Journal http://jcn.sagepub.com/ of Child Neurology Progressive Myelopathy Mimicking Subacute Combined Degeneration After Intrathecal Chemotherapy Youbin Yi, Hyung Jin Kang, Hee Young Shin and Keewon Kim J Child Neurol published online 20 March 2014 DOI: 10.1177/0883073814527157 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2014/03/20/0883073814527157 Published by: http://www.sagepublications.com Additional services and information for Journal of Child Neurology can be found at: Email Alerts: http://jcn.sagepub.com/cgi/alerts Subscriptions: http://jcn.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav >> OnlineFirst Version of Record - Mar 20, 2014 What is This? Downloaded from jcn.sagepub.com at UNIV OF ILLINOIS URBANA on August 22, 2014 Brief Communication Progressive Myelopathy Mimicking Subacute Combined Degeneration After Intrathecal Chemotherapy Journal of Child Neurology 1-4 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814527157 jcn.sagepub.com Youbin Yi, MD, MS1, Hyung Jin Kang, MD, PhD2, Hee Young Shin, MD, PhD2, and Keewon Kim, MD, MS1,3 Abstract Intrathecal chemotherapy including methotrexate is well documented for neurotoxicity of diverse clinical manifestation. Acute or chronic leukoencephalopathy is the most common type of methotrexate-induced neurotoxicity, and subacute myelopathy is rare. Although its pathogenesis is not fully understood, it is postulated that direct damage of methotrexate to the central nervous system plays a major part and elevated levels of homocysteine and its excitatory amino acid neurotransmitter metabolites (homocysteic acid and cysteine sulfinic acid) could mediate, in part, MTX-associated neurotoxicity. On the while, subacute combined degeneration is a progressive degeneration of the dorsal and lateral columns of the spinal cord, mostly due to vitamin B12 deficiency. The authors report a case of a 15-year-old boy with Burkitt leukemia who developed progressive myelopathy after intrathecal triple therapy (methotrexate, cytarabine, and hydrocortisone) whose clinical and radiologic features were compatible with subacute combined degeneration. The pathogenic mechanism could be explained by biochemical alteration by methotrexate and a possible treatment strategy was discussed. Keywords intrathecal, methotrexate, subacute combined degeneration Received October 12, 2013. Received revised December 13, 2013. Accepted for publication February 13, 2014. Intrathecal triple therapy, which is composed of methotrexate, cytarabine, and hydrocortisone, is widely used in children for the treatment of malignancies involving the central nervous system. It is also well known to be related to various degrees of transient and permanent neurotoxicity.1 Acute or chronic leukoencephalopathy is the most common type of methotrexate-induced neurotoxicity, and subacute myelopathy is rare. Subacute combined degeneration, on the other hand, is a progressive disease that shows characteristic ataxic features with diminished sense of pressure, vibration, and touch. It usually occurs due to a deficiency of vitamin B12, but also that of copper.2,3 To the authors’ knowledge, chemotherapyinduced neurotoxicity whose magnetic resonance image (MRI) findings mimic subacute combined degeneration is rare and there have been no such reports in pediatric patients. Here we report a case of intrathecal triple therapy–induced progressive myelopathy in a child with Burkitt leukemia whose magnetic resonance image showed findings resembling subacute combined degeneration. We have also reviewed the literature for suggested pathogeneses and discussions of possible treatments. Case Report A 15-year-old boy was diagnosed with Burkitt leukemia with central nervous system involvement in May 2011. The initial white blood cell count was 11 900/mL. He underwent multiple courses of systemic chemotherapy, with a session of 70 mg of intrathecal cytarabine and 35 mg of hydrocortisone followed by a total of 8 rounds of intrathecal triple therapy of 15 mg of methotrexate, 30 mg of cytarabine, and 15 mg of hydrocortisone. The systemic chemotherapy he received comprised 1 Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul, Republic of Korea 2 Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea 3 Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea Corresponding Author: Keewon Kim, MD, MS, Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongro-gu, Seoul, 110-744, South Korea. Email: [email protected] Downloaded from jcn.sagepub.com at UNIV OF ILLINOIS URBANA on August 22, 2014 2 Journal of Child Neurology Figure 1. Magnetic resonance images (MRIs) on T1- (A, C) and T2-weighted images (B, D) show diffuse high signal intensities along the whole spinal cord. T2-weighted axial images at C2 (E), T4 (F), and T10 (G) levels respectively show high signal intensities on the dorsal columns, which resemble typical findings of subacute combined degeneration. 