Diagnosis, Diagnostics, Immunodiagnosis & Immunodiagnostics:


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3233. Abendroth A.  Arvin AM. Immune evasion as a pathogenic mechanism of varicella zoster virus. [Review] [70 refs] Seminars in Immunology.  13(1):27-39, 2001 Feb.


  Varicella zoster virus (VZV) is a human herpesvirus that causes varicella (chickenpox) during primary infection, establishes latency in dorsal root ganglia and may reactivate years later, producing herpes zoster. VZV must evade antiviral immunity during three important stages of viral pathogenesis, including the cell-associated viremia characteristic of primary infection, persistence in dorsal root ganglia during latency and the initial period of VZV reactivation. Our observations about the immunomodulatory effects of VZV document its capacity to interfere with adaptive immunity mediated by CD4 as well as CD8 T cells, ensuring the survival of the virus in the human population from generation to generation. Copyright 2001 Academic Press. [References: 70]

3234.                        Awasthi M.  Parmar H.  Patankar T.  Castillo M.  Imaging findings in rabies encephalitis.  Ajnr: American Journal of Neuroradiology.  22(4):677-80, 2001 Apr.


  SUMMARY: Rabies encephalitis is perhaps one of the few infectious diseases that command attention and fear not only from the layman but also from physicians. The unique mode of transmission, the virtually exclusive neurotransmission shown by the agent, and the complete hopelessness of the established disease sets rabies apart from other zoonoses transmitted to man. Rabies encephalitis is a fatal disease and its diagnosis is usually based on the clinical presentations and findings. Hence, imaging in rabies is seldom done, and imaging findings in rabies encephalitis have rarely been described. We present the imaging findings in two confirmed cases of rabies encephalitis in which antemortem diagnosis was obtained by corneal impression smears showing the presence of viral antigens. The differential diagnosis of the imaging findings as well as the role and the relevance of imaging in the diagnosis of this disease are discussed. The current literature on the subject is also reviewed.

3235.                       Bestetti A.  Pierotti C.  Terreni M.  Zappa A.  Vago L.  Lazzarin A.  Cinque P. Comparison of three nucleic acid amplification assays of cerebrospinal fluid for diagnosis of cytomegalovirus encephalitis. Journal of Clinical Microbiology.  39(3):1148-51, 2001 Mar.


  The diagnostic reliabilities of three cytomegalovirus (CMV) nucleic acid amplification assays of cerebrospinal fluid (CSF) were compared by using CSF samples from human immunodeficiency virus-infected patients with a postmortem histopathological diagnosis of CMV encephalitis (n = 15) or other central nervous system conditions (n = 16). By using a nested PCR assay, the quantitative COBAS AMPLICOR CMV MONITOR PCR, and the NucliSens CMV pp67 nucleic acid sequence-based amplification assay, sensitivities were 93.3, 86.6, and 93.3%, respectively, and specificities were 93.7, 93.7, and 87.5%, respectively. The COBAS AMPLICOR assay revealed significantly higher CMV DNA levels in patients with diffuse ventriculoencephalitis than in patients with focal periventricular lesions.


3236.                       Hinson VK.  Tyor WR. Update on viral encephalitis. [Review] [45 refs]  Current Opinion in Neurology.  14(3):369-74, 2001 Jun.


  Over 100 viruses have been associated with acute central nervous system infections. The present review focuses on some of the most common agents of viral encephalitis, as well as important emerging viral encephalitides. In this context, the initial detection of West Nile virus in the Western Hemisphere during the 1999 New York City outbreak, the first description of Nipah virus in Malaysia, and the appearance in Asia of a new neurovirulent enterovirus 71 strain that causes severe neurologic disease are highlighted. In addition, advances regarding diagnosis, neuroimaging and treatment of Japanese and herpes simplex encephalitis are presented. [References: 45]

3237.                       Hooper P.  Zaki S.  Daniels P.  Middleton D. Comparative pathology of the diseases caused by Hendra and Nipah viruses. [Review] [17 refs] Microbes & Infection.  3(4):315-22, 2001 Apr.


  Information on the pathogenesis and transmissibility of Hendra and Nipah viruses was obtained by comparing their histopathology. Both viruses induced syncytial cells in vascular tissues and they were primarily vasotropic and/or neurotropic, generating interstitial pneumonia or encephalitis. Nipah virus in pigs was also epitheliotropic in respiratory epithelium and thus contagious. [References: 17]

3238.                       Huang C.  Slater B.  Campbell W.  Howard J.  White D. Detection of arboviral RNA directly from mosquito homogenates by reverse-transcription-polymerase chain  reaction. Journal of Virological Methods.  94(1-2):121-8, 2001 May.


  Many arthropod-borne viruses (arboviruses) are important human pathogens medically. The development of an effective technique to detect the viruses by using nucleic acid amplification, such as polymerase chain reaction (PCR), improves not only clinical diagnosis but also virologic surveillance of mosquito vectors in the field. In this study, the development of an improved and simplified assay is described for detection of mosquitoes infected with eastern equine encephalitis (EEE) virus, Cache Valley (CV), and California (CAL) serogroup viruses from field-collected mosquito pools. As little as 5 microl of homogenate from mosquito pools was used in the reverse transcription (RT) reaction followed by the use of three sets of specific primers for the PCR. Positive pools were determined by finding PCR bands of the expected size for each arbovirus. The confirmation and identification of Bunyaviruses was done by sequencing the PCR product. In 1999, West Nile virus (WNV) was identified as the etiologic agent of an outbreak of human encephalitis in New York City. It is shown that this protocol is also able to detect West Nile viral RNA in a pool of 100 mosquitoes containing one infected mosquito.

3239.                       Singh P.  Kalra N.  Ratho RK.  Shankar S.  Khandelwal N.  Suri S.  Coexistent neurocysticercosis and Japanese B encephalitis: MR imaging correlation.  Ajnr: American Journal of Neuroradiology.  22(6):1131-6, 2001 Jun-Jul.


  BACKGROUND AND PURPOSE: An increased incidence of intestinal helminthic infections has been observed in patients with viral encephalitis in endemic areas. Both Japanese B encephalitis (JE) and neurocysticercosis (NCC) share some common socio-demographic and ecologic factors, and pigs act as the intermediate carrier for both. Our purpose was to show the coexistence of JE and NCC in brain on MR images and highlight the possible role of NCC as an amplifier of JE. METHODS: MR images from 10 cases of coexistent JE and NCC were studied retrospectively. T1-weighted axial and sagittal, proton T2-weighted axial and coronal, and T2-weighted fluid-attenuated inversion recovery axial and coronal sections of the brain were evaluated. NCC was diagnosed on the basis of neuroimaging. Diagnostic serologic testing for JE was conducted using paired blood and CSF samples. RESULTS: The JE changes were bilateral and asymmetrical and were more severe on the side harboring the solitary cyst or the side bearing the greater number of cysts or lodging the degenerating cyst. In each of nine of 10 cases, at least one degenerating cyst was found on the side of predominant JE pathologic abnormality. CONCLUSION: The study suggests that the co-occurrence of JE and NCC is not just a chance coincidence. NCC apparently predisposes a person to JE infection and is a positive modulator of the encephalitic process. The study shows a spectrum of MR imaging findings of coexistent JE and NCC.


Apr 02


4020.                        Barrett AD. Current status of flavivirus vaccines. Ann N Y Acad Sci  2001 Dec;951:262-71


Although there are approximately 68 flaviviruses recognized, vaccines have been developed to control very few human flavivirus diseases. Licensed live attenuated vaccines have been developed for yellow fever (strain 17D) and Japanese encephalitis (strain SA14-14-2) viruses, and inactivated vaccines have been developed for Japanese encephalitis and tick-borne encephalitis viruses. The yellow fever live attenuated 17D vaccine is one of the most efficacious and safe vaccines developed to date and has been used to immunize more than 300 million people. A number of experimental vaccines are being developed, most notably for dengue. Candidate tetravalent live attenuated dengue vaccines are undergoing clinical trials. Other vaccines are being developed using reverse genetics, DNA vaccines, and recombinant immunogens. In addition, the yellow fever 17D vaccine has been used as a backbone to generate chimeric viruses containing the premembrane and envelope protein genes from other flaviviruses. The "Chimerivax" platform has been used to construct chimeric Japanese encephalitis and dengue viruses that are in different phases of development. Similar strategies are being used by other laboratories.

4021.                        Chang GJ, Davis BS, Hunt AR, Holmes DA, Kuno G. Flavivirus DNA vaccines: current status and potential. Ann N Y Acad Sci  2001 Dec;951:272-85

The use of DNA-based vaccines is a novel and promising immunization approach for the development of flavivirus vaccines. This approach has been attempted in vaccine development for various virus species, including St. Louis encephalitis, Russian spring-summer encephalitis, Central European encephalitis, dengue serotypes 1 and 2, Murray Valley encephalitis, Japanese encephalitis, and West Nile viruses. However, very little is known about the factors affecting its efficacy. Recently, we demonstrated that a single intramuscular immunization of DNA vaccine of Japanese encephalitis and West Nile viruses protected mice and horses from virus challenge. Administration of these recombinant plasmid vectors resulted in endogenous expression and secretion of extracellular virus-like particles that correlated well with the induction of protective immunity. These results provided evidence that the virus-like particles composed of premembrane/membrane and envelope proteins are essential for eliciting immune responses similar to those induced by live, attenuated virus vaccines. The biosynthesis and protein processing of premembrane/membrane and envelope proteins that preserve the native conformation and glycosylation profiles identical to virion proteins could be determined by the effectiveness of the transmembrane signal sequence located at the amino-terminus of premembrane protein. The use of DNA vaccines in multivalent and/or combination vaccines designed to immunize against multiple flaviviruses is also a promising area of development.

4022.                        Chiarugi A, Calvani M, Meli E, Traggiai E, Moroni F. Synthesis and release of neurotoxic kynurenine metabolites by human monocyte-derived macrophages. J Neuroimmunol  2001 Nov 1;120(1-2):190-8


We studied the regulation of the kynurenine pathway of tryptophan metabolism in human monocyte-derived macrophages (MDM) with the aim of evaluating macrophage involvement in inflammatory neurological disorders.Cultured MDM metabolized tryptophan and released kynurenine metabolites, including the excitotoxin quinolinic acid (QUIN). Lipopolysaccharides (LPS) or the pro-inflammatory cytokines INFgamma and TNFalpha increased, while IL 4 or IL 10 inhibited the rate of tryptophan metabolism and the release of QUIN.The incubation media of INFgamma-exposed MDM caused neuronal death in primary cultures of mixed cortical cells. Glutamate receptor antagonists or poly(ADP-ribose) polymerase inhibitors significantly reduced this death, thus suggesting new possibilities for the treatment of neuronal damage in neuroinflammatory disorders.

