Dec 6, 1999 - T. David Elkin, MS,* Larry E. Kun, MD,â June Taylor, PhD,â¡ .... process based on intensity gradients developed by John L. Ostuni at the NIH ...
Neurocognitive Deficits in Medulloblastoma Survivors and White Matter Loss Raymond K. Mulhern, PhD,*† Wilburn E. Reddick, PhD,‡§ Shawna L. Palmer, MS,* John O. Glass, MS,‡ T. David Elkin, MS,* Larry E. Kun, MD,†i June Taylor, PhD,‡ James Langston, MD,‡¶ and Amar Gajjar, MD†#
Although previous studies have documented a significant risk of intellectual loss after treatment for childhood medulloblastoma (MED), the pathophysiology underlying this process is poorly understood. The purpose of this study was to test the hypotheses that (1) patients treated for MED in childhood have reduced volumes of normal white matter (NWM) related to their treatment with craniospinal irradiation with or without chemotherapy, and (2) deficits in NWM among patients surviving MED can at least partially explain deficits in their intellectual performance. Eighteen pediatric patients previously treated for MED were matched on the basis of age at the time of evaluation to 18 patients previously treated for low-grade posterior fossa tumors with surgery alone (mean difference, 3.7 months). Evaluations were conducted with age-appropriate neurocognitive testing and quantitative magnetic resonance imaging by using a novel automated segmentation and classification algorithm constructed from a hybrid neural network. Patients treated for MED had significantly less NWM ( p < 0.01) and significantly lower Full-Scale IQ values than those treated for low-grade tumors (mean, 82.1 vs 92.9). In addition, NWM had a positive and statistically significant association with Full-Scale IQ among the patients treated for MED. We conclude that irradiation- or chemotherapy-induced destruction of NWM can at least partially explain intellectual and academic achievement deficits among MED survivors. Mulhern RK, Reddick WE, Palmer SL, Glass JO, Elkin TD, Kun LE, Taylor J, Langston J, Gajjar A. Neurocognitive deficits in medulloblastoma survivors and white matter loss. Ann Neurol 1999;46:834 – 841
Medulloblastoma (MED), a tumor of the posterior fossa region, is the most frequently occurring malignant brain tumor of childhood. Unlike children with nonmalignant tumors of the same region, children surviving treatment for MED and other malignant brain tumors are at risk for a variety of late central nervous system sequelae most often associated with cranial radiation therapy (CRT),1–3 some of which lead to chronic and potentially handicapping neuropsychological morbidity often quantified by IQ.4,5 This has led to treatment approaches that attempt to minimize central nervous system morbidity by delaying CRT in the very young or by reducing CRT dose while simultaneously maintaining or improving the current 60% to 65% survival rates in average-risk patients.6 – 8 Multiple factors, in addition to CRT, are known to increase the risk for IQ impairments in children with MED, including a younger age at treatment, greater time elapsed from treatment, and higher CRT doses.9 –17 The impact of young age at treatment and CRT may be most critical to neuropsychological outcome in MED with IQ declines continuing as late as 10 or
more years from completion of therapy.18 However, the pathophysiology of this dementing process and the relationship between brain morphology and neuropsychological functioning among MED patients is poorly understood. We have developed and validated a novel quantitative magnetic resonance imaging (qMRI) technique for the brain based on neural networks to segment and classify normal white matter, gray matter, and cerebrospinal fluid (CSF). This method results in reliable estimates of the volume of each of these three brain compartments among healthy volunteers as well as cancer patients.19 By using this technique, we have previously demonstrated differences in brain volumes, specifically normal white matter (NWM), among children treated for MED.20 These preliminary data suggested that reduced NWM may be at least partially responsible for IQ loss frequently observed among these children. The purpose of this study was therefore to test the hypotheses that (1) patients treated for posterior fossa MED in childhood have reduced volumes of NWM related to their treatment with craniospinal irradiation
From the *Division of Behavioral Medicine and Departments of ‡Diagnostic Imaging, iRadiation 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.
Received May 16, 1999, and in revised form Jul 6. Accepted for publication Jul 6, 1999.
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Address correspondence to Dr Mulhern, St Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794.
