Intrathecal methotrexate(MTX): Complications
High dose & intrathecal Methotrexate (MTX) is often used for consolidation and CNS relapse prevention because it has been reported to improve the outcome of ALL therapy. However, MTX has side effects such as inhibition of myelin synthesis, antisera, oligodendrocytes, and BBB function. The most serious side effect of MTX is neurotoxicity, which may cause a side effect of up to 3-15% of the total treated patients, which may be transient, but may require occasional coma or death. Subacute effects can be divided into acute, subacute, and chronic neurotoxicity syndromes depending on the time that side effects occur due to IV and IT use.
Acute-phase side effects include somnolence, confusion, headache, nausea, vomiting, and dizziness within several hours after IV administration of high-dose chemical meningitis and within several hours after ITx MTX treatment. Chronic side effects appear within a few months after MTX administration, and symptoms such as cognitive decline, abnormal behavior, and stiffness are present. Subacute-phase side effects are reactions that occur several days to several weeks after ITx MTX treatment. Stroke, like symptoms such as dysphagia / hypersensitivity and aphasia appear and recover soon. Transient diffusion restriction is also observed in the image.
Highly intensive short treatment sequences, delayed elimination of the cerebrospinal fluid (CSF), or long-term cumulative treatment are considered risk factors for the subacute phase. However, MTX inhibits dihydrofolate reductase, resulting in inhibition of thymidylate / purine synthesis due to no folic acid → tetrahydrofolic acid process. There is a hypothesis that homocysteine accumulation occurs and promotes prothrombotic neurovascular endothelium. Another hypothesis is that the hypothesis of involvement of the metabolic pathways of adenosine and biopterins suggests that the reduced risk of subacute MTX neurotoxicity is associated with decreased MTHFR enzyme activity in tetrahydrobiopterin regeneration.
Patients with these side effects should consider whether to continue dosing with MTX ITx, or whether to use other therapies. In another case report, patients with adverse events were treated with IT hydrocortisone + cytarabine (without IV- or IT-MTX) instead of ITx MTX, but no proven effect of CNS prophylaxis. In the future, the CNS prophylaxis is considered to consider IT liposomal cytarabine + IV thiotepa or cranial irradiation.
Acute-phase side effects include somnolence, confusion, headache, nausea, vomiting, and dizziness within several hours after IV administration of high-dose chemical meningitis and within several hours after ITx MTX treatment. Chronic side effects appear within a few months after MTX administration, and symptoms such as cognitive decline, abnormal behavior, and stiffness are present. Subacute-phase side effects are reactions that occur several days to several weeks after ITx MTX treatment. Stroke, like symptoms such as dysphagia / hypersensitivity and aphasia appear and recover soon. Transient diffusion restriction is also observed in the image.
Highly intensive short treatment sequences, delayed elimination of the cerebrospinal fluid (CSF), or long-term cumulative treatment are considered risk factors for the subacute phase. However, MTX inhibits dihydrofolate reductase, resulting in inhibition of thymidylate / purine synthesis due to no folic acid → tetrahydrofolic acid process. There is a hypothesis that homocysteine accumulation occurs and promotes prothrombotic neurovascular endothelium. Another hypothesis is that the hypothesis of involvement of the metabolic pathways of adenosine and biopterins suggests that the reduced risk of subacute MTX neurotoxicity is associated with decreased MTHFR enzyme activity in tetrahydrobiopterin regeneration.
Patients with these side effects should consider whether to continue dosing with MTX ITx, or whether to use other therapies. In another case report, patients with adverse events were treated with IT hydrocortisone + cytarabine (without IV- or IT-MTX) instead of ITx MTX, but no proven effect of CNS prophylaxis. In the future, the CNS prophylaxis is considered to consider IT liposomal cytarabine + IV thiotepa or cranial irradiation.