4023.                        Cuzzubbo AJ, Endy TP, Nisalak A, Kalayanarooj S, Vaughn DW, Ogata SA, Clements DE, Devine PL. Use of recombinant envelope proteins for serological diagnosis of Dengue virus infection in an immunochromatographic assay. Clin Diagn Lab Immunol  2001 Nov;8(6):1150-5


An immunochromatographic test that incorporates recombinant antigens (Dengue Duo Rapid Strip Test; PanBio, Brisbane, Australia) has recently become commercially available. This assay is performed in 15 min and detects both immunoglobulin M (IgM) and IgG in a capture format. The four recombinant proteins used represent the N-terminal 80% of the viral envelope glycoproteins of dengue viruses 1, 2, 3, and 4, respectively. The sensitivity and specificity of the recombinant antigen-based assay were 90 and 86%, respectively. The similar diagnostic performance of these antigens to that of enzyme-linked immunosorbent assays using whole dengue virus suggests that they mimic whole dengue viruses in primary structure and epitope conformation. These results suggest that recombinant proteins can be used in diagnostic assays for dengue to overcome safety issues associated with the use of whole virus.

4024.                        Deubel V, Fiette L, Gounon P, Drouet MT, Khun H, Huerre M, Banet C, Malkinson M, Despres P. Variations in biological features of West Nile viruses. Ann N Y Acad Sci  2001 Dec;951:195-206


Pathological findings in humans, horses, and birds with West Nile (WN) encephalitis show neuronal degeneration and necrosis in the central nervous system (CNS), with diffuse inflammation. The mechanisms of WN viral penetration of the CNS and pathophysiology of the encephalitis remain largely unknown. Since 1996, several epizootics involving hundreds of humans, horses, and thousands of wild and domestic bird cases of encephalitis and mortality have been reported in Europe, North Africa, the Middle East, Russia, and the USA (see specific chapters in this issue). However, biological and molecular markers of virus virulence should be characterized to assess whether novel strains with increased virulence are responsible for this recent proliferation of outbreaks.

4025.                        Hughes AJ, Daniel SE, Lees AJ. Improved accuracy of clinical diagnosis of Lewy body Parkinson's disease. Neurology  2001 Oct 23;57(8):1497-9


The authors studied the accuracy of clinical diagnosis of idiopathic PD (IPD) in 100 consecutive clinically diagnosed cases that came to neuropathological examination. Ninety fulfilled pathologic criteria for IPD. Ten were misdiagnosed: multiple system atrophy (six), progressive supranuclear palsy (two), post-encephalitic parkinsonism (one), and vascular parkinsonism (one). Assessment of the clinical features suggests that an accuracy of 90% may be the highest that can be expected using current diagnostic criteria.

4026.                        Konstantinou D, Paschalis C, Maraziotis T, Dimopoulos P, Bassaris H, Skoutelis A. Two episodes of leukoencephalitis associated with recombinant hepatitis B vaccination in a single patient. Clin Infect Dis  2001 Nov 15;33(10):1772-3


Cases of central nervous system demyelination have been reported after recombinant hepatitis B vaccination, but no causal link has been clearly demonstrated. We present the first case report involving the occurrence of 2 episodes of leukoencephalitis in a previously healthy patient after vaccination and rechallenge with hepatitis B vaccine.


4027.                        Leder K, Weller PF, Wilson ME. Travel vaccines and elderly persons: review of vaccines available in the United States. Clin Infect Dis 2001 Nov 1;33(9):1553-66


Aging is associated with alterations in immune responses and may lead to clinically significant changes in the safety, immunogenicity, and protective efficacy of certain vaccines. This review summarizes published data regarding the effects of age on responses after immunization with vaccines generally administered before travel. The specific vaccines discussed in detail include hepatitis A, typhoid, yellow fever, Japanese encephalitis, and rabies vaccines. There is some evidence of diminished serological responses to hepatitis A and rabies vaccines in older individuals. In addition, increased toxic effects following yellow fever vaccination in elderly recipients have recently been reported. However, many travel-related vaccines have never been studied specifically in elderly populations. Consideration of potential age-related differences in responses to travel vaccines is becoming increasingly important as elderly persons more frequently venture to exotic destinations.

4028.                        Marth E, Kleinhappl B. Albumin is a necessary stabilizer of TBE-vaccine to avoid fever in children after vaccination. Vaccine  2001 Nov 12;20(3-4):532-7


A thiomersal-free and also an albumin-free tick-borne encephalitis-vaccine (TBE-vaccine) was developed. This vaccine was approved by the Austrian health authorities in the year 2000. Contrary to previous experience, 779 cases of fever attacks occurred following the first vaccination of children under 15 years of age. The induction of the immune system by different TBE virus (TBEV) vaccines (FSME-Immun [1999], Ticovac [2000] and FSME-Immun [2001] all from Baxter Hyland Immuno, Vienna) was compared in an in vitro immune stimulation test in order to find an explanation for the unexpected fever attacks. It was shown that only Ticovac, which contains no albumin as a stabilizer, can induce relative high amounts of TNF-alpha (P < or = 0.0001) and lower amounts of IL-1 beta (P < or = 0.05). Increase of both cytokines is first observed following an incubation of 4 h. The maximum is reached after 15 h. After 26 h, it has reverted to the original value. The course of concentration of both cytokines corresponds to the time of observed febrile phases. Albumin or immunoglobulin prevents a rise of cytokines so that it is recommended to add the albumin again to the vaccine.

4029.                        Monath TP. Prospects for development of a vaccine against the West Nile virus. Ann N Y Acad Sci  2001 Dec;951:1-12


Vaccination provides the ultimate measure for personal protection against West Nile disease. The development of a West Nile vaccine for humans is justified by the uncertainty surrounding the size and frequency of future epidemics. At least two companies (Acambis Inc. and Baxter/immuno) have initiated research and development on human vaccines. West Nile encephalitis has also emerged as a significant problem for the equine industry. One major veterinary vaccine manufacturer (Ft. Dodge) is developing formalin-inactivated and naked DNA vaccines. The advantages and disadvantages of formalin-inactivated whole virion vaccines, Japanese encephalitis vaccine for cross-protection, naked DNA, and live attenuated vaccines are described. A novel technology platform for live, attenuated recombinant vaccines (ChimeriVax) represents a promising approach for rapid development of a West Nile vaccine. This technology uses yellow fever 17D as a live vector for envelope genes of the West Nile virus. Infectious clone technology is used to replace the genes encoding the prM and E structural proteins of yellow fever 17D vaccine virus with the corresponding genes of West Nile virus. The resulting virion has the protein coat of West Nile, containing all antigenic determinants for neutralization and one or more epitopes for cytotoxic T lymphocytes. The genes encoding the nucleocapsid protein, nonstructural proteins, and untranslated terminal regions responsible for replication remain those of the original yellow fever 17D virus. The chimeric virus replicates in the host like yellow fever 17D but immunizes specifically

against West Nile virus.

4030.                        Price P, Mathiot N, Krueger R, Stone S, Keane NM, French MA. Immune dysfunction and immune restoration disease in HIV patients given highly active antiretroviral therapy. J Clin Virol  2001 Oct;22(3):279-87


BACKGROUND: Some immune defects caused by HIV infection resolve following treatment with highly active antiretroviral therapy (HAART), but residual immune dysfunction may cause disease. Problems with the regulation of the restored immune system in the first six months of treatment can lead to atypical presentations of mycobacterial, cytomegalovirus (CMV), hepatitis B virus or hepatitis C virus (HCV) disease. We defined these conditions as immune restoration diseases (IRD) and showed that they occur in 30-40% of individuals who begin HAART from low CD4 T cell counts. OBJECTIVES: Analysis of immune dysregulation in patients who have responded to HAART. STUDY DESIGN: Patients with successful immune reconstitution following HAART were selected from a database containing details of all patients managed at Royal Perth Hospital (Western Australia) on the basis a CD4 T cell count <100/microl before HAART and an increase of >4-fold or to >200 CD4 T cells/microl. RESULTS: Patients who had experienced an IRD demonstrated increased levels of bioavailable IL-6 and increased expression of CCR5 and CCR3 on monocytes and granulocytes, but numbers of gammadeltaT-cells were similar to patients with similar CD4 T cell counts without an IRD. Carriage of HLA-A2, -B44 was associated with a history of CMV retinitis and/or encephalomyelitis as an IRD, but not with IRD initiated by Mycobacterium sp., cutaneous varicella zoster or herpes simplex infections or HCV. We also identified a patient with Graves' thyrotoxicosis and pronounced lymphadenopathy after HAART, and demonstrated that thyroid stimulating hormone receptor antibody production was associated with an increase in serum soluble CD30, suggesting acquired immune dysregulation. CONCLUSIONS: IRD are associated with persistent immune activation, where differences in genetic profiles suggest that distinct pathological mechanisms are responsible for retinitis/encephalomyelitis IRD. Further studies are important as dysregulated T-cell responses may cause disease later in the course of immune reconstitution.

4031.                        Razonable RR, Aksamit AJ, Wright AJ, Wilson JW. Cidofovir treatment of progressive multifocal leukoencephalopathy in a patient receiving highly active antiretroviral therapy. Mayo Clin Proc  2001 Nov;76(11):1171-5


Progressive multifocal leukoencephalopathy (PML), a frequently fatal demyelinating disease caused by JC virus, occurs as an opportunistic infection in patients with acquired immunodeficiency syndrome. Curative therapy has been elusive, but recent reports suggest its improvement after institution of highly active antiretroviral therapy (HAART). We describe a case of PML that developed 6 months after the patient, a 55-year-old man, began to receive HAART. The PML progressed despite good virologic and immunologic response to HAART. Substantial symptomatic and radiographic improvement occurred after the addition of cidofovir to the treatment regimen. We reviewed the scientific literature on this rare occurrence of PML after institution of HAART and describe the patient characteristics, potential pathogenesis, and therapeutic options, including the successful use of cidofovir as an adjunctive agent.

