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© 2001 American Society for Clinical Oncology Risks of Young Age for Selected Neurocognitive Deficits in Medulloblastoma Are Associated With White Matter LossFrom the Division of Behavioral Medicine and Departments of Diagnostic Imaging, Radiation Oncology, and Hematology/Oncology, St Jude Children’s Research Hospital; Departments of Pediatrics and Radiology, University of Tennessee College of Medicine; and Departments of Electrical and Biomedical Engineering, University of Memphis, Memphis, TN. Address reprint requests to Raymond K. Mulhern, PhD, St Jude Children’s Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; email raymond.mulhern{at}stjude.org
PURPOSE: To test the hypothesis that inadequate development of normal-appearing white matter (NAWM) is associated with the relationship between young age at the time of craniospinal irradiation (CRT) and deficient neurocognitive performance in survivors of childhood medulloblastoma. PATIENTS AND METHODS: Forty-two patients treated since 1985 participated in this cross-sectional study. All had been treated with CRT with or without chemotherapy and had survived 1 or more years after treatment. Neurocognitive evaluations were conducted with tests of intellect (intelligent quotient; IQ), verbal memory, and sustained attention. Quantitative magnetic resonance imaging, using a hybrid neural network, assessed the volume of NAWM. RESULTS: Neurocognitive test results were below normal expectations for age at the time of testing. A young age at CRT was significantly associated with worse performance on all neurocognitive tests except that of verbal memory. An increased time from completion of CRT was significantly associated with worse performance on all neurocognitive tests except that of sustained attention. After statistically controlling for the effects of time from CRT, we examined the association of NAWM with neurocognitive test results. These analyses revealed that NAWM accounted for a significant amount of the association between age at CRT and IQ, factual knowledge, and verbal and nonverbal thinking, but not sustained attention or verbal memory. CONCLUSION: The present results suggest that, at least for some cognitive functions, deficient development and/or loss of NAWM after CRT may provide a neuroanatomical substrate for the adverse impact of a young age at the time of CRT.
TREATMENT FOR medulloblastoma, the most frequently occurring malignant brain tumor of childhood, can be associated with considerable neurologic, endocrinologic, and neuropsychologic morbidities.1-6 The neuropsychologic consequences of craniospinal irradiation (CRT) in very young children can be devastating. In our recent survey of 19 long-term survivors diagnosed before the age of 4 years who received conventional doses to the cranium (CRT, 23.4 Gy plus local posterior fossa irradiation to 54 Gy) after chemotherapy, the median intelligence quotient (IQ) loss was 22 points at 5 years post-CRT (a rate of loss of 3.9 points per year) and had not yet plateaued.7 Multiple factors are known to increase the risk for IQ impairments in children with medulloblastoma, especially a young age at treatment and higher CRT doses.8-17 Attempts at CRT dose reduction, delaying CRT until a somewhat older age, and elimination of CRT may reduce neuropsychologic toxicity, but the impact of these therapy changes on both long-term survival and ultimate functional outcome is yet unknown.18-20 Another approach to the dilemma of effective treatment versus treatment neurotoxicity could be the identification of brain changes that are predictive of later neuropsychologic toxicity. Early predictors may make it possible to modify treatment among patients at risk, perhaps avoiding severe sequelae. Although modern neuroimaging techniques are effective in detecting early (eg, leukoencephalopathy) as well as late (eg, calcifications) brain changes associated with the central nervous treatment of childhood cancer, the relationship of these changes to the patient’s ultimate functional status has sometimes been ambiguous.21-23 We have recently developed a method of quantifying white matter loss that may help in defining the pathophysiology of the dementing process observed in some patients.24,25 Preliminary results have suggested a reduction in the development of normal-appearing white matter (NAWM) among patients treated for medulloblastoma with tumor resection followed by CRT (with or without chemotherapy) when compared with age-matched controls treated with surgery alone for low-grade tumors of the posterior fossa.26 This difference could not be attributed to differences in intracranial volumes between the two groups of patients. The patients treated for medulloblastoma also had significantly lower IQ values. We speculated that loss of NAWM may provide a neuroanatomic substrate that can at least partially explain intellectual loss after treatment for medulloblastoma. A patient’s age at the time of CRT has traditionally represented a convenient surrogate for as yet unknown biologic mechanisms underlying the relationship between young age and increased neurotoxicity. The objective of the present study was to determine whether CRT effects on developing white matter can provide an explanation for at least part of this relationship. Our approach was to (1) confirm the association of decreased NAWM with intellectual loss among patients treated for medulloblastoma, and (2) to test the hypotheses (a) that younger patients treated for medulloblastoma have reduced volumes of NAWM and neurocognitive performance compared with their older counterparts, and (b) that NAWM can at least partially account for the association between young age at treatment and neurocognitive performance.
