Molecular and Mechanistic Divergence of Seizures in Pediatric Acute Lymphoblastic Leukemia: CNS Infiltration Versus Chemotherapy-Induced Neurotoxicity

Neurological complications, particularly seizures, represent a significant and often under-recognized clinical challenge in pediatric hematologic malignancies. Distinguishing CNS leukemia-associated epilepsy from chemotherapy-induced neurotoxicity is critical for optimizing therapy but remains difficult due to overlapping clinical presentations. This review highlights the distinct molecular mechanisms underlying these two entities. CNS leukemia-associated seizures are primarily driven by blood-brain barrier (BBB) disruption following leukemic infiltration, which triggers a neuroinflammatory cascade involving pro-inflammatory cytokines such as IL-6 and TNF-α, and impairs glutamate homeostasis. In contrast, chemotherapy-induced seizures, particularly those associated with high-dose methotrexate, arise from disrupted folate metabolism, intracellular oxidative stress, and subsequent N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. We provide a comparative analysis of these pathways, integrating current evidence on pharmacogenomic susceptibility-including polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and drug transporter genes-as well as epigenetic factors. By synthesizing these molecular insights, we propose a mechanistic framework for precise clinical differentiation, which may inform biomarker-driven diagnostic approaches and targeted neuroprotective strategies in this vulnerable population.