ARTICLE IN PRESS Case Report Subacute Methotrexate Encephalopathy Mimicking Ischemic Stroke With Dynamic Changes on Magnetic Resonance Imaging Kei Yamanaka, MD,*,† Takuya Okata, MD,* Yoshiki Sambongi, MD,* Ikumi Yamanaka, MD,‡ Kazuki Tanimoto, MD, PhD,‡ Tetsuro Ago, MD, PhD,† Takanari Kitazono, MD, PhD,† and Jiro Kitayama, MD, PhD* We report a 35-year-old woman who suddenly developed left hemiparesis and dysarthria at 13 days after treatment with intrathecal and intravenous methotrexate for intravascular large B cell lymphoma with possible central nervous system infiltration. Seven hours after onset, she developed further right hemiparesis and aphasia. However, the majority of neurologic symptoms disappeared spontaneously and completely by 34 hours. We also recorded the dynamic progression and regression of abnormal signals in the bilateral corona radiata on diffusion-weighted imaging, in parallel with neurologic symptoms. The rapid reversal of MR abnormalities and neurologic symptoms allowed us to diagnose methotrexate encephalopathy, and exclude intravascular large B cell lymphoma recurrence and regular brain infarction. The case provides new data on the dynamic changes of abnormal signals on magnetic resonance imaging in methotrexate encephalopathy over a short recovery time. Key Words: Demyelination—diffusion-weighted image—encephalopathy— intravascular lymphoma—methotrexate—stroke-mimic © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved. Introduction Methotrexate (MTX) is a common anti-cancer or immunomodulatory drug, which interferes with dihydrofolate reductase that converts dihydrofolate to tetrahydrofolate, the active form of folate. As tetrahydrofolate is critical for various metabolic pathways, including DNA/RNA From the *Department of Neurology, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan; †Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and ‡Department of Hematology and Oncology, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan. Received May 18, 2018; revision received May 27, 2018; accepted June 8, 2018. Grant support: The study received no funding or support. Address correspondence to Kei Yamanaka, MD, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: kei-y@intmed2.med.kyushu-u.ac.jp 1052-3057/$ - see front matter © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.06.007 synthesis, amino acid synthesis, and DNA/protein methylation, MTX can inhibit various biological responses. Indeed, intrathecal or high-dose administration of MTX can cause subacute encephalopathy, including demyelination and axonal swelling.1 As the encephalopathy often develops as a stroke-mimic, immediate differentiation of the encephalopathy from ischemic stroke and other stroke-mimics is important. High-intensity areas related to MTX encephalopathy, usually found in the deep white matter, are often reversible on diffusion-weighted images (DWI). Herein, we report a case of MTX encephalopathy where repeated magnetic resonance imaging (MRI) was useful for early diagnosis, and present the dynamic progression and regression of abnormal DWI signals in parallel with neurologic symptoms. Case Report We report a 35-year-old woman who was diagnosed with intravascular large B cell lymphoma (IVLBCL) with possible central nervous system (CNS) infiltration. She received a combination chemotherapy of rituximab, Journal of Stroke and Cerebrovascular Diseases, Vol. &&, No. && (&&), 2018: pp 1-3 1 ARTICLE IN PRESS K. YAMANAKA ET AL. 2 Figure 1. Time course of magnetic resonance images at 3, 7, and 34 hours, and 10, 30, and 180 days, after symptom onset. Diffusion-weighted images (DWI) showed a high-intensity area in the right corona radiata at 3 hours after onset, followed by a progressive increase in signal intensity and the development of a new lesion in the left corona radiata at 7 hours. The bilateral lesion showed a low intensity apparent diffusion coefficient (ADC) signal. The bilateral abnormal signals on DWI and ADC were gradually attenuated after 7 hours. The lesions showed high intensity fluid-attenuated inversion recovery signals on day 10, which then attenuated on follow-up imaging. cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), with administration of intravenous (1.0 mg/m2) and intrathecal (15 mg) MTX to prevent the recurrence of CNS