Voxel-based analysis of T2 hyperintensities in white matter during treatment of childhood leukemia

Abstract

Background and purpose: White matter (WM) hyperintensities on T2-weighted MR imaging are the most common imaging manifestation of neurotoxic effects of therapy for central nervous system (CNS) prophylaxis in childhood acute lymphoblastic leukemia (ALL). This study uses voxel-based analyses (VBA) of T2-weighted imaging of patients during treatment to identify which WM regions are preferentially damaged.

Materials and methods: Two sets of conventional T2-weighted axial images were acquired on a 1.5T MR imaging scanner from 197 consecutive patients (85 female, 112 male; aged 1.0-18.9 years) enrolled on an institutional ALL treatment protocol. Images were acquired after completion of induction therapy and after the final of the 4 courses of intravenous high-dose methotrexate in consolidation therapy (3.9 +/- 0.8 months apart). Voxel-wise statistical testing of the incremental change between normalized longitudinal T2 images was performed with radiologist reading (normal or abnormal) and treatment risk-group as covariates.

Results: Two highly significant bilateral clusters of T2 signal intensity change were identified in both 1-group and 2-group analyses. The regions were symmetric in size, shape, and average signal intensity. Increased T2-weighted signal intensity from these regions both within and between examinations were nonlinear functions of age at examination, and the difference between the examinations was greater for older subjects who received more intense therapy.

Conclusions: These analyses identified specific WM tracts involving predominantly the anterior, superior, and posterior corona radiata and superior longitudinal fasciculus, which were at increased risk for the development of T2-weighted hyperintensities during therapy for childhood ALL. These vulnerable regions may be the cause of subsequent cognitive difficulties consistently observed in survivors.

Figures

Fig 1.

VBA results from the 1-group analysis of all patients (n = 197) regardless of treatment risk group are displayed on the average of the normalized T2-weighted images from the first examination for visualization of the spatial localization and extent of the regions.

Fig 2.

VBA results from the 2-group analysis (LR vs SHR) of all patients (n = 197) are displayed on the average of the normalized T2-weighted images from the first examination for visualization of the spatial localization and extent of the regions.

Fig 3.

Patient examination after completion of IV-MTX demonstrating T2-hyperintensities within the corona radiata. The regions identified by the VBA are shown for visual comparison.

Fig 4.

Average T2 signal intensity from VBA clusters on first (left) and second (right) examinations for all 197 subjects to assess symmetry between clusters from each hemisphere. Linear regressions demonstrate slopes of unity with correlations of 0.982 and 0.984, respectively.

Fig 5.

Average T2 signal intensity from VBA clusters on first (filled circle) and second (open circle) examinations for all 197 subjects as a function of age at examination. Signal intensities from both left and right cluster were combined. Logistic regressions are shown for both examinations (solid, first examination; dashed, second examination).

Fig 6.

Difference in T2 signal intensity between the 2 examinations on the basis of the logistic regressions determined in Fig 5. The logistic regressions from each examination were evaluated for ages ranging from 2 to 18 years, and the differences between values at each age are demonstrated.

Fig 7.

Imaging from a 7-year-old female patient treated for ALL. T1-weighted, T2-weighted, and FLAIR images (A–C, respectively) are shown at an axial level, which demonstrated the hyperintensities within the corona radiata. Corresponding FA, axial, and radial diffusivity maps (D–F, respectively) are shown at the same level. Color bars are shown beside each diffusion tensor imaging parameter map for reference. FA values are unitless, whereas axial and radial values are in micrometers squared per second.