Central Nervous System Infection Clinical Trial
Official title:
Long Term Outcomes of EV71 Central Nervous System Infection
Our study involved 142 children with EV71 CNS infections that included 61 (43%) with viral meningitis, 53 (37%) with severe CNS involvement including encephalitis, polio-like syndrome and encephalomyelitis, and 28 (20%) with cardiopulmonary failure after CNS involvement. These children were subjected to physical and neurological examinations 2.85 (range 1.0-7.39) years after disease onset. Those below the age of 6 years took the Denver developmental screening test, while those 4 years and over took the intelligence quotient (IQ) test.
For the purposes of our study we identified all the EV71 pediatric patients at Chang Gung
Children’s Hospital (CGCH) and at the NTUH between 1998 and 2003. These patients were
clinically confirmed to have hand, foot, and mouth disease (HFMD) of herpangina or febrile
illness, and a positive laboratory-confirmed EV71 infection. The EV 71 infection was
confirmed on the basis of a positive viral isolation of EV71 and/or a positive EV71 IgM
and/or a four-fold rise in EV71 neutralizing antibody serotiters between the acute and the
convalescent sera.
This study involved 621 EV71 patients in total, 534 of them at the CGCH and 87 of them at
the NTUH. Of these, 232 cases (37.4%) had CNS involvement. The clinical severity of the EV71
CNS involvement was classified in terms of the increasing severity of the infection: Group
1: cases with mild CNS involvement i.e. aseptic meningitis; Group 2: cases with severe CNS
involvement including encephalitis, polio-like syndrome or encephalomyelitis; and Group 3:
cases with cardiopulmonary failure after central nervous system involvement. Patients placed
in Group 1, were those experiencing headaches, irritability and CSF pleocytosis (>5x106
leukocytes/L) but no altered level of consciousness or focal signs. Patients placed in Group
2, were encephalitis with an altered level of consciousness plus CSF pleocytosis,
poliomyelitis-like syndrome with acute limb weakness, and decreased reflex and muscle
strength, and encephalomyelitis with the occurrence of both encephalitis and
poliomyelitis-like syndrome. Patients placed in Group 3 were those who had experienced
cardiopulmonary failure (defined as a decreased ejection fraction of the left ventricle as
assessed by echocardiography with or without pulmonary edema/hemorrhage, necessitating
inotropic agent and ventilator support). Patients who experienced cardiopulmonary failure
after CNS involvement have been found to have had a sudden onset of cardiopulmonary failure
several hours or several days after the manifestations of their EV71 CNS infections.5,16 Of
these 232 cases with CNS involvement, 25 (10.8%) patients died of cardiopulmonary failure
and brainstem encephalitis during acute illness. 19 of these 25 patients died within 7 days
of the onset of acute illness, while 14 (6.0%) patients died due to a deep coma or
aspiration pneumonia during the convalescent stage (i.e. more than one month after onset of
their disease).
Of the remaining 193 patients with CNS involvement (172 of these at the CGCH and 21 of these
at the NTUH), 22 refused to be assessed and 29 could not be located. This means that a total
of 142 (73.6%) patients were enrolled in our study and took the assessment between January
2003 and December 2005 after informed consent was obtained from their parents (Figure 1).
The clinical severity and the demography of the 142 patients who were assessed and the 51
patients who were not assessed (p=0.22 for clinical severity, p=0.33 for their age of onset,
and p=0.35 for genders) were similar. It is therefore clear that the size of the study
population involving these 142 patients is representative of the 193 EV71 patients with CNS
involvement.
Clinical and neurological outcome and neurodevelopment assessment All the children were
physically and neurologically examined by a pediatrician or a pediatric neurologist during
an outpatient visit or during their stay at chronic respiratory centers. Their physical
handicap or neurological sequelae, the requirement of ventilator support and the need of
tube feeding were recorded.
EV71 patients who were younger than 6 years of age during our assessment were tested with
the Denver Developmental Screening Test (DDST II). The DDST II has four categories: gross
motor, fine motor, language, and personal-social.17 Each test item was scored as either
passed or failed. The overall assessment of each child was considered normal when the child
passed tasks in 25–75% for his/her age, or delayed when the child failed tasks to the left
of his/her age line.
Cognitive function assessment The Wechsler Intelligence Scale for Children-Third Edition
(WISC-III, Wechsler, 1991) profile was individually assessed by a child psychologist for all
children over four years of age except for 3 of the children who had tracheostomy and could
not talk. The WISC-III is a widely used measure of general intelligence for children aged
4–16 years. The WISC-III is composed of 13 subtests to test children’s cognitive ability of
different dimensions, which are grouped into two scores: the performance IQ score and the
verbal IQ score. The Performance IQ score (7 subtests) includes Picture Completion, Block
Design, Object Assembly, Picture Arrangement, Coding, Symbol Search and Mazes subtests. The
Verbal IQ score (6 subtests) includes Information, Comprehension, Arithmetic, Similarities,
Digit Span and Vocabulary subtests.18 Four factorially derived composite subscales have been
created: (1) Verbal Comprehension: Information, Similarities, Vocabulary, and Comprehension;
(2) Perceptual Organization: Picture Completion, Picture Arrangement, Block Design, and
Object Assembly; (3) Freedom From Distractibility: Arithmetic and Digit span; and (4)
Process Speed: Coding and Symbol Search. 18 Each of the IQ scores and four composite
subscales yield standard scores with a mean of 100 and a standard deviation (S.D.) of 15.
Statistical Analysis Data were analyzed with the SAS Statistical Package (Version 9.1, SAS
Institute, Cary, North Carolina). Data are expressed as mean ±S.D., median (range) or number
(percentage). The Chi-square test was used for categorical data, and the student t-test and
analysis of variance (ANOVA) were used for continuous variables with normal distribution.
The Mann-Whitney rank sum test or Kruskal-Wallis test was used for continuous variables
without a normal distribution in the univariate analysis. If a significant difference was
found with ANOVA, pairwise comparison would be performed with the Scheffe test. Multivariate
analysis of variance (MANOVA) was used to identify the most significant factors affecting
the cognitive function (IQ and the four composite subscales).. P values less than 0.05 were
considered significant.
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Observational Model: Defined Population, Time Perspective: Cross-Sectional
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