IVLBCL. She suddenly presented with left hemiparesis and dysarthria at 13 days after the second course of the chemotherapy. DWI showed a high-intensity area in the right corona radiata with low apparent diffusion coefficient at 3 hours after onset of symptoms, while fluid-attenuated inversion recovery (FLAIR) images and magnetic resonance angiography showed no remarkable abnormality (Fig 1). Seven hours after onset, she developed further right hemiparesis and aphasia. A further high-intensity area appeared in the left corona radiata on DWI, with significant enlargement of the right corona radiata area. However, her symptoms started regressing at 21 hours after onset, and completely disappeared at 72 hours, with significant attenuation of the high-intensity DWI signals, but appearance of abnormal FLAIR signals in the corresponding areas. Based on her clinical course and MRI findings, we diagnosed her as MTX encephalopathy, without IVLBCL recurrence or bilateral lacunar infarction. Although we included MTX in the third course of IVLBCL therapy, she felt slight left dysesthesia. Thus, we excluded MTX from later therapeutic regimens. She was maintained in remission by the MTX-free regimen, without IVLBCL recurrence. The bilateral abnormal signals on FLAIR were significantly attenuated at 180 days. Discussion We report the short term dynamic progression and regression of abnormal DWI signals, in parallel with neurologic symptoms, in a case of MTX encephalopathy. To our knowledge, this is the first report of the dynamic MRI changes in the acute phase of MTX encephalopathy. In our case, MTX encephalopathy developed suddenly as a stroke-mimic at 13 days after intrathecal MTX administration, consistent with previous reports.2,3 Her neurologic symptoms and abnormal DWI signals then resolved spontaneously by 34 hours after symptom onset, although minor abnormal signals remained in the right corona radiata on FLAIR. As additional treatment may be required immediately in cases of encephalopathy caused by IVLBCL, we repeated MRI examination shortly after the development of neurologic symptoms in our case. The spontaneous improvement of both neurologic symptoms and MRI findings over this time was highly suggestive of MTX encephalopathy, rather than IVLBCL recurrence in the CNS or regular brain infarction.4 Thus, short-term MRI follow-up may be useful for differential diagnosis between MTX encephalopathy and other irreversible diseases. Although MTX is involved in various metabolic pathways, the detailed mechanisms underlying reversible MTX encephalopathy remains unclear. In the present case, MTX appeared to cause reversible white matter demyelination, as previously reported.1,5,6 It is reported that genetic polymorphisms attenuating methionine metabolism may increase the risk of MTX encephalopathy7. Methionine is important for CNS myelination. Recent studies demonstrate the importance of epigenomic regulation in the oligodendrocyte lineage, whereby DNA methylation regulates the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes through transcriptional regulation during normal ARTICLE IN PRESS DYNAMIC MRI CHANGES IN METHOTREXATE ENCEPHALOPATHY development and in remyelination processes in adults.8 Thus, MTX may disturb the differentiation of the oligodendrocytic lineage. The reversible white matter lesions support the concept that a disturbance of DNA methylation and altered gene expression, as well as attenuated methionine supply, may underlie MTX encephalopathy. In conclusion, the early detection of dynamic progression and regression of abnormal DWI signals may help early diagnosis of MTX encephalopathy. Acknowledgments: We thank Edanz Group (www.edanze diting.com/ac) for editing a draft of this manuscript. References 1. Vezmar S, Becker A, Bode U, et al. Biochemical and clinical aspects of methotrexate neurotoxicity. Chemotherapy 2003;49:92-104. 2. Inaba H, Khan RB, Laningham FH, et al. Clinical and radiological characteristics of methotrexate-induced 3 acute encephalopathy in pediatric patients with cancer. Ann Oncol 2008;19:178-184. 3. Baehring JM, Fulbright RK. Delayed leukoencephalopathy with stroke-like presentation in chemotherapy recipients. J Neurol Neurosurg Psychiatry 2008;79:535-539. 4. Glass J, Hochberg FH, Miller DC. 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