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Table of Contents
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 261-262

Methotrexate leukoencephalopathy

1 Department of Medical Oncology, Adult Hematolyphoid Unit, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India

Date of Web Publication20-Dec-2019

Correspondence Address:
Jayashree Thorat
81, Main Building, Department of Medical Oncology, Adult Hematolyphoid Unit, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra; Homi Bhabha National Institute, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_73_19

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How to cite this article:
Majumdar S, Goli VB, Thorat J. Methotrexate leukoencephalopathy. Cancer Res Stat Treat 2019;2:261-2

How to cite this URL:
Majumdar S, Goli VB, Thorat J. Methotrexate leukoencephalopathy. Cancer Res Stat Treat [serial online] 2019 [cited 2020 Apr 3];2:261-2. Available from: http://www.crstonline.com/text.asp?2019/2/2/261/273688

Methotrexate (MTX) used in various forms is an essential component of the treatment of acute lymphoblastic leukemia (ALL). MTX is a dihydrofolate reductase inhibitor. High-dose MTX (HDMTX) has several pharmacokinetic advantages. High doses enable an increased entry into the cancer cells, retention in the cells, and better penetration of the sanctuary sites. HDMTX comes with its own side effects, mainly mucositis, myelosuppression, and nephro- and neurotoxicities. Mahajan et al. reported their experience of neurotoxicity in adolescent and adult patients and described the radiological findings. Of the 188 patients, 11 (6%) who received HDMTX (1–3 g/m2) developed subacute encephalopathy. The syndrome was identified by a combination of clinical and radiological features.[1]

A neurological event that presents during anticancer therapy can be due to infections, drug toxicities, disease recurrence, or vascular insult.[2],[3] Careful history, examination, neuroimaging, and cerebrospinal fluid analysis can help ascertain the etiology. Mahajan et al. highlighted that computerized tomography scans can be normal and that a magnetic resonance (MR) imaging is helpful. Because the key finding is due to cytotoxic edema, the imaging shows restricted diffusion. This has been reported earlier by various groups. Mahajan et al. have also reported that the radiological appearance resembled a panda-eye sign in seven of these cases. This finding could be helpful in the clinical context.

The literature on MTX-induced leukoencephalopathy is mainly from the childhood ALL cohort. Inaba et al. and Bhojwani et al. have reported an incidence of 0.8% and 3.8%, respectively.[4],[5] In the study by Bhojwani et al., routine MR imaging was done at four time points during therapy and they demonstrated that 20% of asymptomatic patients had imaging findings of leukoencephalopathy. This highlights the importance of relying on both clinical and radiological features for a correct diagnosis. The complication is completely reversible as reported by Mahajan et al. and the other groups, even though residual imaging findings may persist.

A 6% risk of neurological complication is too high to accept in this curative setting; several factors are related to its occurrence. There is a correlation with the doses used, leucovorin doses, and polymorphisms in the genes that are essential for neurogenesis. However, till date, there is no effective strategy to predict the risk or avoid the complication altogether.

The issue with the use of HDMTX is that we do not know for certain as to what dose is optimal, which schedule should be preferred – infusional or bolus. The dose selection is not based on strong evidence. In ALL and other high-grade lymphomas, there is enough evidence that it is the sustained MTX level that is more important than the peak level. Studies with lower doses and different schedules (bolus or oral) have shown similar efficacy with lesser toxicities.[6] There is a need to explore these regimens in the context of randomized trials. This will not only reduce the toxicities but also overcome the logistic issues associated with HDMTX administration.

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  References Top

Mahajan A, Jain H, Simha V, Vaidya T, Santhosh Kumar GV, Gupta A, et al. Clinical–radiological features of methotrexate-induced subacute leukoencephalopathy in patients with acute lymphoblastic leukemia: “Panda eye sign” on diffusion weighted-magnetic resonance imaging. Cancer Res Stat Treat 2019;2:28-33.  Back to cited text no. 1
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Gupta A, Noronha V, Prabhash K, Joshi A, Patil V, Mahajan A. Cystic brain lesions: Guess the mess. Cancer Res Stat Treat 2018;1:163-6.  Back to cited text no. 2
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Khaddar S, Patil VM, Noronha V, Joshi A, Menon N, Prabhash K. Delirium and seizures in a patient with head-and-neck squamous cell carcinoma on docetaxel, cisplatin, and 5-fluorouracil. Cancer Res Stat Treat 2019;2:105-7.  Back to cited text no. 3
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Inaba H, Khan RB, Laningham FH, Crews KR, Pui CH, Daw NC. Clinical and radiological characteristics of methotrexate-induced acute encephalopathy in pediatric patients with cancer. Ann Oncol 2008;19:178-84.  Back to cited text no. 4
Bhojwani D, Sabin ND, Pei D, Yang JJ, Khan RB, Panetta JC, et al. Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol 2014;32:949-59.  Back to cited text no. 5
Mantadakis E, Cole PD, Kamen BA. High-dose methotrexate in acute lymphoblastic leukemia: Where is the evidence for its continued use? Pharmacotherapy 2005;25:748-55.  Back to cited text no. 6


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