Methotrexate Neurological Toxicities: Current State-of-the-Art

Methotrexate is a highly effective anti-folate drug, used for a range of oncological and inflammatory conditions. Toxic effects of methotrexate on the bone marrow, mucosa, liver and kidneys are widely appreciated; however, clinicians may be less familiar with neurotoxic side-effects. Neurotoxicity is primarily reported in those receiving high-dose or intrathecal methotrexate; however, it may occur in patients receiving low-dose treatment. Symptoms range from acute headache/somnolence, sub-acute onset of seizures/stroke-like symptoms, to long-term cognitive and behavioural difficulties. Stroke-like symptoms occur several days after administration when the patient may be out of the hospital, meaning that acute care providers must be able to recognise and appropriately manage these conditions. The mechanism by which methotrexate causes neurotoxicity remains poorly understood, and although some treatments and preventative agents have been identified, they lack robust evidence at present, representing a key area for future research. This article aims to provide a state-of-the-art review of methotrexate neurotoxicity, which will increase physician awareness of this condition, its presentation, and to highlight evidence and research gaps relating to treatment and prevention.