Methotrexate-induced acute neurotoxicity in patients with osteosarcoma: a case report

Methotrexate is commonly used to treat osteosarcoma and acute lymphoblastic leukemia. Methotrexate can rarely cause neurotoxicity with a wide range of presentations including seizure, hemiparesis, dysarthria, dysphagia, and more. Acute neurotoxicity typically occurs within 2-14 days after methotrexate administration. The incidence of methotrexate-induced neurotoxicity, risk factors, treatments, and recurrence of neurotoxicity on methotrexate rechallenge all largely come from literature involving patients with acute lymphoblastic leukemia.

We present a case of methotrexate-induced neurotoxicity and leukoencephalopathy in a 20-year-old Hispanic male with osteosarcoma who improved after treatment with dextromethorphan and aminophylline. To better understand methotrexate-induced neurotoxicity in patients with osteosarcoma specifically, we conducted a literature review of 16 cases, including ours.

To the knowledge of these authors, this is the largest compilation of cases of methotrexate-induced neurotoxicity involving patients with osteosarcoma. There is no standard treatment for methotrexate-induced neurotoxicity. In our review we discuss dextromethorphan, aminophylline, and ketamine use in the treatment of methotrexate-induced neurotoxicity. Methotrexate is a crucial, first-line treatment for osteosarcoma and if safe, would be beneficial to continue even after acute neurotoxicity. Unfortunately, methotrexate is often discontinued after the first episode of neurotoxicity, owing to fear of recurrence on rechallenge. In our review, 5 of 16 patients were known to be rechallenged with methotrexate. None had recurrence of neurotoxicity with subsequent methotrexate treatment. While our study is limited by the number of cases, our findings suggest that methotrexate rechallenge in patients with osteosarcoma could be considered. Our review adds to the limited existing literature on patients with osteosarcoma with methotrexate-induced neurotoxicity and can aid in the understanding of the complicated pathophysiology, available treatments, and decision of whether to proceed with methotrexate rechallenge.