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Pediatric Imaging |
1 From the Depts of Diagnostic Radiology and Organ Imaging (W.C. W.C., Y.L.C., R.G.H., C.M.), Paediatrics (K.W.C., C.K.L.), and Clinical Oncology, Medical Physics Div (D.K.W.Y.), Chinese Univ of Hong Kong, Prince of Wales Hosp, 30–32 Ngan Shing St, Shatin, Hong Kong SAR, China; and Dept of Radiology, Great Ormond Street Hospital for Children, London, England (D.J.R.). Received Dec 3, 2002; revision requested Feb 6, 2003; final revision received Apr 11; accepted May 20. Address correspondence to W.C.W.C. (e-mail: winnie@med.cuhk.edu.hk).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONAPPENDIXREFERENCES |
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MATERIALS AND METHODS: Twenty-three children (10 boys, mean age of 6.3 years; 13 girls, mean age of 6.6 years) with acute lymphoblastic leukemia were examined prospectively with magnetic resonance (MR) imaging and MR spectroscopy at 0, 8, and 20 weeks and 1, 2, and 3 years after diagnosis. White matter changes were diagnosed on the basis of hyperintense abnormalities on T2-weighted MR images. Single-voxel hydrogen 1 MR spectroscopy results from the right frontoparietal region of 21 children who received intravenous high-dose methotrexate were analyzed for cerebral metabolite changes. Multilevel models were used to assess the change in metabolites from baseline levels at subsequent follow-up.
RESULTS: At 20 weeks, MR spectroscopy showed a significant reduction (P < .05) of mean N-acetylaspartate to choline ratio and increase in mean choline to creatine ratio (P < .05) in the children given high-dose methotrexate. This decline in N-acetylaspartate to choline ratio subsequently reversed and increased, possibly because of normal age-related brain maturation. Seventeen of 21 (81%) children showed metabolite changes at MR spectroscopy, while five of 22 (23%) showed white matter changes at MR imaging at 20 weeks. One more child developed white matter changes at 32 weeks. The associated changes resolved or reduced with time.
CONCLUSION: MR spectroscopy demonstrated metabolite changes in the brain after high-dose methotrexate treatment in the absence of structural white matter abnormalities at MR imaging. MR spectroscopy might thus be a more sensitive method of monitoring the effects of high-dose methotrexate in the brain.
© RSNA, 2003
Index terms: Brain, white matter • Leukemia, in infants and children, 9*.342 • Leukemia, therapy, 9*.34, 9*.12968 • Magnetic resonance (MR), spectroscopy, 131.12141, 132.12141 • Methotrexate
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONAPPENDIXREFERENCES |
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The most commonly used method was introduced in the 1970s and 1980s and involved cranial irradiation (originally 24 Gy but later 18 Gy [4]) and intrathecal chemotherapy with methotrexate. This treatment reduces the rate of isolated CNS relapse to between 5% and 10% (1,5), but it is associated with damage to normal brain tissue, including white matter changes, atrophy, mineralizing microangiopathy, and development of secondary tumors (6,7). Cranial irradiation is also a cause of long-term neuropsychologic impairment (8). Recent protocols have involved (a) risk stratification to avoid cranial irradiation in children with acute lymphoblastic leukemia with standard and intermediate risk and (b) reduced dose of cranial radiation in those with high-risk acute lymphoblastic leukemia, without compromising event-free survival.
High-dose methotrexate is effective for CNS prophylaxis in children with acute lymphoblastic leukemia, but the treatment is known to cause white matter abnormality (leukoencephalopathy), detected as regions of hyperintensity on T2-weighted magnetic resonance (MR) images (9,10). The reported incidence of white matter abnormality shown in the early posttreatment period (11) is much higher compared with that in the later stages (12–14). Most of these changes are transient in nature, and they disappear within 12–24 months with negative follow-up imaging results (12).
