincident with improvement of both memory and lesions on MRI. CONCLUSIONS: This case provides strong clinical and radiological evidence of the reversibility of this disease process and supports the recommendations for empiric treatment of post transplant patients with laboratory evidence of HHV-6 infection, culture or polymerase chain reaction, plus clinical symptoms compatible with HHV-6 infection.

Adult↗

Meta-analysis of prophylactic treatments against Pneumocystis carinii pneumonia and toxoplasma encephalitis in HIV-infected patients.

In a meta-analysis, we examined the efficacy of aerosolized pentamidine, trimethoprim-sulfamethoxazole, and dapsone or dapsone/pyrimethamine for the prevention of Pneumocystis carinii pneumonia and toxoplasma encephalitis in patients with HIV infection. Of 22 trials, 13 compared trimethoprim-sulfamethoxazole with aerosolized pentamidine, nine compared dapsone alone or in combination with pyrimethamine with aerosolized pentamidine, and eight compared trimethoprim-sulfamethoxazole with dapsone/pyrimethamine. In total, 1484 patients were treated with trimethoprim-sulfamethoxazole, 1548 patients with dapsone/pyrimethamine or dapsone, and 1800 patients with aerosolized pentamidine. For dapsone/pyrimethamine versus aerosolized pentamidine, the risk ratio for P. carinii pneumonia was 0.90 (95% confidence interval [CI], 0.71-1.15), and for toxoplasma encephalitis it was 0.72 (95% CI, 0.54-0.97). For trimethoprim-sulfamethoxazole versus aerosolized pentamidine, the risk ratio of P. carinii pneumonia was 0.59 (95% CI, 0.45-0.76), and for toxoplasma encephalitis it was 0.78 (95% CI, 0.55-1.11). For trimethoprim-sulfamethoxazole versus dapsone/pyrimethamine, the risk ratio of P. carinii pneumonia was 0.49 (95% CI, 0.26-0.92), and for toxoplasma encephalitis it was 1.17 (95% CI, 0.68-2.04). Although current evidence does not allow a definitive recommendation, administration of trimethoprim-sulfamethoxazole for prophylaxis of P. carinii pneumonia and toxoplasmosis in patients with HIV infection is consistent with the available data.

AIDS-Related Opportunistic Infections↗

Monoclonal antibodies to the E1 and E2 glycoproteins of Sindbis virus: definition of epitopes and efficiency of protection from fatal encephalitis.

Protection of mice from fatal neuroadapted Sindbis virus encephalitis can be accomplished by passive transfer of monoclonal antibodies (MAbs) to either the E1 or E2 glycoprotein of Sindbis virus. Both neutralizing and non-neutralizing MAbs can be protective. To define further the characteristics of MAbs that provide protection from fatal disease, antigenic epitopes on the E1 and E2 glycoproteins were identified using a competitive binding enzyme immunoassay. Four distinct epitopes on E1 and three on E2 were defined. MAbs to all E1 epitopes, both neutralizing (three) and non-neutralizing (one) protected mice from fatal encephalitis. MAbs to the E2 neutralizing epitopes (two) protected mice from fatal encephalitis while those to the non-neutralizing epitope did not. The efficiency of protection from fatal Sindbis virus encephalitis of four neutralizing and non-neutralizing protective anti-E1 and anti-E2 MAbs representing different epitopes was compared. The neutralizing MAbs (against epitopes E2-ab, E2-c and E1-c) gave 50% protection at lower doses (2 to 20 micrograms) than the non-neutralizing MAb representing epitope E1-e (150 micrograms) when given before virus challenge. When given after virus challenge, MAbs to E2-ab and E2-c protected at lower doses (0.03 to 0.3 micrograms) than did either MAbs to E1-c (greater than 100 micrograms) or E1-e (10 micrograms). The MAbs to E1-e, E2-ab and E2-c were required in larger amounts to afford protection before than after challenge, while the opposite was true for MAb to E1-c.

Animals↗

Major histocompatibility complex (MHC) antigen expression in HIV encephalitis.

In order to study possible immunopathogenic mechanisms in Human Immunodeficiency Virus (HIV) encephalitis, immunocytochemical localization of Class I and Class II major histocompatibility complex (MHC) antigens was studied in formalin-fixed tissue sections from the brains of 10 individuals who had died with this disorder. Using the avidin biotin peroxidase technique and monoclonal antibodies to these antigens, increased expression of Class I antigens was found in five out of 10 and of Class II antigens in six out of 10 cases of HIV encephalitis. This contrasted with results obtained with the HIV-specific anti-P24 antibody which reacted with only a small number of cells in four cases. Class I and II antigens were detected mainly in perivascular monocytes/macrophages and also in multinucleated giant cells. In two cases, slight labelling was also detected in these cells more diffusely in the brain parenchyma. Immune and viral antigens were not detected in glial cells or neurons. Neither normal control cases nor brain sections from patients who had died from other neurological diseases were labelled with any of the antibodies apart from two cases of varicella-zoster virus-associated encephalitis in which increased expression of Class II antigens occurred. These findings support the notion that indirect immune-mediated mechanisms may be important in the pathogenesis of HIV encephalitis.

