A quantitative MR imaging assessment of leukoencephalopathy in children treated for acute lymphoblastic leukemia without irradiation

Abstract

Purpose: Intravenous methotrexate (IV-MTX), an effective treatment for acute lymphoblastic leukemia (ALL), has a significant toxic effect on the central nervous system, with leukoencephalopathy (LE) being the most common form. The purpose of this study was to use objective quantitative MR imaging to prospectively assess the temporal evolution of LE extent and intensity.

Methods: Forty-five children (low-risk, 10 mol/L/12F; mean age, 5.0 years at diagnosis; standard/high-risk, 11 mol/L/12F; mean age, 9.2 years at diagnosis) treated for ALL on a single institutional protocol were evaluated longitudinally to assess the extent of LE (proportion of white matter impacted) through tissue segmentation and the relative intensity of LE through relative elevations in T1 and T2 relaxation rates. One-sided Wilcoxon-Mann-Whitney tests were used to assess differences in quantitative measures at 4 different points in therapy both within and between risk arms.

Results: The proportion of white matter affected in both patient groups increased significantly with additional courses of IV-MTX, whereas the intensity of LE also increased steadily; however, both the intensity and extent of LE declined significantly approximately 1.5 years after completion of IV-MTX. Increases in the T1 and T2 relaxation rates above normal-appearing white matter were significantly correlated with each other and were dependent on the proportion of white matter affected.

Conclusion: Higher doses and more courses of IV-MTX were associated with increased intensity and extent of LE. There was a significant reduction in both the intensity and extent of LE after completion of therapy. The impact of these changes on neurocognitive functioning and quality of life in survivors remains to be determined.

Figures

Fig 1.

A single section from a typical examination after completion of IV-MTX demonstrating LE appearance on FLAIR image, segmented tissue map, quantitative T1 and quantitative T2 maps (left to right). LE is most evident in the frontal white matter.

Fig 2.

Predicted probability of developing LE according to a general linear model previously reported for patients on the standard- or high-risk arm (light gray bars) and patients on the low-risk arm (black bars) of the treatment protocol. Quantitative MR measures were evaluated post 1, 4, and 7 courses of IV-MTX and at end of therapy (EOT).

Fig 3.

Proportion of white matter affected (extent of LE) for patients on the standard- or high-risk arm (light gray bars) and patients on the low-risk arm (black bars) of the treatment protocol. Statistical results from a nonparameteric one-sided Wilcoxon-Mann-Whitney test are shown for both within and between groups at each of the 4 time points. Quantitative MR measures were evaluated post 1, 4, and 7 courses of IVMTX and at end of therapy (EOT).

Fig 4.

Increase in T1 relaxation rate of LE over NAWM (intensity of LE) for patients on the standard- or high-risk arm (light gray bars) and patients on the low-risk arm (black bars) of the treatment protocol. Statistical results from a nonparameteric one-sided Wilcoxon-Mann-Whitney test are shown for both within and between groups at each of the 4 time points. Quantitative MR measures were evaluated post 1, 4, and 7 courses of IV-MTX and at end of therapy (EOT).

Fig 5.

Increase in T2 relaxation rate of LE over NAWM (intensity of LE) for patients on the standard- or high-risk arm (light gray bars) and patients on the low-risk arm (black bars) of the treatment protocol. Statistical results from a nonparameteric one-sided Wilcoxon-Mann-Whitney test are shown for both within and between groups at each of the 4 time points. Quantitative MR measures were evaluated post 1, 4, and 7 courses of IV-MTX and end of therapy (EOT).

Fig 6.

Scatter plot of increase in T1 and T2 relaxation rates for patients on both arms of the treatment protocol. The solid line is the result of a simple linear robust regression analysis. Increases in T1 and T2 relaxation relative to NAWM were highly correlated.