4032.                        Roehrig JT, Staudinger LA, Hunt AR, Mathews JH, Blair CD. Antibody prophylaxis and therapy for flavivirus encephalitis infections. Ann N Y Acad Sci  2001 Dec;951:286-97


The outbreak of West Nile (WN) encephalitis in the United States has rekindled interest in developing direct methods for prevention and control of human flaviviral infections. Although equine WN vaccines are currently being developed, a WN vaccine for humans is years away. There is also no specific therapeutic agent for flaviviral infections. The incidence of human WN virus infection is very low, which makes it difficult to target the human populations in need of vaccination and to assess the vaccine's economic feasibility. It has been shown, however, that prophylactic application of antiflaviviral antibody can protect mice from subsequent virus challenge. This model of antibody prophylaxis using murine monoclonal antibodies (MAbs) has been used to determine the timing of antibody application and specificity of applied antibody necessary for successful prophylaxis. The major flaviviral antigen is the envelope (E) glycoprotein that binds cellular receptors, mediates cell membrane fusion, and contains an array of epitopes that elicit virus-neutralizing and nonneutralizing antibodies. The protective efficacy of an E-glycoprotein-specific MAb is directly related to its ability to neutralize virus infectivity. The window for successful application of prophylactic antibody to prevent flaviviral encephalitis closes at about 4 to 6 days postinfection concomitant with viral invasion of the brain. Using murine MAbs to modify human disease results in a human antimouse antibody (HAMA) response that eventually limits the effectiveness of subsequent murine antibody applications. To reduce the HAMA response and make these MAbs more generally useful for humans, murine MAbs can be "humanized" or human MAbs with analogous reactivities can be developed. Antiflaviviral human or humanized MAbs might be practical and cost-effective reagents for preventing or modifying flaviviral diseases.


4033.                        Seo SK, Regan A, Cihlar T, Lin DC, Boulad F, George D, Prasad VK, Kiehn TE, Polsky B. Cytomegalovirus ventriculoencephalitis in a bone marrow transplant recipient receiving antiviral maintenance: clinical and molecular evidence of drug resistance. Clin Infect Dis  2001 Nov 1;33(9):e105-8


We describe a case of CMV ventriculoencephalitis in a severely immunocompromised bone marrow transplant recipient who was receiving combination therapy with ganciclovir and foscarnet for treatment of viremia and retinitis. Analysis of sequential viral isolates recovered from the patient's cerebrospinal fluid suggested that disease developed because of the presence of viral resistance and, possibly, low tissue penetration of antiviral agents.


4034.                        Wang T, Anderson JF, Magnarelli LA, Bushmich S, Wong S, Koski RA, Fikrig E. West Nile virus envelope protein: role in diagnosis and immunity. Ann N Y Acad Sci  2001 Dec;951:325-7


The role of antibodies to the West Nile virus envelope (E) protein in serodiagnosis and protection was examined. The E protein was expressed and purified in recombinant form. Antibodies to the E protein were detected in patients with West Nile virus infection. Passive immunization with rabbit anti-E protein sera also partially protected mice from challenge with West Nile virus. The humoral response to the West Nile virus E protein is therefore useful as an aid in the diagnosis and may also play a role in immunity to infection.


4035.                        Wong SC, Ooi MH, Wong MN, Tio PH, Solomon T, Cardosa MJ. Late presentation of Nipah virus encephalitis and kinetics of the humoral immune response. J Neurol Neurosurg Psychiatry  2001 Oct;71(4):552-4


Nipah virus is a newly discovered paramyxovirus transmitted directly from pigs to humans. During a large encephalitis outbreak in Malaysia and Singapore in 1998-9, most patients presented acutely. A 12 year old child is described who developed encephalitis 4 months after exposure to the virus. She was diagnosed by a new indirect IgG enzyme linked immunosorbent assay (ELISA), which is also described. The late presentation and IgG subclass responses had similarities to subacute sclerosing panencephalitis. Nipah virus should be considered in patients with encephalitis even months after their possible exposure.

July 02


4567.      Baric RS, Yount B, Lindesmith L, Harrington PR, Greene SR, Tseng FC, Davis N, Johnston RE, Klapper DG, Moe CL. Expression and self-assembly of norwalk virus capsid protein from Venezuelan equine encephalitis virus replicons. J Virol. 2002 Mar;76(6):3023-30.


The Norwalk virus (NV) capsid protein was expressed using Venezuelan equine encephalitis virus replicon particles (VRP-NV1). VRP-NV1 infection resulted in large numbers of recombinant NV-like particles that were primarily cell associated and were indistinguishable from NV particles produced from baculoviruses. Mutations located in the N-terminal and P1 domains of the NV capsid protein ablated capsid self-assembly in mammalian cells.


4568.      Brault AC, Powers AM, Holmes EC, Woelk CH, Weaver SC. Positively charged amino acid substitutions in the e2 envelope glycoprotein are associated with the emergence of venezuelan equine encephalitis virus. J Virol. 2002 Feb;76(4):1718-30.


Epidemic-epizootic Venezuelan equine encephalitis (VEE) viruses (VEEV) have emerged repeatedly via convergent evolution from enzootic predecessors. However, previous sequence analyses have failed to identify common sets of nucleotide or amino acid substitutions associated with all emergence events. During 1993 and 1996, VEEV subtype IE epizootics occurred on the Pacific Coast of the states of Chiapas and Oaxaca in southern Mexico. Like other epizootic VEEV strains, when inoculated into guinea pigs and mice, the Mexican isolates were no more virulent than closely related enzootic strains, complicating genetic studies of VEE emergence. Complete genomic sequences of 4 of the Mexican strains were determined and compared to those of closely related enzootic subtype IE isolates from Guatemala. The epizootic viruses were less than 2% different at the nucleotide sequence level, and phylogenetic relationships confirmed that the equine-virulent Mexican strains probably evolved from enzootic progenitors on the Pacific Coast of Mexico or Guatemala. Of 35 amino acids that varied among the Guatemalan and Mexican isolates, only 8 were predicted phylogenetically to have accompanied the phenotypic change. One mutation at position 117 of the E2 envelope glycoprotein, involving replacement of Glu by Lys, resulted in a small-plaque phenotype characteristic of epizootic VEEV strains. Analysis of additional E2 sequences from representative enzootic and epizootic VEEV isolates implicated similar surface charge changes in the emergence of previous South American epizootic phenotypes, indicating that E2 mutations are probably important determinants of the equine-virulent phenotype and of VEE emergence. Maximum-likelihood analysis indicated that one change at E2 position 213 has been influenced by positive selection and convergent evolution of the epizootic phenotype.


4569.      Chiappini E, Calabri G, Galli L, Salvi G, de Martino M. Varicella-zoster virus acquired at 4 months of age reactivates at 24 months and causes encephalitis. J Pediatr. 2002 Feb;140(2):250-1.


Varicella-zoster virus (VZV) reactivation in the brain caused encephalitis in a 2-year-old immunocompetent child who had chickenpox 20 months before. Radiologic findings were consistent with large to medium-vessel-vasculitis. VZV-DNA was detected in cerebrospinal fluid. Early acquisition of VZV may predispose to major neurologic complications that can occur years after the primary infection.


4570.      D'Aversa TG, Weidenheim KM, Berman JW. CD40-CD40L interactions induce chemokine expression by human microglia: implications for human immunodeficiency virus encephalitis and multiple sclerosis. Am J Pathol. 2002 Feb;160(2):559-67.


CD40 is a protein on microglia that is up-regulated with interferon (IFN)-gamma and is engaged by CD40L, found on CD4+ T cells, B cells, and monocytes. These interactions may be important in central nervous system inflammatory diseases. Microglia have been shown to be a source of chemokines, whose expression plays a key role in central nervous system pathologies. We examined the expression of CD40 on microglia in human immunodeficiency virus (HIV) encephalitic brain, and the effects of CD40-CD40L interactions on the expression of chemokines by cultured microglia. We found significantly increased numbers of CD40-positive microglia in HIV-infected brain tissue. Treatment of cultured microglia with IFN-gamma and CD40L increased expression of several chemokines. IFN-gamma- and CD40L-induced MCP-1 protein was mediated by activation of the ERK1/2 MAPK pathway, and Western blot analysis demonstrated phosphorylation of ERK1/2 upon stimulation of microglia. In contrast, IFN-gamma- and CD40L-induced IP-10 protein production was mediated by the p38 MAPK pathway. Our data suggest a mechanism whereby CD40L+ cells can induce microglia to secrete chemokines, amplifying inflammatory processes seen in HIV encephalitis and multiple sclerosis, and implicate CD40-CD40L interactions as a target for interventional strategies.


4571.      del Mar Mosquera M, de Ory F, Moreno M, Echevarria JE. Simultaneous detection of measles virus, rubella virus, and parvovirus B19 by using multiplex PCR. J Clin Microbiol. 2002 Jan;40(1):111-6.


We describe here a multiplex reverse transcription-PCR (RTMNPCR) assay designed to detect and differentiate measles virus, rubella virus, and parvovirus B19. Serial dilution experiments with vaccine strains that compared cell culture isolation of measles in B95 cells and rubella in RK13 cells showed sensitivity rates of 0.004 50% tissue culture infective dose (TCID(50)) for measles virus and 0.04 TCID(50) for rubella virus. This RTMNPCR can detect as few as 10 molecules for measles virus and rubella virus and one molecule for parvovirus B19 in dilution experiments with plasmids containing inserts of the primary reaction amplification products. Five pharyngeal exudates from measles patients and 2 of 15 cerebrospinal fluid samples from measles-related encephalitis were found to be positive for measles virus by this RTMNPCR. A total of 3 of 27 pharyngeal exudates from vaccinated children and 2 pharyngeal exudates, plus one urine sample from a case of congenital rubella syndrome, were found to be positive for rubella virus by RTMNPCR, whereas 16 of 19 sera from patients with erythema infectiosum were determined to be positive for parvovirus B19 by RTMNPCR. In view of these results, we can assess that this method is a useful tool in the diagnosis of these three viruses and could be used as an effective surveillance tool in measles eradication programs.


