Journal of Pediatric Psychology, Vol. 25, No. 2, 2000, pp. 59-68
© 2000 Society of Pediatric Psychology
Intellectual, Neuropsychological, and Academic Functioning in Long-Term Survivors of Leukemia
University of Otago
All correspondence should be sent to Gail Tripp, Department of Psychology, P.O. Box 56, Dunedin, New Zealand. E-mail: gtripp{at}psy.otago.ac.nz .
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Abstract |
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Objective: To assess the effects of treatment for acute lymphoblastic leukemia (ALL) on children's cognitive functioning.
Method: Participants were long-term survivors of ALL treated with cranial irradiation and central nervous system (CNS) chemotherapy (n = 20), or CNS chemotherapy only (n = 21), healthy children (n = 21), and children with chronic asthma (n = 21). The groups were compared on measures of intellectual, neuropsychological, and academic functioning.
Results: CNS chemotherapy, with and without cranial irradiation, was associated with significantly lower levels of intellectual and academic functioning. Children with chronic asthma obtained lower scores than healthy controls, but these differences were not significant. Tests of neuropsychological functioning did not consistently separate the groups.
Conclusions: CNS chemotherapy and, to a lesser extent, chronic illness both contribute to the poorer performance of long-term survivors of ALL on measures of intellectual and academic functioning.
Key words: children; leukemia; cranial irradiation; CNS chemotherapy; IQ; neuropsychological; academic.
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Introduction |
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Prior to 1960, acute lymphoblastic leukemia (ALL) was almost invariably fatal. Fortunately, improvements in treatment have reduced the mortality rate to such an extent that ALL is now viewed as a chronic life-threatening illness (Brown & Madan-Swain, 1993
). However, improved survival rates have not been achieved
without neuropsychological sequelae. Studies of long-term survivors of
childhood ALL suggest that a number suffer from deficits in cognitive
functioning (Brown & Madan-Swain,
1993). A significant body of literature confirms that children's
cognitive functioning is compromised by prophylactic therapy. This treatment
is given to prevent leukemia cells infiltrating the central nervous system
(CNS) and consists of CNS chemotherapy alone or in combination with cranial
irradiation.
The majority of the cross-sectional studies that have included control
groups report that combined prophylactic treatment, CNS chemotherapy and
cranial irradiation, is associated with intellectual impairment. Children who
have survived leukemia typically obtain lower IQ scores than matched healthy
children or children treated for solid tumors outside the CNS (e.g.,
Anderson, Smibert, Ekert, & Godber,
1994; Dowell, Copeland,
Francis, Fletcher, & Stovall, 1991;
Said, Waters, Cousens, & Stevens,
1989). Children in this latter group do not receive prophylactic
treatment.
Mixed results have emerged from prospective studies, in which children were
assessed at diagnosis and follow-up intervals
(Berg et al., 1983;
Jannoun & Chessells, 1987;
Meadows et al., 1981;
Meadows, Massari, & Obringer,
1984; Mulhern, Fairclough,
& Ochs, 1991; Rubenstein,
Varni, & Katz, 1990;
Stehbens & Kisker, 1984).
These studies differ on a number of dimensions that may explain their variable
findings: study design, sample size, nature and inclusion of control groups,
assessment measures, age at testing, follow-up interval, and the control of
illness and demographic variables.
Combined prophylactic treatment has also been linked to neuropsychological
impairment and academic difficulties. Deficits in fine motor skills,
visual-spatial abilities, verbal and nonverbal memory, psychomotor speed and
shifting of attention, auditory perception, word fluency, contingency naming,
and the ability to follow directions have all been reported (e.g.,
Ciesielski et al., 1994;
Copeland et al., 1988a;
Cousens, Ungerer, Crawford, & Stevens,
1991; Dowell et al.,
1991; Jannoun & Chessells,
1987; Mulhern, Wasserman,
Fairclough, & Ochs, 1988;
Taylor, Albo, Phebus, Sachs, & Bierl,
1987). Academic difficulties are evident in parent and teacher
reports of school performance and scores on standardized tests of achievement
(e.g., Deasy-Spinetta, Spinetta, &
Oxman, 1988; Mulhern et al.,
1991).