Patient Selection and Medical Therapy Patients eligible for this study were English-speaking, were younger than 21 years of age at diagnosis, had histologically proven medulloblastoma arising in the posterior fossa, and were at least 1 year from completion of CRT with no evidence of progressive disease. To test our hypothesis that changes in neurocognitive performance are related to NAWM, we restricted patients to those who had received magnetic resonance imaging (MRI) in 1995 or later, a time when quantitative MRI (qMRI) sequences were routinely instituted for patient surveillance. Neurocognitive testing and qMRI have been routinely collected on 62 medulloblastoma survivors as a component of their medical treatment protocols for which the patient or legal guardian had given written informed consent. However, because of differences in treatment protocol design and logistics, these examinations were not always planned to coincide. Therefore, for the purpose of this analysis, we further restricted our selection to those with neurocognitive testing within 6 months of a qMRI examination. On the basis of these criteria, 42 patients remained eligible. The 42 medulloblastoma survivors were treated with surgical resection of the tumor and 23.4 to 36 Gy of CRT with a boost to the posterior fossa for a total dose of 49.0 to 54.0 Gy; 29 patients also received pre- and/or post-CRT chemotherapy with cisplatin/etoposide, carboplatin/etoposide plus cyclophosphamide/vincristine, cisplatin/etoposide plus cyclophosphamide/vincristine, carboplatin/cyclophosphamide/etoposide, or mechlorethamine, vincristine, procarbazine, and prednisone; 13 patients experienced one or more postoperative complications (infection, seven; posterior fossa syndrome, seven) and three developed seizures after completion of therapy. Of the 42 patients, 16 had participated in a previous study of white matter loss;26 12 of the 16 received new studies for inclusion in this analysis.
Neurocognitive Testing Protocol
qMRI Segmentation Protocol
The brain parenchyma volume of the index slice was then assessed using a fully automated hybrid neural network segmentation and classification method.25 The segmentation procedure used a Kohonen Self-Organizing Map by which a three-unit input vector, composed of the nonnormalized T1, T2, and PD signal intensities for a single pixel in the MR image, produced nine Self-Organizing Map output vectors.24,25 Each of the nine levels in the segmented images were then classified according to tissue type (gray matter, white matter, CSF, blood vessels and membranes, partial volumes of gray/white matter, and partial volumes of gray/CSF) or background using a multilayered back-propagation neural network. White matter that typically appears abnormal on visual inspection of T2-weighted images was automatically deleted from quantification of white matter; therefore, only NAWM is included in our analyses. Gray matter was colored yellow, white matter was colored green, CSF was colored a light blue, and blood vessels and membranes were colored dark violet. For contrast purposes, the background was colored black (Fig 2). A histogram of pixels for each color was completed to determine the number of pixels present in each category and then multiplied by pixel volume to determine the sampled volume of each tissue type.24,25
Data Analyses Our primary objective was to test the hypothesis that NAWM can account for the finding, consistent over many studies, that young age at CRT is associated with lowered neurocognitive performance. In terms of statistical inference, NAWM is a putative mediator of the relationship between age and neurocognitive performance (ie, a younger age at CRT results in decreased NAWM, which results in decreased neurocognitive performance).35 To demonstrate this effect, four conditions must be met: (1) a younger age at CRT must be significantly associated with reduced NAWM at the time of examination, (2) a younger age at CRT must be significantly associated with decreased neurocognitive performance at the time of examination, (3) reduced NAWM at the time of examination must be significantly associated with decreased neurocognitive performance at the time of examination, and (4) the strength of the association between a younger age at CRT and decreased neurocognitive performance must be significantly reduced after statistically controlling for the effects of NAWM. These four conditions are tested in the present study by partial correlations computed separately for each of the neurocognitive outcome variables. To control for differences in head size and brain development between the time of CRT and the time of the index qMRI and neurocognitive testing, we statistically controlled for time from CRT in all analyses. Because the hypotheses predicted directional relationships between variables, one-tailed probability tests of significance (alpha = 0.05) were used.
