Methotrexate-Induced Leukoencephalopathy Reversed by Aminophylline and High-Dose Folinic Acid

Abstract

Methotrexate is an antimetabolite with an importantrole in the treatment of acute lymphoblastic leukaemia(ALL). In ALL both high-dose intravenous and intrathe-cal methotrexate is used. The antitumour effect of metho-trexate is due to the inhibition of dihydrofolate reductasewhich recycles oxidized folates to their reduced state.Polyglutamation of methotrexate leads to purine sythesisinhibition and prolongs the intracellular retention of thedrug [1, 2].Neurotoxicity associated with methotrexate includesheadaches, nausea, emesis, lethargy, blurred vision, apha-sia, hemiparesis, paresis, convulsions and arachnoiditis.Leukoencephalopathy can occur acutely or as a chronictoxic effect, especially if high-doses, multiple treatmentsor radiotherapy are also administered [3, 4]. The inci-dence varies with the route of administration, with lessthan 10% of those treated intravenously developing leu-koencephalopathy compared with up to 40% of patientstreated intrathecally in combination with intravenoustherapy [5, 6]. Leukoencephalopathy has even been de-scribed in patients taking low-dose weekly methotrexatefor the treatment of rheumatoid arthritis [7].There is an increase in adenosine in the cerebrospinalfluid in patients who develop methotrexate-induced neu-rotoxicity [1]. Because adenosine dilates cerebral bloodvessels, alters neurotransmitter release and postsynapticresponses, and slows the discharge rate of neurones, it ispossible that raised adenosine levels account for some ofthe neurotoxicity of methotrexate. Aminophylline, amethylxanthine, acts as a competitive adenosine antago-nist and has been reported to relieve neurological toxici-ties following methotrexate administration [1, 2].Folinic acid rescue is standard therapy following high-dose intravenous methotrexate to prevent toxicity. High-dose folinic acid, in addition to standard folinic acid res-cue, has been reported to relieve methotrexate-inducedleukoencephalopathy following intravenous and intrathe-cal methotrexate [8].A 20-year-old female university student presented inSeptember 2000 with symptoms of bone marrow failure,circulating lymphoblasts in the peripheral blood and adiagnosis of standard risk precursor B cell ALL was made.Induction therapy with the LALA 94 protocol [9] wascommenced which includes intrathecal methotrexate15 mg, cytosine arabinoside 40 mg and hydrocortisone50 mg on day 1, 3, 8, 15 and 22 of the treatment schedule.Initial cerebrospinal fluid examination was negative formalignant cells. On day 19 the patient developed a rapiddeterioration in conscious state with diminished verbaloutput and behavioural changes. The patient was able tofollow simple one-stage commands only. There were nosigns of meningism and no facial asymmetry. Extra-ocularmuscle movements were normal with normal appearingfundi. The reflexes were sluggish with bilateral Babinski