Pathologic Studies of Fatal Cases in Outbreak of Hand, Foot, and Mouth Disease, Taiwan

Shieh, Wun‐Ju; Jung, Shih‐Ming; Hsueh, Chuen; Kuo, Tseng‐Tong; Mounts, Anthony W.; Parashar, Umesh D.; Yang, Chen Fu; Guarner, Jeannette; Ksiazek, Thomas G.; Dawson, Jacqueline E.; Goldsmith, Cynthia S.; Chang, Gwong‐Jen J.; Oberste, Steve; Pallansch, Mark A.; Anderson, Larry J.; Zaki, Sherif R.

doi:10.3201/eid0701.700146

Cited by 52 publications

(29 citation statements)

References 8 publications

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“…In contrast, cerebellar cortical lesions were observed in only 2 of 15 monkeys. The localization pattern of EV71-infected lesions was highly consistent with those observed in humans with severe EV71 encephalitis at autopsy [Lum et al, 1998;Wang et al, 1999;Chan et al, 2000;Wong et al, 2000;Shieh et al, 2001]. This finding suggests a similarity in the susceptibility of human and monkey CNS tissues to EV71 infection.…”

Section: Discussionsupporting

confidence: 72%

Pyramidal and extrapyramidal involvement in experimental infection of cynomolgus monkeys with enterovirus 71

Nagata

Shimizu

Ami

et al. 2002

Journal of Medical Virology

113

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Among the enteroviruses, polioviruses and enterovirus 71 (EV71) are two major neurotropic viruses causing serious neurological manifestations. While polioviruses are being eradicated globally by vaccination, EV71 still has the potential to cause a large outbreak such as that in Taiwan in 1998, in which there were many fatalities. In this study, we determined the neurovirulence of EV71 by neuropathological analysis of cynomolgus monkeys after experimental infection with five EV71 strains, which were isolated from individual patients with fatal encephalitis; meningitis; and hand, foot, and mouth disease. After intraspinal inoculation, the monkeys developed neurological manifestations within 1-6 days post-inoculation, irrespective of the inoculated strains. These manifestations included not only pyramidal tract signs such as flaccid paralysis, but also extrapyramidal tract signs such as tremor and ataxia. Histological and viral examinations confirmed virus replication in the spinal cord, brainstem, cerebellar cortex, and dentate nuclei, and cerebrum. The strains isolated during the 1970s and 1990s showed no particular differences with respect to neurotropism. Thus, it is clear that EV71 has a wider neurotropism than that of polioviruses.

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Section: Discussionsupporting

confidence: 72%

Pyramidal and extrapyramidal involvement in experimental infection of cynomolgus monkeys with enterovirus 71

Nagata

Shimizu

Ami

et al. 2002

Journal of Medical Virology

113

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“…Similar to the neurological manifestations in humans, cynomolgus monkeys display both pyramidal tract signs (flaccid paralysis) and extrapyramidal tract signs (including tremor and ataxia) with a broad viral antigen distribution that involves the spinal cord, brainstem, cerebellar cortex, dentate nuclei and cerebrum following intraspinal and intravenous inoculation of EV71 [22,23]. The neuropathological features are highly consistent with those observed in humans with severe EV71 encephalitis at autopsy [5,18,24-26], which is indicative of the similarity of the susceptibilities of human and cynomolgus monkey CNS tissues to EV71. EV71 exhibits a wider neurotropism than does poliovirus in cynomolgus monkeys, and wild-type strains, including those isolated from patients with fatal encephalitis or hand, foot, and mouth disease (HFMD), exhibit no marked differences with respect to neurovirulence after infection; thus, this monkey species may not be suitable for assessing the neurovirulence level of the virus [22,23].…”

Section: Reviewmentioning

confidence: 78%

Animal models of enterovirus 71 infection: applications and limitations

Wang

2014

J Biomed Sci

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Human enterovirus 71 (EV71) has emerged as a neuroinvasive virus that is responsible for several outbreaks in the Asia-Pacific region over the past 15 years. Appropriate animal models are needed to understand EV71 neuropathogenesis better and to facilitate the development of effective vaccines and drugs. Non-human primate models have been used to characterize and evaluate the neurovirulence of EV71 after the early outbreaks in late 1990s. However, these models were not suitable for assessing the neurovirulence level of the virus and were associated with ethical and economic difficulties in terms of broad application. Several strategies have been applied to develop mouse models of EV71 infection, including strategies that employ virus adaption and immunodeficient hosts. Although these mouse models do not closely mimic human disease, they have been applied to determine the pathogenesis of and treatment and prevention of the disease. EV71 receptor-transgenic mouse models have recently been developed and have significantly advanced our understanding of the biological features of the virus and the host-parasite interactions. Overall, each of these models has advantages and disadvantages, and these models are differentially suited for studies of EV71 pathogenesis and/or the pre-clinical testing of antiviral drugs and vaccines. In this paper, we review the characteristics, applications and limitation of these EV71 animal models, including non-human primate and mouse models.

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“…Literature has reported that virus RNA and antibody can be detected at the affected area of brainstem encephalitis among patients with EV71 HFMD, suggesting that EV71 virus may be neurotropic [12,13]. The potential mechanism of CNS damage from EV71 infection is as follows: (1) EV71 viruses enter the blood circulation through throat or intestinal lymph nodes, resulting in the first viremia, and (2) viruses then invade and proliferate in reticuloendothelial tissue, deep lymph nodes, liver, spleen, and bone marrow and then enter the blood circulation, resulting in the second viremia [14].…”

Section: Pathophysiology Of Cns Damage From Ev71 Virus Infectionmentioning

confidence: 98%

MRI and associated clinical characteristics of EV71-induced brainstem encephalitis in children with hand–foot–mouth disease

et al. 2011

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Pathologic Studies of Fatal Cases in Outbreak of Hand, Foot, and Mouth Disease, Taiwan

Cited by 52 publications

References 8 publications

Pyramidal and extrapyramidal involvement in experimental infection of cynomolgus monkeys with enterovirus 71

Pyramidal and extrapyramidal involvement in experimental infection of cynomolgus monkeys with enterovirus 71

Animal models of enterovirus 71 infection: applications and limitations

MRI and associated clinical characteristics of EV71-induced brainstem encephalitis in children with hand–foot–mouth disease

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