Copyright © 1999 by the American Neurological Association
with or without chemotherapy, and (2) deficits in NWM among patients surviving MED can at least partially explain deficits in their neuropsychological performance. Patients and Methods 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 tumors arising in the posterior fossa, and were at least 1 year from completion of all therapy with no evidence of progressive disease. To test our hypothesis that changes in qMRI and neuropsychological function among patients treated for MED are related to treatment with irradiation and chemotherapy as opposed to tumor and tumor surgery, we constituted a control group of survivors of low-grade astrocytoma (LGA) of the posterior fossa who were treated with surgery alone. qMRI and neuropsychological testing have been routinely collected on 26 LGA and 72 MED patients since 1995. 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 neuropsychological testing within 6 months of a qMRI examination. On the basis of these criteria, 19 LGA patients and 29 MED patients remained eligible. To experimentally control for age-related differences in head size and brain development at the time of qMRI, we age-matched patients between groups. We were able to closely match 18 of the 29 MED patients with 18 LGA patients (mean age difference 5 3.7 months). The 18 MED survivors (12 male and 6 female) were treated by surgical resection of the tumor and 23.4- to 36-Gy craniospinal irradiation with a boost to the posterior fossa for a total dose of 49.0 to 54.0 Gy; 9 also received pre-CRT and/or post-CRT chemotherapy with cisplatin/ etoposide (CDDP/VP-16), (carboplatin-etoposide (Carbo/VP16) 1 cyclophosphamide/vincristine (Cyclo/Vcr), CDDP/ VP-16 1 Cyclo/Vcr, Carbo/Cyclo/VP-16, or mechlorethamine, Oncovin, procarbazine, and prednisone (MOPP). The mean interval between diagnosis and qMRI for MED patients was 3.8 years (SD 5 2.6). Among children in the MED group, four experienced postoperative complications (infection, 2; posterior fossa syndrome, 2) and two developed seizures after completion of therapy. The 18 LGA survivors (14 male and 4 female) were treated by surgical resection of the tumor only. The mean interval between diagnosis and qMRI for the LGA patients was 2.6 years (SD 5 1.1). Among children in the LGA group, two experienced postoperative complications (infection, 1; posterior fossa syndrome, 1) and none developed seizures.
Neuropsychological Testing Protocol Neuropsychological testing, requiring approximately 1.5 hr, and qMRI evaluation, requiring approximately .5 hr, were conducted during routine outpatient clinic visits to our institution. Psychological testing involved traditional IQ evaluation, using the age-appropriate version of the Wechsler Intelligence Scale for Children-III or the Wechsler Adult
Intelligence Scale-Revised.21,22 Based on these tests, we derived Verbal IQ, Performance IQ, and Full-Scale IQ (FSIQ) scores, each with a normative mean of 100 and an SD of 15. Verbal IQ is composed of five subtests that measure verbal comprehension and knowledge, one of which is timed. Performance IQ includes five subtests that measure visualperceptual and nonverbal skills, four of which are timed. FSIQ is a composite of Verbal and Performance IQ scores. Special precautions were taken to identify children with hearing loss (10 MED and 0 LGA) and to ensure adequate correction in the speech frequencies before testing.
qMRI Segmentation Protocol MRI evaluations were performed on a 1.5-T Magnetom (Siemens Medical Systems, Iselin, NJ) whole-body imager, using the standard circular polarized volume head coil. T1weighted (T1), T2-weighted (T2), and proton densityweighted (PD) images were acquired on all patients as transverse 5-mm-thick slices with a 1-mm gap interleaved to avoid cross talk between slice excitations. The T2 and PD images were acquired simultaneously, resulting in two imaging sequences per examination. Image registration, a process of alignment so that the individual points in an image correspond to the same anatomical tissue in a related image, was accomplished with a robust, automatic volume registration process based on intensity gradients developed by John L. Ostuni at the NIH Laboratory of Diagnostic Radiology Research.23 All available examinations for each age-matched pair of patients were inspected to determine a base set that matched most closely with regard to slice and head positioning. The examination to be used in the data analyses was then registered to the base examination, thus reducing variations in positioning between the astrocytoma and MED age-matched pair. A single transverse section at the basal ganglia level was selected as the index slice for evaluation. This index slice adequately sampled cortical white matter, gray matter, central gray matter structures, and ventricular CSF. To eliminate excessive background signals, each index slice was preprocessed to remove extrameningeal tissue and bone from further analysis. The brain parenchyma volume of the index slice was then assessed by using a fully automated hybrid neural network segmentation and classification method.19 Segmentation is the process by which the qMR image is decomposed into similar regions based on signal intensity. Classification is the identification of these segmented regions by tissue type. 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 selforganizing map output vectors.19 Each of the nine levels in the segmented images was 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. Partial volume regions from the volumetric analysis were then eliminated. Each prototypical vector classified as either partial gray/CSF or gray/white matter was set to zero to produce an equivalent null vector. The final pass of the segmen-
