Abstract
Introduction
Methotrexate (MTX) is widely used in the treatment of hematologic malignancies and can produce acute, subacute, and chronic neurotoxicity following systemic or intrathecal administration. Clinical manifestations include stroke-like deficits, seizures, encephalopathy, myelopathy, leukoencephalopathy, and posterior reversible encephalopathy syndrome (PRES). Although characteristic magnetic resonance imaging (MRI) abnormalities have been described, the basis for their recurrent localization to specific neuroanatomic regions remains incompletely understood. Existing literature has largely characterized MTX neurotoxicity by clinical syndrome, timing, or imaging appearance, while comparatively less attention has been directed toward why particular cerebral regions appear repeatedly susceptible. This study aimed to characterize recurring MRI phenotypes of MTX-associated neurotoxicity and develop an integrated mechanistic framework linking these radiographic patterns to regional neuroanatomic vulnerability.
Main Body
Published case reports, case series, imaging studies, and mechanistic literature related to MTX-associated neurotoxicity were reviewed. Representative MRI cases were selected to illustrate recurring patterns of lesion distribution and imaging characteristics, and three recurring radiographic phenotypes were identified: diffusion-restrictive deep white-matter injury, fluid-attenuated inversion recovery (FLAIR)-dominant leukoencephalopathy, and posterior cortical/subcortical injury consistent with PRES. Mechanistic literature was then examined for regional factors that might account for these distributions, including cerebral perfusion and medullary arterial anatomy, oligodendrocyte and myelin biology, folate and homocysteine metabolism, N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity, adenosine-dependent vascular regulation, and deep medullary venous drainage. These findings were integrated into a proposed model of regional susceptibility. The first phenotype was an acute diffusion-restrictive deep white-matter pattern involving the centrum semiovale, corona radiata, and adjacent deep white matter, with minimal or absent early FLAIR abnormality. This pattern is proposed to reflect regional perfusion vulnerability related to low baseline white-matter blood flow and distal medullary arterial supply, predisposing these territories to cytotoxic injury. The second phenotype was FLAIR-dominant leukoencephalopathy involving periventricular and deep white matter, with extension into the centrum semiovale, corona radiata, and corpus callosum. This distribution is consistent with increased susceptibility of heavily myelinated, oligodendrocyte-rich regions to sustained metabolic and cellular injury. Deep medullary venous anatomy may further increase periventricular vulnerability by limiting interstitial clearance and prolonging local exposure to homocysteine and adenosine. The third phenotype was a posterior cortical/subcortical pattern consistent with PRES, characterized by bilateral parieto-occipital involvement and vasogenic edema. This pattern may reflect MTX-associated increases in adenosine with disruption of cerebral vasodilation and autoregulatory control, promoting vasogenic edema in posterior regions. Across all three phenotypes, homocysteine-mediated NMDA receptor excitotoxicity may act as a shared molecular stressor.
Conclusion
MTX neurotoxicity demonstrates recurring rather than random MRI distributions. The observed phenotypes support a model in which systemic metabolic and vasoregulatory injury interacts with region-specific vascular, cellular, molecular, and venous characteristics. This framework links established MTX-associated biochemical disturbances with the neuroanatomic distribution of injury and provides an explanation for the heterogeneous but reproducible MRI manifestations of MTX neurotoxicity. Improved understanding of the mechanisms underlying MTX neurotoxicity may help identify strategies to prevent neurologic complications and guide management when MTX remains clinically necessary.