However, the clinical importance of this white matter abnormality is still unclear (15). In addition, investigators in previous studies have not found any relationship between the presence of white matter changes and the results of neuropsychologic testing (11,16,17). To our knowledge, there has been no longitudinal study of MR imaging performed in conjunction with hydrogen 1 (1H) MR spectroscopy to examine the early and long-term effects of treatment in children with acute lymphoblastic leukemia. The aim of our study was to assess the development of white matter and cerebral metabolite changes during and after treatment in children with acute lymphoblastic leukemia.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONAPPENDIXREFERENCES |
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The mean age of male patients at diagnosis was 6.3 years (age range, 1.8–14.6 years). The mean age of female patients was 6.6 years (age range, 2.7–10.0 years). All patients had a normal developmental history except one, who had Down syndrome. None of these patients had laboratory evidence of CNS leukemia (blast cells in the cerebrospinal fluid) at the time of diagnosis. From February to October 1997, the chemotherapy protocol used in nine patients was the HKALL93 protocol, which was based on the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukemia, UKALLXI (18,19).
From late October 1997 to December 2000, the chemotherapy protocol used in the remaining 14 patients was the HKALL97 protocol, which was based on the Berlin-Frankfurt-Munster study group protocol, ALL-BFM 95 (20). The details of the treatment protocol are described in Table 1. For each patient, the age at diagnosis, the dose and number of courses of intravenous high-dose methotrexate and intrathecal methotrexate, and additional treatments were recorded. A summary of these data are given in Table 2.
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Patients 2, 5, 8, 9, and 20 subsequently developed relapse. Patients 2, 5, and 9 required bone marrow transplantation at 2.80 years (34 months), 2.75 years (33 months), and 3.25 years (39 months) after diagnosis, respectively. The preparative regimen included total body irradiation of 14 Gy and administration of cyclophosphamide. Patients 8 and 20 received cranial irradiation of 12 Gy at 1.08 years (13 months) and 2 years (24 months) after diagnosis, respectively.
MR Imaging and Analysis, Spectral Analysis
All patients underwent MR imaging according to a planned schedule: at 0 weeks (diagnosis), 8 weeks (before high-dose methotrexate treatment), 20 weeks (after high-dose methotrexate treatment), 1 year (during maintenance chemotherapy), 2 years (at completion of maintenance therapy), and 3 years. Patients were examined with a 1.5-T MR imager (Gyroscan ACS-NT; Philips Medical Systems, Best, the Netherlands) by using a standard birdcage head coil. Transverse T2-weighted turbo spin-echo (repetition time msec/echo time msec, 3,300/100) images and coronal fluid-attenuated inversion recovery (8,000/110/2,400 [inversion time]) images were obtained to assess morphologic lesions and to position the volume of interest for MR spectroscopy.
With the use of a point-resolved spectroscopic sequence (2,000/272), one water-suppressed spectrum was acquired for each volume of interest. Data were acquired at a spectral bandwidth of 1,000 Hz, and 64 signals were acquired for each spectrum. A volume measuring 5 x 2 x 2 cm was selected in the right frontoparietal lobe, with predominance of white matter inclusion throughout the study. The frontoparietal lobe was selected to include a large volume of brain tissue with predominance of white matter and minimal cerebrospinal fluid contamination, which makes it suitable as a representative region to reflect the generalized effect of chemotherapy in the brain.
A volume of interest with white matter voxel predominance was planned because white matter is more susceptible to injurious effects of chemotherapy. Technically, this area was convenient for voxel positioning and shimming. Spectral analysis was performed by one physicist (D.K.W.Y.), who was blinded to the time points of examinations and MR imaging findings. A time-domain fitting routine variable projection method (21) implemented in the MR User Interface, or MRUI, software package (A. van den Boogaart, Katholieke Universiteit Leuven, Belgium) was used for the determination of peak areas. Residual water was first removed from the measured free induction decay by means of time-domain Hankel-Lanczos singular value decomposition filtering (22). The resonance frequency and line-width of N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) were selected manually; these parameters were used as the starting values in the nonlinear least squares fitting algorithm.