Encephalitis↗

Outcome after childhood encephalitis.

The prognosis for 73 children treated for encephalitis between 1973 and 1983 was evaluated. 70 children participated in a follow-up examination 2.4 to 12.9 years after the acute phase of the disease. The 61 school-aged children had lower performance and full-scale IQs than their randomly selected, age- and sex-matched controls. Visual acuity was more often reduced, and they more often had focal slowing on EEG and electronystagmogram abnormalities. Clinically, these differences were not significant. Encephalitis with a poor prognosis occurred seldom, the incidence being 3.5 cases per one million children at risk annually. These results show that the prognosis for childhood encephalitis is much better than anticipated on the basis of experience mainly with herpes simplex virus encephalitis.

Adolescent↗

Ondine's curse in listeria monocytogenes brain stem encephalitis.

A case of necrotizing brain stem encephalitis due to listeria monocytogenes is described in a 48-year-old man who had brain stem encephalitis of complicated course and with selective destruction of the vasomotoric and respiratory centers. He developed that very rare Ondine's curse syndrome, being only able to breathe when awake. The literature on Ondine's curse and brain stem encephalitis due to LM is reviewed. Brain stem encephalitis has a mortality near 100%. The only treatment for Ondine's curse is lifelong artificial ventilation.

Encephalitis↗

Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis.

Rasmussen's encephalitis is a progressive childhood disease of unknown cause characterized by severe epilepsy, hemiplegia, dementia, and inflammation of the brain. During efforts to raise antibodies to recombinant glutamate receptors (GluRs), behaviors typical of seizures and histopathologic features mimicking Rasmussen's encephalitis were found in two rabbits immunized with GluR3 protein. A correlation was found between the presence of Rasmussen's encephalitis and serum antibodies to GluR3 detected by protein immunoblot analysis and by immunoreactivity to transfected cells expressing GluR3. Repeated plasma exchanges in one seriously ill child transiently reduced serum titers of GluR3 antibodies, decreased seizure frequency, and improved neurologic function. Thus, GluR3 is an autoantigen in Rasmussen's encephalitis, and an autoimmune process may underlie this disease.

Animals↗

Comparative study of the antiviral activity of acyl derivatives of 2,2'-anhydro-1-beta-D-arabinofuranosylcytosine and other nucleosides against encephalitis in mice.

Anti-deoxyribonucleic acid virus activities of 3'-O-acyl derivatives of 2,2'-anhydro-1-beta-d-arabinofuranosyl cytosine (cyclo-C) and 1-beta-d-arabinofuranosylcytosine (Ara-C) were evaluated by using an in vivo test system in mice. Among the derivatives tested, 3'-O-decanoyl cyclo-C hydrochloride was the most effective against herpes simplex virus-induced encephalitis in mice when the drug was administered directly into infected brains of mice (target-organ treatment). A comparative study of the treatment of herpetic encephalitis in mice with 3'O-decanoyl cyclo-C and other nucleosides, including Ara-C, 9-beta-d-arabinofuranosyladenine (Ara-A), and 5-iodo-2'-deoxyrudine (IUdR), proved Ara-A to be more efficacious than the other nucleosides, followed by 3'-O-decanoyl cyclo-C, which was more active than Ara-C and IUdR. Administration of 3'-O-acyl cyclo-C's by intraperitoneal injection, however, failed to demonstrate activity against herpetic encephalitis in mice. The antivaccinial activity of 3'-O-decanoyl cyclo-C was also compared with that of other compounds against encephalitis and dermal tail lesions in mice caused by vaccinia virus infection. Interaperitoneally administered 3'-O-decanoyl cyclo-C and Ara-C also showed no significant activity against the diseases. Under these test conditions, N-methylisatin-beta-thiosemicarbazone (Marboran) was the most active compound, followed by Ara-A.

Animals↗

Virion and soluble antigens of japanese encephalitis virus.

Japanese encephalitis virions contain a 58 X 10-3-molecular-weight envelope glycoprotein antigen that can be solubilized with sodium lauryl sulfate and separated from other virion structural polypeptides and viral ribonucleic acid by gel filtration chromatography. The 58 X 10-3-molecular-weight envelope protein is the major antigen responsible for cross-reactivity of the virion in complement fixation tests with other closely related arboviruses. A naturally occurring soluble complement-fixing antigen is found in Japanese encephalitis mouse brain preparations after removal of particulate antigens. After partial purification by gel filtration and isoelectric focusing, the 53 X 10-3-molecular weight soluble complement-fixing antigen is more type specific than the Japanese encephalitis envelope antigen in complement fixation tests. Further, the Japanese encephalitis soluble complement-fixing antigen is stable to treatment with sodium lauryl sulfate and 2-mercaptoethanol, whereas virion complement-fixing antigens are unstable after this treatment.