4572.      Garg RK. Subacute sclerosing panencephalitis. Postgrad Med J. 2002 Feb;78(916):63-70. Review.


Subacute sclerosing panencephalitis (SSPE) is a progressive neurological disorder of childhood and early adolescence. It is caused by persistent defective measles virus. Brain biopsies or postmortem histopathological examination show evidence of astrogliosis, neuronal loss, degeneration of dendrites, demyelination, neurofibrillary tangles, and infiltration of inflammatory cells. Patients usually have behavioral changes, myoclonus, dementia, visual disturbances, and pyramidal and extrapyramidal signs. The disease has a gradual progressive course leading to death within 1-3 years. The diagnosis is based upon characteristic clinical manifestations, the presence of characteristic periodic EEG discharges, and demonstration of raised antibody titre against measles in the plasma and cerebrospinal fluid. Treatment for SSPE is still undetermined. A combination of oral isoprinosine (Inosiplex) and intraventricular interferon alfa appears to be the best effective treatment. Patients responding to treatment need to receive it life long. Effective immunisation against measles is the only solution presently available to the problem of this dreaded disease.


4573.      Gupta A, Prayson RA. Pathologic quiz case: a 3-year-old boy with new-onset partial seizures. Arch Pathol Lab Med. 2002 Mar;126(3):379-80. No abstract available.

4574.      Jackson AC, Melanson M, Rossiter JP. Familial herpes simplex encephalitis. Ann Neurol. 2002 Mar;51(3):406-7. No abstract available.

4575.      Jordan-Sciutto KL, Wang G, Murphey-Corb M, Wiley CA.  Cell cycle proteins exhibit altered expression patterns in lentiviral-associated encephalitis. J Neurosci. 2002 Mar 15;22(6):2185-95.


Cell cycle proteins regulate processes as diverse as cell division and cell death. Recently their role in neuronal death has been reported in several models of neurodegeneration. We have reported previously that two key regulators of the cell cycle, the retinoblastoma susceptibility gene product (pRb) and transcription factor E2F1, exhibit altered immunostaining patterns in simian immunodeficiency virus encephalitis (SIVE). Here we show that E2F1 and the inactivated, hyperphosphorylated form of pRb (ppRb) also exhibit altered immunostaining patterns in human immunodeficiency virus encephalitis (HIVE). Quantification of E2F1 and ppRb staining by immunofluorescent confocal microscopy confirms a significant increase in E2F1 and ppRb in both HIVE and the simian model. This increase in E2F1 and ppRb staining correlates with an increase in the presence of activated macrophages, suggesting a link between changes in cell cycle proteins and the presence of activated macrophages. Changes in ppRb and E2F1 staining in SIVE also correlate with alterations in E2F/DNA binding complexes present in the nuclear and cytoplasmic fractions from both midfrontal cortex and basal ganglia. These findings suggest that changes in cell cycle proteins occur in both HIVE and the simian model and that these changes have functional implications for gene expression in neural cells under encephalitic conditions mediated by macrophage activation or infiltration.


4576.                  Lim CC, Lee KE, Lee WL, Tambyah PA, Lee CC, Sitoh YY, Auchus AP, Lin BK, Hui F Nipah virus encephalitis: serial MR study of an emerging disease. Radiology. 2002 Jan;222(1):219-26.


PURPOSE: To report the serial magnetic resonance (MR) imaging findings of the Nipah virus. MATERIALS AND METHODS: Twelve patients underwent serial MR imaging. Eight patients were examined at the outbreak; 11, at 1 month; and seven, at 6 months. Contrast material-enhanced MR images, diffusion-weighted images, and single-voxel proton MR spectroscopic images were reviewed. Clinical and neurologic assessment, as well as analysis of the size, location, and appearance of brain lesions on MR images, were performed. RESULTS: During the outbreak, all eight patients had multiple small foci of high signal intensity within the white matter on T2-weighted images. In six patients, cortical and brain stem lesions were also detected, and five patients had diffusion-weighted MR imaging-depicted hyperintensities. One month after the outbreak, five patients had widespread tiny foci of high signal intensity on T1-weighted images, particularly in the cerebral cortex. Diffusion-weighted images showed decreased prominence or disappearance of lesions over time. There was no evidence of progression or relapse of the lesions at 6-month follow-up. MR spectroscopy depicted reduction in N-acetylaspartate-to-creatine ratio and elevation of choline-to-creatine ratios. CONCLUSION: The Nipah virus has findings unlike other viral encephalitides: small lesions that are primarily within the white matter, with transient punctate cortical hyperintensities on T1-weighted images.

4577.                  Mankowski JL, Queen SE, Tarwater PM, Fox KJ, Perry VH. Accumulation of beta-amyloid precursor protein in axons correlates with CNS expression of SIV gp41. J Neuropathol Exp Neurol. 2002 Jan;61(1):85-90.


Axonal damage represented by accumulation of beta-amyloid precursor protein (beta-APP) develops in numerous central nervous system (CNS) diseases including human immunodeficiency virus (HIV) infection. To study the underlying mechanisms of axonal damage associated with HIV CNS infection, the amount of axonal beta-APP immunostaining in the corpus callosum of 24 simian immunodeficiency virus (SIV)-infected macaques and 3 control macaques was measured by computerized image analysis. The amounts of beta-APP accumulation were then compared with time post-inoculation, extent and character of CNS inflammation, and viral load in the CNS measured by the amount of immunohistochemical staining for the viral transmembrane protein gp41. Significant increases over control values were present in 10 of 24 SIV-infected animals. SIV encephalitis was present in 9 of the 10 animals with elevated beta-APP Increases in beta-APP correlated most strongly with levels of SIV gp41 in the brain (p = 0.005), but significant associations with macrophage infiltration and microglial activation (p = 0.04) and infiltration by cytotoxic lymphocytes (p = 0.05) also were identified. These data demonstrate that beta-APP accumulation in the white matter of SIV-infected macaques develops during SIV infection in close correlation with levels of viral replication and may serve as a sensitive marker of neuronal/axonal damage mediated by viral proteins.



4578.                  Monath TP, Arroyo J, Levenbook I, Zhang ZX, Catalan J, Draper K, Guirakhoo F. Single mutation in the flavivirus envelope protein hinge region increases neurovirulence for mice and monkeys but decreases viscerotropism for monkeys: relevance to development and safety testing of live, attenuated vaccines. J Virol. 2002 Feb;76(4):1932-43.


A chimeric yellow fever (YF) virus/Japanese encephalitis (JE) virus vaccine (ChimeriVax-JE) was constructed by insertion of the prM-E genes from the attenuated JE virus SA14-14-2 vaccine strain into a full-length cDNA clone of YF 17D virus. Passage in fetal rhesus lung (FRhL) cells led to the emergence of a small-plaque virus containing a single Met-->Lys amino acid mutation at E279, reverting this residue from the SA14-14-2 to the wild-type amino acid. A similar virus was also constructed by site-directed mutagenesis (J. Arroyo, F. Guirakhoo, S. Fenner, Z.-X. Zhang, T. P. Monath, and T. J. Chambers, J. Virol. 75:934-942, 2001). The E279 mutation is located in a beta-sheet in the hinge region of the E protein that is responsible for a pH-dependent conformational change during virus penetration from the endosome into the cytoplasm of the infected cell. In independent transfection-passage studies with FRhL or Vero cells, mutations appeared most frequently in hinge 4 (bounded by amino acids E266 to E284), reflecting genomic instability in this functionally important region. The E279 reversion caused a significant increase in neurovirulence as determined by the 50% lethal dose and survival distribution in suckling mice and by histopathology in rhesus monkeys. Based on sensitivity and comparability of results with those for monkeys, the suckling mouse is an appropriate host for safety testing of flavivirus vaccine candidates for neurotropism. After intracerebral inoculation, the E279 Lys virus was restricted with respect to extraneural replication in monkeys, as viremia and antibody levels (markers of viscerotropism) were significantly reduced compared to those for the E279 Met virus. These results are consistent with the observation that empirically derived vaccines developed by mouse brain passage of dengue and YF viruses have increased neurovirulence for mice but reduced viscerotropism for humans.

4579.                  Nau R, Bruck W. Neuronal injury in bacterial meningitis: mechanisms and implications for therapy. Trends Neurosci. 2002 Jan;25(1):38-45. Review.


In bacterial meningitis, long-term neurological sequelae and death are caused jointly by several factors: (1) the systemic inflammatory response of the host, leading to leukocyte extravasation into the subarachnoid space, vasculitis, brain edema and secondary ischemia; (2) stimulation of resident microglia within the CNS by bacterial compounds; and (3) possible direct toxicity of bacterial compounds on neurons. Neuronal injury is mediated by the release of reactive oxygen intermediates, proteases, cytokines and excitatory amino acids, and is executed by the activation of transcription factors, caspases and other proteases. In experimental meningitis, dexamethasone as an adjunct to antibiotic treatment leads to an aggravation of neuronal damage in the hippocampal formation, suggesting that corticosteroids might not be the ideal adjunctive therapy. Several approaches that interfere selectively with the mechanisms of neuronal injury are effective in animal models, including the use of nonbacteriolytic protein synthesis-inhibiting antibiotics, antioxidants and inhibitors of transcription factors, matrix metalloproteinases, and caspases.


4580.                  Perez C, Montes M. Cutaneous leukocytoclastic vasculitis and encephalitis associated with Myccoplasma pneumoniae infection Arch Intern Med. 2002 Feb 11;162(3):352-4.  No abstract.

4581.                  Portela LV, Brenol JC, Walz R, Bianchin M, Tort AB, Canabarro UP, Beheregaray S, Marasca JA, Xavier RM, Neto EC, Goncalves CA, Souza DO.  Serum S100B levels in patients with lupus erythematosus: preliminary observation. Clin Diagn Lab Immunol. 2002 Jan;9(1):164-6.