Prior knowledge used in the fitting process consisted of equal damping factors for NAA, Cho, and Cr; the same phase was used for all peaks, which was equal to the zero-order phase estimated by the fitting algorithm. The ratios of NAA/Cho, NAA/Cr, and Cho/Cr were determined in the right frontoparietal region of each patient at each examination. The total examination time for MR spectroscopy was about 20 minutes and included shimming and parameter optimization procedures.
All MR images were reviewed by two radiologists (W.C.W.C., Y.L.C.), and it was determined by means of mutual agreement whether there were any white matter changes, defined as newly developed areas of hyperintensity on both T2-weighted and fluid-attenuated inversion recovery MR images. Comparison was made with the baseline MR image. A rating of 0–3 was assigned according to a modification of the system of Wilson et al (11): 0, no evidence of white matter changes; 1, patchy, mildly increased signal intensity in the periventricular white matter; 2, moderate changes that extended almost to the gray-white junction, sparing the subcortical U fibers; and 3, severe changes, confluent from the level of the frontal horns to that of the trigone, with or without involvement of the U fibers. The two radiologists were not aware of the treatment administered or the risk group of the patients concerned.
Statistical Analysis
Statistical analysis was performed by the statistician from the center for clinical trials and epidemiological research at the Prince of Wales Hospital. Multilevel models were used to assess the changes in NAA/Cho, NAA/Cr, and Cho/Cr ratios at subsequent follow-up with regard to baseline levels. Multilevel modeling is an extension of ordinary least squares regression but takes into account the within and between subject heterogeneity (23). For longitudinal data, multilevel models allow measurements to be obtained at unequal intervals and with varied numbers of measurements (ie, subjects who may have one or several measurements). The random-intercepts model (that allows only the intercept—that is, the mean response at baseline—to vary between subjects) was used. Details of the model are given in the Appendix. The models are fitted by the method of the restricted iterative generalized least squares algorithm of the MLn for Windows software package, version 2.0 (Institute of Education, University of London, England). The likelihood ratio test is used to assess the statistical significance of the estimates at the 5% level of significance. The model assumptions are checked by means of inspection of the standardized residuals for normality and constant variance.
The t test was used to assess the differences between age distribution according to sex. For analysis of white matter changes detected with MR imaging, the Mann-Whitney test was used to assess the relationship between the presence or absence of white matter changes with age at diagnosis (months) and the total dose of high-dose methotrexate administered. For the analysis of metabolite change detected with MR spectroscopy, the Mann-Whitney test was used to assess the difference in the median metabolite ratios between groups with different treatment protocols and in patients with and those without white matter changes. The Mann-Whitney test was also used to assess the difference in the median metabolite ratios at 0 and 8 weeks.
The Spearman correlation coefficient was used to determine the correlation between the change in brain metabolites, patient age at diagnosis, and cumulative dose of high-dose methotrexate. The results were analyzed with the Statistical Package for Social Science, or SPSS, for Windows, version 10.0 (SPSS, Chicago, Ill). Two-tailed probability values of less than .05 were considered to indicate a significant difference. Power analysis was performed with nQuery Advisor (Elashoff 2000, Los Angeles, Calif) to justify the sample size in this study.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONAPPENDIXREFERENCES |
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MR Imaging and White Matter Changes
After completion of induction chemotherapy (8 weeks), all 23 patients showed normal morphologic features on MR images. At 20 weeks after the start of chemotherapy—that is, 2 weeks after the completion of CNS prophylactic therapy with high-dose methotrexate—five of 22 (23%) patients were found to have bilateral hyperintense white matter changes on T2-weighted MR images. None of the patients with white matter changes came from the standard-risk group. Four of 13 patients in the intermediate-risk group developed white matter changes. The fifth patient who developed white matter changes (patient 20) originated from the high-risk group but had also received chemotherapy similar to that in the intermediate-risk group.