Amino Acids↗

Monoclonal immunoglobulin M antibody to Japanese encephalitis virus that can react with a nuclear antigen in mammalian cells.

An immunoglobulin M (IgM) class monoclonal antibody raised against Japanese encephalitis virus reacted with an epitope on the nonstructural virus protein P74 (NV4 in the old nomenclature) of several flaviviruses and also with an antigen present in the nuclei of a variety of mammalian cell types. This antigen had a characteristic granular distribution by immunofluorescence and may correspond to a polypeptide of molecular weight 56,000 seen in nitrocellulose transfers of sodium dodecyl sulfate-polyacrylamide gels. Cross-reactivity with nuclear antigen was also occasionally observed in the IgM antibody fraction of mice early after infection with Japanese encephalitis virus and also in acute sera from some clinical cases of encephalitis containing IgM antibody to Japanese encephalitis virus.

Animals↗

Antigenic analysis of Japanese encephalitis virus by using monoclonal antibodies.

Hybridoma cells were produced by fusing P3X63Ag8.653 mouse myeloma cells with spleen cells from BALB/c mice immunized with Japanese encephalitis (JE) virus, Nakayama-RFVL strain. The resulting 26 clones produced hemagglutination inhibition antibodies against the homologous strain. The hemagglutination inhibition reactivity of each clone was tested against six flaviviruses: JE, Murray Valley encephalitis (MVE), Egypt 101 strain of West Nile (WN), St. Louis encephalitis (SLE), Russian spring summer encephalitis, and dengue type 1. The 26 monoclonal antibodies fell into four groups: 14 JE species-specific antibodies, 6 antibodies reactive to JE and MVE viruses, 3 antibodies to three or four viruses in the JE-MVE-WN-SLE subgroup, and 3 antibodies to all six flaviviruses. Furthermore, antigenic comparison of 27 strains of JE virus was carried out by using five JE species-specific monoclonal antibodies. Of these, 24 strains were isolated in various parts of Japan, and 3 strains came from Southeast Asia. In reactivity, the 27 strains were classified into at least four antigenic groups. The results showed that the Nakayama-Yakken strain is a mutant strain which lacks the Nakayama strain-specific antigen and that the recently isolated strains are immunologically different from Nakayama and JaGAr 01 strains. One clone (NARMA 13) produced a JE species-specific antibody which showed almost the same titer against 26 JE virus strains, whereas one clone (NARMA 5) produced a Nakayama strain-specific antibody which reacted only to the Nakayama-RFVL and Nakayama-Yoken strains.

Animals↗

Diagnosis of toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome by using a new serologic method.

The present study was performed to develop a serological method for diagnosing toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome (AIDS). The trophozoite form of Toxoplasma gondii, fixed with either Formalin or acetone, was used in a modification of an agglutination method previously shown to differentiate between the acute and the chronic (latent) stages of infection with toxoplasma in immunologically normal persons. By using these antigens in separate tests and evaluating the data for statistical significance, 70% of patients with AIDS with biopsy-proven toxoplasmic encephalitis were distinguished from control, ambulatory patients with AIDS with toxoplasma antibodies but without signs or symptoms of central nervous system involvement. In a separate study, the agglutination tests identified from controls 84% of patients with AIDS with two or more brain lesions detected by computed-tomographic or magnetic-resonance-imaging scans and suspected of having toxoplasmic encephalitis. Thus, these agglutination tests should prove valuable for the noninvasive diagnosis of toxoplasmic encephalitis in patients with AIDS.

Acquired Immunodeficiency Syndrome↗

Susceptibility to measles virus-induced encephalitis in mice correlates with impaired antigen presentation to cytotoxic T lymphocytes.

In measles virus (MV) infection in humans, meningitis and encephalitis are important complications. However, little is known of the pathogenesis of MV encephalitis, in particular about the role of the immune response. We have examined the role of cytotoxic T lymphocytes (CTL) in a mouse model of MV-induced encephalitis. We report here that the resistance of inbred strains of mice to MV-induced encephalitis correlated with the major histocompatibility complex (MHC) haplotype and that only resistant mouse strains mounted an effective CTL response to MV. Mice with low susceptibility to MV infection, such as the BALB/c strain (H-2d), generated CTL, whereas the highly susceptible strains, C3H (H-2k) and C57BL/6 (H-2b), revealed very poor CTL responses. MV-induced CTL were usually CD8+, and the generation of these cells was independent of the route of inoculation or the time postinfection. CD4+ T cells were generally only weakly lytic. The nucleocapsid protein was the major target antigen for CTL in BALB/c mice, although in some experiments the hemagglutinin was also recognized. CTL from C3H and C57BL/6 mice did not lyse MV-infected target cells. However, targets infected with vaccinia virus recombinants expressing the nucleocapsid protein or hemagglutinin were lysed, but levels of cytotoxicity were still low. Experiments using target cells transfected with single MHC class I genes suggested inefficient antigen presentation of MV proteins by the MHC molecules of the H-2k and H-2b haplotypes.

Animals↗