An observational MRI study of methotrexate-treated children with acute lymphoblastic leukemia in remission and subtle cognitive decline.

Background: For children diagnosed with acute lymphoblastic leukemia (ALL), methotrexate (MTX) treatment carries the risk of leukoencephalopathy and other treatment-related brain damage. However, earlier and more sensitive evaluation is needed to elucidate the specific effects of MTX treatment in this group. This study aimed to evaluate changes in brain metabolites, diffusion and anisotropy features, and cognitive performance in children with ALL after MTX treatment.

Methods: In this observational study conducted from December 2013 to December 2015, 30 children with ALL and 30 healthy children were recruited and evaluated using baseline magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and neurocognitive tests. After MTX treatment and ALL remission, the children with ALL underwent MR examination and neurocognitive tests again. Quantitative alterations of MR and cognitive test results from the baseline data were calculated.

Results: At baseline, the ALL group (age 6.9±3.3 years; 14 boys) and the healthy controls (age 6.0±3.1 years, 14 boys) had comparable neurocognitive performance and MR results. After MTX treatment, 6.7% (2/30) of children with ALL showed abnormalities on diffusion- and T1- and T2-weighted images. The N-acetylaspartate/creatine and N-acetylaspartate/choline values of children with ALL decreased, whereas their choline/creatine values increased significantly. The fractional anisotropy (FA) values decreased in the frontal lobe (P=0.03) and the genu of the corpus callosum (P=0.01). The FA values in the genu of the internal capsule (P=0.08), the occipital lobe (P=0.20) and the splenium of the corpus callosum (P=0.30) did not change from baseline. The apparent diffusion coefficient (ADC) values decreased in the frontal lobe (P=0.03). The ADC values in the genu of the corpus callosum (P=0.11), the genu of the internal capsule (P=0.93), and the occipital lobe (P=0.65) did not change from baseline. Due to the presence of outliers and the small sample, the ADC values in the splenium of the corpus callosum were discarded. Neurocognitive performance decreased slightly after MTX treatment, with noticeable declines in working memory and processing speed. Changes in FA values were positively correlated with the reduction in the N-acetylaspartate/creatine ratio at the genu of the corpus callosum of children with ALL aged above 6 years.

Conclusions: MTX treatment causes subtle cognitive decline in children with ALL in remission and dramatically affects their brain metabolites, but changes in white matter diffusion features are limited to the frontal lobe and corpus callosum.