1 cycle of cyclophosphamide, vincristine, and prednisolone; 2 cycles of cyclophosphamide, vincristine, prednisolone, doxorubicin, and methotrexate; and 1 cycle of etoposide with high-dose cytarabine. In addition, he underwent 2 sessions of high-dose systemic methotrexate of 14 g. Five months from the onset of the disease, after the 8th round of intrathecal chemotherapy, a second isolated central nervous system relapse was proven by positive cerebrospinal fluid cytology. Another round of intrathecal triple therapy was instilled, and the cerebrospinal fluid cytology converted to negative. Two more rounds of intrathecal triple therapy followed. Between the 10th and 11th round of intrathecal chemotherapy, he started to feel difficulty urinating. He subsequently developed gait ataxia and bilateral lower extremity weakness. His proprioception and sense of light touch were decreased in the bilateral lower extremities. Cerebellar function tests were normal. Nine days after the symptom onset, the 11th intrathecal triple therapy was administered. After that, magnetic resonance imaging revealed diffuse high signal intensities along the dorsal columns of the whole spinal cord on T2-weighted images, which resembled typical findings of subacute combined degeneration (Figure 1). Because his serum vitamin B12 was normal (3354 ng/L) and serum copper was decreased (524 mg/L), copper (II) sulfate pentahydrate 4 mL was given over 15 minutes intravenously based on the suspicion that reduced copper level might have induced his neurologic condition. In spite of copper supplementation, his symptoms worsened. On the 7th day of copper supplementation, the 27th day from the symptom onset, bilateral facial palsy and decreased facial sensation developed. Nerve conduction studies revealed bilateral Downloaded from jcn.sagepub.com at UNIV OF ILLINOIS URBANA on August 22, 2014 Yi et al 3 facial neuropathy and there were no responses on the bilateral blink reflex test. Magnetic resonance image revealed bilateral symmetric enhancement of the facial nerve, which was compatible with chemotherapy-induced cranial neuropathy. His hypesthesia and weakness progressed to the upper extremities by 15 days after the start of the copper supplementation and he became unable to walk in the following 15 days. Nerve conduction studies showed combined peripheral lesions of generalized sensorimotor peripheral neuropathy. Fifty-nine days after the onset of the urinary and gait disturbance, left third cranial nerve palsy and dysphagia developed. He also complained of mild dyspnea, but his chest radiographs showed no specific lung lesions. Follow-up magnetic resonance images on the 61st day from the symptom onset showed an increased extent of the high signal intensities to the bilateral lateral columns of the thoracic spinal cord on T2-weighted imaging. Two days after the onset of dyspnea, he was transferred to the intensive care unit because of respiratory failure induced by pneumonia. He expired because of respiratory failure 9 months after the onset of the leukemia. Discussion We documented a case of progressive myelopathy that exhibited the typical radiologic characteristics of subacute combined degeneration. The patient was diagnosed as Burkitt leukemia and treated with several rounds of intrathecal triple therapy and systemic chemotherapy. Because the magnetic resonance images resemble subacute combined degeneration with T2 high signal intensities in the dorsal and lateral columns of the spinal cord, laboratory tests for vitamin B12 and copper were performed. The serum level of vitamin B12 was normal and that of copper was only mildly decreased. Copper administration was carried out, but it did not help prevent progression of his neurologic symptoms. His neurologic symptoms deteriorated over time. After 11 rounds of intrathecal triple therapy, on the 224th day from the first intrathecal triple therapy administration and the 84th day from the last one, the patient expired not from malignancy but from respiratory failure, supposedly associated with neurologic deterioration. Methotrexate is a folate analogue that is used in the treatment of various malignant diseases including acute lymphoblastic leukemia. It certainly plays a critical role in treating those threatening diseases but also increases the risk of neurotoxicity, which might be transient but might also be irreversible and severe enough to even cause death.4 Subacute combined degeneration, on the other hand, refers to the progressive degeneration of the posterior and lateral columns of the spinal cord, and it can also involve the brain and peripheral nervous system.5 The direct cause of subacute combined degeneration is defective transmethylation of myelin6 caused by dysfunction of the methyl-transfer pathway. In other