Descriptive Data Of the participating 42 patients, 26 were male; 36 were white, five were black, and one was Hispanic. Patients ranged in age from 2.2 to 16.1 years at diagnosis (mean, 8.2 years; SD, 3.8 years), 2.9 to 16.4 years at the time of CRT (mean, 8.5 years; SD, 3.7 years), and 6.3 to 21.5 years at the time of examination (mean, 13.4 years; SD, 4.2 years). Nine of the patients were very young (< 4 years) at the time of diagnosis. From the completion of CRT, 1.8 to 11.0 years (mean, 4.9 years; SD, 2.5 years) had elapsed to the time of examination. The mean values for estimated IQ, IQ component subtests, and tests of verbal memory as well as sustained attention were one to two SDs below normal expectations for age (Table 1).
Visual inspection by the neuroradiologist of MRIs at the level of the index slice revealed that 10 of the 42 patients had T2 abnormalities: five had encephalomalacia or other white matter changes (two of these five also had lacunes), and five had lacunes only. These volumes were not quantified and were eliminated from the volumes of NAWM. Pearson Product-Moment Correlation Coefficients were computed among variables in our proposed model (Table 2). These revealed that age at CRT was significantly correlated with all neurocognitive outcomes except verbal memory, with performance generally improving for children who were older at the time of CRT. Performance on the measures of IQ and verbal memory, but not sustained attention, tended to deteriorate as time from CRT increased. NAWM was associated with age at CRT but not with time since CRT. These univariate relationships provided preliminary justification for testing the proposed model of NAWM in explaining the relationship between a younger age at CRT and neurocognitive outcomes.
Estimated IQ The hypothesis that NAWM explains the relationship between younger age at CRT and lower IQ was tested by computing four partial correlations, each controlling for the effects of time since CRT. The resulting squared partial correlation coefficients (R2) represent the unique proportion of variance explained in the outcome by the predictor variable. Age at CRT had a significant positive association with NAWM after controlling for time since CRT (R2 = 0.170; P = .006). Age at CRT had a significant positive association with IQ after controlling for time since CRT (R2 = 0.226; P = .002). NAWM had a significant positive association with IQ after controlling for time since CRT (R2 = 0.253; P = .001). The final analysis revealed that, after controlling for both time since CRT and NAWM, the association between age at CRT and IQ was significantly diminished (R2 = 0.052; P > .10), supporting the hypothesis that NAWM largely explains the association between age at CRT and IQ. In combination, these findings suggest that approximately 70% of the association between age at CRT and IQ was explained by NAWM volumes. The same approach was taken in the analysis of each of the three IQ subtests measuring factual knowledge, verbal abstract reasoning, and nonverbal abstract reasoning, as well as the tests of verbal memory and sustained attention.
Factual Knowledge
Verbal Abstract Thinking
Nonverbal Abstract Thinking
Verbal Memory
Sustained Attention
Normal-Appearing Gray Matter
In summary, we first confirmed in this sample of long-term survivors of childhood medulloblastoma the significance of associations between young age at the time of CRT and increased time from CRT with worse neurocognitive performance. We then controlled for the effects of time and tested the hypothesis that development of NAWM in the brain explained the association between young age at CRT and neurocognitive performance. Strong evidence for this effect was found for estimated overall IQ and its components of fund of factual information, verbal abstract thinking, and nonverbal abstract thinking. However, the association between age at CRT and neurocognitive performance could not be attributed to NAWM development, as measured using our representational index slice, for the attention and memory outcomes. The present study reinforces the critical roles of age at CRT and time interval from CRT for IQ development among long-term survivors of childhood medulloblastoma that have been reported earlier.14-18 In addition, the present study found a mean estimated full-scale IQ of 86 for children surviving medulloblastoma, which is very similar to the value predicted from regression analysis of 42 children 2 to 10 years of age given 24 or 36 Gy of CRT for leukemia or brain tumors.14 Reinforcing these findings, the Pediatric Oncology Group recently reported on age and CRT dose effects in a clinical trial of medulloblastoma treatment.18 Eligible patients had been treated on the Pediatric Oncology Group Study 8631 for low-risk medulloblastoma, which randomized patients to receive standard-dose (36 Gy) or reduced-dose (23.4 Gy) CRT; both groups received 54 Gy to the posterior fossa. Those who were alive and free of progressive disease 6.1 to 9.9 years since completing treatment were eligible for the study. Of the 35 eligible, 22 participated in a battery of tests that included measurement of intellectual and academic development as well as ratings of health-related quality of life. Problems with cognition were the most frequent reported quality-of-life impairment in the survivors (73%), with 12 of 22 having a need for special educational intervention. The median full-scale IQ of survivors was 83, similar to the present series. Statistical analyses supported the hypothesis that younger patients and patients receiving standard-dose CRT were at greater risk for neuropsychologic problems than older children or those receiving reduced-dose CRT. CRT-induced CNS damage results from oligodendrocyte and endothelial cell damage.36 