What should be done if a patient experiences seizures after starting methotrexate (anti-folate medication)?

Management of Seizures After Starting Methotrexate

Immediately discontinue methotrexate and initiate antiepileptic treatment for seizure control, as methotrexate-induced neurotoxicity is a recognized complication that requires cessation of the causative agent. 1

Immediate Actions

• Stop methotrexate immediately upon presentation with seizures, as this is the primary intervention for methotrexate-induced neurotoxicity 1
• Administer antiepileptic medications to control active seizures, following standard seizure management protocols 1
• Initiate leucovorin (folinic acid) rescue therapy as soon as possible, as this is the antidote for methotrexate toxicity and effectiveness decreases dramatically after 24 hours 2, 3
• Ensure adequate hydration and urinary alkalinization with sodium bicarbonate to prevent methotrexate precipitation in renal tubules and enhance elimination 2, 3

Diagnostic Evaluation

• Obtain urgent brain MRI with T2-weighted and diffusion-weighted sequences to assess for methotrexate-induced leukoencephalopathy, which typically shows bilateral symmetrical white matter changes, cortical and subcortical enhancement, or restricted diffusion 4, 5, 6
• Check serum methotrexate levels to guide duration and intensity of leucovorin therapy 3
• Assess renal function (creatinine, BUN) as impaired clearance increases neurotoxicity risk 3
• Monitor complete blood count to evaluate for concurrent hematologic toxicity 2
• Evaluate for other causes of seizures including CNS infection, electrolyte abnormalities, and progression of underlying disease 1

Risk Factors to Assess

Methotrexate neurotoxicity occurs in 1-4.5% of patients receiving high-dose therapy and is more common with certain risk factors: 4

• High-dose intravenous or intrathecal methotrexate administration (particularly doses >1 g/m²) 3, 4
• Renal impairment leading to delayed methotrexate clearance 3
• Prior craniospinal irradiation, which significantly increases leukoencephalopathy risk 3
• Concurrent medications that may interact, including valproic acid (which can have reduced levels with methotrexate, potentially causing breakthrough seizures in epilepsy patients) 7
• Pediatric patients appear at higher risk for intermediate-dose methotrexate neurotoxicity 3

Clinical Presentations of Methotrexate Neurotoxicity

Methotrexate can cause several distinct neurological syndromes:

Acute/Subacute Neurotoxicity (Days to Weeks After Administration)

• Stroke-like encephalopathy with confusion, hemiparesis, transient blindness, seizures, and coma 3, 5
• Focal neurological deficits such as aphasia or motor weakness that may be transient 5
• Seizures (generalized or focal), which may present as status epilepticus 4, 6
• High fever may accompany the neurological symptoms 4

Chronic Leukoencephalopathy

• Progressive cognitive decline, confusion, irritability, somnolence, ataxia, dementia, and potentially fatal outcomes 3, 8
• Behavioral changes including hypersexuality and memory disturbances (Klüver-Bucy syndrome) 8
• Olfactory or uncinate seizures from temporal lobe involvement 8

Intrathecal Methotrexate-Specific Toxicity

• Acute chemical arachnoiditis with headache, back pain, nuchal rigidity, and fever occurring 2-4 hours after injection 1
• Subacute myelopathy with paraparesis/paraplegia 1, 3
• Aseptic meningitis occurring in 10-50% of patients receiving intrathecal methotrexate 1

Treatment Protocol

Leucovorin Rescue Therapy

• Administer leucovorin up to 100 mg/m² IV if methotrexate levels are unknown or elevated 2, 9
• Continue leucovorin until neurological symptoms resolve and methotrexate levels are undetectable 2, 3
• Do NOT administer leucovorin within 2 hours of glucarpidase if that agent is used, as leucovorin is a substrate for glucarpidase 3

Supportive Management

• Maintain aggressive IV hydration to enhance renal elimination 2, 3
• Alkalinize urine with sodium bicarbonate to prevent tubular precipitation 2, 3
• Monitor serum methotrexate concentrations to guide therapy duration 3
• Consider glucarpidase for toxic methotrexate levels with delayed clearance due to renal impairment 3

For Intrathecal Overdose

• Intensive systemic support with high-dose systemic leucovorin 3
• Rapid CSF drainage and ventriculolumbar perfusion may be necessary 3
• Consider intrathecal or intravenous glucarpidase based on published case reports 3

Prognosis and Recovery

• Subacute neurotoxicity is often reversible with appropriate management, typically showing MRI improvement within days to weeks 1, 5, 6
• Chronic leukoencephalopathy may be progressive and discontinuation of methotrexate does not always result in complete recovery 3, 8
• Variable recovery for myelopathy, with the majority showing clinical improvement when treated with steroids via lumbar route and high-dose folate metabolites 1

Prevention Strategies for Future Patients

• Mandatory folic acid supplementation (1-5 mg daily, except on methotrexate day) for all patients on methotrexate 1, 2
• Avoid very high doses when possible, especially in patients with renal impairment 1
• Screen for renal function before each dose and adjust dosing accordingly 3
• Avoid concurrent craniospinal radiotherapy when possible 1, 3
• Monitor for early neurological symptoms and educate patients to report new headaches, confusion, or focal deficits immediately 4

Critical Pitfall to Avoid

Do not restart methotrexate after a seizure episode without careful consideration, as reintroduction must be decided on an individual basis weighing the necessity of cancer treatment against the risk of recurrent neurotoxicity 1. In many cases, alternative chemotherapy regimens should be strongly considered, particularly if the patient experienced severe or prolonged neurological symptoms.