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tation was executed again with the trained set of prototypical vectors. This segmentation forced each pixel to be assigned to a nearest output neuron classified as one of the pure tissue types (ie, gray matter, white matter, CSF, blood vessels and membranes, or background). The T2-weighted image for each patient was inspected for possible white matter hyperintensities that indicate an abnormality in the tissue. Four of the 18 MED patients and none of the LGA patients had such regions of hyperintensity. These regions were manually selected, classified as abnormal tissue, and excluded from all volumetric analyses. The resulting six classified regions were mapped to a color scheme similar to that used for positron emission tomography. Gray matter was colored yellow and white matter was colored green. Areas considered abnormal white matter were colored orange, the CSF was colored a light blue, and blood vessels and membranes were colored dark violet. For contrast purposes, the background was colored black (Fig 1). A histogram for each color was then completed to determine the number of pixels present. The pixel count was then multiplied by pixel volume to determine the sampled volume of each tissue type. Reliability and validity data for this method have been previously established.19,20 Segmentation of serial
MRIs obtained from normal volunteers revealed high intrasubject reproducibility, especially with regard to white matter and CSF volumes. When the classification of white matter, gray matter, and ventricular CSF, using the segmentation algorithm, was compared with the classification by an experienced neuroradiologist, the intraclass coefficients were high (0.95, 0.91, and 0.98, respectively). Furthermore, in normal adults, the proportions of intracranial volume (ICV) allocated to white matter, gray matter, and CSF, using our index slice parameters, are similar to those obtained by using whole-brain techniques.24,25
Data Analyses We hypothesized that (1) MED patients would have lower IQ values than LGA patients, (2) MED patients would have lower volumes of NWM than LGA patients, and (3) a significant association between NWM and IQ would be obtained. To test the first two hypotheses, t tests (two-tailed) for matched pairs were conducted. Pearson product moment correlation coefficients were computed between brain volumes in the segmented slice and IQ values to test the third hypothesis. We established a 5 0.05 for significance, al-
Fig 1. Input images to unsupervised segmentation neural network. The images are shown at the level of the index slice. From left to right these are T1, T2, proton density, and pseudocolor display images after segmentation and classification for a patient treated for medulloblastoma (top) and an age-matched patient treated for low grade astrocytoma of the posterior fossa (bottom). The extrameningeal tissues shown in the illustration (scalp, subcutaneous fat, muscle, and calvarium) are manually removed. In the final image, gray matter is represented by yellow, normal white matter by dark green, and cerebrospinal fluid by blue. A comparison of the pseudocolor images illustrates the reduced volumes of normal white matter observed in patients treated for medulloblastoma.
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correlation between NWM and Performance IQ was also in the predicted direction in the MED group but failed to reach statistical significance. No significant associations between NWM and any IQ score were noted among the patients with LGA. For patients in the LGA and MED groups, no statistically significant relationships between gray matter or CSF volumes and IQ scores were noted. Regression lines representing correlations between volumes of normal white matter and IQ values revealed lower intercepts and increased slopes for the patients in the MED and LGA groups with regard to FSIQ and Verbal IQ and to a lesser extent for Performance IQ (Fig 2). This implies that, in the context of reduced volumes of normal white matter shown by patients in the MED group, normal white matter may be more essential for IQ development.
though tests reaching 0.10 are also presented to illustrate trends in the data.
Results Neuropsychological Data Patients in the MED group had significantly lower mean Performance IQ [t(17) 5 2.899; p , 0.01] and FSIQ [t(17) 5 2.438; p , 0.05] values than those in the LGA group. Verbal IQ in the MED group was not statistically significantly lower than in the LGA group (Table 1). For the MED group, mean Verbal IQ, Performance IQ, and FSIQ were all significantly lower than expected in the general population ( ps , 0.01). Comparisons within the MED group revealed that Performance IQ was significantly lower than Verbal IQ [t(17) 5 2.727; p , 0.05]. However, mean IQ values of the LGA group did not differ significantly from the norm and no statistically significant Verbal IQ versus Performance IQ differences were noted.
