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      Mechanisms of escape phenomenon of spinal cord and brainstem in human rabies

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          Abstract

          Background

          Rabies virus preferentially involves brainstem, thalamus and spinal cord in human furious and paralytic rabies beginning in the early stage of illness. Nevertheless, rabies patient remains alert until the pre-terminal phase. Weakness of extremities develops only when furious rabies patient becomes comatose; whereas peripheral nerve dysfunction is responsible for weakness in paralytic rabies.

          Methods

          Evidence of apoptosis and mitochondrial outer membrane permeabilization in brain and spinal cord of 10 rabies patients was examined and these findings were correlated with the presence of rabies virus antigen.

          Results

          Although apoptosis was evident in most of the regions, cytochrome c leakage was relatively absent in spinal cord of nearly all patients despite the abundant presence of rabies virus antigen. Such finding was also noted in brainstem of 5 patients.

          Conclusion

          Cell death in human rabies may be delayed in spinal cord and the reticular activating system, such as brainstem, thus explaining absence of weakness due to spinal cord dysfunction and preservation of consciousness.

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          Most cited references39

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          Survival after treatment of rabies with induction of coma.

          We report the survival of a 15-year-old girl in whom clinical rabies developed one month after she was bitten by a bat. Treatment included induction of coma while a native immune response matured; rabies vaccine was not administered. The patient was treated with ketamine, midazolam, ribavirin, and amantadine. Probable drug-related toxic effects included hemolysis, pancreatitis, acidosis, and hepatotoxicity. Lumbar puncture after eight days showed an increased level of rabies antibody, and sedation was tapered. Paresis and sensory denervation then resolved. The patient was removed from isolation after 31 days and discharged to her home after 76 days. At nearly five months after her initial hospitalization, she was alert and communicative, but with choreoathetosis, dysarthria, and an unsteady gait.
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            Human rabies: a disease of complex neuropathogenetic mechanisms and diagnostic challenges.

            Rabies is inevitably fatal and presents a horrifying clinical picture. Human rabies can manifest in either encephalitic (furious) or paralytic (dumb) forms. The brainstem is preferentially involved in both clinical forms, though there are no clinical signs of brainstem dysfunction. Differences in tropism at the inoculation site or the CNS, in the route of spread, or in the triggering of immune cascades in the brainstem may account for clinical variation. Rabies still poses diagnostic problems, particularly the paralytic form, which closely resembles Guillain-Barré syndrome, or when a patient is comatose and cardinal signs may be lacking. Molecular methods allow reliable detection of rabies-virus RNA in biological fluids or tissue before death. Deviations from the recommendations on prophylaxis of the World Health Organization lead to unnecessary loss of life. To date, attempts to treat human rabies have been unsuccessful.
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              Pathogenicity of different rabies virus variants inversely correlates with apoptosis and rabies virus glycoprotein expression in infected primary neuron cultures.

              The mouse-adapted rabies virus strain CVS-24 has stable variants, CVS-B2c and CVS-N2c, which differ greatly in their pathogenicity for normal adult mice and in their ability to infect nonneuronal cells. The glycoprotein (G protein), which has previously been implicated in rabies virus pathogenicity, shows substantial structural differences between these variants. Although prior studies have identified antigenic site III of the G protein as the major pathogenicity determinant, CVS-B2c and CVS-N2c do not vary at this site. The possibility that pathogenicity is inversely related to G protein expression levels is suggested by the finding that CVS-B2c, the less pathogenic variant, expresses at least fourfold-higher levels of G protein than CVS-N2c in infected neurons. Although there is some difference between CVS-B2c- and CVS-N2c-infected neurons in G protein mRNA expression levels, the differential expression of G protein appears to be largely determined by posttranslational mechanisms that affect G protein stability. Pulse-chase experiments indicated that the G protein of CVS-B2c is degraded more slowly than that of CVS-N2c. The accumulation of G protein correlated with the induction of programmed cell death in CVS-B2c-infected neurons. The extent of apoptosis was considerably lower in CVS-N2c-infected neurons, where G protein expression was minimal. While nucleoprotein (N protein) expression levels were similar in neurons infected with either variant, the transport of N protein into neuronal processes was strongly inhibited in CVS-B2c-infected cells. Thus, downregulation of G protein expression in neuronal cells evidently contributes to rabies virus pathogenesis by preventing apoptosis and the apparently associated failure of the axonal transport of N protein.
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                Author and article information

                Journal
                BMC Infect Dis
                BMC Infectious Diseases
                BioMed Central (London )
                1471-2334
                2005
                16 November 2005
                : 5
                : 104
                Affiliations
                [1 ]Molecular Biology Laboratory for Neurological Diseases, Department of Medicine, Chulalongkorn University Hospital, Rama 4 Road, Bangkok, Thailand
                [2 ]Department of Pathology, Chulalongkorn University Hosital, Rama 4 Road, Bangkok, Thailand
                Article
                1471-2334-5-104
                10.1186/1471-2334-5-104
                1310615
                16288653
                e46acc6d-12e5-42a6-801f-f5c5f746291a
                Copyright © 2005 Juntrakul et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 August 2005
                : 16 November 2005
                Categories
                Research Article

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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