Skip to main content
Advertisement

Main menu

  • Home
  • Content
    • Current Issue
    • Publication Preview--Ahead of Print
    • Past Issue Archive
    • Case of the Week Archive
    • Classic Case Archive
    • Case of the Month Archive
    • COVID-19 Content and Resources
  • For Authors
  • About Us
    • About AJNR
    • Editors
    • American Society of Neuroradiology
  • Submit a Manuscript
  • Podcasts
    • Subscribe on iTunes
    • Subscribe on Stitcher
  • More
    • Subscribers
    • Permissions
    • Advertisers
    • Alerts
    • Feedback
  • Other Publications
    • ajnr

User menu

  • Subscribe
  • Alerts
  • Log in

Search

  • Advanced search
American Journal of Neuroradiology
American Journal of Neuroradiology

American Journal of Neuroradiology

  • Subscribe
  • Alerts
  • Log in

Advanced Search

  • Home
  • Content
    • Current Issue
    • Publication Preview--Ahead of Print
    • Past Issue Archive
    • Case of the Week Archive
    • Classic Case Archive
    • Case of the Month Archive
    • COVID-19 Content and Resources
  • For Authors
  • About Us
    • About AJNR
    • Editors
    • American Society of Neuroradiology
  • Submit a Manuscript
  • Podcasts
    • Subscribe on iTunes
    • Subscribe on Stitcher
  • More
    • Subscribers
    • Permissions
    • Advertisers
    • Alerts
    • Feedback
  • Follow AJNR on Twitter
  • Visit AJNR on Facebook
  • Follow AJNR on Instagram
  • Join AJNR on LinkedIn
  • RSS Feeds
Case ReportCase Report

Magnetization Transfer Imaging Provides No Evidence of Demyelination in Methotrexate-Induced Encephalopathy

F.R. Miese, F.R. Schuster, K. Pierstorff, M. Karenfort, H.J. Laws, A. Borkhardt and A. Saleh
American Journal of Neuroradiology June 2011, 32 (6) E110-E112; DOI: https://doi.org/10.3174/ajnr.A2181
F.R. Miese
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
F.R. Schuster
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
K. Pierstorff
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
M. Karenfort
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
H.J. Laws
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
A. Borkhardt
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
A. Saleh
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • References
  • PDF
Loading

Abstract

SUMMARY: Subacute MTX-induced encephalopathy is characterized by an abrupt onset of focal neurologic deficits within days after intrathecal or systemic therapy. Demyelination is one proposed mechanism. We describe the neuroimaging features of 2 patients with clinical symptoms of subacute encephalopathy after intrathecal and systemic MTX therapy. DWI showed restricted diffusion, indicating cytotoxic edema. MTI yielded no evidence of demyelination in either patient because there was no loss of MTR in areas of restricted diffusion.

Abbreviations

ADC
apparent diffusion coefficient
ALL
acute lymphoblastic leukemia
DWI
diffusion-weighted imaging
IT
intrathecal
IV
intravenous
MTI
magnetization transfer imaging
MTR
magnetization transfer ratio
MTX
methotrexate

In the prophylaxis of central nervous system leukemia, IT MTX has largely replaced cranial irradiation and has lead to improved survival outcomes.1 Toxic effects of MTX include mucositis, myelosuppression, nephrotoxicity, hepatotoxicity, and neurotoxicity with acute (within hours), subacute (days to weeks after administration), and chronic (after months and years) encephalopathy.2

Subacute MTX-induced encephalopathy is characterized by a delayed onset of strokelike symptoms, such as aphasia, hemiparesis, and ataxia. Complete resolution of symptoms after therapy is usually seen in patients with encephalopathy. The pathophysiology of MTX-induced encephalopathy is incompletely understood. Demyelination and adenosine release have been proposed to contribute to the development of the disease.3–5

DWI has been used to diagnose cytotoxic edema in subacute MTX-induced encephalopathy6 but does not assess demyelination. MTI is a diagnostic tool known to be sensitive to demyelination.7 We report on 2 cases of subacute MTX- induced encephalopathy following IT MTX therapy in pediatric patients with ALL, who presented with typical neuroimaging without signs of demyelination on MTI.

