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Cognitive and Academic Functioning in Survivors of Pediatric Bone Marrow Transplantation

From the Division of Behavioral Medicine, Department of Biostatistics and Epidemiology, and Department of Hematology/Oncology, Division of Bone Marrow Transplantation, St Jude Children’s Research Hospital, Memphis, TN.

Address reprint requests to Sean Phipps, PhD, Division of Behavioral Medicine, St Jude Children’s Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; email sean.phipps{at}stjude.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate cognitive and academic functioning in survivors of pediatric bone marrow transplants (BMTs) at 1 and 3 years after a BMT.

PATIENTS AND METHODS: In a prospective, longitudinal design, patients underwent a comprehensive battery of neurocognitive measures before admission for transplantation and at 1, 3, and 5 years after a BMT. This article describes a cohort of 102 survivors with follow-up data available for 1 year after a BMT, including 54 survivors with follow-up available for 3 years. This represents the largest cohort of pediatric BMT survivors yet reported in a prospective study.

RESULTS: In the cohort as a whole, there were no significant changes on global measures of intelligence (intelligence quotient [IQ]) and academic achievement at either 1 or 3 years after a BMT, despite adequate power to detect an IQ change of three points or greater. Likewise, performance on specific tests of neuropsychologic function remained stable. No significant differences were observed between patients whose conditioning regimen included total-body irradiation (TBI) and those whose did not. The primary predictor of neurocognitive outcome was patient age, with younger patients more likely to show declines over time. The subset of patients who were less than 3 years of age at the time of transplantation seemed to be particularly vulnerable to cognitive sequelae.

CONCLUSION: The use of BMTs with or without TBI entails minimal risk of late neurocognitive sequelae in patients who are 6 years of age or older at the time of transplantation. However, patients who are less than 6 years of age at the time of transplantation, and particularly those less than 3 years of age, seem to be at some risk of cognitive declines.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE POPULATION OF survivors of pediatric bone marrow transplants (BMTs) has grown rapidly over the past decade, prompting increased attention to the potential adverse late effects of this procedure.^1-3 Survivors of BMTs are thought to be at risk for neurocognitive impairments as a result of their exposure to a number of potentially neurotoxic agents, including those used in conditioning, such as total-body irradiation (TBI), busulfan, and other high-dose ablative chemotherapies, as well as those agents used for the prophylaxis and/or treatment of graft-versus-host disease (GVHD).^1-4 The concern regarding potential neurocognitive deficits from BMTs has been based largely on extrapolation from studies of acute lymphoblastic leukemia survivors who received CNS therapy,^5-8 because empiric data from pediatric BMT survivors have been limited.

The published reports of neurocognitive outcomes in pediatric BMTs have been characterized by methodologic difficulties, such as small sample sizes or retrospective designs, and the results have been contradictory. Several studies have reported normal neurodevelopment with no evidence of declines in cognitive function.^9-15 In contrast, other studies have indicated declines in cognitive or academic function as a result of BMTs.^16-21 Likewise, there have been inconsistencies regarding the correlates of cognitive outcomes in BMT survivors. Most studies have failed to show a relationship between cognitive changes and diagnostic background, type of transplant, or conditioning regimen used, including the use or dosage of TBI. However, at least one study has suggested a greater risk of cognitive impairment as a function of TBI, particularly in the subset of patients who were 3 years of age or younger at the time of their BMT.¹⁷ Contradictory findings have also been reported regarding the significance of patient age at the time of transplant, with some studies reporting poorer cognitive outcomes as a function of younger age at the time of BMT^16-18,21 and others failing to note this effect.^13,15,20

In the largest prospective study published to date, Kramer et al²⁰ reported a significant decline in global intelligence quotient (IQ) indices from baseline to 1 year after BMT in a cohort of 67 pediatric survivors. The mean decline was approximately six IQ points or 0.4 SD units. Analyses from a smaller subset of this cohort who were followed up through 3 years after BMT revealed that the decline in IQ was maintained over time, but no further decline in functioning was seen. Change in cognitive function over time was not related to diagnosis, type of transplant, conditioning regimen, TBI dosage, sex, or age at the time of BMT. The absence of such a relationship with patient age at the time of BMT in the Kramer study must be viewed in the context of the younger age range of this cohort as a whole, who had a mean age of 45 months, with the majority of patients less than 3 years of age at the time of BMT.²⁰