S100B is an astrocytic calcium-binding protein which has been proposed as a biochemical marker of brain damage or dysfunction in acute and chronic diseases. We investigated whether serum S100B levels could be related to systemic lupus erythematosus (SLE) activity. Patients were grouped as having inactive SLE (ISLE), active SLE without central nervous system (CNS) involvement (ASLE), or active SLE with unequivocal neurologic or psychiatric manifestation (NPSLE). The control group consisted of age- and sex-matched healthy blood donors. S100B levels were determined using a luminescence immunoassay. All SLE groups had higher levels of serum S100B than the control group. Among the SLE groups, significantly higher levels of serum S100B protein were found in the NPSLE group than in the ISLE and ASLE groups, and there was no significant difference in S100B levels between the ISLE and ASLE groups. These preliminary results point to a putative relevance of serum S100B protein levels in SLE patients, specifically concerning CNS involvement present in this disease.


4582.                  Shenoy S, Wilson G, Prashanth HV, Vidyalakshmi K, Dhanashree B, Bharath R.  Primary meningoencephalitis by Naegleria fowleri: first reported case from Mangalore, South India. J Clin Microbiol. 2002 Jan;40(1):309-10.


A fatal case of primary amebic meningoencephalitis (PAM) in a 5-month-old infant is described. The disease may have been contracted during bathing. The source of water was from an artificial well. The clinical presentation, the isolation of the ameba from the cerebrospinal fluid, the poor response to amphotericin B, and the ultimate fatal outcome are all consistent with the diagnosis of PAM. On the basis of its ability to grow at temperatures above 30 degrees C, the morphology of the trophozoite, and the presence of flagellate forms, the ameba was identified as Naegleria fowleri. Pathogenic N. fowleri amebae were recovered from samples of water from the well. To our knowledge this case represents the second case of PAM in an infant in the absence of the history of swimming.


4583.                  Skiest DJ. Focal neurological disease in patients with acquired immunodeficiency syndrome. Clin Infect Dis. 2002 Jan 1;34(1):103-15. Review.

Focal neurological disease in patients with acquired immunodeficiency syndrome may be caused by various opportunistic pathogens and malignancies, including Toxoplasma gondii, progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV), and Epstein-Barr virus-related primary central nervous system (CNS) lymphoma. Diagnosis may be difficult, because the findings of lumbar puncture, computed tomography (CT), and magnetic resonance imaging are relatively nonspecific. Newer techniques have led to improved diagnostic accuracy of these conditions. Polymerase chain reaction (PCR) of cerebrospinal fluid specimens is useful for diagnosis of PML, CNS lymphoma, and CMV encephalitis. Recent studies have indicated the diagnostic utility of new neuroimaging techniques, such as single-photon emission CT and positron emission tomography. The combination of PCR and neuroimaging techniques may obviate the need for brain biopsy in selected cases. However, stereotactic brain biopsy, which is associated with relatively low morbidity rates, remains the reference standard for diagnosis. Highly active antiretroviral therapy has improved the prognosis of several focal CNS processes, most notably toxoplasmosis, PML, and CMV encephalitis.


4584.                  Straumanis JP, Tapia MD, King JC. Influenza B infection associated with encephalitis: treatment with oseltamivir. Pediatr Infect Dis J. 2002 Feb;21(2):173-5.


Encephalitis associated with acute influenza infection is unusual in nonepidemic years. A case of a 10-year-old child with influenza B encephalitis and profound weakness who was treated with oseltamivir is presented. This case illustrates several of the unusual findings associated with influenza infections and the result of treatment of influenza B encephalitis with oseltamivir.


4585.                  Wallington T, Weir E. Varicella control and vaccine coverage: issues and challenges. CMAJ. 2002 Mar 5;166(5):631-2. No abstract.

4586.                  Whitley RJ, Gnann JW. Viral encephalitis: familiar infections and emerging pathogens. Lancet. 2002 Feb 9;359(9305):507-13. Review.


Significant advances have been made in our understanding of the natural history and pathogenesis of viral encephalitides. The development of PCR has greatly increased our ability to diagnose viral infections of the central nervous system, particularly for herpes and enteroviral infections. Advancing knowledge has led to the recognition that some encephalitides can be reliably prevented by vaccination (eg, Japanese encephalitis and rabies). For other pathogens such as the arboviruses, the focus has been on prevention by vector control. Finally, effective therapy has been established for a very limited number of viral infections (eg, acyclovir for herpes simplex encephalitis). Other potentially useful treatments, such as pleconaril for enteroviral meningoencephalitis are under clinical evaluation. We review current understanding of viral encephalitides with particular reference to emerging viral infections and the availability of existing treatment regimens.



4587.                  Wilcox RD. Cidofovir: progress in the treatment of progressive multifocal encephalopathy (PML)? HIV Clin. 2002 Winter;14(1):1-2. No abstract.

4588.                  Zeller V, Truffot C, Agher R, Bossi P, Tubiana R, Caumes E, Jouan M, Bricaire F, Katlama C.  Discontinuation of secondary prophylaxis against disseminated Mycobacterium avium complex infection and toxoplasmic encephalitis. Clin Infect Dis. 2002 Mar 1;34(5):662-7.


We retrospectively studied outcomes for patients infected with human

immunodeficiency virus who received highly active antiretroviral therapy (HAART) and had stopped receiving secondary prophylaxis against toxoplasmic encephalitis (TE) or disseminated Mycobacterium avium complex (MAC) infection. Nineteen patients had a history of TE, and 26 had a history of disseminated MAC infection. The median duration of secondary prophylaxis was 27 months, and the median duration of HAART before discontinuation of secondary prophylaxis was 22 months. Median CD4(+) cell counts at the time of cessation of secondary prophylaxis against TE or disseminated MAC infection were 404 and 105 cells/mm(3), respectively. Plasma virus load was undetectable in 68% of the patients who had a history of TE and in 31% of patients who had a history of disseminated MAC infection. Patients were followed up for a median of 29 months after discontinuation of secondary prophylaxis; no relapses occurred in patients with a history of TE, and 3 relapses occurred in patients with a history of disseminated MAC infection (incidence, 4 relapses per 100 person-years).


4589.                  Zerr DM, Gupta D, Huang ML, Carter R, Corey L. Effect of antivirals on human herpesvirus 6 replication in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002 Feb 1;34(3):309-17.


Human herpesvirus 6 (HHV-6) appears to cause central nervous system (CNS) syndromes, especially in hematopoietic stem cell transplant (HSCT) recipients. We reviewed our experience with HHV-6-associated CNS disease to evaluate both the clinical and virological presentation and response to antiviral therapy. A search of our virology database from January 1998 through June 2000 identified 11 HSCT recipients who had HHV-6 DNA detected by polymerase chain reaction in cerebrospinal fluid (CSF); 8 of whom had CNS dysfunction without another clear etiology identified. HHV-6 levels in serum and CSF were evaluated before and after ganciclovir and/or foscarnet therapy. Median log HHV-6 CSF levels appeared to decrease over time concurrent with antiviral therapy (serum level, 2.0 vs. 0 copies/mL [P=.38]; CSF level, 4.4 vs. 2.0 copies/mL [P=.13], sign test). Our data suggests that HHV-6 may cause moderate to severe CNS disease after HSC transplantation. Prospective studies are needed to define the spectrum of HHV-6-associated disease and to determine whether antiviral therapy offers clinical benefit.


4590.                  Ziegner UH, Kobayashi RH, Cunningham-Rundles C, Espanol T, Fasth A, Huttenlocher A, Krogstad P, Marthinsen L, Notarangelo LD, Pasic S, Rieger CH, Rudge P, Sankar R, Shigeoka AO, Stiehm ER, Sullivan KE, Webster AD, Ochs HD.  Progressive neurodegeneration in patients with primary immunodeficiency disease on IVIG treatment. Clin Immunol. 2002 Jan;102(1):19-24.


We have identified 14 patients with diverse primary immunodeficiencies who have developed progressive neurodegeneration of unknown etiology. All patients had received immunoglobulin replacement therapy for a mean duration of 6.5 years (range of 0.5-13.5 years) at the time of first neurological symptoms. Diagnostic tests of blood and cerebrospinal fluid analyses included chemistry, cultures, PCR for viral genomes, and cytology. In addition, neuroimaging and electrophysiologic studies were performed. Brain tissue histology (n = 5) revealed nonspecific encephalitis with microglial infiltration and neuronal loss. Twelve patients died 6 months to 15 years (median 4.3 years) after onset of neurologic findings. No evidence of any infectious disease that could have explained our patients' progressive encephalopathy was found either during their lifetimes or postmortem. These patients may have had an unusual manifestation of primary immunodeficiency diseases, an autoimmune reaction against neuronal tissue, a yet undefined infectious agent, or a complication of IVIG therapy. To help determine the etiology of this rare complication, an international surveillance system for primary immunodeficiency patients who develop progressive neurodegeneration of unknown cause is recommended. (c)2001 Elsevier Science.


Oct 2002

5277.                  Antunes NL, Souweidane MM, Lis E, Rosenblum MK, Steinherz PG. Methotrexate leukoencephalopathy presenting as Kluver-Bucy syndrome and uncinate seizures. Pediatr Neurol. 2002 Apr;26(4):305-8.


Methotrexate causes several biochemical changes that impact the nervous system. The neurotoxicity usually affects the cerebral white matter, causing a leukoencephalopathy that can be chronic and progressive with cognitive decline. A 15-year-old male developed olfactory seizures and behavioral abnormalities (hypersexuality, placidity, and memory disturbances) compatible with partial Kluver-Bucy syndrome after treatment for central nervous system leukemia with intraventricular methotrexate. A magnetic resonance imaging study revealed evidence of white matter disease affecting both temporal lobes. A brain biopsy revealed a necrotizing encephalopathy compatible with methotrexate-related white matter injury. It may be prudent to verify normal cerebrospinal fluid dynamics before the administration of intraventricular methotrexate in children with a history of central nervous system leukemia.


5278.                  Bauer J, Bien CG, Lassmann H. Rasmussen's encephalitis: a role for autoimmune cytotoxic T lymphocytes. Curr Opin Neurol. 2002 Apr;15(2):197-200. Review.


The present review describes advances in Rasmussen's encephalitis (also known as Rasmussen's syndrome), an unihemispheric intractable epileptic disease with persistent inflammation. Specific attention is given to the recent recognition of cytotoxicity by CD8+/granzyme-B-positive T lymphocytes as a new pathogenic mechanism of neuronal damage.

5279.                  Beaman MH, Wesselingh SL. 4: Acute community-acquired meningitis and encephalitis. Med J Aust. 2002 Apr 15;176(8):389-96. Review.


