Correspondence

Enterovirus 71 Infection and Neurologic Complications

N Engl J Med 2000; 342:356-358February 3, 2000

Article

To the Editor:

In their article on neurologic complications associated with enterovirus 71 infection, Huang et al. (Sept. 23 issue)1 reported the presence of severe brain-stem lesions, as evidenced by findings on magnetic resonance imaging in many patients and by autopsy findings in one. Our own pathological findings (unpublished data), based on a detailed autopsy examination of four patients,2 also showed inflammation confined to the gray matter of the spinal cord and medulla and the tegmentum of the midbrain and pons. In all our patients, as in theirs, there was no inflammation in pontine nuclei. We noted inflammation in the dentate nucleus, hypothalamus, and thalamus but not in the cerebrum.

The reason for this distribution of inflammation is unknown, but it may be related to the predilection of enterovirus 71 for specific neurons. Another possibility is that the virus may enter the central nervous system by way of the peripheral cranial and spinal nerves and infect the neurons it first encounters in the tegmentum of the brain stem and the gray matter of the spinal cord before spreading along neuronal pathways. Interestingly, this pattern of inflammation appears to be similar to that of bulbar poliomyelitis, in which there is also involvement of the tegmentum of the brain stem but not of the anterior pons.3 However, although we noted that the inferior olives were inflamed, Bodian described the absence of inflammation in these areas in patients with bulbar poliomyelitis.3 Thus, in addition to neurologic and other manifestations,1 pathological features also appear to distinguish encephalitis of the brain stem caused by enterovirus 71 infection from bulbar poliomyelitis.

To strengthen the causal link between enterovirus 71 infection and encephalitis further, immunolocalization of viral antigens in inflamed tissues of the central nervous system was performed, and positive neuronal staining was obtained in our four patients.4 Direct localization, by immunohistochemical methods or other means, is essential in order to confirm the presence of encephalitis caused by enterovirus 71 infection. In the series of Huang et al., only two patients had virus isolated from a clinically relevant site — the cerebrospinal fluid in one and tissues of the central nervous system in the other.1 In a majority of their patients (95 percent), isolates of enterovirus 71 were obtained from the throat and rectum. In a major epidemic, such as the one in Taiwan, patients with other types of fulminant viral encephalitis (e.g., Japanese encephalitis) could be identified inadvertently, and the enterovirus 71 isolated from a peripheral site could, in fact, be nonpathogenic.

We agree with Huang et al. that the children with encephalitis of the brain stem caused by enterovirus 71 probably died as a result of neurogenic pulmonary edema due to destruction of the medulla.2,5 There was no histologic evidence of myocarditis in any of the cases we examined.

Kum Thong Wong, M.B., B.S., M.R.C.Path.
Lucy Chai See Lum, M.B., B.S., M.R.C.P.
Sai Kit Lam, Ph.D.
University of Malaya, 50603 Kuala Lumpur, Malaysia

5 References

1. 1

   Huang C-C, Liu C-C, Chang Y-C, Chen C-Y, Wang S-T, Yeh T-F. Neurologic complications in children with enterovirus 71 infection. N Engl J Med 1999;341:936-942
   Full Text | Web of Science | Medline

2. 2

   Lum LCS, Wong KT, Lam SK, et al. Fatal enterovirus 71 encephalomyelitis. J Pediatr 1998;133:795-798
   CrossRef | Web of Science | Medline

3. 3

   Bodian D. Poliomyelitis. In: Minckler J, ed. Pathology of the nervous system. Vol. 3. New York: McGraw-Hill, 1972:2323-44.
   

4. 4

   Wong KT, Chua KB, Lam SK. Immunohistochemical detection of infected neurons as a rapid diagnosis of enterovirus 71 encephalomyelitis. Ann Neurol 1999;45:271-272
   CrossRef | Web of Science | Medline

5. 5

   Lum LCS, Wong KT, Lam SK, Chua KB, Goh AYT. Neurogenic pulmonary oedema and enterovirus 71 encephalomyelitis. Lancet 1998;352:1391-1391
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: The biphasic clinical manifestation of enterovirus 71 infection that we saw, with a prodrome of hand-foot-and-mouth disease or herpangina that lasted an average of 3.2 days followed by neurologic manifestations, clearly indicates the causal link between enterovirus 71 infection and disorders of the central nervous system. Indeed, 66 percent of our patients had isolates of enterovirus 71 obtained from throat swabs, 44 percent had isolates obtained from stool specimens, and only 5 percent had isolates obtained from cerebrospinal fluid or brain tissue. Very low rates of virus isolation in cerebrospinal fluid, ranging from 0 to 3 percent, were reported in previous outbreaks of enterovirus 71 infection in Bulgaria, Hungary, Japan, and Australia.1 With poliovirus infections, the virus is also only occasionally recovered from cerebrospinal fluid. The diagnosis of poliomyelitis is often established on the basis of a virus recovered from a peripheral site, such as the throat or rectum.2,3 We believe that the diagnosis of enterovirus 71–related infection of the central nervous system may be established in a similar manner. Moreover, we found high titers in our patients of enterovirus 71–specific antibody by means of a neutralization test (data not shown), which is additional evidence of recent enterovirus 71 infection. We also demonstrated by immunohistochemical methods that enterovirus 71 antigens were present in the brain-stem tissue of the patient who underwent autopsy.

