Published online November 20, 2006
PEDIATRICS Vol. 118 No. 6 December 2006, pp. e1785-e1788 (doi:10.1542/peds.2006-1547)
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ARTICLE

Long-term Cognitive and Motor Deficits After Enterovirus 71 Brainstem Encephalitis in Children

Mei-Chih Huang, RN, PhDa, Shih-Min Wang, MD, PhDb, Yung-Wen Hsu, PhDc, Hui-Chen Lin, MDd, Chia-Yu Chi, MDd and Ching-Chuan Liu, MD, MPHd

a Departments of Nursing
b Emergency Medicine
c Occupational Therapy
d Pediatrics, National Cheng Kung University and Hospital, Tainan, Taiwan


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. Several large outbreaks of enterovirus 71 infections have occurred in Taiwan during the past decade. Brainstem encephalitis was the most common neurologic complication. This study was designed to determine the long-term cognitive and motor outcomes of children with enterovirus 71 brainstem encephalitis.

METHODS. We conducted a prospective follow-up study of children who met the case definition for enterovirus 71 brainstem encephalitis. Subjects were stratified into isolated brainstem encephalitis (stage II), autonomic nervous system dysregulation (stage IIIa), and pulmonary edema (stage IIIb). The subjects and their parents or guardians were interviewed using structured questionnaires and received comprehensive cognitive and neurologic examinations. Motor coordination, visual-motor skill, and intellectual ability were evaluated.

RESULTS. Follow-up studies were conducted in 63 previously healthy children with enterovirus 71 brainstem encephalitis (49 stage II, 7 stage IIIa, and 7 stage IIIb). The mean time to follow-up was 2.8 ± 1.0 years (range: 1.4–4.9 years). Boys outnumbered girls by 3 to 2. The mean age at diagnosis was 2.4 ± 1.4 years (range: 0.3–7.1 years). The most common abnormal neurologic findings on admission were altered consciousness (47.6%), followed by abnormal activities of daily living (52.4%), cerebellar dysfunction (17.5%), and cranial nerve palsy (15.9%). At follow-up, 51 of 63 children had no detectable deficits. Among the remaining 12 children, 3 died during the follow-up. The remaining 9 children (14.3%) had residual deficits. Two of these with stage IIIb disease continued to have severe motor and respiratory failure.

CONCLUSIONS. Residual defects were still present in a significant proportion of children with enterovirus 71 brainstem encephalitis at >2 years after their hospitalization. Children with stage II disease were most likely to have residual cerebellar defects. Those with stage IIIb disease continued to have severe respiratory and motor impairment. Long-term follow-up of this cohort is needed to determine the ultimate prognosis.

Key Words: enterovirus 71 • brainstem encephalitis • outcome • follow-up

Abbreviations: EV71—enterovirus 71 • HFMD—hand, foot, and mouth disease • BE—brainstem encephalitis • WPPSI-R—Wechsler Preschool and Primary Scale of Intelligence-Revised • M-ABC—Movement Assessment Battery for Children

There are >60 distinct serotypes of enteroviruses within the family Picornaviridae.1 Enterovirus 71 (EV71) was first isolated from patients with encephalitis, aseptic meningitis, or myocarditis in California between 1969 and 1972.2 Subsequently, several large epidemics of EV71 have been described in Eastern Europe, Southeast Asia, and Australia.3–9 EV71 usually causes hand, foot, and mouth disease (HFMD) or herpangina, but the infection can progress to a polio-like, acute flaccid paralysis or brainstem encephalitis (BE). The rate of neurologic disease in the 1998 epidemic in Taiwan is estimated to be 3.1 per 1000 EV71 clinically apparent infections.8 BE is the most common neurologic complication in children.8–12 The highest mortality rate occurs in children who developed pulmonary edema.9

This study was designed to determine the long-term outcome of children who survived hospitalization for EV71 BE. Attention was focused on cognitive and motor outcomes, because the disease is most often localized to the brainstem, pons, and midbrain.13


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Population
The study population consisted of Taiwanese children who were under the age of 12 years when they were hospitalized for EV71 BE. They were prospectively followed at regular intervals at the Department of Pediatrics and Emergency Medicine of National Cheng Kung University Hospital from 1998 to 2004 and were invited to return for further assessment. Informed consent was obtained from their parents or guardians. The Human Investigations Committee at National Cheng Kung University Hospital approved this study.

Case Definition
BE (stage II) was defined as an illness characterized by myoclonus, ataxia, nystagmus, oculomotor palsies, and bulbar palsy, in various combinations, with or without confirmation by neuroimaging. Autonomic nervous system dysregulation (stage IIIa) was defined as the occurrence of cold sweats, mottled skin, tachycardia, tachypnea, and hypertension. Pulmonary edema (stage IIIb) was defined as the occurrence of respiratory distress, tachycardia, tachypnea, rales, and copious frothy sputum with chest radiologic findings of bilateral pulmonary infiltrates without cardiomegaly.

Questionnaires
A pediatrician used a standardized questionnaire to obtain information from parents or guardians and health care providers. This included information on demographic characteristics, comorbid illnesses, current medications, memory loss, cognitive function, and ability to perform activities of daily living. A structured form was used to extract data from the patients' records.

Cognitive Testing
Cognitive tests were administered by certified psychologists using an age-appropriate scale. The Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R) was used for subjects 3 to <6 years of age.14 The Wechsler Intelligence Scale for Children-Revised15,16 was used for subjects 6–16 years of age. The mean standard score for each test is 100 with an SD of 15. Scores lower than 2 SD from mean were considered abnormal.