Acute meningitis and encephalitis are medical emergencies that require prompt assessment (usually by cerebral imaging and lumbar puncture) and treatment; specialist consultation is recommended. In acute meningitis, early administration of antibiotics can be life-saving (usually high-dose penicillin and/or a third-generation cephalosporin); antibiotics may be needed before referral to hospital. Emergence of penicillin and cephalosporin resistance in Streptococcus pneumoniae has necessitated more complex antibiotic regimens that include vancomycin or rifampicin for empirical treatment of meningitis. Adjunctive dexamethasone therapy may be of benefit in children with Haemophilus influenzae meningitis; there is no controlled evidence of its benefit in adults, but it could be considered in those with raised intracranial pressure. In possible encephalitis, empirical therapy with intravenous aciclovir should be given to cover herpes simplex virus (HSV) until the cause is established; HSV encephalitis may be fatal and leaves up to 50% of survivors with long-term sequelae.

5280.                  Beschorner R, Schluesener HJ, Gozalan F, Meyermann R, Schwab JM. Infiltrating CD14+ monocytes and expression of CD14 by activated parenchymal microglia/macrophages contribute to the pool of CD14+ cells in ischemic brain lesions. J Neuroimmunol. 2002 May;126(1-2):107-15.


CD14, a key pattern recognition receptor of the innate immune system, is a surface molecule on monocytic cells involved in cellular activation. We investigated 18 autopsy cases of focal cerebral infarctions (FCI) by immunohistochemistry to examine CD14 expression following ischemia. Controls confirmed constitutive CD14 expression by few perivascular cells. In contrast to quiescent CD14- parenchymal microglial cells, following ischemia activated microglia/macrophages expressed abundant CD14. In FCI, CD14+ cells increased both in perivascular spaces and in brain parenchyma within 1-2.5 days and remained elevated until late stages. Early CD14 expression suggests an essential part of CD14 in the acute inflammatory response following stroke.

5281.                  Chan PK, Chik KW, To KF, Li CK, Shing MM, Ng KC, Yuen PM, Cheng AF. Case report: human herpesvirus 7 associated fatal encephalitis in a peripheral blood stem cell transplant recipient. J Med Virol. 2002 Apr;66(4):493-6.


Previous studies have suggested a neuroinvasive and neuropersistent potential of human herpesvirus 7 (HHV-7). In this report, a case of fatal encephalitis is described and its association with HHV-7 infection is discussed. An 8-year-old girl received a peripheral blood stem cell transplant for relapsed acute lymphoblastic leukaemia. The post-transplant period was uneventful and a course of intrathecal chemotherapy was given on Day-30. On Day-41, she developed acute encephalopathy with diplopia and nystagmus. She ran a rapid downhill course and succumbed despite antiviral treatment. The only positive pathological finding was the multiple microscopic foci of haemorrhage associated with neuronal degeneration detected in the brain stem. All microbiological investigations were negative, except for the presence of HHV-7 DNA in cerebrospinal fluid and brain stem tissue samples. Copyright 2002 Wiley-Liss, Inc.


5282.                  Dunlop O, Bjorklund R, Bruun JN, Evensen R, Goplen AK, Liestol K, Sannes M, Maehlen J, Myrvang B. Early psychomotor slowing predicts the development of HIV dementia and autopsy-verified HIV encephalitis. Acta Neurol Scand. 2002 Apr;105(4):270-5.


OBJECTIVES- To ask if slowed motor speed predicts later human immunodeficiency virus (HIV) dementia and HIV encephalitis. METHODS- In 100 deceased acquired immunodeficiency syndrome (AIDS) patients prior results from repeated testing of the movement reaction time test were correlated with later clinical signs of HIV dementia and with neuropathological signs of HIV encephalitis. Autopsy was performed in 72 patients. RESULTS- Movement reaction time 1-2 years prior to death, or at the time of clinical AIDS diagnosis predicted both development of HIV dementia (P<0.05) and HIV encephalitis at autopsy (P<0.01). CONCLUSION- Testing for early psychomotor slowing may be used to identify patients at risk of HIV dementia and HIV encephalitis.


5283.                  Fontoura P, Vale J, Lima C, Scaravilli F, Guimaraes J. Progressive myoclonic ataxia and JC virus encephalitis in an AIDS patient. J Neurol Neurosurg Psychiatry. 2002 May;72(5):653-6.



A case of progressive myoclonic ataxia in an AIDS patient is described, which evolved over a 13 month period. The ataxia persisted as the only clinical finding for several months before the appearance of a severe tetraparesis and cachexia. Throughout the clinical progression, magnetic resonance imaging (MRI) revealed the presence of bilateral, progressive, isolated, and symmetrical lesions involving the red nuclei, subthalami, thalami, lenticular nuclei, and primary motor cortices. Neuropathological examination, supplemented by in situ hybridisation for JC virus DNA, confirmed that the lesions were those of progressive multifocal leucoencephalopathy (PML). The exceptional clinical presentation of PML in this case is the first report of progressive myoclonic ataxia caused by PML. The selective nature of the lesions confirms the role of the dentato-rubral-thalamo-cortical tract in the pathogenesis of progressive myoclonic ataxia. The atypical MRI findings further emphasise the need for expanded diagnostic criteria for PML in AIDS patients and support the use of more aggressive diagnostic methods as new treatments become available.


5284.                  Gerber JE, Johnson JE, Scott MA, Madhusudhan KT. Fatal meningitis and encephalitis due to Bartonella henselae bacteria. J Forensic Sci. 2002 May;47(3):640-4.


Bacterial infection due to Bartonella henselae commonly develops in children and young adults following cat/dog contacts and/or cat/dog scratches. Regional lymphadenopathy is its most common clinical expression. However, encephalitis and Parinaud's syndrome (oculoglandular syndrome) have also been reported as has systemic illness. A review of the international literature in all languages revealed no fatal complications in immunocompetent hosts. A four-year-old white child with no underlying illness began to have seizure-like activity. She was taken to a local hospital and subsequently transferred to a medical center. The child was treated aggressively for seizures and fever of unknown origin. However, her condition rapidly declined and she died without a specific diagnosis. At autopsy there was marked cerebral edema with no gross evidence of acute meningitis. Microscopic exams revealed multiple granulomatous lesions as well as a meningitis and encephalitis. A variety of cultures and stains were negative for acid fast and fungal organisms. Warthin-Starry stains of involved tissue including brain and liver revealed pleomorphic rod shaped bacilli consistent with Barronella henselae. Analysis of brain tissue with polymerase chain reaction (PCR) and Southern blot for the deoxyribonucleic acid (DNA) was definitive for DNA of Bartonella henselae bacteria.

5285.                  Gibbs AN, Moroney J, Foley-Nolan D, O'Connell PG. Neuromyelitis optica (Devic's syndrome) in systemic lupus erythematosus: a case report. Rheumatology (Oxford). 2002 Apr;41(4):470-1. No abstract.

5286.                  Gorry PR, Taylor J, Holm GH, Mehle A, Morgan T, Cayabyab M, Farzan M, Wang H, Bell JE, Kunstman K, Moore JP, Wolinsky SM, Gabuzda D. Increased CCR5 affinity and reduced CCR5/CD4 dependence of a neurovirulent primary human immunodeficiency virus type 1 isolate. J Virol. 2002 Jun;76(12):6277-92.


Most human immunodeficiency virus type 1 (HIV-1) viruses in the brain use CCR5 as the principal coreceptor for entry into a cell. However, additional phenotypic characteristics are necessary for HIV-1 neurotropism. Furthermore, neurotropic strains are not necessarily neurovirulent. To better understand the determinants of HIV-1 neurovirulence, we isolated viruses from brain tissue samples from three AIDS patients with dementia and HIV-1 encephalitis and analyzed their ability to induce syncytia in monocyte-derived macrophages (MDM) and neuronal apoptosis in primary brain cultures. Two R5X4 viruses (MACS1-br and MACS1-spln) were highly fusogenic in MDM and induced neuronal apoptosis. The R5 viruses UK1-br and MACS2-br are both neurotropic. However, only UK1-br induced high levels of fusion in MDM and neuronal apoptosis. Full-length Env clones from UK1-br required lower CCR5 and CD4 levels than Env clones from MACS2-br to function efficiently in cell-to-cell fusion and single-round infection assays. UK1-br Envs also had a greater affinity for CCR5 than MACS2-br Envs in binding assays. Relatively high levels of UK1-br and MACS2-br Envs bound to CCR5 in the absence of soluble CD4. However, these Envs could not mediate CD4-independent infection, and MACS2-br Envs were unable to mediate fusion or infection in cells expressing low levels of CD4. The UK1-br virus was more resistant than MACS2-br to inhibition by the CCR5-targeted inhibitors TAK-779 and Sch-C. UK1-br was more sensitive than MACS2-br to neutralization by monoclonal antibodies (2F5 and immunoglobulin G1b12 [IgG1b12]) and CD4-IgG2. These results predict the presence of HIV-1 variants with increased CCR5 affinity and reduced dependence on CCR5 and CD4 in the brains of some AIDS patients with central nervous system disease and suggest that R5 variants with increased CCR5 affinity may represent a pathogenic viral phenotype contributing to the neurodegenerative manifestations of AIDS.


5287.                  Karim A, Ahmed S, Rossoff LJ. Legionnaire's disease associated with acute encephalitis and arrhythmia. Crit Care Med. 2002 May;30(5):1028-9.


OBJECTIVE: To report an unusual, life-threatening combination of neurologic, cardiac, and gastrointestinal symptoms in the presence of a community-acquired pneumonia. DESIGN: Case report. SETTING: University hospital. PATIENT: Previously healthy young male. INTERVENTION: Diagnostic fiberoptic bronchoscopy, lumber puncture, magnetic resonance imaging of the brain, and institution of systemic antibiotics. MAIN RESULT: Gradual clinical improvement of a multiple-system illness. CONCLUSION: Legionellosis should be considered in the differential diagnosis of patients presenting with neurologic, cardiac, and gastrointestinal symptoms, particularly in the presence of radiographic pneumonia. Furthermore, Legionella meningoencephalitis may present with findings on magnetic resonance imaging previously thought to be characteristic of herpes encephalitis.

5289.                  Kastrukoff LF, Kim SU. Oligodendrocytes from human donors differ in resistance to herpes simplex virus 1 (HSV-1). Glia. 2002 Apr 1;38(1):87-92.


