Methotrexate-related leukoencephalopathy

Last revised by Rohit Sharma on 20 Mar 2023

Methotrexate-related leukoencephalopathy, resulting from the administration of methotrexate, is an uncommon yet important type of toxic encephalopathy. Methotrexate is administered via oral, intravenous, or intrathecal routes for many clinical indications, but its use as a chemotherapy agent for hematological and other malignancies is particularly relevant in regard to its neurotoxic effects. Neurotoxicity related to methotrexate can manifest in a spectrum of acute and chronic leukoencephalopathies 1,2, and while acute manifestations tend to be transient, chronic methotrexate-related encephalopathy can result in permanent neurological deficits 1.

Methotrexate-related leukoencephalopathy most often occurs in pediatric patients during treatment for acute lymphoblastic leukemia but can occur in patients of any age with other indications for methotrexate administration 1,2.

The risk of developing acute leukoencephalopathy appears to be dose-dependent 1,3. High-dose intravenous methotrexate, such as that used for malignancies, has been associated with the development of acute leukoencephalopathy in ~10% (range 3-15%) of cases, with recurrence rates of 10-56% if therapy is continued 2. Intrathecal administration is associated with an even higher increased risk of acute leukoencephalopathy when compared to high-dose intravenous administration 1.

Acute methotrexate-related leukoencephalopathy often manifests 2-14 days after administration, with clinical features similar to other encephalopathies 1,4. These clinical features develop over minutes to hours, with common manifestations including a headache, confusion, disorientation, lethargy, seizures, and focal neurological deficits that may be unilateral or bilateral 1,2,5. Of note, and unlike many other encephalopathies, these clinical features often 'wax and wane' over the course of the disease 2. For example, focal neurological deficits may initially manifest on one side of the body and then 'alternate' to affect the other side of the body later 2.

While this acute syndrome is transient, with recovery occurring within 1-7 days of symptom onset, chronic methotrexate-related leukoencephalopathy develops more slowly and ultimately results in permanent focal neurological deficits 1.

In addition to causing neurotoxicity, methotrexate is also associated with myelosuppression, mucositis, lung disease, nephrotoxicity, and hepatotoxicity 1.

Methotrexate (C20H22N8O5) is a cell cycle-specific folate analog, that in malignancy, works by competitively inhibiting dihydrofolate reductase and thus, depleting DNA precursors 1,6. However, the mechanism by which methotrexate causes leukoencephalopathy is unclear 2. It has been postulated that methotrexate has a role in promoting the release of adenosine which is known to play a role in dilating cerebral blood vessels, altering neuronal function, and causing transient cytotoxic edema 1,2.

Generally, there are no CT or MRI features that are characteristic of acute methotrexate-related leukoencephalopathy when compared to other toxic encephalopathies 2

CT changes are non-specific, primarily demonstrating low attenuation in the white matter of both cerebral hemispheres 1,2

Generally, patients have transient diffuse high signal in the centrum semiovale, initially sparing subcortical U-fibers, as seen on T2-weighted and FLAIR sequences 1,2. These changes may be unilateral, bilateral, or alternating between the two over the course of the disease 1,2. These changes are quite non-specific.

However, what does seem promising as a characteristic radiological marker are the changes appreciated on DWI, indicative of cytotoxic edema 2. DWI will often demonstrate regions of true restricted diffusion across multiple vascular territories in the centrum semiovale, again either unilateral, bilateral, or alternating, that eventually disappear after symptom resolution 1,2. These DWI changes are thought to be reliable and early signs of acute methotrexate-related leukoencephalopathy 2.  

On post gadolinium MR images, abnormal contrast enhancement may or may not be seen 9.

Evidence-based management of acute methotrexate-related leukoencephalopathy is limited.

Case series-level evidence suggests that aminophylline, a non-selective adenosine receptor agonist, and leucovorin, an active form of folinic acid, may be beneficial in isolation or in combination for acute leukoencephalopathy 2,7,8. It is uncertain whether these agents have any role in prophylaxis, although leucovorin is often part of many methotrexate-containing chemotherapy regimens 2. Symptomatic therapy is also recommended, such as antiseizure agents in patients with seizures 2.

The decision to restart methotrexate therapy should be made on a case-by-case basis depending on the severity of the leukoencephalopathy, an assessment of risks and benefits, and a discussion with the patient and/or their family 2.

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