Research examining the cognitive sequelae of CNS chemotherapy given without
cranial irradiation is less conclusive. Some studies have failed to find any
evidence of lower IQ, deficits in neuropsychological functioning, or academic
difficulties (e.g., Copeland et al.,
1988a; Copeland, Moore,
Francis, Jaffe, & Culbert, 1996;
MacLean et al., 1995;
Mulhern, Ochs, & Fairclough,
1992). Other studies report lower Verbal and Full Scale IQ scores,
memory problems, impaired performance on tasks involving simultaneous
processing, deficits in the areas of motor performance, attention, and
symbolic manipulation, and poorer academic performance (Brown et al.,
1992a,
1992b;
Mulhern et al., 1988;
Ochs et al., 1991). The
observed variability in the effects of CNS chemotherapy may be an artifact of
study design. The studies cited differ in several important ways including
allocation of participants to treatment; use of comparison groups; time
between diagnosis, treatment, and testing; and the outcome measures used.
These inconsistent findings have been interpreted as evidence that cranial
irradiation, usually combined with CNS chemotherapy, places children with
leukemia at greater risk for the development of cognitive deficits than
treatment with CNS chemotherapy only. This hypothesis is supported by the
results of studies, directly comparing the two treatments, which show combined
treatment is associated with more severe cognitive and academic deficits than
CNS chemotherapy alone (e.g. Copeland et
al., 1988a; Dowell et al.,
1991; Pfefferbaum-Levine et
al., 1984; Rowland et al.,
1984).
The more severe deficits observed in children treated with combined
prophylactic therapy, together with evidence that CNS chemotherapy alone can
impair children's cognitive functioning, suggests that the effects of CNS
chemotherapy and cranial irradiation may be additive. Tentative support for
this hypothesis comes from the work of Dowell et al.
(1991), who investigated the
individual and combined effects of CNS chemotherapy and cranial irradiation on
the cognitive functioning of children with cancer. These researchers report
strong support for an effect of cranial irradiation and some support for CNS
chemotherapy having an additive effect. In this and the other studies cited,
children were treated with high dose (2400 cGy) radiotherapy.
Our understanding of the specific effects of prophylactic treatment on
cognitive and academic functioning is limited by the failure of most studies
to control for the nonspecific effects of chronic illness. Children with
leukemia spend considerable time in the hospital, miss significant amounts of
school, tire more easily than healthy children, and are restricted in the more
active aspects of learning. These factors have been related to lowered
performance on IQ tests, particularly on WISC-R subtests with a strong
educational component (Neisser et al.,
1996).
A limited number of studies have attempted to separate chronic illness and
prophylactic treatment effects with the inclusion of solid tumor control
groups (e.g., Copeland et al.,
1988a,
1988b,
1996;
Waber et al., 1990). Children
treated with combined prophylactic therapy, but not CNS chemotherapy only,
show deficits in functioning relative to solid tumor controls, confirming the
detrimental effects of combined prophylactic therapy. The similar performance
of children treated with CNS chemotherapy and the solid tumor controls is more
difficult to interpret. Although children in the solid tumor groups do not
receive CNS treatment, they are administered systemic chemotherapy, which is
thought to have a detrimental effect on fine motor performance and psychomotor
speed (Copeland et al., 1988a,
1988b;
Dowell, Copeland, & Judd,
1989). The cognitive and academic functioning of children treated
with combined prophylactic therapy and CNS chemotherapy only needs to be
compared with that of chronically ill children who have not been treated for
cancer.
This study compared the intellectual, neuropsychological, and academic functioning of children who are long-term survivors of ALL, treated with combined prophylactic therapy or CNS chemotherapy only, with that of healthy children and children with chronic asthma. Children with chronic asthma were selected for the illness control group as they are often hospitalized, miss significant amounts of school, and experience sleep disturbance resulting in daytime fatigue.
