Episodes of Acute Methotrexate-Related Neurotoxicity Linked to Compromised Long-term Neurocognitive Function
Introduction
Methotrexate is a critical component of curative chemotherapy for pediatric acute lymphoblastic leukemia (ALL); however, its use is associated with both acute neurologic toxicity and long-term neurocognitive dysfunction. While symptoms of acute neurotoxicity, including stroke-like symptoms, seizure, and aphasia, typically resolve within weeks, the long-term implications of acute neurologic injury are largely unknown. Therefore, we evaluated the association between acute methotrexate-related neurotoxicity and long-term neurocognitive performance.
Methods
Pediatric ALL patients diagnosed at Texas Children’s Hospital (2008-2021) completed validated, age-appropriate measures of intelligence quotient, working memory, attention, processing speed, and fine motor function at least 12 months post diagnosis. Electronic medical records were reviewed to identify cases of acute neurotoxicity, defined as neurologic episodes occurring within 21 days of intravenous (IV) or intrathecal methotrexate and presentations consistent with Ponte di Legno Delphi Consensus definitions. The frequency of impairment (scores >1.5 standard deviations below normative means) was estimated for each domain. Associations between acute neurotoxicity and cognitive performance were evaluated using linear regression, adjusting for age, sex, race/ethnicity, treatment intensity, and time to neurocognitive assessment.
Results
Neurocognitive assessments were completed on 180 survivors of pediatric ALL, including 26 (14.4%) with a history of acute methotrexate-related neurotoxicity during therapy. Participants were a median age of 5 years at diagnosis (range: 0-18 years), 62% Latino, 60% male, and 51% treated with high dose IV methotrexate. Neurocognitive evaluations were completed a median of 4.1 years post diagnosis (range: 1.1 – 12.4 years). Survivors performed significantly (p<0.05) below normative averages on measures of working memory, attention, processing speed, and fine motor function, with 21.8% (95% CI: 15.1-29.8) and 32.5% (95% CI: 25.2-40.5) exhibiting impairment in attention and fine motor function, respectively. Overall, individuals with a history of acute methotrexate-related neurotoxicity exhibited poorer performance in most domains evaluated. After accounting for age, a history of acute methotrexate-related neurotoxicity was associated with significantly poorer performance in measures of attention (p=0.018) and fine motor function (p=0.017).
Conclusion
Survivors of pediatric ALL remain at increased risk for long-term cognitive weakness. For the domains of attention and fine motor function, impairment was most pronounced in the nearly 15% of pediatric patients with acute neurologic toxicity during ALL therapy. Because impairment in these domains negatively affects academic and vocational attainment, it may be important to identify and monitor patients with acute neurotoxicity during treatment in an effort to intervene early and mitigate lasting adverse effects.