Isolated oral methotrexate-induced cerebellar leukoencephalopathy: a rare and underrecognized imaging pattern

An 86-year-old man with T-cell large granular lymphocytic leukemia on long-term weekly oral methotrexate presented with progressive imbalance, ataxia, recurrent falls, and altered mental status. Initial neuroimaging ([ Figures 1 ]–[ 3 ]) showed posterior-fossa involvement with abnormalities in the deep cerebellar white matter and middle cerebellar peduncles, consistent with vasogenic edema. Differential diagnoses included atypical posterior reversible encephalopathy syndrome (PRES),[ 1 ] John Cunningham (JC) virus-associated progressive multifocal leukoencephalopathy (PML),[ 2 ] and metronidazole-induced neurotoxicity,[ 3 ] the latter considered less likely due to dentate nuclei sparing. Infectious, metabolic, and neoplastic etiologies were excluded. Methotrexate-induced cerebellar leukoencephalopathy was favored, likely related to folate antagonism and impaired methylation affecting cerebellar white matter.[ 4 ] [ 5 ] [ 6 ] The neurological symptoms and imaging findings markedly improved after methotrexate discontinuation ([ Figure 4 ]). Figure 1 Non-contrast brain computed tomography (CT) scan, axial ( A ) and coronal ( B ) images. Bilateral and symmetric hypoattenuation in the deep cerebellar white matter surrounding the dentate nuclei (red arrows). Figure 2 Brain magnetic resonance imaging (MRI) scan, coronal fluid-attenuated inversion recovery (FLAIR) ( A,B ) and axial T2-weighted ( C ) images. Greater conspicuity of the abnormality in the middle cerebellar peduncles and deep cerebellar white matter surrounding the dentate nuclei, characterized by T2/FLAIR hypersignal consistent with vasogenic edema (red arrows). Figure 3 Brain MRI scan, axial diffusion-weighted imaging ( A,C ), axial apparent diffusion coefficient (ADC) maps ( B,D ), and coronal postcontrast T1 gradient-echo sequence ( E ). No restricted diffusion or enhancement in the affected cerebellar regions. Figure 4 Four-month follow-up brain MRI scan. Axial FLAIR ( A,C ) and T2-weighted images ( B,D ) demonstrating near-complete resolution of vasogenic edema involving the middle cerebellar peduncles and deep cerebellar white matter, with residual cystic-like changes/small cavitations in the latter. Authors' Contributions Conceptualization: AS; Data curation: AS; Project administration: LFF; Supervision: AKS, KJA, MLD; Validation: KJA; Visualization: MLD, KJA; Writing: AS, LFF; Writing – review & editing: LFF. Data Availability Statement No new data were generated or analyzed in this study. Ethical Considerations The present case report was conducted in accordance with the principles of the Declaration of Helsinki. Institutional Review Board (IRB) approval was not required for this type of study according to institutional policies. All patient data were fully anonymized, and no identifiable information is included. Use of Artificial Intelligence Artificial intelligence tools were used to assist with language editing of the manuscript. All scientific content, interpretations, and conclusions were developed and verified by the authors. Editor-in-Chief: Hélio A. G. Teive 0000-0003-2305-1073 Associate Editor: Karen Nunez-Wallace 0000-0003-2114-4735 Publication History Received: 16 December 2025 Accepted: 12 April 2026 Article published online: 13 August 2026 © 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda. Rua Rego Freitas, 175, loja 1, República, São Paulo, SP, CEP 01220-010, Brazil Bibliographical Record Aaliyah Shaikh, Abdulrahman Kareem Sidani, Kevin J. Abrams, Márcio Luís Duarte, Leonardo Furtado Freitas. Isolated oral methotrexate-induced cerebellar leukoencephalopathy: a rare and underrecognized imaging pattern. Arq Neuropsiquiatr 2026; 84: s00461827043. DOI: 10.1055/s-0046-1827043