If treatment effects are additive, as suggested, children who received combined prophylactic therapy should perform more poorly on measures of cognitive and academic functioning than those who received CNS chemotherapy only, who should perform less well than the children in the illness and healthy control groups. If the experience of chronic illness is responsible for some of the cognitive and academic difficulties observed in long-term survivors of leukemia, the illness control group should perform less well than the healthy control group. Differences between the illness and healthy control groups are most likely to appear on tests influenced by educational opportunities.
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Method |
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Participants
Four groups of children ages 6 to 16 years participated in the study. The first group included 20 children who were long-term survivors of cancer treated with cranial irradiation and CNS chemotherapy (combined group). The majority of these children (n = 18) had survived ALL, with the remaining two diagnosed with non-Hodgkin's lymphoma. The second group included 21 children who were longterm survivors of ALL treated with CNS chemotherapy but not cranial irradiation (chemotherapy group). The third group included 21 children with chronic asthma while the fourth group included 21 children who had never experienced a chronic illness. All of the children in the combined treatment group received 1800 cGy of radiotherapy, with the exception of one child who received 1260 cGy. Children in both treatment groups received intrathecal Methotrexate (see the appendix for details).
The children in the leukemia groups were recruited through "follow-up" oncology clinics at three New Zealand hospitals. Long-term survivors of ALL who had no evidence of central nervous system disease at diagnosis, had experienced complete continuous remission for at least 2 years, and were ages 6 to 16 years were invited to participate. An exception was made for one child in the chemotherapy group, who had been in remission for 20 months only. Children with asthma who were frequent visitors to asthma clinics at one of the hospitals and had no other serious illness were invited to participate. The children's asthma was rated as mild (19%), moderate (67%), or severe (14%).1 Healthy children were recruited from among the friends, acquaintances, and classmates of the children with leukemia, and from local schools.
The families of children with leukemia and chronic asthma were sent a written invitation to participate through the hospital where they were treated. Potential healthy control group families received information about the study from families of children with leukemia who were participating in the study or their child's class teacher. Families interested in participating returned their signed consent forms directly to the researchers. This method of recruitment, while protecting privacy, prevented comparison of families who did and did not volunteer.
Participation rates from the three follow-up oncology clinics were 78%, 76%, and 67%. Rates for the asthma clinics were 23% (asthma education clinic) and 37% (pediatric outpatients). For the healthy controls, participation rates were 100% for those approached by the parents of a child who had survived leukemia (n = 3), and 34% for families recruited through local schools.
Procedure
Testing was typically carried out over two sessions in a quiet room near
the hospital where the children had been treated (leukemia survivors) or at
the university. A small number of children were assessed in a quiet room in
their own home. Before beginning the cognitive assessment, the child and their
parent(s) were interviewed and completed questionnaires about the child's
school progress, behavior, and psychosocial functioning. Each child's teacher
completed a telephone interview about the child's academic progress and
questionnaires about the child's behavior.
Measures and Administration
Parents were asked to complete the Child Behavior Checklist (CBCL;
Achenbach & Edelbrock,
1983) and teachers the Teacher Report Form (TRF;
Achenbach & Edelbrock,
1986). The Wechsler Intelligence Scale for Children-Revised
(WISC-R; Wechsler, 1974) was
administered to children ages 6 years to 16 years 6 months. Participants 16
years 6 months and older were administered the Wechsler Adult Intelligence
Scale-Revised (WAIS-R; Wechsler,
1981). Academic achievement was assessed with the Wide Range
Achievement Test (Jastak & Jastak,
1965). The children also completed a battery of neuropsychological
tests, which included the Trail Making Test for Children (TMT-C,
Reitan, 1969); the Benton
Visual Retention Test (BVRT; Form C, Administration A,
Benton, 1974); the Verbal
Selective Reminding Test (VSRT; Buschke
& Fuld, 1974); the Token Test
(Benton & Hamsher, 1976);
and the Controlled Oral Word Association Test (COWAT;
Benton & Hamsher, 1976).
(Detailed information on the administration and scoring of the
neuropsychological tests is available from Gail Tripp.)
