Methotrexate-Induced Encephalopathy Mimicking Acute Ischemic Stroke in an Adolescent With Osteosarcoma: A Case Report

Introduction

Methotrexate-induced encephalopathy is a rare but serious complication of high-dose methotrexate therapy, often seen in patients undergoing treatment for osteosarcoma. The condition is notoriously challenging to diagnose, as its neurological symptoms often mimic those of other conditions, particularly ischemic stroke. We present a case of methotrexate-induced encephalopathy in a 16-year-old girl with osteosarcoma, whose initial presentation mimicked acute ischemic stroke. This case illustrates the diagnostic complexities involved and highlights the potential for spontaneous neurological recovery without the use of standard rescue interventions.

Case Report

The patient, a 16-year-old girl, was diagnosed with high-grade osteosarcoma of the distal left femur and began neoadjuvant chemotherapy with high-dose intravenous (IV) methotrexate (12 g/m2, with a total dose of 15 400 mg), doxorubicin, and cisplatin (the MAP regimen). During week 10 of chemotherapy, 2 weeks after the last methotrexate dose, the patient developed sudden-onset slurred and non-fluent speech, followed by rapid progression to global aphasia and altered consciousness within 1 hour. On examination at presentation, she was alert but responded slowly to verbal stimuli, with evident aphasia. Cranial nerve examination revealed no obvious focal deficits. Motor responses were symmetric. Urgent brain magnetic resonance imaging (MRI) performed 2 hours after symptom onset revealed bilateral areas of restricted diffusion in the centrum semiovale, without corresponding signal abnormalities on fluid-attenuated ınversion recovery (FLAIR) imaging (Figure 1). Given the clinical presentation and radiological findings, she was treated with thrombolytic therapy for a presumed acute ischemic stroke. Computed tomography angiography of the cerebral vasculature showed no large-vessel occlusion.

After thrombolysis, the patient’s neurological symptoms improved gradually over the next 18 hours. The following day, she developed new neurological deficits, including right-sided hemiparesis and recurrent dysarthria. Follow-up MRI revealed resolution of the right-sided lesion, while on the left side, a new area of restricted diffusion developed, overlapping the location of the previous lesion. FLAIR sequences remained unremarkable (Figure 2). These findings were atypical for acute ischemic stroke and helped to diagnose chemotherapy-induced neurotoxicity.

She received supportive care with close monitoring. Her neurological function improved significantly over the next 2 days, with full motor strength regained and dysarthria resolved. She was discharged after 5 days of follow-up. At discharge, she was fully alert, with normal language function, intact motor strength, and no residual focal neurological deficits.

After recovery, she resumed MAP regimen chemotherapy 1 week after discharge. Multidisciplinary care involving oncology, neurology, and rehabilitation specialists was essential for her recovery and continued treatment. Surgical resection of the osteosarcoma was successful after finishing chemotherapy, and the patient continued rehabilitation without any neurologic deficit.

Discussion

Methotrexate-induced encephalopathy is a recognized condition, with common features including headache, nausea, vomiting, confusion, disorientation, and seizures; focal neurological deficits, such as hemiparesis, ataxia, and aphasia, can also be present [1]. One of the main challenges in diagnosing methotrexate-induced encephalopathy is its overlap with other neurological conditions, particularly ischemic stroke. In the present case, the patient’s rapid neurological deterioration, marked by dysphasia, cognitive slowing, and hemiparesis, initially suggested a stroke, prompting the administration of thrombolytic therapy. However, the follow-up imaging and clinical course revealed no significant vascular occlusion, suggesting that methotrexate-induced encephalopathy, rather than ischemic stroke, was the cause of the symptoms. These findings are consistent with other reports, in which methotrexate-induced encephalopathy presents with stroke-like symptoms, complicating diagnosis. Similar stroke-like presentations have been reported in prior series, underscoring the diagnostic complexity of this condition [2].

