Dextromethorphan and Methylxanthines Might Be Useful in the Treatment of Methotrexate-Induced Neurotoxicity

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To the Editors:
We read with interest the article “Evaluation and Management of Acute-Onset Hemiparesis in an Adolescent With Leukemia” by Subrahmanian et al.1 The authors report a 15-year-old boy with delayed-onset methotrexate (MTX) neurotoxicity. The patient had normal MTX clearance, and his serum MTX level was undetectable. He received intravenous fluids and leucovorin rescue. We would like to make several comments about other possible additional treatments.
As the authors note, a potential mechanism of MTX-induced neurotoxicity is the accumulation of adenosine in the central nervous system (CNS). In this context, methylxanthines might be useful on the basis of their ability to displace adenosine from receptors in the CNS. In 1 study,2 after or during a 1-hour infusion of aminophylline, 4 of 6 patients had complete resolution of symptoms of neurotoxicity that had not improved after other measures. Infusion of aminophylline seems to be a safe and easy-to-administer treatment.3,4
Methotrexate exerts its antileukemic action via inhibition of the enzyme dihydrofolate reductase, ultimately reducing the amount of tetrahydrofolate available for DNA synthesis leading to cell death. Depletion of 5-methyltetrahydrofolate leads to the disruption of the remethylation of homocysteine to methionine, and elevated levels of homocysteine in the plasma5,6 and cerebrospinal fluid7,8 have been reported in patients who received high-dose MTX and have clinical evidence of CNS neurotoxicity. Homocysteine and its metabolites, as homocysteic acid, are excitatory agonists of N-methyl-D-aspartate (NMDA) receptors.9 Dextromethorphan (DM) is a drug that acts as a noncompetitive antagonist of NMDA receptors and has also been used in the treatment of MTX neurotoxicity. In 1 study,8 in 5 patients with severe subacute toxicity who were treated with 1 to 2 mg/kg per day of oral DM, all 5 had resolution of symptoms. In a larger study,10 involving 18 patients treated with 1 to 3 mg/kg per day of DM, 16 of the patients fully recovered. Symptoms of acute neurotoxicity typically occur within 24 hours. In this retrospective study,10 patients who received DM within the first 24 hours of becoming symptomatic exhibited improvement 4 times faster as compared with patients who had a delay of 24 hours or more in receiving DM. Although future prospective studies will be needed to investigate the role of DM and methylxanthines in reversing or preventing MTX neurotoxicity, the administration of these drugs can be an easy-to-administer additional treatment.
On the other hand, as the presented case illustrates,1 the neurotoxic effects of anticancer therapy can be lifelong. In an experimental model of MTX-induced cognitive deficits,11 intrathecal MTX induced persistent alterations in glutaminergic tone that might contribute to persistent cognitive deficits. In this model, this noncompetitive antagonist at the NMDA receptor was useful to improve the cognitive function. These experimental models will improve our understanding of the pathogenesis of MTX-induced neurotoxicity and can be useful to identify a subset of patients who might derive the greatest benefit from other interventions aimed at reducing MTX neurotoxicity.

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