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Results |
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Sample Characteristics. Demographic and illness characteristics for the four groups are presented in Table I. The groups were not matched on all variables. The mean age of children in the combined group was significantly older than that of the other groups, F(3, 82) = 5.40, p <.01. Socioeconomic status (SES) was not consistent across the four groups,
2(6,
N = 83) = 13.29, p <.05. The chemotherapy group included
fewer low SES families, 2(1, N = 83) = 8.44,
p <.005. Children in the two leukemia groups spent more nights in
the hospital than children with chronic asthma, F(2, 59) = 9.9,
p <.001. Time in remission was significantly longer for the
combined group, F(1, 40) = 17.77, p <.001. Finally,
chi-square analysis showed that leukemic risk was not independent of group,
2 (2, N = 41) = 6.36, p <.05. The
combined group included more children who were considered high risk,
2 (1, N = 41) = 5.96, p <.02. Factors
that predict mortality are used to classify patients in high, average, or low
categories of risk.
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Because the groups were not matched for age or SES, the relationship between age and neuropsychological test performance and between SES and intellectual, academic, and neuropsychological functioning was examined. Where we detected significant relationships, age and/or SES was treated as a covariate in group comparisons. To control for the effects of different remission times, we compared the performance of the two leukemia groups with time in remission as a covariate.
Intellectual Functioning. Summary scores from the WISC-R are presented in Table II.2 Significant group differences were found for Full Scale IQ, F(3, 77) = 7.64, p <.001; Verbal IQ, F(3, 77) = 8.22, p <.001; and Performance IQ, F(3, 77) = 5.49, p <.01. Children in the healthy control group obtained higher scores on all three scales than the two leukemia groups. In addition, the illness control group obtained higher Full Scale and Verbal IQ scores than the combined group and a higher Performance IQ score than the chemotherapy group.
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Significant group differences were also identified for three deviation quotients: Verbal Comprehension, F(3, 77) = 7.48, p <.001; Perceptual Organization, F(3, 77) = 5.24, p <.01; and Freedom From Distractibility, F(3, 77) = 4.95, p <.01. The healthy group obtained higher scores than the combined group for all three deviation quotients and a higher Verbal Comprehension score than the chemotherapy group. The illness control group obtained higher scores than the combined group for Verbal Comprehension and Perceptual Organization.
A profile analysis3
was conducted on the WISCR subtest scaled scores to determine the similarity
of response patterns across the groups. The levels comparison was significant,
F(3, 77) = 7.12, p <.001, indicating the mean subtest
scores differed across the groups. Multivariate comparisons using Wilk's
lead to rejection of the Flatness F(11,
67) = 8.74, p <.001, and Parallelism
F(33, 198) = 1.56, p <.05, hypotheses.
Rejection of these hypotheses indicates the profiles are not flat and the
groups differ in their pattern of subtest scores. Profile contrasts were used
to determine where the profiles of the three illness groups differed from that
of the healthy control group. A one-tailed confidence interval was created for
each subtest using the means and standard deviations from the healthy control
group. Group means outside this confidence interval were said to differ
significantly from the healthy control group. For this analysis, the alpha
level was adjusted using the Bonferroni correction to control for Type I
errors. Significant differences between the healthy control group and the
three illness groups are indicated in Table
III.
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Academic Performance. Scores on the various measures of academic
functioning are presented in Table
II. Covariance analysis of the WRAT Arithmetic standard score,
with SES as the covariate, was significant, F(3, 73) = 4.13,
p =.009. Pairwise comparisons, with 
set at.01, indicated the
combined group obtained significantly lower scores than the healthy control
group.
Teacher reported academic progress, 2(3, N = 83) =
17.16, p <.001, and parent concerns about learning,
2(3, N = 83) = 18.42, p <.001, were not
independent of group. Partitioning of the contingency tables showed the two
leukemia groups were making slower academic progress, 2(1,
N = 83) = 15.55, p <.001, and having more difficulty
learning, 2(1, N = 83) = 11.75, p <.001
than children in the two control groups. Parent reported school competence
T-scores were significantly different across groups, F(3, 65) = 7.60,
p =.0002. The combined group obtained significantly lower T-scores
than the two control groups, whereas the chemotherapy group obtained lower
scores than the healthy control group.