Motor Function
The Movement Assessment Battery for Children (M-ABC) test17 was used to assess general motor performance. M-ABC consists of 4 age bands suitable for a specific age group. Each age band consists of 8 items that measure 3 aspects of motor ability: manual dexterity, ball skills, and balance.

The tests were performed by a pediatric occupational therapist who was unaware of the underlying medical conditions. Total scores were expressed as percentile. Children with scores at or below the 5th percentile for their age were identified as having motor difficulties. Scores between the 5th and 15th percentile were considered to be borderline.

Visual-Motor Integration
The Beery-Buktenica Developmental Test of Visual-Motor Integration18 was used to assess visual-motor skills. The tests were applied by a pediatric occupational therapist blinded to the underlying medical conditions. Children with scores at or below the 5th percentile for their age were identified as abnormal in this study.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Description of Subjects
Sixty-three previously healthy children with EV71 BE (49 stage II, 7 stage IIIa, and 7 stage IIIb) were followed for 2.8 ± 1.0 years (range: 1.4–4.9 years). The mean age at the time of diagnosis was 2.4 ± 1.4 years (range: 0.3–7.1 years). Boys outnumbered girls by 3 to 2. There were no significant differences in social or demographic characteristics by stage of BE. Neurologic examinations were completed in 63 subjects. Cognitive and M-ABC tests were completed in 54 and the Beery-Buktenica Developmental Test of Visual-Motor Integration test in 53 subjects. Three children with stage IIIB disease died during the follow-up period.

Neurocognitive and Motor Outcomes
The neurologic findings during hospitalization and at follow-up are summarized in Table 1. The most frequent neurologic abnormalities during hospitalization were altered consciousness (30 of 63 [47.6%]), followed by abnormal activities of daily living (33 of 63 [52.4%]), cerebellar dysfunction (11 of 63 [17.5%]), and cranial nerve palsy (10 of 63 [15.9%]). Most of these had resolved by the time of follow-up.


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  		TABLE 1 Abnormal Findings on Neurologic Examination of Children With EV71 BE on Admission and at Follow-up

 
Residual cognitive or motor disorders were noted at follow-up in 9 of the 63 patients (14.3%; Table 2). Among the 9 children with residual deficits, 3 (4.8%) had cognitive and 7 (11.1%) had motor defects (mostly cerebellar dysfunction). Two children with stage IIIb disease continued to have severe motor dysfunction and respiratory failure complicated by urinary and fecal incontinence.


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  		TABLE 2 Residual Cognitive and/or Motor Disorders Detected Among 9 of 63 Children With EV71 BE

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
This is the first study to evaluate the long-term cognitive and motor sequelae of EV71 BE. The inflammatory lesions in this disease are usually localized to the posterior two thirds of the medulla oblongata and pons and the anterior two thirds of the spinal cord.9,13 The histopathological findings in the spinal cord mimic those of poliomyelitis.12 There is increasing evidence that subcortical structures, including the basal ganglia, brainstem, and cerebellum, are involved in cognitive and behavioral processes in humans.19 Animal studies have demonstrated that both the brainstem and basal ganglia are intricate parts of these cerebrocerebellar pathways.20 Cerebellar dysfunction is the most common neurologic deficit in children with stage II disease.9,21,22 Pulmonary edema with hypoxia is the major cause of death in children with stage IIIb EV71 infection.9 Failure to provide prompt pulmonary resuscitation with a patent airway may lead to a hypoxic-ischemic encephalopathy superimposed on the direct brainstem insult caused by the virus. Aggressive resuscitation needs to be instituted as soon as possible to prevent global brain damage.

Altered consciousness during the acute illness and the potential to develop cognitive impairment in EV71 BE seems to be multifactorial. The current findings indicate that long-term cognitive function is usually preserved in children after EV71 BE. This is based on both objective tests, as well as confirmatory reports by parents and guardians.

The strengths of this study are the relatively large study population and use of well-standardized tests by trained examiners. There was some selection bias. We included patients referred to us, as well as those admitted to our hospital. It is, therefore, possible that the series was overweighted with the most severe or atypical cases. This would be expected to be associated with poorer outcomes.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
We found that the long-term cognitive function of children with EV71 BE was generally quite good. Nevertheless, residual defects, mostly consisting of cerebellar dysfunction, were still present in 10.2% of children with EV71 BE stage II at ~3 years after hospitalization. Children with EV71 BE stage IIIb continued to have severe respiratory and motor impairment. Close monitoring of cerebellar dysfunction and early rehabilitation are recommended. Long-term follow-up of this cohort is needed to determine the ultimate prognosis.


   ACKNOWLEDGMENTS
 
This study was supported by a grant from the Center for Disease Control, Department of Health, Taiwan (DOH92-DC-1006).

We thank Dr Calvin M. Kunin for providing invaluable suggestions and a critical review of the article. We sincerely thank all of the participants and their parents. We also thank Chao-Ping Liao for assistance in follow-up of the patients.


   FOOTNOTES
 
Accepted Jul 11, 2006.

Address correspondence to Ching-Chuan Liu MD, MPH, Department of Pediatrics, National Cheng Kung University Hospital, 138 Sheng Li Rd, Tainan, 70428, Taiwan. E-mail: liucc{at}mail.ncku.edu.tw

The authors have indicated they have no financial relationships relevant to this article to disclose.

Drs Huang and Wang contributed equally to this work.


   REFERENCES
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics




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