Case Reports

Patient 1, a 13-year-old girl with biphenotypic ALL, received chemotherapy according to the COALL-07–03 protocol (high-risk standard).8 Twelve days after the third treatment with 12 mg of IT MTX, she developed prickling sensations and a central facial nerve paresis on the right side.

Conventional MR imaging showed changes on T2-weighted imaging with faint hyperintensity of the white matter in both hemispheres. DWI hyperintensity and low ADC were observed in the centrum semiovale of both hemispheres, corresponding to restricted diffusion.

MTI used two 2D gradient-echo sequences. The first acquisition had no saturation pulse. The second used a saturation pulse 1.2 kHz below H2O frequency. The MTR is the percentage of signal-intensity loss induced: MTR = (S0 − Ss) / S0 × 100%, where S0 is the signal intensity of a pixel obtained from the sequence without the saturation pulse and SS is the signal intensity with the saturation pulse.

MTR maps showed symmetric values of the white matter, and there was no loss of MTR in areas of DWI or T2 hyperintensity (Fig 1). Contrast-enhanced T1-weighted images and time-of-flight angiography findings were normal.

Fig 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig 1.

A, Diffusion-weighted image shows bilateral white matter hyperintensity. B, ADC map with low ADC is suggestive of cytotoxic edema. C, T2-weighted image shows white matter hyperintensity. D, MTR map shows normal white matter without signs of demyelination.

Treatment with 600-mg vitamin B6, 50-mg vitamin B12, and 2 × 80 mg of tetrahydrobiopterin per day was started. Her neurologic status improved quickly. Seven days later, no more neurologic problems could be detected.

Patient 2, an 11-year-old girl, was treated with the protocol ALL-BFM 20009 for central nervous system negative precursor ALL. Ten days after the third series of high-dose IT MTX, the patient developed inarticulate speech, paraesthesia of the left arm and leg, and a hemiparesis of the left body. Cranial MR imaging showed a focal hyperintensity on T2-weighted images in the left centrum semiovale and restricted diffusion, 3.5 hours after the onset of symptoms. MTI findings were normal, with symmetric and homogeneous MTR of the white matter of both hemispheres (Fig 2).

Fig 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig 2.

A, Diffusion-weighted image shows bilateral white matter hyperintensity. B, ADC map shows low ADC, suggestive of cytotoxic edema. C, T2-weighted image shows white matter hyperintensity. D, MTR map shows normal white matter without signs of demyelination.

The treatment started with 600-mg theophylline, 600-mg vitamin B6, and 100-μg vitamin B12 per day and 30-mg folic acid every 6 hours. Due to clinical deterioration, the treatment with theophylline was discontinued the next day and a tetrahydrobiopterin therapy was initiated. Vitamin B12 and B6 were continued. Within a few days, the symptoms vanished. The treatment continued according the ALL-BFM 2000 protocol without any further MTX therapy.

Discussion

Subacute MTX-induced encephalopathy is a rare complication after chemotherapy including systemic or IT MTX in pediatric patients with cancer. The acute onset of focal neurologic deficits within days after chemotherapy with vincristine and intravenous high-dose MTX was first described in 1978 in children receiving chemotherapy for osteosarcoma.10 MTX encephalopathy has an incidence of 1%–3%11 in association with high-dose MTX and IT MTX therapy in children with ALL.12 Symptoms include hemiparesis, bilateral weakness, dysphasia, confusion, and movement disorders. Symptoms may fluctuate and spread to involve both hemispheres.6 Resolution of neurologic symptoms usually occurs within days.

DWI hyperintensity with low ADC was typical in subacute MTX-induced encephalopathy.6 T2 hyperintensity developing in several days has been reported to be irreversible in some cases.12 To the best of our knowledge, no reports of MTI in this condition are available in the literature. Our imaging findings are consistent with cytotoxic edema in both cases. The absence of vascular pathology and the patients' symptoms within 14 days after IT MTX are in accordance with subacute MTX-induced encephalopathy.

The pathogenesis of subacute MTX-induced encephalopathy remains incompletely understood. Demyelination has been a proposed mechanism in the development of this condition3,4 based on a study by Chu et al,5 who reported increased choline/creatine ratios in MR spectroscopy 20 weeks after combined IV-IT MTX in children treated for ALL, interpreted to be indicative of a myelinization disorder. Conversely, Davidson et al13 found low choline/water ratios after high-dose IV MTX, reported to reflect disturbances of myelin metabolism.

