Can methotrexate (MTX) cause seizures?

Methotrexate and Seizures

Yes, methotrexate can cause seizures, particularly with high-dose intravenous or intrathecal administration, though this is a rare but serious neurotoxic complication that requires immediate recognition and drug discontinuation. 1

Mechanism and Risk Factors

The FDA drug label explicitly warns that serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia treated with intermediate-dose intravenous methotrexate (1 g/m²). 1 These patients commonly demonstrate leukoencephalopathy and/or microangiopathic calcifications on imaging studies. 1

Primary Mechanisms:

• Adenosine accumulation in the CNS appears to be a key mediator of methotrexate neurotoxicity, as methotrexate inhibits purine synthesis leading to adenosine release, which acts as a CNS depressant. 2
• Disruption of monoamine metabolism, specifically reduced dopamine metabolite concentrations in the brain, has been demonstrated in animal models of methotrexate encephalopathy. 3
• Drug interactions can precipitate seizures in epilepsy patients; methotrexate competes with valproic acid for albumin binding, causing increased free VPA that is rapidly metabolized, leading to subtherapeutic levels and seizure relapse. 4

High-Risk Scenarios:

• Intrathecal or high-dose intravenous administration carries the highest risk for acute neurotoxicity including seizures. 1, 5
• Pediatric patients with acute lymphoblastic leukemia receiving intermediate-to-high dose methotrexate. 1, 5
• Patients on concurrent valproic acid for epilepsy control, where methotrexate can reduce VPA levels. 4
• Prior craniospinal irradiation significantly increases risk of leukoencephalopathy and seizures. 1

Clinical Presentation

Acute Neurologic Syndrome:

The FDA describes a transient acute neurologic syndrome with high-dose regimens that manifests as a stroke-like encephalopathy, including:

• Confusion and altered mental status 1
• Hemiparesis 1
• Transient blindness 1
• Seizures 1
• Coma 1

Timing and Progression:

• Seizures occur with increasing frequency at higher cumulative doses in animal models, suggesting dose-dependent neurotoxicity. 3
• Most cases present during or shortly after methotrexate administration, though symptoms can develop unpredictably. 6
• While typically transient and resolving within days, severe and fatal cases have been reported, particularly in adolescent patients with ALL even without radiation exposure. 5

Diagnostic Approach

• Obtain urgent brain MRI with diffusion-weighted imaging (DWI) to identify reversibly restricted diffusion patterns characteristic of methotrexate-induced encephalopathy. 6
• Look for leukoencephalopathy and microangiopathic calcifications on imaging studies. 1
• Measure CSF adenosine concentrations if available, as levels are markedly elevated (mean 217 nmol/L vs 51 nmol/L in controls) even with minimal toxicity. 2
• In epilepsy patients on valproic acid, check VPA levels immediately as methotrexate can cause precipitous drops. 4

Management

Immediate Actions:

• Discontinue methotrexate immediately upon recognition of neurotoxicity. 1
• Administer aminophylline 2.5 mg/kg IV over 1 hour, as this adenosine receptor antagonist can provide complete resolution or pronounced improvement in methotrexate-induced neurotoxicity including seizures. 2
• Provide standard antiepileptic therapy for acute seizure management while addressing the underlying methotrexate toxicity.

Leucovorin Rescue:

• For significant methotrexate toxicity, administer leucovorin (folinic acid) rescue with higher doses as needed. 7, 8
• Maintain adequate hydration and consider urine alkalinization to enhance methotrexate clearance. 7

Special Considerations:

• Discontinuation of methotrexate does not always result in complete recovery from chronic leukoencephalopathy. 1
• Fatal outcomes have been documented despite cessation of therapy, particularly with severe neurotoxicity. 5
• For patients requiring continued methotrexate after acute neurotoxicity, the majority tolerate subsequent doses without recurrence, though a subset develops persistent irreversible symptoms. 5

Prevention Strategies

• Avoid methotrexate in patients with pre-existing seizure disorders unless absolutely necessary, and ensure optimal antiepileptic drug levels. 4
• Evacuate significant third-space fluid accumulations (pleural effusions, ascites) before treatment, as methotrexate exits slowly from these compartments causing prolonged half-life and unexpected toxicity. 1
• Monitor plasma methotrexate levels in high-risk patients receiving intermediate or high doses. 1
• Ensure adequate folic acid supplementation (at least 5 mg per week) to reduce overall methotrexate toxicity, though this specifically targets hepatic and GI effects rather than neurotoxicity. 9

Critical Pitfall

The most dangerous pitfall is failing to recognize that low-dose weekly methotrexate can also cause seizures through drug interactions, not just high-dose regimens. 4 Any patient on methotrexate who develops new neurologic symptoms including seizures requires immediate evaluation, regardless of dose or route of administration.