Primary cultures of human oligodendrocytes (HOLs) were established from six different donors. Differences in resistance to infection with herpes simplex virus 1 (HSV-1) were determined between the primary cultures of HOL in tissue culture infective dose 50 (TCID(50)), indirect immunofluoresence (IF), and serial electron microscopy (EM) studies. Virus production at different multiplicities of infection (MOIs) indicated that differences in HSV-1 replication were statistically significant and MOI-dependent. Overall, virus yield from the HOL cultures infected at an MOI of 1 increased up to 6 days postinfection (PI); no additional enhancement occurred at 7 days PI. However, differences in the replication capacity of the six HOL cultures observed at 5 days PI persisted at 6 and 7 days PI. When taken together, the results of these investigations indicate that, similar to experimental animals, resistance to HSV-1 differs between primary cultures of HOL and is donor-dependent. The results also raise the possibility that similar to experimental animals, resistance to HSV-1, mediated at the level of HOL, may be genetically determined. Furthermore, permissive infections of primary cultures of HOL were established with HSV-1 over a wide range of MOIs, similar to results obtained with viral infection of primary murine oligodendrocytes, but neither latent nor abortive infections of HOL were induced in vitro, even at very low MOIs. Resistance to HSV-1, mediated by glial cells, is a nonimmune mechanism that may influence the development of acute CNS infection in man as well as individual susceptibility to this virus. Copyright 2002 Wiley-Liss, Inc.

5290.                  Lee JH, Na DG, Choi KH, Kim KJ, Ryoo JW, Lee SY, Suh YL. Subcortical low intensity on MR images of meningitis, viral encephalitis, and leptomeningeal metastasis. AJNR Am J Neuroradiol. 2002 Apr;23(4):535-42.


BACKGROUND AND PURPOSE: Subcortical low-intensity lesion on T2-weighted images is an uncommon manifestation of ischemia, multiple sclerosis, and Sturge-Weber disease. This study was performed to determine whether subcortical low signal intensity is an MR feature of meningitis, viral encephalitis, or leptomeningeal metastasis and to investigate a cause of subcortical low intensity. METHODS: We retrospectively reviewed MR images of 117 patients with meningitis, encephalitis (viral or unknown), or leptomeningeal metastasis for the presence of subcortical low intensity, meningeal enhancement, signal intensity change of cortex, and change in subcortical low intensity on follow-up images. Diffusion-weighted (DW) images and apparent diffusion coefficient (ADC) maps were obtained in 55 patients. Subcortical low-intensity lesions were also quantitatively analyzed on T2-weighted, fluid-attenuated inversion recovery (FLAIR), and DW images. RESULTS: Subcortical low intensity was found in nine (23.7%) of 38 patients with encephalitis (viral, 31; unknown origin, 7), five (24%) of 21 with leptomeningeal metastasis, and five (9%) of 58 with meningitis. Leptomeningeal enhancement was observed in 100% and cortical hyperintensity in 14 (74%) of 19 patients with subcortical low intensity. Leptomeningeal enhancement was seen in 46 (47%) and cortical hyperintensity in 33 (34%) of 98 patients without subcortical low intensity. Subcortical low intensity disappeared or decreased in extent on follow-up MR images in all seven patients who underwent follow-up. ADC of subcortical low-intensity lesions was lower than that of the contralateral area and decreased by 9.3 +/- 11.4%. CONCLUSION: Subcortical low intensity was uncommonly found in meningitis, viral encephalitis, and leptomeningeal metastasis. It is a nonspecific MR sign of various meningeal and cortical diseases. Although the cause of subcortical low intensity remains uncertain, free radical formation may play a role as a causative factor.


5291.                  MacLean HJ, Douen AG. Severe amnesia associated with human herpesvirus 6 encephalitis after bone marrow transplantation. Transplantation. 2002 Apr 15;73(7):1086-9.


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.


5292.                  Misra UK, Kalita J. Prognosis of Japanese encephalitis patients with dystonia compared to those with parkinsonian features only. Postgrad Med J. 2002 Apr;78(918):238-41.


OBJECTIVES: A number of movement disorders have been reported in Japanese encephalitis (JE). The prognostic significance of these movement disorders, however, has not been evaluated. The present study reports the prognostic significance of parkinsonian features and dystonia in JE. PATIENTS AND METHODS: During 1992 and 1998, 50 JE patients were managed; 35 of them developed movement disorders (the study group). The diagnosis of JE was based on clinical, radiological, and serological criteria. Parkinsonian features were rated by the unified Parkinson's disease rating scale and dystonia by the dystonia rating scale. The patients with parkinsonian features only were classified into group I and those with additional dystonia or dyskinesia into group II. The outcome was defined at the end of three months into poor, partial, and complete recovery depending on how the patients coped with daily living activities. RESULTS: The patients' ages ranged from 2 to 64 years and 11 were females. The admission mean Glasgow coma scale score was 6.9 (range 4-13). The movement disorders were noted after 1-4 weeks of ictus. There were 16 patients in group I and 19 in group II. The parkinsonian features were more pronounced in group II than in group I. At three months of follow up, fewer patients had parkinsonian features in group I than group II. Hypophonia, however, persisted in 12 patients in group I and 16 in group II until the three month follow up. In group II, the mean dystonia score was 3.2 which regressed to 1.8 at three months. Tremor was present in five patients in groups I and eight in group II. Cranial computed tomography was abnormal in six and magnetic resonance imaging abnormal in 15 patients in group I and in nine and 12 patients respectively in group II. The thalamus was most frequently involved (11 patients in each group), basal ganglia (four in group I and six in group II), and midbrain (six in group I and one in group II). Group II patients had poorer recovery compared with group I. In group I, at the end of three months functional recovery was complete in 10, partial in two, and poor in three patients. In group II, four patients had complete, seven partial, and eight poor recovery. CONCLUSION: JE results in a transient form of parkinsonian syndrome, which is associated with a lower frequency of tremor and prominent hypophonia. The presence of dystonia suggests more severe illness and poorer prognosis.


5293.                  Redington JJ, Tyler KL. Viral infections of the nervous system, 2002: update on diagnosis and treatment. Arch Neurol. 2002 May;59(5):712-8. Review. No abstract.

5294.                  Saha M, Kumar S, Das A, Gupta RK. Similarities and differences of MR findings between Japanese encephalitis and Wilson's disease. Eur Radiol. 2002 Apr;12(4):872-6.


Although Japanese Encephalitis (JE) and Wilson's disease (WD) are different entities, MR findings in both these conditions are quite similar. The purpose of this retrospective study was to find out the similarities and differences between JE and WD on MR imaging. The study group comprised 25 proven cases of JE and 10 cases of WD. Spin echo (SE) TI- and T2-weighted imaging was performed on a 1.5-T MR system. Fourteen of these 35 cases (10 JE, 4 WD) were also examined using T1-weighted magnetization transfer (MT) SE sequence before and after contrast administration. Although both JE and WD showed similar topographical distribution of lesions, predominant involvement of the basal ganglia and thalami, there were some differences. Brain stem lesion was more frequent for WD than for JE, and posteromedial part of the thalami was spared in WD. The lesion characteristics were also different between both; in WD mixed intensity in the basal ganglia and hyperintense linear rim at the peripheral putamen was observed frequently, whereas hyperintense basal ganglia on T2-weighted images, subacute hemorrhage in the thalami and meningeal enhancement were seen only in the patients with JE. These characteristic lesion criteria may help in differentiation of JE from WD on MR imaging.


5295.                  Sethi S, Bhargava SC. Kleine-Levin syndrome following acute non-specific encephalitis. Indian J Pediatr. 2002 May;69(5):451.  No abstract.

5296.                  Shimizu T, Matsuishi T, Iwamoto R, Handa K, Yoshioka H, Kato H, Ueda S, Hara H, Tabira T, Mekada E. Elevated levels of anti-CD9 antibodies in the cerebrospinal fluid of patients with subacute sclerosing panencephalitis. J Infect Dis. 2002 May 1;185(9):1346-50.


Subacute sclerosing panencephalitis (SSPE) is a slowly progressive and highly lethal disease of the central nervous system. Although the primary cause of SSPE is believed to be persistent infection of neuron and glial cells by a measles virus, the precise mechanism of the progression of this disease has not yet been elucidated. CD9, a member of the tetraspanin family, is expressed in myelin and other nervous tissues. This study detected significant amounts of anti-CD9 antibodies in the cerebrospinal fluid (CSF) of all patients with SSPE included in the study. Anti-CD9 antibodies were also detected in the CSF of some patients with other neurologic disorders, but those patients had lower levels of anti-CD9 antibodies than did the patients with SSPE. The level of anti-CD9 antibodies was elevated and reached a peak that coincided with the appearance of brain atrophy. These findings shed light on a new aspect of the causes and progression of SSPE.

5297.                  Stone R. Infectious disease. Siberia's deadly stalker emerges from the shadows. Science. 2002 Apr 26;296(5568):642-5. No abstract.

5298.                  Warrilow D, Northill JA, Pyke A, Smith GA. Single rapid TaqMan fluorogenic probe based PCR assay that detects all four dengue serotypes. J Med Virol. 2002 Apr;66(4):524-8.


Public health laboratories require rapid diagnosis of dengue outbreaks for application of measures such as vector control. We have developed a rapid single fluorogenic probe-based polymerase chain reaction assay for the detection of all four dengue serotypes (FUDRT-PCR). The method employs primers and probe that are complementary to the evolutionarily conserved 3' untranslated region of the dengue genome. The assay detected viral RNA of strains of all four dengue serotypes but not of the flaviviruses Japanese encephalitis virus, Murray Valley encephalitis virus, Kunjin, Stratford, West Nile, Alfuy or Yellow fever. When compared to an existing nested-PCR assay for the detection of dengue on clinical samples, FUDRT-PCR detected dengue 1 (100%, n=14), dengue 2 (85%, n=13), dengue 3 (64%, n=14) and dengue 4 (100%, n=3) with the indicated sensitivities. FUDRT-PCR enables diagnosis of acute dengue infection in four hours from sample receipt. In addition, a single-test procedure should result in a reduction in the number of tests performed with considerable cost savings for diagnostic laboratories. Copyright 2002 Wiley-Liss, Inc.