Patient 11 developed white matter changes with neurologic symptoms, including involuntary movements and visual hallucinations at 32 weeks, which was 14 weeks after completion of CNS prophylactic therapy with high-dose methotrexate. This patient also belonged to the intermediate-risk group (chemotherapy but no cranial irradiation). The patient’s condition stabilized, but persistent white matter abnormalities were observed up to 2 years, which subsequently showed improvement at 3-year follow-up (Fig 1). This female patient had Down syndrome and had the highest grade of white matter changes (grade 3) among all our patients. The remaining five patients with white matter changes did not have neurologic symptoms.
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For the sequential changes of white matter abnormality in those who developed white matter changes, all four patients from the intermediate-risk group had grade 1 white matter changes at 20 weeks. These abnormal changes were no longer visible at 1-year follow-up. The remaining patient (patient 20), who was in the high-risk group, showed an increase in the volume of white matter changes, progressing from 20 weeks to 1 year, but the volume of abnormal white matter appeared to stabilize and reduced in extent at 2 years. This patient received cranial irradiation 48 weeks after the time of initial diagnosis, which probably contributed to the increase in severity of the white matter changes.
At 3-year follow-up, two additional patients developed white matter changes. Patients 2 and 5 had both received total body irradiation of 14 Gy and bone marrow transplantation at 2.80 and 2.75 years after diagnosis, respectively, because of disease relapse. The incidence of white matter changes related chronologically to administration of high-dose methotrexate in our study was therefore 28% (six of 21 patients), and the changes occurred in the early phase (2 and 14 weeks) after completion of high-dose methotrexate treatment. These white matter changes were transient, and most of these abnormalities (67%, four of six patients) disappeared by 1 year after initial diagnosis or 34 weeks after completion of high-dose methotrexate treatment. The results of MR white matter changes with grading for each individual patient are shown in Table 3.
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MR Spectroscopy
Patients 5 and 6, who belonged to the high-risk group, did not receive high-dose methotrexate. They therefore acted as control subjects in this study, and their MR spectroscopy results were analyzed separately. Of the 21 remaining patients, spectra were obtained from 15 patients at 0 weeks, 19 patients at 8 weeks, 19 patients at 20 weeks, 20 patients at 1 year, 18 patients at 2 years, and 17 patients at 3 years. MR spectroscopy results were missing in some of the MR studies because the patient was sedated inadequately or because the patient’s condition did not allow the more lengthy MR spectroscopy examination to be conducted. For the six patients who did not undergo MR spectroscopy at 0 weeks, we used the results at 8 weeks as baseline. This was justified by the observation that no significant difference was found between the ratios at 0 and 8 weeks for those patients who had MR spectroscopy results available at both time points (Wilcoxon signed rank test, P = .69).
A series of MR spectra from patient 11 and the location of the volume of interest selected for MR spectroscopy are shown in Figure 2. Charts (with means and 95% CIs) of the MR spectroscopic outcome measures and NAA/Cho, NAA/Cr, and Cho/Cr ratios at different time intervals are shown in Figures 3–5. From the graphs, we observed that there was an overall increase in NAA/Cho and NAA/Cr ratios with time or with increasing patient age (P < .05), while the change in Cho/Cr with time was relatively minimal (P value ranged from .646 to .816), except at 20 weeks. No lactate or other abnormal metabolite peaks were identified in our patients.
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The summary of NAA/Cho ratios at different time points is given in Table 4. For the two control subjects who did not receive high-dose methotrexate treatment, one showed an increase in NAA/Cho ratio, and one showed no change in NAA/Cho ratio at 20 weeks with regard to baseline levels. For the high-dose methotrexate treatment group, 17 of 21 patients (81%) had a decrease of NAA/Cho ratio at 20 weeks with regard to baseline levels. Patient 15 had no change, while patient 12 had a slight increase in the ratio from baseline level. Patients 8 and 13 did not have MR spectroscopy results at 20 weeks for comparison with baseline levels. In view of the small number of subjects in the control group in this study, there was not enough power to say whether a statistically significant difference was present between the patients who received high-dose methotrexate treatment and the control subjects.