Proposed Conceptual Model Previous publications have suggested that a younger age at the time of treatment for MED is associated with increased risk for intellectual delay. We explored the relationship of age at CRT to NWM and FSIQ (Fig 3). From using independent R2 values based on Pearson product moment correlation coefficients, age at CRT accounted for 19.9% of the variance in NWM and NWM accounted for 30.8% of the variance in FSIQ. Age at CRT accounted for 18.7% of the variance in FSIQ without controlling for NWM. However, after controlling for the effects of NWM, age at CRT only accounted for 6.2% of the variance in FSIQ. The obtained model suggests that variations in the patient’s NWM may provide a more direct explanation for variations in FSIQ than the patient’s age at CRT.
qMRI Brain Volumes As derived from the index slice, ICV did not differ significantly between the matched pairs of the MED and LGA groups (Table 2), allowing for the analysis of volumes of NWM, gray matter, and CSF uncorrected for head size.26,27 The volume of NWM was significantly lower among patients in the MED group than their matched controls in the LGA group [t(17) 5 2.976, p , 0.01], although significant differences in gray matter were not found. CSF volumes demonstrated a trend to be higher in the MED group than the LGA group, although the difference failed to reach statistical significance. Finally, within the MED group, no significant difference in NWM was detected between those receiving high-dose (36 Gy) or low-dose (24 Gy) CRT or between those who had or had not received adjuvant chemotherapy.
Discussion To our knowledge, this is the first study to demonstrate that NWM volume, as measured by qMRI among survivors of MED, is significantly lower than among age-matched controls treated for low-grade tumors of the posterior fossa with surgical resection alone. The implication is that these differences are secondary to treatment of children with MED with CRT with or without chemotherapy. Although previous
IQ and qMRI Associations Correlation coefficients between IQ and qMRI values were calculated separately for the MED and LGA groups (Table 3). As predicted in the MED group, NWM volume was significantly positively correlated with both Verbal IQ and FSIQ values ( p , 0.05). The
Table 1. Results of Intellectual Testing for Survivors of Medulloblastoma and Low-Grade Astrocytoma of the Posterior Fossa Medulloblastoma
Low-Grade Astrocytoma
Variable
Mean
SD
Mean
SD
p
Wechsler Intelligence Scalesa Verbal IQ Performance IQ Full Scale IQ
87.3 79.6 82.1
11.5 11.9 10.9
94.8 92.9 92.9
14.8 17.2 15.8
NS ,0.01 ,0.05
Normative mean 5 100; SD 5 15.
a
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Table 2. Brain Volumes for Survivors of Medulloblastoma and Low-Grade Astrocytoma of the Posterior Fossa Derived from MRI Index Slice Medulloblastoma
Low-Grade Astrocytoma
Volume (ml)
Mean
SD
Mean
SD
p
Intracranial volume White matter volume Gray matter volume CSF volume
82.5 21.4 43.7 8.2
5.4 4.4 4.5 4.0
85.3 24.8 45.3 6.1
6.0 5.7 5.0 4.6
ns ,0.01 ns ,0.10
MRI 5 magnetic resonance imaging; CSF 5 cerebrospinal fluid.
Table 3. Univariate Correlations Between Brain Volumes for Survivors of Medulloblastoma and Low-Grade Astrocytoma of the Posterior Fossa and Intellectual Testing Medulloblastoma
Low-Grade Astrocytoma
Variable
NWM
Gray
CSF
NWM
Gray
CSF
Wechsler Intelligence Scales Verbal IQ Performance IQ Full Scale IQ
0.49a 0.44b 0.56a
20.22 20.06 20.09
0.26 0.02 0.14
0.00 0.31 0.18
0.12 0.03 0.08
20.28 20.38 20.38
p , 0.05; bp , 0.10.
a
NWM 5 normal white matter; CSF 5 cerebrospinal fluid.
Fig 2. Correlation of volumes of normal white matter with IQ scores normalized for age for patients treated for medulloblastoma and age-matched controls treated for low-grade astrocytoma. Relevant white matter volumes, IQ values, and correlation coefficients are shown in Tables 1 through 3.
studies have demonstrated that children treated for MED have lowered IQs, the present study is unique in the finding of a significant positive association between IQ and NWM. CRT-induced central nervous system damage results from oligodendrocyte and endothelial cell damage.28 The initial endothelial injury within small vessels initiates a cascade of biochemically toxic reactions, including increased formation of oxygen free radicals. These reactions lead to cell swelling, increased vascular permeability, fibrinoid necrosis of the vessel wall, ischemia, edema, and cell death.29 Late effects of the cascade are evidenced on neuroimaging by diffuse and multifocal white matter hyperintensities, as well as cal-
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cifications in the cortical gray matter and basal ganglia. The presence and severity of these imaging changes correlates with CRT dose, as do a variety of concurrent neuropsychological syndromes in children treated for cancer, including problems with attention, memory, mental processing speed, and intellectual deterioration.30 –32 Similar cognitive processing problems have been noted among other patients with primary white matter pathology, such as those with leukodystrophy,33 periventricular leukomalacia,34 and multiple sclerosis.35 The finding in the present study of a mean FSIQ of 82 for children surviving MED after CRT is very similar to the value predicted from regression analysis of 42 children, 2 to 10 years of age, given 24 or 36 Gy
Fig 3. Proposed conceptual model of the relationship between age at the time of cranial radiation therapy (CRT), normal white matter (NWM), and Full-Scale IQ (FSIQ). R2 values indicate the amount of variance in the outcome variables accounted for by the predictor variable. NWM accounts for a significant ( p , 0.05) amount of variance in FSIQ among survivors of medulloblastoma. Furthermore, after correcting for the association between NWM and FSIQ, the association between age at CRT and FSIQ is diminished (dashed line). This suggests that age effects on IQ in medulloblastoma may be explained by differences in NWM.