We used the MTR in our patients as a means of imaging known to be sensitive to demyelination.7 In a number of demyelinating conditions, such as multiple sclerosis,14 experimentally induced demyelination in vitro,15 and neuropsychiatric systemic lupus erythematodes,16 studies have demonstrated the decrease of MTR.

Our cases revealed no differences in the MTR between white matter areas with and without cytotoxic edema. We conclude that subacute MTX-induced encephalopathy may not be the result of toxic demyelination.

Footnotes

  • F.R. Miese and F.R. Schuster contributed equally to the report. Report concept and design and data acquisition and analysis/interpretation; manuscript revision for intellectual content and approval of the final version of the submitted manuscript: F.R. Miese, F.R. Schuster, K. Pierstorff, M. Karenfort, H.-J. Laws, A. Borkhardt and A. Saleh. Manuscript drafting: F.R. Miese, F.R. Schuster. Guarantor of the integrity of the entire study: A. Saleh. Literature research, MR imaging studies analysis, and manuscript editing: F.R. Miese, F.R. Schuster, M. Karenfort, H.-J. Laws, A. Borkhardt, and A. Saleh.

References

  1. 1.↵
    1. Carroll WL,
    2. Bhojwani D,
    3. Min DJ,
    4. et al
    . Pediatric acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2003:102–31
  2. 2.↵
    1. Quinn CT,
    2. Kamen BA
    . A biochemical perspective of methotrexate neurotoxicity with insight on nonfolate rescue modalities. J Investig Med 1996;44:522–30
    PubMed
  3. 3.↵
    1. Eichler AF,
    2. Batchelor TT,
    3. Henson JW
    . Diffusion and perfusion imaging in subacute neurotoxicity following high-dose intravenous methotrexate. Neuro Oncol 2007;9:373–77
    Abstract/FREE Full Text
  4. 4.↵
    1. Sandoval C,
    2. Kutscher M,
    3. Jayabose S,
    4. et al
    . Neurotoxicity of intrathecal methotrexate: MR imaging findings. AJNR Am J Neuroradiol 2003;24:1887–90
    Abstract/FREE Full Text
  5. 5.↵
    1. Chu WC,
    2. Chik KW,
    3. Chan YL,
    4. et al
    . White matter and cerebral metabolite changes in children undergoing treatment for acute lymphoblastic leukemia: longitudinal study with MR imaging and 1H MR spectroscopy. Radiology 2003;229:659–69
    CrossRefPubMed
  6. 6.↵
    1. Baehring JM,
    2. Fulbright RK
    . Delayed leukoencephalopathy with stroke-like presentation in chemotherapy recipients. J Neurol Neurosurg Psychiatry 2008;79:535–39
    Abstract/FREE Full Text
  7. 7.↵
    1. McGowan JC,
    2. Filippi M,
    3. Campi A,
    4. et al
    . Magnetisation transfer imaging: theory and application to multiple sclerosis. J Neurol Neurosurg Psychiatry 1998;64(suppl 1):S66–69
    PubMed
  8. 8.↵
    1. Escherich G,
    2. Horstmann MA,
    3. Zimmermann M,
    4. et al
    . Cooperative study group for childhood acute lymphoblastic leukaemia (COALL): long-term results of trials 82,85,89,92 and 97. Leukemia 2010;24:298–308
    CrossRefPubMed
  9. 9.↵
    1. Möricke A,
    2. Zimmermann M,
    3. Reiter A,
    4. et al
    . Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 2010;24:265–84
    CrossRefPubMed
  10. 10.↵
    1. Allen JC,
    2. Rosen G
    . Transient cerebral dysfunction following chemotherapy for osteogenic sarcoma. Ann Neurol 1978;3:441–44
    CrossRefPubMed
  11. 11.↵
    1. Dufourg MN,
    2. Landman-Parker J,
    3. Auclerc MF,
    4. et al
    . Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children. Leukemia 2007;21:238–47. Epub 2006 Dec 14
    CrossRefPubMed
  12. 12.↵
    1. Inaba H,
    2. Khan RB,
    3. Laningham FH,
    4. et al
    . Clinical and radiological characteristics of methotrexate-induced acute encephalopathy in pediatric patients with cancer. Ann Oncol 2008;19:178–84
    Abstract/FREE Full Text
  13. 13.↵
    1. Davidson A,
    2. Payne G,
    3. Leach MO,
    4. et al
    . Proton magnetic resonance spectroscopy ((1)H-MRS) of the brain following high-dose methotrexate treatment for childhood cancer. Med Pediatr Oncol 2000;35:28–34
    CrossRefPubMed
  14. 14.↵
    1. Giacomini PS,
    2. Levesque IR,
    3. Ribeiro L,
    4. et al
    . Measuring demyelination and remyelination in acute multiple sclerosis lesion voxels. Arch Neurol 2009;66:375–81
    CrossRefPubMed
  15. 15.↵
    1. Odrobina EE,
    2. Lam TY,
    3. Pun T,
    4. et al
    . MR properties of excised neural tissue following experimentally induced demyelination. NMR Biomed 2005;18:277–84
    CrossRefPubMed
  16. 16.↵
    1. Emmer BJ,
    2. Steens SC,
    3. Steup-Beekman GM,
    4. et al
    . Detection of change in CNS involvement in neuropsychiatric SLE: a magnetization transfer study. J Magn Reson Imaging 2006;24:812–16
    CrossRefPubMed
  • Received April 14, 2010.
  • Accepted after revision April 16, 2010.
  • Copyright © American Society of Neuroradiology
View Abstract
PreviousNext
Back to top