The purpose of the study presented here was to assess changes in neurocognitive function over time in a large cohort of survivors of pediatric BMT, using a prospective, longitudinal design. In our earlier report from this cohort, we described 25 survivors who were followed up only to 1 year.¹⁴ That cohort has now grown to a number that provides for the reliable detection of relatively small changes on tests of intellectual function and also allows adequate power for the examination of predictors of cognitive outcome, such as age and use of TBI. The report presented here will focus on changes observed from before BMT to 1 year after BMT and from 1 year to 3 years after BMT in that subset of the cohort for whom extended follow-up data are available. This analytic approach was taken to allow for comparison to the earlier report by Kramer et al,²⁰ which was the largest prospective study available before this report. We hypothesized that declines in cognitive function after BMT would be seen and that such declines would be greater (1) at 3 years after BMT, (2) in patients who were conditioned with TBI, and (3) in patients who were younger at the time of transplant.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
All patients scheduled to undergo BMTs at St Jude Children’s Research Hospital were eligible for the study, with the exception of those who were being treated for brain tumors or for whom English was not the primary language. Between February 1991 and May 1998, 260 patients were enrolled onto the study and received a baseline neurocognitive evaluation. Of these 260, 118 (45%) died before receiving any follow-up assessments; follow-up data at 1 year after BMT were obtained for 102 patients; and 40 patients, most of whom were in the pretransplant to 1-year posttransplant time period, were alive but had not yet received any follow-up evaluation. Of the 102 patients who received follow-up evaluations at 1 year after BMT, 54 were also evaluated at 3 years after BMT. The demographic and medical characteristics of the surviving cohorts who were assessed at 1 and 3 years after BMT are listed in Table 1.

Measures
All patients were assessed with an age-appropriate battery of cognitive/developmental measures, including measures of academic achievement and specific neuropsychologic functions when indicated. The following instruments were used.

Global intelligence/development. Bayley Scales of Infant Development (BSID, BSID-II)^23,24: This widely used instrument provides for the assessment of children between the ages of 1 and 42 months. It provides two global scores: the Mental Development Index (MDI) and the Psychomotor Development Index (PDI). Although these scores are technically different from IQ scores, they are standardized in the same manner, with a mean of 100 and SD of 15, and the MDI is often used interchangeably with and interpreted in the same manner as the IQ. In 1993, the BSID-II was introduced, and this version was included for pre-BMT evaluations in our study in 1994. As with other instruments in which there was a change in version during the course of our study, all patients who required a Bayley test at the time of a follow-up evaluation were tested with the same version that had been used in their pre-BMT evaluation.

Wechsler Intelligence Scales (WPPSI-R, WISC-R, WISC-III, WAIS-R)^25-28: All patients who were older than 3 years of age at the time of their pre-BMT evaluation were evaluated with the appropriate Wechsler scale. The Wechsler Pre-School and Primary Scales of Intelligence (WPPSI-R)²⁵ test was used for patients aged 3 to 6 years. The Wechsler Intelligence Scale for Children (WISC) was used for patients aged 6 to 16 years. At the outset of the study, patients between the ages of 6 and 16 were evaluated with the WISC-R,²⁶ and in 1993 the WISC-III²⁷ was introduced to the study. Again, any patient who had been evaluated with the WISC-R for their baseline assessment was evaluated with this instrument for all subsequent follow-ups. Patients who were older than 16 years of age were assessed with the Wechsler Adult Intelligence Scales (WAIS-R).²⁸ These are the most widely used instruments for the assessment of global intelligence, and the psychometric properties and validity of the scales are well documented.

Academic achievement. Wide Range Achievement Test (WRAT-R, WRAT-III)^29,30: This instrument provides age- and grade-normed standard scores in the domains of reading, spelling, and arithmetic for children aged 6 and older. The WRAT-III was introduced into the study in 1994. Standard scores are provided, with a mean of 100 and an SD of 15.

Perceptual-motor skills. Beery Developmental Test of Visual-Motor Integration (DTVMI)³¹: This widely used drawing task is normed for children between the ages of 4 and 16. Standard scores are provided, with a mean of 100 and an SD of 15.

Visual-spatial skills. Test of Visual-Perceptual Skills (TVPS), nonmotor³²: Four subtests from this battery were administered, measuring visual discrimination, visual memory, visual-spatial relationships, and visual figure-ground. The test has been normed for children between the ages of 4 and 12, and scores are standardized, with a mean of 10 and an SD of 3.

Attention and memory. Rey Auditory Verbal Learning Task (AVLT)³³: This test involves presenting patients with a list of 15 words that are repeated in a series of five trials, as well as a delayed recall task. There are no standard scores for this task, although published data from other study populations are available for comparison.

Processing speed. Symbol Digits Modalities Test (SDMT)³⁴: This is a timed task that requires patients to respond to as many items as possible by supplying a number for each of several unique symbols. A written response is required on the first trial and a verbal response on the second. Standard scores are not available, but comparisons can be made with published data from other studies.

