Introduction: Intrathecal (IT) cytarabine, an antineoplastic agent with poorly understood neurotoxicity, is commonly administered to children with newly diagnosed leukemia on the first day of induction chemotherapy for central nervous system prophylaxis. Five recent case reports demonstrated severe diffuse cerebral vasospasm leading to neurologic sequelae 4-11 days after administration of IT cytarabine. While these patients developed overt consequences, subclinical vasospasm may lead to more subtle forms of neurotoxicity in a larger group of patients. Recognition of subclinical vasospasm could prevent both overt and subtle consequences.
Objective and Hypothesis: We evaluated cerebral blood flow velocities (CBFVs), a marker of vasospasm, as measured by transcranial Doppler (TCD) ultrasound, before and after the administration of IT cytarabine. We hypothesized that IT cytarabine increases CBFVs in pediatric leukemia patients in the first two weeks after treatment.
Methods: In this prospective before and after study, TCDs were performed on each subject prior to induction chemotherapy and subsequently around days +1, +4, and +8 of induction, before other IT medication administration and within the window of expected vasospasm based on prior cases.
Results: In this interim analysis, we found elevated CBFVs compared to age-matched normal values in all arterial distributions measured (though more prominently in anterior circulation), even prior to the administration of IT chemotherapy. Substantial increases in CBFVs were observed after the administration of IT cytarabine in some subjects, though this trend was not observed in all cases.
Conclusions: The observed elevations in CBFVs are likely in part due to decreased blood viscosities that resulted from hematologic changes secondary to leukemia. The observed changes in CBFVs after IT cytarabine administration are probably partially due to treatment effects, but the variability between patients suggests that patient and/or disease-specific characteristics may predispose certain children to cerebral vasospasm and its neurologic sequelae. This ongoing study aims to identify clinical features that allow risk stratification in order to develop clinical pathways for preventing neurotoxicity.