Neuropsychological Test Performance. To meet the assumptions of ANCOVA, raw scores on the TMT-C were log transformed and the error score from the BVRT was submitted to a square root transformation. Data from three healthy children was excluded from analysis of the Token Test; these children had extreme scores that were not corrected by data transformation. Raw scores on the Token Test, COWAT, VSRT, and the transformed score for part A of the TMT-C were submitted to ANCOVA with age as the covariate. The BVRT number correct and transformed error score and transformed score for part B of the TMT-C were submitted to ANCOVA with age and SES as covariates. (The neuropsychological test scores are not in the tables but are available from Gail Tripp.)
Although the healthy control group typically performed better than the
three illness groups (COWAT, BVRT, TMT-C part B, Token Test), few significant
differences emerged. Significant differences were found for the Token Test,
F(3, 75) = 6.13, p =.001, and part A of the TMT-C,
F(3, 70) = 6.75, p <.001. Pairwise comparisons, with
critical set at.01, showed the healthy control group performed better
than the leukemia groups on the Token Test. Both control groups completed part
A of the TMT-C more quickly than the chemotherapy group.
Effects of Time in Remission. To assess the effects of time in remission on the relative performance of the two leukemia groups, the scores of these two groups were compared after controlling for time in remission. Time in remission was correlated with each of the dependent variables; where significant relationships were detected, performance on these variables was submitted to ANCOVA with time in remission as the covariate (i.e., Full Scale and Verbal IQ, Verbal Comprehension, WRAT Arithmetic, BVRT, TMT-C, COWAT, VSRT). Age at testing and SES were also entered as covarites where appropriate. None of these comparisons was significant. Controlling for time in remission reduced between-group differences, in some instances reversing performance order (see Table II).
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Discussion |
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The results of this study indicate that prophylactic CNS chemotherapy, with and without cranial irradiation, is associated with significantly lower levels of intellectual and academic functioning. Chronic asthma is associated with lower, but not significantly different, levels of functioning in these areas.
The lower levels of intellectual and academic functioning observed in the leukemia survivors treated with combined prophylactic therapy is consistent with the results of a number of previous cross-sectional studies. More important, the results of this study provide strong evidence for lower levels of intellectual and academic functioning among children treated with CNS chemotherapy only.
Direct comparisons between the two leukemia groups were not statistically
significant. However, when the performance of the two groups was considered in
relation to the control groups, the combined therapy group was clearly more
impaired. These differences were most evident in the profile analysis of the
WISC-R subtest scores and in the presence of significant differences between
the illness control and combined therapy group, but not between the illness
control and chemotherapy groups. The subtlety of the differences between the
two leukemia groups may reflect the low dose of irradiation received by
children in the combined group. There is some evidence that low dose cranial
irradiation (i.e., 1800 cGy) has a milder effect on cognitive functioning than
higher doses (Cousens et al.,
1991).
The introduction suggested that the effects of CNS chemotherapy and cranial
irradiation might be additive. Differences in the performance of the two
leukemia groups, relative to the control groups, offers some support for this
hypothesis. In particular, the profile analysis on the WISC-R subtests
suggests cranial irradiation impacts on verbal skills over and above the
effects of CNS chemotherapy. However, before concluding that treatment effects
are additive, one must consider the possible impact of demographic/illness
characteristics on test performance. The children in the combined therapy
group are older, reflecting a longer period of time between treatment and
testing. Cousens, Waters, Said, and Stevens
(1988) suggest that IQ
deficits are progressive, increasing for up to 6 years following diagnosis.
Differences between the two leukemia groups may reflect the effects of time in
remission rather than treatment effects. Results from the covariance analyses
certainly support this argument. The older age of the combined group might
also explain the greater differences on the verbally mediated tests. Some of
the WISC-R verbal subtests similarities, for example, require more complex and
abstract reasoning. Deficits in these areas may become more obvious in
adolescence.