Procedure
The study was approved by the hospital’s institutional review board, and all participants provided informed consent before undergoing any evaluations. Patients who were scheduled to be admitted for BMTs and who met the eligibility criteria for the study were seen for evaluation 2 to 3 weeks before admission, as part of routine pretransplant diagnostic procedures. Only four eligible patients (1.5%) declined to participate. Initially, all patients enrolled onto the study received a comprehensive assessment battery as described above. However, we subsequently abbreviated the pre-BMT evaluation significantly and performed comprehensive assessments beginning at 1 year post-BMT only for survivors. The rationale for this was (1) our preliminary analysis had revealed an absence of change in the first year after BMT; (2) the high mortality of the procedure in the first year implied that a great deal of time would be spent collecting baseline data on patients for whom there would be no follow-up; and (3) we were interested in reducing the time and instrument burden on patients and families. Thus the pre-BMT evaluation was reduced to the complete Bayley scale or a short form of the appropriate Wechsler scale, and the WRAT for children of school age and older. We administered four subtests from the Wechsler scales: Information, Similarities, Block Design, and Digit Span, using the first three to compute a deviation IQ or prorated full-scale IQ. In our cohort, the correlation of this short form with full-scale IQ is 0.938.

Patients who survived to the follow-up evaluation were re-evaluated with the complete neuropsychologic battery at 1, 3, and 5 years after BMT. Two survivors who had received baseline evaluations declined to participate further in the study. An additional four patients who had completed both the baseline and 1 year post-BMT assessments subsequently declined to participate further in the study. Otherwise, no additional patients have been lost to follow-up, and all other attrition has been due to death.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Approach to Changes in IQ Instruments
The wide age range of the patients studied, as well as the long time frame of the study, necessitated the use of multiple measures of global IQ. Thus some patients may have been evaluated with the Bayley or Bayley II scales before transplantation and the WPPSI-R 1 year after, or the WPPSI-R at baseline and the WISC-R or WISC-III subsequently, and so on. Having to combine scores from different measures is unavoidable in a study such as this but introduces a degree of imprecision and uncertainty in the results. We considered providing separate analyses for each combination of tests, but there are 12 possible combinations of test measures between any two observation points (six involving changes and six where both tests are identical); thus it is impractical to look at each combination separately. Rather, we compared results between those patients who had any change in IQ test versus those who had been tested with the same test on both occasions. For comparisons of pre-BMT to 1-year post-BMT scores, 11 (12.2%) of 90 paired observations involved a change in test instrument. Using change in IQ score as the dependent measure, there was no difference observed between patients who had had a change in instrument versus those who had not (P > .20). For comparisons of 1-year post-BMT to 3-years post-BMT scores, 16 (30.8%) of 52 paired observations involved a change in instrument. Again, there was no significant difference between patients who had been assessed with the same or different instruments at the two time points (P > .90). Therefore, for subsequent analyses, we combined the data from all patients, regardless of change in IQ measure.

Pre-BMT to 1-Year Post-BMT Comparisons: Global IQ and Academic Achievement
In the cohort as a whole, there was no significant change in global IQ measures from before BMT to 1 year after BMT (paired t test; Table 2). This analysis provides better than 80% power to detect a change of three IQ points or greater, at alpha = 0.05. Likewise, no significant changes were observed on any of the IQ subtests. The absence of change in this cohort is highlighted by the median difference score of zero on all IQ indices. A total of 18 patients (20.0%) showed a decline of 10 IQ points or greater, compared with 12 (13.3%) who showed a gain of 10 points or greater. For school-age children, there was no evidence of change in academic achievement during this time frame. Descriptively, the academic achievement scores are low at baseline, ranging from one half to two thirds of an SD below normative values, but these values do not change over time (Table 2).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Our results may initially seem to contradict those of Kramer et al,²⁰ but the discrepancies are explained in large part by a differential outcome as a function of age. Kramer et al reported a significant decline in their cohort as a whole, in comparison to our findings of stability. However, the Kramer et al cohort had a mean age of 31/2 years, compared with 101/2 years in the study presented here. If we compare our youngest two subgroups of patients, whose mean age would be comparable to that of the patients in the Kramer et al cohort, our findings are consistent. In fact, our youngest patients showed an even greater decline than that reported by Kramer et al, and their cognitive function continued to decline through 3 years. Kramer et al did not find age to be a predictor of outcome in their study, but this may be due to the constricted age range of their cohort, in which the great majority of patients were age 3 and under. The wider age range of our sample provides a greater likelihood of detecting age effects.

Although we found that change in test instruments across observations was not predictive of outcome in the cohort as a whole, the youngest subset of patients, who required assessment with the Bayley scales at baseline, may represent a special case because there is some evidence of bias toward a decline when switching from using the Bayley scales to the WPPSI-R scale.²⁴ The possibility that our findings regarding this subset of patients could be an artifact of changes in test instrumentation cannot be ruled out. Small numbers preclude statistical analysis on just this subset. However, our examination of outcomes on a case-by-case basis leads us to conclude that the decline in the 3-year-or-younger age group may be exaggerated somewhat because of changes in instrumentation, but it is likely to represent a real phenomenon. Unfortunately, this problem is unavoidable with the currently available assessment instruments. Greater confidence in these findings will come only with a larger numbers of children under the age of 3 who are assessed with the same instrument.