CRT for leukemia or brain tumors.15 The critical roles of age at the time of irradiation, dose of CRT, and time interval from irradiation for IQ development among long-term survivors of childhood MED have been reported earlier.12,14 In the series by Dennis and colleagues,12 25 survivors had a mean FSIQ of 78 an average of 6 years after treatment with CRT. In multivariate analysis, both younger age at CRT and increased time from CRT were significantly associated with lower IQ, but no CRT dose effects were reported. Packer and associates14 reported a trend for IQ scores to be lower among survivors in his series, but even children younger than age 7 years at diagnosis had a relatively normal median IQ of 92. Recently, Mulhern and collaborators36 have reported on age and CRT dose effects in a clinical trial of MED treatment. Eligible patients had been treated in the Pediatric Oncology Group (POG) study No. 8631 for low-risk MED, which randomized patients to receive standard-dose (36 Gy) or reduced dose (23.4 Gy) CRT. Those who were alive and free of progressive disease 6.1 to 9.9 years since completing treatment were eligible for this study. Of the 35 eligible, 22 participated in a battery of tests including intellectual and academic development as well as ratings of healthrelated quality of life. Problems with cognition were the most frequently reported quality of life impairment in the survivors (73%), with 12 of 22 having a need for special educational intervention. The median FSIQ 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 neuropsychological problems than older children or those receiving reduced dose CRT. It is only the recent development of quantitative neuroimaging techniques that has allowed us to study the development of ICV, white matter, gray matter, and CSF volumes in healthy persons,24 –27 and those with neurological diseases.33 ICV peaks at age 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.26 Studies of normal adults have also shown that the volumes of these “compartments” can explain at least some variation in IQ.27 For example, the small but positive correlation between NWM and FSIQ, found among the LGA patients in the present study, is very close to the correlation found among healthy adult in the study by Andreasen and colleagues.27 With regard to white matter disorders, the amount of white matter loss may be of greater importance than the location of the loss, and white matter loss appears to have the greatest detrimental effect on mental functions within widely distributed systems, such as attention and memory, rather than on more localized functions, such as language.35 Because rapidly proliferating cells are more vulnerable to the deleterious effects of CRT, children receiving CRT for MED before the age of 4 years are at the 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. This may, in part, explain the significantly lower IQ scores among children who are younger at CRT. 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 and because of the requirement of matching patients on the basis of age. As a result, statistical sensitivity to some findings (eg, differences in CSF between the LGA and MED groups) was reduced. We also did not attempt to statistically control for parental education or ethnic background, two factors known to account for significant variance among IQ values in the general population.37 Another drawback is that the psychological testing and qMRI were stud-
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ied in a cross-sectional as opposed to a longitudinal design. To fully substantiate our hypothesis that white matter loss is responsible for IQ declines, we would need to demonstrate that white matter loss antedates IQ loss by repeated observations of individual patients over time. Finally, we acknowledge that IQ values are probably not as sensitive to white matter lesions as specific psychological tests of attention, memory, and efficiency of new learning. In conclusion, despite these limitations, the results of the present study suggest that variations in the volume of normal white matter remaining after CRT with or without chemotherapy may at least partially explain changes in IQ and related cognitive functions. One interpretation of these findings is that white matter is a primary neuroanatomical substrate mediating the adverse effects of various risk factors identified in previous investigations (eg, age, dose, and time). 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 stimulate reconsideration of the aggressiveness of 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 must be developed. In the absence of the ability to reduce the aggressiveness of therapy or to protect normal white matter, pharmacological38 and cognitive/behavioral interventions39 should be instituted after treatment to ensure that children surviving MED attain the best possible quality of life.
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18. This study was supported in part by the National Cancer Institute, through a Cancer Center Support (CORE) grant (P30-CA21765), and by the American Lebanese Syrian Associated Charities (ALSAC).
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