In an effort to separate the effects of prophylactic treatment from the effects of chronic illness, we included a group of children with chronic asthma. The experience of chronic illness appeared to have subtle effects on both intellectual and academic functioning. As hypothesized, chronic illness affected performance on measures of academic performance and on measures of cognitive functioning that are influenced by educational opportunities. These results suggest that some, but by no means all, of the problems experienced by the long-term survivors of leukemia are chronic illness effects. Returning to the proposed additive model of treatment effects, we suggest that CNS chemotherapy and, to a lesser extent, chronic illness both contribute to the pattern of deficits experienced by children who have survived leukemia. It is not clear that lowdose cranial irradiation contributes further.
The general absence of group differences on the measures of neuropsychological functioning is somewhat surprising. Although the two leukemia groups typically performed less well than the control groups on the neuropsychological tests, there were few significant differences. There are at least two possible explanations for these results. First, the areas of functioning selected for assessment may not be affected by CNS chemotherapy or cranial irradiation. Since we chose these areas in response to their known sensitivity to treatment effects, this explanation seems unlikely. A second possibility is that the measures used to assess the different areas of functioning were not sufficiently sensitive to detect group differences. The measures included were largely designed for use with adults, with limited child norms, necessitating covariance analysis of raw scores. With better normed tests, significant group differences might well emerge, as they did on the WISC-R.
Despite the difficulties with the neuropsychological measures and differences in the illness and demographic characteristics of the groups, our study has a number of important strengths. First, the inclusion of both illness and healthy control groups facilitated the separation of treatment and illness effects. Furthermore, the inclusion of a non-cancer illness group allowed for the determination of chronic illness effects that were not confounded by treatment with systemic chemotherapy. Second, the children in the two leukemia groups were recruited through follow-up oncology clinics, not from populations of children with identified learning difficulties. As a result, the children recruited are more similar to the larger population of children who have survived leukemia, increasing the generalizability of the findings. Finally, by assessing a range of abilities, we could demonstrate that children who survive leukemia are not uniformly impaired across all areas of functioning.
Future research should aim to recruit additional samples of children whose demographic and illness characteristics are well matched. This will confirm whether differences between the two leukemia groups are genuine, or an artifact of years in remission. Given the current evidence of increased verbal deficits among children treated with combined therapy, greater attention needs to be paid to the assessment of verbally mediated skills.
Moving beyond the methodological issues, our findings have important
clinical implications for health professionals working with children who
survive leukemia. Clearly, children treated with CNS chemotherapy, with and
without cranial irradiation, are at risk for impairments in intellectual and
academic functioning. Ideally, the cognitive functioning of all children who
survive leukemia should be regularly assessed as soon as practicable after the
diagnosis and continuing for some years after treatment
(Brown & Madan-Swain,
1993). Because deficits may be subtle, a comprehensive battery of
neuropsychological measures should be administered. Such assessments will
identify cognitive impairments as they appear and may be helpful in the design
of appropriate remediation programs.
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Acknowledgments |
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This research was supported by the Health Research Council of New Zealand (95/470), the Child Cancer Foundation (Otago), and the University of Otago. Dr. Raymond-Speden received a Taranaki Cancer Society Scholarship. We thank all the children, families, and teachers who gave their time so willingly to participate. We also thank Ms. Gay Ross, Drs. Paddy Grant, Scott MacFarlane, David Mauger, Jane Skeen, and Loche Teague, without whom this research would not have been possible.
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Notes |
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1 Mild, relatively infrequent asthma attacks controlled by selective ß-agonists. Moderate, chronic asthma that required continuous non-steroid medication. Severe, chronic asthma requiring preventative steroid treatment.
2 The above average mean IQ scores for the healthy control group almost
certainly reflects the use of the WISC-R to assess IQ. FSIQ scores on the
WISC-R are between 5.3 and 5.9 points higher than those obtained with the
WISC-III.
3 One participant in the combined therapy group was not administered the
mazes subtest; in order to include this child's data in the profile analysis,
we substituted the child's mean Performance score for the missing mazes
subtest score.
Received May 11, 1998; accepted November 12, 1998
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References |
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