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No statistically significant correlation was observed between the change of metabolite ratios from baseline levels with respect to patient age at diagnosis (Spearman correlation coefficient, P = .71, .18, and .51 for NAA/Cho, NAA/Cr, and Cho/Cr, respectively) and the cumulative dose of intravenous high-dose methotrexate (Spearman correlation coefficient, P = .42, .74, and .55 for NAA/Cho, NAA/Cr, and Cho/Cr, respectively).
Sample Size and Power Analysis
A power analysis was performed on the basis of the change in NAA/Cho ratios at 20 weeks with regard to baseline levels. A sample size of 14 patients will have 80% power to indicate a difference in means of 0.160 (ie, mean NAA/Cho level of 1.880 at baseline [µ1] and mean NAA/Cho level of 1.720 at 20 weeks [µ2]), assuming an SD of differences of 0.190, by using a paired t test with a .05 two-sided significance level.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONAPPENDIXREFERENCES |
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MR Imaging and White Matter Changes
In the present study, baseline MR images were obtained in all patients (at 0 or 8 weeks) and were normal. Any white matter abnormality, such as preleukemic delayed myelination, was therefore excluded, and the subsequent development of white matter abnormality was considered to be treatment induced. A total of eight patients were found to have bilateral hyperintense white matter changes on T2-weighted MR images throughout the study period. Six of them developed white matter changes soon after completion of high-dose methotrexate treatment. Two patients developed white matter changes at 3 years, long after completion of high-dose methotrexate treatment. This could be related to additional therapy, however, rather than the initial treatment with high-dose methotrexate.
The occurrence of white matter changes detected in this study is temporally related to the intravenous administration of intermediate-dose methotrexate and is most likely caused by this drug, perhaps in conjunction with intrathecal therapy. This observation agrees with findings in the studies of Wilson et al (11) and Paakko et al (12), in which white matter changes first appeared after consolidation treatment. The transient nature of the white matter change in our patients could be caused by toxic edema or a demyelinating process. The former mechanism is supported by the postmortem examination of one of the children with osteogenic sarcoma in the study of Ebner et al (28), who received high-dose methotrexate therapy. Histologic findings demonstrated widespread white matter edema in the brain with areas of gliosis. Younger age at diagnosis has been suggested to be a predisposing factor for white matter changes (11,22), but we could not substantiate that in the present study.
MR Spectroscopy
Since there are major maturational changes of the brain during childhood, the composition of the brain and therefore the ratios of metabolites reflected at 1H MR spectroscopy are also expected to change with age. Van der Knapp et al (29) studied the metabolite ratio in the paraventricular region, encompassing predominantly white matter in normal children, and they observed an increase in NAA/Cho and NAA/Cr ratios and a decrease in Cho/Cr ratio with age. In this study, a reversal of the normal trend was observed in NAA/Cho ratio with a significant reduction at 20 weeks, followed by an increase, probably as a result of return to normal age-related brain maturation. This transient change was most likely due to the effect of treatment.
We postulate that the metabolite changes observed in MR spectroscopy are mostly the effects of methotrexate in view of the close chronologic timing with the high-dose methotrexate therapy. NAA is generally accepted as a marker of neuronal structure or function, and the observed transient decrease in NAA level implies that the effect of high-dose methotrexate is related to disturbance in neuronal metabolism. Increase in Cho level is well documented in demyelinating disease (30–32). Cho/Cr increase has also been shown in subacute radiation-induced brain parenchymal injury (33).
