Neurotoxicity
Methotrexate
Methotrexate is a dihydrofolate reductase inhibitor commonly used in hematologic malignancies as well as many rheumatologic diseases. Methotrexate can be administered orally, intravenously or intrathecally (IT). Low to moderate doses of intravenous methotrexate typically do not cause neurotoxicity, but intrathecal administration, commonly given for prophylaxis and treatment of meningeal diseases, can cause neurotoxicity. High doses administered intravenously can also cause neurotoxicity. Neurotoxicity presentation is variable depending on route of administration.
Aseptic meningitis
A common neurotoxicity in patients receiving IT administration is aseptic meningitis, which occurs in 10-50% of patients. Signs and symptoms of meningitis present within hours of administration and are self-limiting, usually resolving within 2-3 days. If patients do experience aseptic meningitis, retreatment with methotrexate is not contraindicated as symptoms usually improve upon subsequent treatments. Additionally, pretreatment with corticosteroids during subsequent treatments may also prevent symptoms of aseptic meningitis.
Transverse myelopathy
A rare but serious complication of IT methotrexate is transverse myelopathy, which presents within hours to days of treatment but can be delayed for up to 1 week after administration. The syndrome initially presents with back pain and evolves to ascending paralysis, sensory loss and eventual loss of bowel and bladder control. Imaging with MRI may show cord edema, which may aid in diagnosis. There is no treatment of transverse myelopathy, but further courses of methotrexate are contraindicated. In case reports, administration of corticosteroids has shown no benefit. Recovery following transverse myelopathy is variable.
Acute encephalopathy
Another rare neurotoxicity with IT methotrexate is acute encephalopathy with tissue necrosis if there is a blockage of cerebrospinal fluid flow. There is no treatment and symptoms usually resolve. Encephalopathy with intravenous methotrexate is associated with high doses (greater than 1g/m2). Patients can present with encephalopathy manifested by somnolence and/or seizures. Some patients may also experience focal neurologic deficits consistent with “stroke-like” symptoms. Evaluation of cerebrospinal fluid and head CT are unrevealing, but EEG changes consistent with encephalopathy may be seen. Encephalopathy typically presents days after treatment and resolves without intervention.
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