5299.                  Weil AA, Glaser CA, Amad Z, Forghani B. Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain reaction result. Clin Infect Dis. 2002 Apr 15;34(8):1154-7.


A statewide encephalitis diagnostic project of the California State Department of Health Services found that herpes simplex virus 1 DNA may not be detectable by molecular methods early in the clinical course of herpes simplex encephalitis.


Pathogenesis :

5300.                  Inoue T, Kira R, Nakao F, Ihara K, Bassuny WM, Kusuhara K, Nihei K, Takeshita K, Hara T.  Contribution of the interleukin 4 gene to susceptibility to subacute sclerosing panencephalitis. Arch Neurol. 2002 May;59(5):822-7.


BACKGROUND: Although the exact pathogenesis of subacute sclerosing panencephalitis (SSPE) remains to be determined, both viral and host factors seem to be involved. OBJECTIVE: To identify host genetic factors involved in the development of SSPE. METHODS: We investigated the association of polymorphisms in the T helper (Th)1 and Th2 cytokine, and related genes (interferon [IFN]-gamma, IFN-gamma receptor 1 [IFN-gamma R1], IFN-gammaR2 [IRF-1], interleukin 12 receptor beta 1 [IL-12Rbeta1], IL-4, IL-4R, and IL-10 genes) with SSPE in Japanese subjects. RESULTS: A significant association (P =.03) was observed between SSPE and the T allele of the biallelic polymorphism at position -589 in the promoter region of the IL-4 gene. The IRF-1 allele 1 tended to interact with the IL-4 promoter -589 T genotype in the development of SSPE (P =.06), as judged on logistic regression analysis. The frequency of the genotype combination of IL-4 promoter -589 T and IRF-1 allele 1 (at least 1 allele) in patients with SSPE was much higher than that in the controls (47.7% vs 22.0%; P =.003, chi2 analysis). However, there was no association between other polymorphisms and SSPE. CONCLUSION: To our knowledge, this study is the first to demonstrate the possibility that the IL-4 promoter gene -589 T gene polymorphism with increased IL-4 synthesis in combination with IRF-1 allele 1 confers host genetic susceptibility to SSPE in Japanese subjects.

5301.                  Lee E, Lobigs M. Mechanism of virulence attenuation of glycosaminoglycan-binding variants of Japanese encephalitis virus and Murray Valley encephalitis virus. J Virol. 2002 May;76(10):4901-11.


The in vivo mechanism for virulence attenuation of laboratory-derived variants of two flaviviruses in the Japanese encephalitis virus (JEV) serocomplex is described. Host cell adaptation of JEV and Murray Valley encephalitis virus (MVE) by serial passage in adenocarcinoma cells selected for variants characterized by (i) a small plaque phenotype, (ii) increased affinity to heparin-Sepharose, (iii) enhanced susceptibility to inhibition of infectivity by heparin, and (iv) loss of neuroinvasiveness in a mouse model for flaviviral encephalitis. We previously suggested that virulence attenuation of the host cell-adapted variants of MVE is a consequence of their increased dependence on cell surface glycosaminoglycans (GAGs) for attachment and entry (E. Lee and M. Lobigs, J. Virol. 74:8867-8875, 2000). In support of this proposition, we find that GAG-binding variants of JEV and MVE were rapidly removed from the bloodstream and failed to spread from extraneural sites of replication into the brain. Thus, the enhanced affinity of the attenuated variants for GAGs ubiquitously present on cells and extracellular matrices most likely prevented viremia of sufficient magnitude and/or duration required for virus entry into the brain parenchyma. This mechanism may also account, in part, for the attenuation of the JEV SA14-14-2 vaccine, given the sensitivity of the virus to heparin inhibition. A pronounced loss of the capacity of the GAG-binding variants to produce disease was also noted in mice defective in the alpha/beta interferon response, a mouse strain shown here to be highly susceptible to infection with JEV serocomplex flaviviruses. Despite the close genetic relatedness of JEV and MVE, the variants selected for the two viruses were altered at different residues in the envelope (E) protein, viz., Glu(306) and Asp(390) for JEV and MVE, respectively. In both cases the substitutions gave the protein an increased net positive charge. The close spatial proximity of amino acids 306 and 390 in the predicted E protein structure strongly suggests that the two residues define a receptor-binding domain involved in virus attachment to sulfated proteoglycans.

5302.                  Lin TY, Chang LY, Hsia SH, Huang YC, Chiu CH, Hsueh C, Shih SR, Liu CC, Wu MH. The 1998 enterovirus 71 outbreak in Taiwan: pathogenesis and management. Clin Infect Dis. 2002 May 1;34 Suppl 2:S52-7.


The most recently discovered enterovirus, enterovirus 71 (EV71), is neurotropic and may cause severe disease and sudden death in children. In 1998, a large outbreak of enterovirus infection occurred in Taiwan that resulted in 405 severe cases in children and 78 deaths. Of the 78 children who died, 71 (91%) were <5 years old. EV71 was the primary agent in fatal cases of infection. Most of these patients died within 1-2 days of admission to the hospital. We hypothesize that EV71 directly attacks the central nervous system and causes neurogenic pulmonary edema and cardiac decompensation through the mechanism of sympathetic hyperactivity and inflammatory responses. Early recognition of risk factors and  intensive care are crucial to successful treatment of this fulminant infection. After poliovirus is eradicated, EV71 will become the most important enterovirus that affects children, and development of a vaccine may be the only effective measure against it.


5303.                  Shi PY, Tilgner M, Lo MK, Kent KA, Bernard KA. Infectious cDNA clone of the epidemic west nile virus from New York City. J Virol. 2002 Jun;76(12):5847-56.


We report the first full-length infectious clone of the current epidemic, lineage I, strain of West Nile virus (WNV). The full-length cDNA was constructed from reverse transcription-PCR products of viral RNA from an isolate collected during the year 2000 outbreak in New York City. It was cloned into plasmid pBR322 under the control of a T7 promoter and stably amplified in Escherichia coli HB101. RNA transcribed from the full-length cDNA clone was highly infectious upon transfection into BHK-21 cells, resulting in progeny virus with titers of 1 x 10(9) to 5 x 10(9) PFU/ml. The cDNA clone was engineered to contain three silent nucleotide changes to create a StyI site (C to A and A to G at nucleotides [nt] 8859 and 8862, respectively) and to knock out an EcoRI site (A to G at nt 8880). These genetic markers were retained in the recovered progeny virus. Deletion of the 3'-terminal 199 nt of the cDNA transcript abolished the infectivity of the RNA. The plaque morphology, in vitro growth characteristics in mammalian and insect cells, and virulence in adult mice were indistinguishable for the parental and recombinant viruses. The stable infectious cDNA clone of the epidemic lineage I strain will provide a valuable experimental system to study the pathogenesis and replication of WNV.

5304.                  Sweet TM, Valle LD, Khalili K. Molecular biology and immunoregulation of human neurotropic JC virus in CNS. J Cell Physiol. 2002 Jun;191(3):249-56. Review.


The human polyomavirus, JC virus (JCV), provides an excellent model system to investigate the reciprocal interaction of the immune and nervous systems. Infection with JCV occurs during childhood and the virus remains in the latent state with no apparent clinical symptoms. However, under immunosuppressed conditions, the virus enters the lytic cycle and upon cytolytic destruction of glial cells, causes the fatal demyelinating disease of the central nervous system (CNS), named progressive multifocal leukoencephalopathy (PML). In this short review, we discuss the molecular pathogenesis of PML by highlighting the role of the immune system in modulating JCV gene activation and replication, and the latency/reactivation of this virus upon immunosuppression. Further, due to the higher incidence of PML among AIDS patients, we further elaborate on the cross-talk between JCV and HIV-1 by direct and indirect pathways that lead to enhanced expression of the JCV genome. Copyright 2002 Wiley-Liss, Inc.


5305.                  Munch G, Robinson SR. Alzheimer's vaccine: a cure as dangerous as the disease? J Neural Transm  2002 Apr;109(4):537-9


Studies in transgenic mouse models of Alzheimer's disease suggested the potential for a vaccine development. However, some patients in the human clinical trials developed symptoms of brain inflammation, demonstrating the high risk of a deliberately induced auto-immune response.


5306.                  Tiroumourougane SV, Raghava P, Srinivasan S. Japanese viral encephalitis. Postgrad Med J  2002 Apr;78(918):205-15


One of the leading causes of acute encephalopathy in children in the tropics is Japanese encephalitis (JE). Transmitted by the culex mosquito, this neurotropic virus predominately affects the thalamus, anterior horns of the spinal cord, cerebral cortex, and cerebellum. It mainly affects children <15 years and is mostly asymptomatic. The occasional symptomatic child typically presents with a neurological syndrome characterised by altered sensorium, seizures, and features of intracranial hypertension. Aetiological diagnosis is based on virus isolation or demonstration of virus specific antigen or antibodies in the cerebrospinal fluid/blood. Though no antiviral drug is available against JE, effective supportive management can improve the outcome. Control of JE involves efficient vector control and appropriate use of vaccines.




5307.                  Dhib-Jalbut S. Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis. Neurology  2002 Apr 23;58(8 Suppl 4):S3-9


MS is an immunologically mediated disease, as determined by observation of the response to immunotherapy and the existence of an animal model, experimental autoimmune encephalitis. Interferon (IFN) beta-1b, IFN beta-1a, and glatiramer acetate, the therapies used for relapsing or remitting MS, have mechanisms of action that address the immunologic pathophysiology of MS. The IFNs bind to cell surface-specific receptors, initiating a cascade of signaling pathways that end with the secretion of antiviral, antiproliferative, and immunomodulatory gene products. Glatiramer acetate, a synthetic molecule, inhibits the activation of myelin basic protein-reactive T cells and induces a T-cell repertoire characterized by anti-inflammatory effects. Although the two classes of drugs have some overlapping mechanisms of action, the IFNs rapidly block blood-brain barrier leakage and gadolinium (Gd) enhancement within 2 weeks, whereas glatiramer acetate produces less rapid resolution of Gd-enhanced MRI activity. IFN beta has no direct effects in the CNS, but glatiramer acetate-specific T cells are believed to have access to the CNS, where they can exert anti-inflammatory and possibly neuroprotective effects.


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