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

doi:10.3174/ajnr.A2181

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 − S_s) / S₀ × 100%, where S₀ is the signal intensity of a pixel obtained from the sequence without the saturation pulse and S_S 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.

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.

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 condition^3,4 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.

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Received April 14, 2010.
Accepted after revision April 16, 2010.

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[1] 1.↵
Carroll WL,
Bhojwani D,
Min DJ,
et al
. Pediatric acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2003:102–31

[2] Carroll WL,

[3] Bhojwani D,

[4] Min DJ,

[5] et al

[6] 2.↵
Quinn CT,
Kamen BA
. A biochemical perspective of methotrexate neurotoxicity with insight on nonfolate rescue modalities. J Investig Med 1996;44:522–30
PubMed

[7] Quinn CT,

[8] Kamen BA

[9] 3.↵
Eichler AF,
Batchelor TT,
Henson JW
. Diffusion and perfusion imaging in subacute neurotoxicity following high-dose intravenous methotrexate. Neuro Oncol 2007;9:373–77
Abstract/FREE Full Text

[10] Eichler AF,

[11] Batchelor TT,

[12] Henson JW

[13] 4.↵
Sandoval C,
Kutscher M,
Jayabose S,
et al
. Neurotoxicity of intrathecal methotrexate: MR imaging findings. AJNR Am J Neuroradiol 2003;24:1887–90
Abstract/FREE Full Text

[14] Sandoval C,

[15] Kutscher M,

[16] Jayabose S,

[17] et al

[18] 5.↵
Chu WC,
Chik KW,
Chan YL,
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
CrossRef PubMed

[19] Chu WC,

[20] Chik KW,

[21] Chan YL,

[22] et al

[23] 6.↵
Baehring JM,
Fulbright RK
. Delayed leukoencephalopathy with stroke-like presentation in chemotherapy recipients. J Neurol Neurosurg Psychiatry 2008;79:535–39
Abstract/FREE Full Text

[24] Baehring JM,

[25] Fulbright RK

[26] 7.↵
McGowan JC,
Filippi M,
Campi A,
et al
. Magnetisation transfer imaging: theory and application to multiple sclerosis. J Neurol Neurosurg Psychiatry 1998;64(suppl 1):S66–69
PubMed

[27] McGowan JC,

[28] Filippi M,

[29] Campi A,

[30] et al

[31] 8.↵
Escherich G,
Horstmann MA,
Zimmermann M,
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
CrossRef PubMed

[32] Escherich G,

[33] Horstmann MA,

[34] Zimmermann M,

[35] et al

[36] 9.↵
Möricke A,
Zimmermann M,
Reiter A,
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
CrossRef PubMed

[37] Möricke A,

[38] Zimmermann M,

[39] Reiter A,

[40] et al

[41] 10.↵
Allen JC,
Rosen G
. Transient cerebral dysfunction following chemotherapy for osteogenic sarcoma. Ann Neurol 1978;3:441–44
CrossRef PubMed

[42] Allen JC,

[43] Rosen G

[44] 11.↵
Dufourg MN,
Landman-Parker J,
Auclerc MF,
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
CrossRef PubMed

[45] Dufourg MN,

[46] Landman-Parker J,

[47] Auclerc MF,

[48] et al

[49] 12.↵
Inaba H,
Khan RB,
Laningham FH,
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

[50] Inaba H,

[51] Khan RB,

[52] Laningham FH,

[53] et al

[54] 13.↵
Davidson A,
Payne G,
Leach MO,
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
CrossRef PubMed

[55] Davidson A,

[56] Payne G,

[57] Leach MO,

[58] et al

[59] 14.↵
Giacomini PS,
Levesque IR,
Ribeiro L,
et al
. Measuring demyelination and remyelination in acute multiple sclerosis lesion voxels. Arch Neurol 2009;66:375–81
CrossRef PubMed

[60] Giacomini PS,

[61] Levesque IR,

[62] Ribeiro L,

[63] et al

[64] 15.↵
Odrobina EE,
Lam TY,
Pun T,
et al
. MR properties of excised neural tissue following experimentally induced demyelination. NMR Biomed 2005;18:277–84
CrossRef PubMed

[65] Odrobina EE,

[66] Lam TY,

[67] Pun T,

[68] et al

[69] 16.↵
Emmer BJ,
Steens SC,
Steup-Beekman GM,
et al
. Detection of change in CNS involvement in neuropsychiatric SLE: a magnetization transfer study. J Magn Reson Imaging 2006;24:812–16
CrossRef PubMed

[70] Emmer BJ,

[71] Steens SC,

[72] Steup-Beekman GM,

[73] et al

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

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

Abstract

Abbreviations

Case Reports

Discussion

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References

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