In this issue

American Journal of Neuroradiology: 32 (6)
American Journal of Neuroradiology
Vol. 32, Issue 6
1 Jun 2011
  • Table of Contents
  • Index by author
Advertisement
Print
Download PDF
Email Article

Thank you for your interest in spreading the word on American Journal of Neuroradiology.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Magnetization Transfer Imaging Provides No Evidence of Demyelination in Methotrexate-Induced Encephalopathy
(Your Name) has sent you a message from American Journal of Neuroradiology
(Your Name) thought you would like to see the American Journal of Neuroradiology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Magnetization Transfer Imaging Provides No Evidence of Demyelination in Methotrexate-Induced Encephalopathy
F.R. Miese, F.R. Schuster, K. Pierstorff, M. Karenfort, H.J. Laws, A. Borkhardt, A. Saleh
American Journal of Neuroradiology Jun 2011, 32 (6) E110-E112; DOI: 10.3174/ajnr.A2181

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Magnetization Transfer Imaging Provides No Evidence of Demyelination in Methotrexate-Induced Encephalopathy
F.R. Miese, F.R. Schuster, K. Pierstorff, M. Karenfort, H.J. Laws, A. Borkhardt, A. Saleh
American Journal of Neuroradiology Jun 2011, 32 (6) E110-E112; DOI: 10.3174/ajnr.A2181
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One
Purchase

Jump to section

  • Article
    • Abstract
    • Abbreviations
    • Case Reports
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • References
  • PDF

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Cited By...

  • No citing articles found.
  • Crossref
  • Google Scholar

This article has not yet been cited by articles in journals that are participating in Crossref Cited-by Linking.

More in this TOC Section

  • Atypical Diffusion-Restricted Lesion in 5-Fluorouracil Encephalopathy
  • Dural Infantile Hemangioma Masquerading as a Skull Vault Lesion
  • Multimodal Imaging of Spike Propagation: A Technical Case Report
Show more Case Reports

Similar Articles

Advertisement

News and Updates

  • Lucien Levy Best Research Article Award
  • Thanks to our 2022 Distinguished Reviewers
  • Press Releases

Resources

  • Evidence-Based Medicine Level Guide
  • How to Participate in a Tweet Chat
  • AJNR Podcast Archive
  • Ideas for Publicizing Your Research
  • Librarian Resources
  • Terms and Conditions

Opportunities

  • Share Your Art in Perspectives
  • Get Peer Review Credit from Publons
  • Moderate a Tweet Chat

American Society of Neuroradiology

  • Neurographics
  • ASNR Annual Meeting
  • Fellowship Portal
  • Position Statements

© 2023 by the American Society of Neuroradiology | Print ISSN: 0195-6108 Online ISSN: 1936-959X

Powered by HighWire