Fig. 2. Proposed pathogenesis pathways involved in ifosfamide neurotoxicity and the proposed sites of action of methylene blue: (1) Inhibition of extrahepatic mono-amine oxidation of chloroethylamine to chloroacetaldehyde; (2) Restoration of hepatic nicotinamide ade- nine dinucleomide hydrogen (NADH) oxidative functions; (3) Sub- stitute for electron transport flavoprotein (ETF) enzyme (electron acceptor) (ada-pted from Donegan S. J Oncol Pharm Pract. 2001; 6:153-65 [13], with permission). cessation of drug administration, it may not in some patients with high grade toxicity. Because ifosfamide-induced encephalopathy can resolve sponta- neously 48-72 hours following its onset, patients with mild symptoms may not need treatment with MB. Patients with more severe symptoms R e f e r e n c e s 1. Giovanis P, Garna A, Marcante M, Nardi K, Giusto M. Ifosfamide encephalopathy and use of methylene blue: a case report of different sequential neurotoxicity. Tumori. 2009;95:545-6. 2. Ajithkumar T, Parkinson C, Shamshad F, Murray P. Ifosfamide encephalopathy. Clin Oncol (R Coll Radiol). 2007;19:108-14. 3. Alici-Evcimen Y, Breitbart WS. Ifosfamide neuropsychiatric toxicity in patients with cancer. Psychooncology. 2007;16:956-60. 4. Rieger C, Fiegl M, Tischer J, Ostermann H, Schiel X. Incidence and severity of ifosfamide- induced encephalopathy. Anticancer Drugs. 2004;15:347-50. 5. Meanwell CA, Blake AE, Kelly KA, Honigsberger L, Blackledge G. Prediction of ifosfamide/mesna associated encephalopathy. Eur J Cancer Clin Oncol. 1986;22:815-9. 6. Klastersky J. Side effects of ifosfamide. Oncology. 2003;65 Suppl 2:7-10. 7. McVay JI, Wood AM. Suspected ifosfamide-induced neurotoxicity. Pharmacotherapy. 1999;19:1450-5. 8. Pelgrims J, De Vos F, Van den Brande J, Schrijvers D, Prové A, Vermorken JB. Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature. Br J Cancer. 2000;82:291-4. You-Jung Shin, Ifosfamide-Induced Encephalopathy and with grade 3-4 toxicity may derive greater benefit from MB. How- ever, as the encephalopathy resolves spontaneously in most cases, even in patients with severe symptoms, and since controlled clinical trials have not been conducted to determine the efficacy of MB in severe ifosfamide- induced encephalopathy, the evidence to support its use is not strong [10]. In most cases, MB is considered for use in the management of acute symptoms [12]. While some patients have experienced improvements in CNS function as rapidly as within 10 minutes, others have required several days to recover [10]. MB has been increasingly used both for the treatment and prevention of ifosfamide-induced encephalopathy [8,11]. MB is thought to counteract some of the metabolic pathways of ifosfamide [11]. It may act as an al- ternative electron acceptor, replacing the inhibited flavoproteins and thus restoring the mitochondrial respiratory chain. It may also oxidize NADH, allowing the dehydrogenation of aldehydes. MB has also been found to inhibit plasma and extrahepatic monoamine oxidases (Fig. 2) [3,8,13]. The recommended dose of intravenous MB for treatment of ifosfamide- induced encephalopathy is 50 mg every 4 hours (1% aqueous solution over 5 minutes), whereas the dose for secondary prophylaxis of ifos- famide-induced encephalopathy is 50 mg every 6 hours, either intra- venously or orally [8]. However, the efficacy of MB in patients with severe ifosfamide-induced encephalopathy is still controversial. C o n f l i c t s o f I n t e r e s t Conflict of interest relevant to this article was not reported. 9. David KA, Picus J. Evaluating risk factors for the development of ifosfamide encephalopathy. Am J Clin Oncol. 2005;28:277-80. 10. Patel PN. Methylene blue for management of Ifosfamide-induced encephalopathy. Ann Phar- macother. 2006;40:299-303. 11. Küpfer A, Aeschlimann C, Cerny T. Methylene blue and the neurotoxic mechanisms of ifos- famide encephalopathy. Eur J Clin Pharmacol. 1996;50:249-52. 12. Turner AR, Duong CD, Good DJ. Methylene blue for the treatment and prophylaxis of ifos- famide-induced encephalopathy. Clin Oncol (R Coll Radiol). 2003;15:435-9. 13. Donegan S. Novel treatment for the management of ifosfamide neurotoxicity: rationale for the use of methylene blue. J Oncol Pharm Pract. 2001;6:153-65. 14. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Bethesda, MD: National Cancer Institute; 2003. 15. Brunello A, Basso U, Rossi E, Stefani M, Ghiotto C, Marino D, et al. Ifosfamide-related en- cephalopathy in elderly patients : report of five cases and review of the literature. Drugs Aging. 2007;24:967-73. VOLUME 43 NUMBER 4 DECEMBER 2011 263