High-dose methotrexate (HDMTX) remains a fundamental component of chemotherapy for osteosarcoma and acute lymphoblastic leukemia. However, its administration can lead to methotrexate-induced encephalopathy, a condition that frequently presents as a stroke mimic. Consequently, clinicians must recognize this subacute neurotoxicity to avoid unnecessary treatments like thrombolysis. Similarly, early identification ensures that patients receive appropriate supportive care rather than invasive interventions.

Identifying Methotrexate-Induced Encephalopathy

Recently, a case involving a 16-year-old girl with osteosarcoma highlighted these diagnostic hurdles. Following her high-dose methotrexate infusion, she experienced sudden dysphasia and cognitive slowing. Furthermore, her symptoms progressed to global aphasia and altered consciousness within just one hour. Therefore, the medical team initially suspected an acute ischemic stroke. Initial MRI scans showed bilateral diffusion restriction in the centrum semiovale. However, these findings lacked corresponding signal changes on fluid-attenuated inversion recovery (FLAIR) sequences.

Because the clinical picture resembled a stroke, the patient received intravenous alteplase. Nevertheless, subsequent imaging revealed shifting diffusion abnormalities without any vascular occlusion. Such patterns are inconsistent with arterial stroke but align perfectly with methotrexate-induced encephalopathy. In response, doctors withheld methotrexate and provided supportive care. Ultimately, the patient achieved a complete neurological recovery within three days. She successfully resumed her chemotherapy one week later and remained asymptomatic at her one-year follow-up.

Distinguishing MIE from Ischemic Stroke

Notably, radiology plays a vital role in differentiating these two conditions. In cases of methotrexate-induced encephalopathy, MRI typically demonstrates transient and often symmetrical restricted diffusion in the white matter. Specifically, these lesions usually spare the cerebral cortex and do not respect vascular territories. Additionally, the lack of early FLAIR abnormalities is a key diagnostic clue. Moreover, the clinical course is typically reversible. While stroke deficits often persist, MIE symptoms generally resolve spontaneously within a few days. Therefore, awareness of these patterns is essential for oncologists and neurologists alike.

Frequently Asked Questions

When does methotrexate-induced encephalopathy typically occur?

Symptoms usually manifest as a subacute event, appearing between 2 and 14 days after methotrexate administration. However, some rare cases may present within hours of the infusion, as seen in recent clinical reports.

Is it safe to rechallenge a patient with methotrexate after an episode?

Yes, most patients can safely resume methotrexate therapy after achieving full neurological recovery. Specifically, research indicates that a high percentage of patients do not experience a recurrence during future cycles.

Does this condition require specific medical treatment?

Management is primarily supportive. Although some practitioners consider aminophylline or leucovorin, most instances of methotrexate-induced encephalopathy resolve fully with observation and supportive care alone.

Disclaimer: This content is for informational and educational purposes only. It does not constitute medical advice or establish a doctor-patient relationship. Refer to the latest local and national guidelines for clinical practice.

References

Duong TV et al. Methotrexate-Induced Encephalopathy Mimicking Acute Ischemic Stroke in an Adolescent With Osteosarcoma: A Case Report. Am J Case Rep. 2026 Apr 05. doi: 10.12659/AJCR.951751. PMID: 41936065.

Vezmar S, et al. Methotrexate-induced stroke-like encephalopathy: Beware the stroke mimic. nih.gov. 2022.

Shuper A, et al. Stroke-like encephalopathy following high-dose intravenous methotrexate in an adolescent with osteosarcoma: a case report. nih.gov. 2023.