Can methotrexate (disease-modifying antirheumatic drug, DMARD) cause seizures?

Methotrexate Can Cause Seizures and Other Neurological Toxicities

Yes, methotrexate can cause seizures and various forms of neurotoxicity, particularly at high doses or with intrathecal administration, though it can occur even with standard therapeutic doses. 1, 2

Neurological Side Effects of Methotrexate

• Serious neurotoxicity, including generalized or focal seizures, has been reported with methotrexate use, particularly in pediatric patients with acute lymphoblastic leukemia treated with intermediate-dose intravenous methotrexate (1 gm/m²) 1
• Methotrexate can cause leukoencephalopathy, which may manifest with confusion, irritability, somnolence, ataxia, dementia, seizures, and coma 1
• A stroke-like encephalopathy has been observed in patients treated with high-dose regimens, with manifestations including confusion, hemiparesis, transient blindness, seizures, and coma 1
• Neurological complications can occur with various routes of administration, including oral, intramuscular, intravenous, and intrathecal methotrexate 1, 3

Mechanisms of Methotrexate-Induced Seizures

• Methotrexate-induced seizures may be mediated through the glutamatergic system, as demonstrated in animal models where methotrexate decreased glutamate uptake in brain slices by 20-30% 2
• Adenosine release in the central nervous system due to methotrexate's inhibition of purine synthesis may contribute to neurotoxicity 4
• Animal studies have shown disruption of monoamine metabolism, particularly dopamine metabolites, which may contribute to brain dysfunction 5
• Methotrexate can cause structural changes in the brain, particularly affecting white matter, leading to leukoencephalopathy that may manifest with seizures 1, 6

Risk Factors and Clinical Presentation

• Neurotoxicity can occur at all dosages of methotrexate, though it's more common with high-dose regimens 1
• Patients with previous cranial irradiation may be at higher risk for leukoencephalopathy following methotrexate administration 1
• Clinical presentations can include:
  • Tonic-clonic seizures 2
  • Status epilepticus 3
  • Altered mental status and high fever 3
  • Uncinate seizures (olfactory hallucinations) 6
  • Behavioral abnormalities 6

Management Considerations

• Discontinuation of methotrexate should be considered in patients who develop seizures or other significant neurological symptoms 1
• Aminophylline has shown promise in treating methotrexate-induced neurotoxicity in some cases, possibly by displacing adenosine from its receptors 4
• Glutamate receptor antagonists (MK-801, DNQX) and adenosine have demonstrated protective effects against methotrexate-induced seizures in animal models 2
• Neurological symptoms may not always resolve completely after discontinuation of methotrexate 1

Monitoring and Prevention

• Healthcare providers should be vigilant for neurological symptoms in patients receiving methotrexate, particularly those on high doses or receiving intrathecal administration 1, 3
• Magnetic resonance imaging may reveal white matter changes in patients with methotrexate-induced neurotoxicity 3, 6
• Emergency department and intensive care providers should consider methotrexate in the differential diagnosis when treating patients with new neurological symptoms who have recently received methotrexate 3

While methotrexate remains a cornerstone treatment for various rheumatological and oncological conditions, its potential to cause seizures and other neurological complications should be recognized and monitored closely.