Because of the effective nationwide vaccination program, an epidemic of Japanese encephalitis is no longer a cause of major concern for Taiwanese children. The clinical manifestations of Japanese encephalitis include nuchal rigidity, opisthotonos, dystonia, rigidity, convulsions, coma, and coarse tremors, which differ from the symptoms largely affecting the brain stem in our patients with enterovirus 71 infection. The majority of the survivors of Japanese encephalitis have mental retardation, seizure disorders, motor deficits, or subtle behavioral and intellectual abnormalities, effects that are quite different from those caused by enterovirus 71 infection. The characteristic findings on magnetic resonance imaging that are associated with Japanese encephalitis include lesions of the thalamus, basal ganglia, and hippocampus,4 again in contrast with the predominant involvement of the brain stem, especially the pontine tegmentum, in patients with enterovirus 71 infection. We believe that the presence of hand-foot-and-mouth disease or herpangina, myoclonus, cerebellar and oculomotor signs, and characteristic findings on magnetic resonance imaging in the brain stem all help to distinguish rhombencephalitis caused by enterovirus 71 infection from Japanese encephalitis and other viral infections, such as bulbar poliomyelitis. We found no evidence that Japanese encephalitis had contributed to the involvement of the central nervous system in our patients with culture-confirmed enterovirus 71 infection, although serologic testing for the presence of Japanese encephalitis was not performed.

Chao-Ching Huang, M.D.
Ching-Chuan Liu, M.D., M.P.H.
National Cheng Kung University, Tainan 704, Taiwan

Ying-Chao Chang, M.D.
Chang Gung Children's Hospital, Kaohsiung 833, Taiwan

4 References

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   Gilbert GL, Dickson KE, Waters MJ, Kennett ML, Land SA, Sneddon M. Outbreak of enterovirus 71 infection in Victoria, Australia, with a high incidence of neurologic involvement. Pediatr Infect Dis J 1988;7:484-488
   CrossRef | Web of Science | Medline

2. 2

   Grandien M, Forsgren M, Ehrnst A. Enteroviruses and reoviruses. In: Schmidt NJ, Emmons RW, eds. Diagnostic procedures for viral, rickettsial and chlamydial infections. 6th ed. Washington, D.C.: American Public Health Association, 1989:513-69.
   

3. 3

   Cherry JD. Enteroviruses: coxsackieviruses, echoviruses, and polioviruses. In: Feigin RD, Cherry JD, eds. Textbook of pediatric infectious diseases. 4th ed. Vol. 2. Philadelphia: W.B. Saunders, 1998:1787-839.
   

4. 4

   Bale JF. Viral infections of the nervous system. In: Swaiman KF, Ashwal S, eds. Pediatric neurology: principles & practice. 3rd ed. St. Louis: Mosby, 1999:1001-24.
   

Citing Articles (7)

Citing Articles

1. 1

   Mong How Ooi, See Chang Wong, Penny Lewthwaite, Mary Jane Cardosa, Tom Solomon. (2010) Clinical features, diagnosis, and management of enterovirus 71. The Lancet Neurology 9:11, 1097-1105
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2. 2

   Hwa-Jung Choi, Jae-Hyoung Song, Kwi-Sung Park, Seung-Hwa Baek, Eun-Sook Lee, Dur-Han Kwon. (2010) Antiviral activity of yogurt against enterovirus 71 in vero cells. Food Science and Biotechnology 19:2, 289-295
   CrossRef

3. 3

   Kum Thong Wong, Badmanathan Munisamy, Kien Chai Ong, Hideaki Kojima, Nagata Noriyo, Kaw Bing Chua, Beng Beng Ong, Kazuo Nagashima. (2008) The Distribution of Inflammation and Virus in Human Enterovirus 71 Encephalomyelitis Suggests Possible Viral Spread by Neural Pathways. Journal of Neuropathology and Experimental Neurology 67:2, 162-169
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4. 4

   Takuya Iwasaki. (2007) Contribution of experimental paradigms of viral infectious diseases to diagnostic pathology. Seminars in Diagnostic Pathology 24:4, 237-242
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5. 5

   Damian Guang Wei Foo, Sylvie Alonso, Vincent Tak Kwong Chow, Chit Laa Poh. (2007) Passive protection against lethal enterovirus 71 infection in newborn mice by neutralizing antibodies elicited by a synthetic peptide. Microbes and Infection 9:11, 1299-1306
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6. 6

   Noriyo Nagata, Hiroyuki Shimizu, Yasushi Ami, Yoshio Tano, Ayako Harashima, Yuriko Suzaki, Yuko Sato, Tatsuo Miyamura, Tetsutaro Sata, Takuya Iwasaki. (2002) Pyramidal and extrapyramidal involvement in experimental infection of cynomolgus monkeys with enterovirus 71. Journal of Medical Virology 67:2, 207-216
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7. 7

   Ya-Ching Lin, Cheng-Nan Wu, Shin-Ru Shih, Mei-Shang Ho. (2002) Characterization of a vero cell-adapted virulent strain of enterovirus 71 suitable for use as a vaccine candidate. Vaccine 20:19-20, 2485-2493
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