words, vitamin B12 deficiency, the main cause of subacute combined degeneration, causes lack of methionine and, in turn, S-adenosylmethionine, a universal methyl-group donor in the brain.7 Methotrexate and methotrexate polyglutamates are known to inhibit the enzyme dihydrofolate reductase and thymidylate synthase.8,9 This leads to a deficiency of 5-methyltetrahydrofolate, which is a donor of the methyl group for producing methionine and, in turn, S-adenosylmethionine, as in subacute combined degeneration. Therefore, intrathecal methotrexate treatment can induce demyelination of the central nervous system, which is identical to that from subacute combined degeneration. In our patient, however, it has not been proven whether intrathecal methotrexate was the actual cause of his neurologic deterioration. Although intravenous replacement of copper did not ameliorate his condition, nutritional deficiency might have contributed to it. Paraneoplastic neurologic disorders should be also ruled out. In this patient, antineuronal antibodies were not screened because his neurologic symptoms did not follow typical features of paraneoplastic neurologic disorders. Nevertheless, it was highly probable, in retrospective speculation, that intrathecal methotrexate was the major cause of his neurologic deterioration, given that his radiologic findings were typical of subacute combined degeneration, vitamin B12 level was in normal range, and methotrexate and vitamin B12 share biochemical pathways in transmethylation of myelin. Importantly, clinicians should consider the possibility of methotrexate-induced neurotoxicity when they encounter a magnetic resonance image showing subacute combined degeneration features because these patients may need a different treatment strategy. Although our case showed a vitamin B12 level in the normal range and no cobalamin supplementation was administered, recent case reports in adult patients have shown improved neurologic symptoms after high-dose multiple folate metabolite substitution, including S-adenosylmethionine and methionine as well as folate and cobalamin10 in spite of a normal level of cobalamin. Considering the mechanism of methotrexateinduced neurotoxicity and a previous report of elevated homocysteine in the cerebrospinal fluid of methotrexate-treated pediatric patients,11 a deficiency of S-adenosylmethionine and methionine is implicated in the occurrence of subacute combined degeneration-mimicking neurotoxicity. Based on what is known, immediate discontinuation of intrathecal methotrexate treatment and supplementation of methionine or S-adenosylmethionine would be the best treatment option. However, further research is required to establish an effective and definite treatment protocol. In conclusion, occurrence of typical features of subacute combined degeneration, clinically and radiologically, after intrathecal methotrexate treatment is not widely known. This is the first report of a pediatric case of the condition. It is of clinical significance for physicians to recognize the possibility of developing subacute combined degeneration-like neurologic deficit during intrathecal chemotherapy because changing chemotherapeutic regimen and supplementing folate metabolites might recover the condition. Author Contributions YBY conceptualized and drafted the first manuscript. HJK, HYS, and KWK reviewed and edited the manuscript. KWK supervised the study. Downloaded from jcn.sagepub.com at UNIV OF ILLINOIS URBANA on August 22, 2014 4 Journal of Child Neurology Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The authors received no financial support for the research, authorship, and/or publication of this article. Ethical Approval Institutional review board approval and informed consent were waived per our institutional policy for publishing retrospective case reports with no patient identifier. References 1. Reddy AT, Witek K. Neurologic complications of chemotherapy for children with cancer. Curr Neurol Neurosci Rep. 2003;3:137-142. 2. Winston GP, Jaiser SR. Copper deficiency myelopathy and subacute combined degeneration of the cord—why is the phenotype so similar? Med Hypotheses. 2008;71:229-236. 3. Ferrara JM, Skeen MB, Edwards NJ, Gray L, Massey EW. Subacute combined degeneration due to copper deficiency. J Neuroimaging. 2007;17:375-377. 4. Vezmar S, Becker A, Bode U, Jaehde U. Biochemical and clinical aspects of methotrexate neurotoxicity. Chemotherapy. 2003;49: 92-104. 5. Russell JSR, Batten F, Collier J. Subacute combined degeneration of the spinal cord. 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Elevation of homocysteine and excitatory amino acid neurotransmitters in the CSF of children who receive methotrexate for the treatment of cancer. J Clin Oncol. 1997;15:2800-2806. Downloaded from jcn.sagepub.com at UNIV OF ILLINOIS URBANA on August 22, 2014