Beyond ischemic stroke, other etiologies were considered. Inflammatory and demyelinating disorders, such as chronic lymphocytic ınflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), were deemed unlikely given the lack of brainstem involvement, absence of contrast enhancement, and rapid spontaneous recovery without corticosteroid therapy. Posterior reversible encephalopathy syndrome was also excluded, as the lesions lacked the characteristic posterior cortical–subcortical vasogenic edema and T2-FLAIR hyperintensity typically seen in this condition, and there were no associated systemic risk factors, such as hypertension or renal dysfunction. Instead, the focal, transient diffusion restriction confined to the centrum semiovale, combined with lesion migration on follow-up imaging, favored a diagnosis of methotrexate-induced toxic leukoencephalopathy.

Alternative chemotherapy-related neurotoxicities were also considered. Cisplatin toxicity typically presents as cumulative peripheral neuropathy or ototoxicity, while acute central nervous system manifestations are uncommon. Doxorubicin is not generally associated with acute encephalopathy. In contrast, the characteristic imaging pattern and reversible clinical course observed in this case align more closely with methotrexate-related neurotoxicity.

There are 4 similar case reports involving patients with osteosarcoma. Valle et al reported a case with the abrupt onset of left-sided paresthesia, initially diagnosed as a stroke [3]. Additionally, recurrent symptoms appear to be a common presentation in these cases, as observed in our patient. In 3 of the 4 cases, recurrent or new symptoms occurred after the initial presentation, often within 1 day of onset [3–5].

Neuroimaging plays a central role in distinguishing methotrexate-induced encephalopathy from vascular etiologies. Restricted diffusion on MRI is a common finding but differs from ischemic stroke in that lesions are often bilateral, non-territorial, and transient, and can lack persistent T2-FLAIR signal change on subsequent imaging [6]. Recognition of this imaging phenotype is critical for avoiding misdiagnosis and unnecessary invasive interventions. Nevertheless, given the increased risk of arterial thromboembolism in patients with cancer [7], thrombolysis remains a reasonable consideration when stroke cannot be confidently excluded in the acute setting.

The management of methotrexate-induced encephalopathy remains an area of discovery, as there is no universally accepted treatment protocol. However, several approaches have been explored to mitigate the effects of neurotoxicity. One of the most commonly used interventions is rescue with leucovorin [8], a form of folate supplementation, which is typically used to counteract the effects of methotrexate-induced toxicity. The addition of aminophylline has also been considered in some cases, to further support treatment efficacy, although evidence supporting its use is limited [9]. Another potential therapeutic option is the administration of dextromethorphan, a medication with neuroprotective properties that has shown promise in some case reports [10]. Despite the absence of definitive clinical guidelines, these treatments are generally well tolerated and may provide some benefit in alleviating symptoms. In most reported cases, neurological symptoms recover completely over hours to days, and no residual deficit nor intellectual impairment are identified [11]. Consistent with these observations, our patient achieved complete recovery with supportive care alone, suggesting that conservative management can be appropriate in selected cases.

Overall, this case underscores the diagnostic complexity of methotrexate-induced encephalopathy and the value of integrating clinical evolution with serial neuroimaging. Recognizing this reversible stroke mimic may prevent unnecessary interventions. Although leucovorin rescue is commonly used to mitigate methotrexate-related neurotoxicity, our case questions its routine necessity, supporting a more individualized management approach.

Conclusions

Methotrexate-induced encephalopathy presents significant diagnostic challenges, as its symptoms often resemble those of other neurological conditions, especially stroke. Imaging findings may not always provide clear differentiation in the early phase. Importantly, early recognition of methotrexate-induced encephalopathy is essential to prevent unnecessary interventions, as full neurological recovery can occur with supportive care alone, even in the absence of standard treatments, such as leucovorin rescue. These uncertainties underscore the need for individualized treatment strategies and further research to refine both the diagnostic methods and therapeutic approaches for methotrexate-induced encephalopathy.