In the present study, Cho/Cr levels showed a significant increase from baseline levels at 20 weeks; therefore, methotrexate is also likely to be causing demyelination. Another possible explanation for this spectral change is the presence of gliosis, which has been reported in a child who received high-dose methotrexate (28). Neuronal loss and the proliferation of glial cells are characterized by low NAA levels, high Cho levels, and presence of lactate (34). The absence of lactate peaks in our patients suggests that gliosis was not responsible for the observed spectral changes. Our results also showed that spectroscopic changes were not associated with white matter abnormalities at MR imaging. In those six patients with white matter changes at the early stage after high-dose methotrexate treatment, the decrease of NAA/Cho levels at week 20 reversed to the normal increase even before the resolution of white matter changes in two of them. There was no sign of relapse either clinically or at subsequent 1-year follow-up MR examination. The observation of a transient decrease in NAA/Cho levels, followed by a normal increase in patients who experienced white matter changes after high-dose methotrexate treatment, is a reassuring sign that the radiologic change observed was due to treatment and not disease.
The decline in NAA/Cho ratio at 20 weeks occurred with or without white matter changes. There was no significant difference in the change of metabolite ratios at 20 weeks from baseline levels between the two groups. A possible explanation for this observation was that the volume of interest for MR spectroscopy was placed in the standardized position at the right frontoparietal region of the brain, while the white matter changes occurred in the periventricular white matter, particularly around the trigones. The metabolite ratios therefore represented a general effect of chemotherapy on the brain and did not specifically reflect the changes in the areas of white matter change.
Waldrop et al (35) performed 1H MR spectroscopy in regions remote from the primary brain tumor after chemotherapy and radiation therapy and demonstrated declining NAA levels. Statistically, we found a significant decrease of mean NAA/Cho ratio overall, although a few patients showed no or opposite change. Furthermore, the observation of change in NAA/Cho ratio in patients without evidence of MR white matter change indicates that 1H MR spectroscopy is a more sensitive method for demonstrating reaction to high-dose methotrexate therapy.
Paakko et al (12) and Harila-Saari et al (17) showed that a minority of patients treated for childhood acute lymphoblastic leukemia had MR imaging abnormalities, but paradoxically, most children with neurologic symptoms had normal MR imaging findings. Kramer et al (36) found no abnormalities on MR images in 90% of acute lymphoblastic leukemia survivors who received cranial irradiation up to 18–24 Gy, whereas 70% of these children had below average intelligence. Conventional MR imaging is therefore not sensitive in predicting long-term CNS damage. The higher sensitivity of 1H MR spectroscopy in detecting neuronal abnormality has been documented in studies involving patients with adrenoleukodystrophy (37) and herpes simplex encephalitis (38). The relative concentration of NAA decreased before changes were detectable at MR imaging.
In studying the effects of radiation on the brain, 1H MR spectroscopy demonstrated a significantly lower NAA level in irradiated but morphologically normal brains at MR imaging compared with that in control subjects (39). Our study has also found that 1H MR spectroscopy is more sensitive when compared with conventional MR imaging in detecting effects of high-dose methotrexate on the brain.
Investigators in previous studies (11,12) found that children younger than 5 years who underwent chemotherapy for acute lymphoblastic leukemia had a higher risk of developing white matter abnormality and neuropsychologic deficiencies. It was postulated that the developing brain might be more susceptible to the side effects of treatment. In the study of Kingma et al (16), although higher cranial irradiation dose and younger age of diagnosis were associated with a lower score at neuropsychologic examination, there was no correlation with MR imaging abnormalities. We could not show a significant difference in the incidence of white matter changes in children of different ages at the time of presentation nor a decrease of NAA/Cho ratio at 20 weeks from baseline levels in relation to age.
There are several limitations in our study. First, the patient population was small and heterogeneous. Our findings need to be verified by studying a larger patient population. Second, there is lack of neuropsychologic assessment for all patients. Except for two patients with neurologic symptoms, the remaining patients were able to attend a normal school with no report of any substantial alteration in their academic abilities. Third, the single-voxel MR spectroscopy technique used in this study has limited spatial resolution, since only one selected area of the brain can be studied at a time.