Late effects are evidenced on neuroimaging by diffuse and multifocal white matter hyperintensities, as well as calcifications in the cortical gray matter and basal ganglia.37 It is only with the recent development of quantitative neuroimaging techniques that the development of intracranial volume, white matter, gray matter, and CSF volumes has been studied in healthy persons.32-34 Intracranial volume peaks at the age of 10 years and remains constant, gray matter volume peaks at 4 years and declines steadily thereafter, white matter volume peaks at age 20 and remains constant, and CSF volume remains stable until age 20, when it begins to increase. Studies of normal adults have shown that the volumes of these compartments can account for at least some variation in IQ.38 The finding in the present study that lower volumes of NAWM are associated with significantly lower IQ scores among children who are younger at CRT is not surprising. Because rapidly proliferating cells are more vulnerable to the deleterious effects of CRT, children receiving CRT for medulloblastoma before the age of 4 years are at greatest risk for both neuronal and glial cell damage. Those receiving CRT after this age continue to remain at risk for glial damage until young adulthood. With regard to effects on mental functions, amount of white matter loss may be of greater importance than location of loss, especially within widely distributed as opposed to highly localized neural systems.39 This may explain, in part, why NAWM was more highly associated with some neurocognitive test scores than others, suggesting that the use of additional neurocognitive measures may be useful. In our studies to date, we have used qMRI techniques to measure NAWM from a single slice at the level of the basal ganglia meant to represent overall brain white matter loss. Using this qMRI approach, the present study was able to show as association between NAWM volume and IQ scores. Although the importance of NAWM could not be established for measures of verbal memory and sustained attention, significant relationships between age at CRT and these outcome measures were nonetheless observed. Because abnormal-appearing white matter was eliminated from our analyses, the NAWM measurements are affected by the failure to develop NAWM as well as the development of abnormal white matter. Investigations of alternative methods of estimating abnormal and NAWM are being conducted to further our understanding of these relationships. For example, we are presently using up to seven transverse MRIs, as opposed to the single image used in the present study, to estimate white matter volume. The addition of fluid-attenuated inversion recovery (FLAIR) sequences will allow for quantification of abnormal areas of white matter. Recent studies of white matter development using corpus callosum volumes from sagittal MRIs have indicated differences between children diagnosed with attention deficit hyperactivity disorder and controls,40-45 suggesting that this approach may be useful in examining the source of problems with attention among our patients. The present study has several limitations that restrict our ability to generalize the findings and that should be remedied in future studies. The sample size was limited because of attempts to experimentally control for the timing of examinations. Furthermore, not all patients participated in all tests. As a result, statistical sensitivity to some findings was reduced. Many of these limitations are a related to the fact that the psychologic testing and qMRI were studied in a cross-sectional as opposed to a longitudinal design. We have recently reported a longitudinal study of patients treated for medulloblastoma that demonstrated a significant loss of NAWM volume from presentation throughout the first year of therapy.46 To fully substantiate our hypothesis that white matter loss is at least partially responsible for IQ declines, we would need to demonstrate that white matter loss antedates IQ loss by repeated observations of individual patients over time. To validate our hypothesis that white matter loss can explain age-related effects on IQ, it would be optimal to study longitudinal patterns of IQ and white matter changes over time for younger and older patient groups. Despite these design improvements, the possibility remains that the association between white matter changes and changes in neurocognitive functioning is an epiphenomenon. That is, other, yet undiscovered, pathologic processes may have a direct but independent impact on both white matter and intellectual development. In conclusion, the results of the present study suggest that variations in the development of NAWM remaining after CRT with or without chemotherapy are associated with changes in IQ and component cognitive functions. One interpretation of these findings is that white matter may be a neuroanatomic substrate for the adverse effects of various risk factors for neurocognitive damage that have been identified in previous investigations (eg, young age). Although speculative at this point, if these relationships are confirmed in larger prospective studies, early signs of white matter injury during chemotherapy or CRT using qMRI may result in changes in the treatment plan because of correlation with late neurotoxicity. However, in many instances therapy cannot be altered; therefore, new methods of protecting white matter from CRT will need to be developed.
Supported in part by the National Cancer Institute, Bethesda, MD (grant nos. P30-CA21765, U01-CA81445), and by the American-Lebanese-Syrian Associated Charities, Memphis, TN. We thank Diane Fairclough, DrPH, and Jim Boyett, PhD, for their thoughtful comments on the manuscript.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