The stability of this cohort in cognitive function is mirrored by stability in academic achievement among the school-aged subset of the cohort. This is perhaps even more surprising given the long absences from school that occur during the year after a transplant. Although there is no evidence of any decline in academic achievement, the mean scores for this cohort are low, ranging from one half to two thirds of an SD below test norms. The reasons for this are not clear. It does not seem to be a function of prior therapy, because those who had been exposed to any type of prior CNS therapy fared no worse at baseline than did those who had not. Regardless of the reason for the lower scores, this highlights the necessity of longitudinal rather than cross-sectional designs. For example, our mean arithmetic achievement score of 91, if obtained in a cross-section of survivors, would test as significantly different from test norms. This could easily lead to the mistaken conclusion that BMT therapies lead to deficits in academic achievement, when there is clearly no evidence of decline in our longitudinal sample.

The findings presented here fail to show any relationship between use of TBI and neurocognitive outcome, despite adequate power to detect such an effect. This is consistent with most prior reports. When this result is contrasted with neurocognitive outcomes reported in children who receive 18- or 24-Gy cranial radiation therapy prophylactically for leukemia, there is a suggestion that there may be a threshold between 18 and 14 Gy below which neurotoxicity is largely reduced or eliminated. Obviously, more data are required before such a conclusion can be made definitively.

Despite the clear stability in global IQ measures, some subtests from the Wechsler scales showed a trend toward a decline over time, notably those that tap attention, concentration, and working memory. Difficulties with these "executive functions" have been reported in leukemia survivors who received CNS therapy,^7,8 as well as in some reports with BMT survivors.²¹ Thus these nonsignificant trends in the data will bear close scrutiny in the future as this sample continues to expand. The only measure in which survivors demonstrated a statistically significant decline was the Beery visual-motor integration task.³⁰ The poor performance seen on this drawing task, coupled with the very good performance on the nonmotor Test of Visual-Perceptual Skills,³¹ suggests a relative difficulty in fine-motor functioning. This is also consistent with earlier reports from BMT survivors, which suggested motor difficulties.^15-17 It should be noted however, that the decline on this measure was only marginally significant, and, further, anecdotal observations from the staff who performed the psychometric assessment suggest that this measure is one that often engenders a reduction in effort when it is seen repeatedly.

Our global interpretation of the current data set is that BMT, even with TBI, poses low to minimal risk for late cognitive and academic deficits in patients who are at least 6 years of age at the time of transplant. For patients aged 5 and younger, and particularly for those younger than 3 years of age, the risk of cognitive impairment is increased, regardless of whether or not TBI is used in conditioning. These conclusions are put forth with caution, given the relatively small numbers of young patients in our surviving cohort, but are consistent with prior research involving younger cohorts.^19,20 Changes in transplant conditioning regimens (eg, eliminating TBI) for younger children may not be indicated, but these children will require close developmental monitoring, and intervention programs should be implemented early if any signs of difficulty are present.

	ACKNOWLEDGMENTS

 
Supported in part by grant no. CA 60616 from the National Cancer Institute, Bethesda, MD, and by the American Lebanese Syrian Associated Charities, Memphis, TN.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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4. Phipps S, Barclay D: Psychosocial consequences of pediatric bone marrow transplantation. Pediatr Hematol Oncol 3:171-182, 1996

5. Said JA, Waters B, Cousens P, Martens MM: Neuropsychological sequelae of central nervous system survivors of childhood acute lymphoblastic leukemia. J Consult Clin Psychol 57:251-256, 1989[Medline]

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9. Kaleita TA, Shields WD, Tesler A, et al: Normal neurodevelopment in four young children treated for acute leukemia or aplastic anemia. Pediatrics 83:753-757, 1989[Abstract/Free Full Text]

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15. Simms S, Kazak AE, Gannon T, et al: Neuropsychological outcome of children undergoing bone marrow transplantation. Marrow Transplant 22:181-184, 1998

16. Smedler AC, Ringden K, Bergman H, et al: Sensory-motor and cognitive functioning in children who have undergone bone marrow transplantation. Acta Paediatr Scand 79:613-621, 1990[Medline]

17. Smedler AC, Bolme P: Neuropsychological deficits in very young bone marrow transplant recipients. Acta Pediatr 84:429-433, 1995[Medline]

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19. Chou RH, Wong GB, Kramer JH, et al: Toxicities of total-body irradiation for pediatric bone marrow transplantation. Radiat Oncol Biol Phys 34:843-851, 1996

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Submitted June 23, 1999; accepted October 22, 1999.

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