Therefore, we could not verify whether there were metabolic changes in other regions of the brain. The recent development of fast two- or three-dimensional chemical shift MR imaging techniques that offer the possibility of studying many voxels simultaneously (40) may allow a more comprehensive study of the toxic effect of chemotherapy. Investigators in previous studies have suggested that abnormalities detected with conventional MR imaging are poorly correlated with neuropsychologic assessment; the clinical usefulness of MR imaging in the routine follow-up of asymptomatic patients undergoing treatment for acute lymphoblastic leukemia (11,17) is limited. Our results showed that 1H MR spectroscopy could depict changes before white matter abnormalities became visible at MR imaging. The ability of 1H MR spectroscopy to monitor neuronal toxic change may be more sensitive in the prediction of neurologic or neurocognitive effects of treatment strategies.
A study of the relationship between metabolite change detected with 1H MR spectroscopy and neuropsychologic assessment remains a challenge for future research. In this study, a statistically significant difference between the change in metabolite ratios and the cumulative dose of intravenous high-dose methotrexate is not found at the dose levels being used; however, with a wider range of drug doses, a difference may be observed. This would be useful when modification of drug protocol is considered by either increasing or reducing the current dose for better treatment or prophylaxis: The adverse effect of the drug on the CNS can be assessed with use of 1H MR spectroscopy.
The goal of the current CNS prophylaxis treatment protocol for children with acute lymphoblastic leukemia is to minimize neuropsychologic deficits, yet at the same time to be effective in preventing relapse of disease. To strive for the right balance, a careful measurement of the neurotoxic effects of the drugs used on the brain is required so that a more precise drug dose can be found. 1H MR spectroscopy is a possible tool for this purpose.
We conclude that the incidence of the white matter changes detected with MR imaging in children with acute lymphoblastic leukemia is about 30% and occurs at week 2 to week 14 after completion of high-dose methotrexate treatment. Most of these changes appear to be transient and are not associated with neurologic deficits. 1H MR spectroscopy shows a transient decrease in NAA/Cho ratio after high-dose methotrexate therapy in most patients with acute lymphoblastic leukemia, either with or without white matter changes. The metabolite ratio then returns to a physiologic increase with brain maturation. We postulate that 1H MR spectroscopy is a more sensitive tool to reflect the effect of high-dose methotrexate on the brain, even in the absence of visible white matter changes, and it therefore complements conventional MR imaging for the follow-up of children receiving treatment for acute lymphoblastic leukemia. 1H MR spectroscopy might be useful in determining the optimal drug dose for acute lymphoblastic leukemia treatment in the future by minimizing neurotoxic effects while maximizing the effectiveness of the drugs.
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APPENDIX |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONAPPENDIXREFERENCES |
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and ßi are fixed parameters that represent the average response at baseline and the slope coefficient for the ith occasion, respectively. The quantities eij and µj are random variables. eij is the residual and is assumed to be distributed normally with mean 0 and constant within-subject variation, and 
e2 x µj represents the extent to which the jth subject intercept departs from the average population response and is also assumed to be distributed normally with mean 0 and between-subject variation, µ2. Both e2 and µ2 are random parameters.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: Cho = choline, CNS = central nervous system, Cr = creatine, NAA = N-acetylaspartate
Author contributions: Guarantor of integrity of entire study, W.C.W.C.; study concepts and design, D.J.R., K.W.C.; literature research, W.C.W. C., D.J.R., Y.L.C.; clinical studies, K.W.C., C.K.L.; data acquisition, W.C.W.C., D.J.R., D.K.W.Y.; data analysis/interpretation, W.C.W.C., Y.L.C., C.M.; statistical analysis, W.C.W.C., D.K.W.Y.; manuscript preparation, W.C.W.C., K.W.C., R.G.H.; manuscript definition of intellectual content, W.C.W.C., Y.L.C., D.J.R., R.G.H., C.M.; manuscript editing, W.C.W.C., Y.L.C., D.J.R., C.M.; manuscript revision/review, W.C.W.C., Y.L.C., C.M., D.J.R., R.G.H.; manuscript final version approval, all authors
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONAPPENDIXREFERENCES |
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