induced encephalopathy, as well as a review of the proposed pathophys- iology of ifosfamide-induced encephalopathy and the use of MB in its management. C a s e R e p o r t s 1. Case 1 A 54-year-old, gravida 2, para 2, married woman presented with re- current epithelial ovarian cancer (endometrioid adenocarcinoma). She had noninsulin dependent diabetes mellitus, diabetic retinopathy, and hyper- tension. Seven years earlier, she underwent coronary artery bypass grafting due to coronary artery disease. Three years ago, she was transferred to our center after laparoscopic bilateral salpingo-oophorectomy which led to a diagnosis of epithelial ovarian cancer. She underwent a debulking operation, including total ab- dominal hysterectomy and pelvic and paraaortic lymph node dissection, total omentectomy, appendectomy, peritoneal mass excision, and left ureter resection and anastomosis. The tumor was categorized as Interna- tional Federation of Obstetrics and Gynecology (FIGO) stage IIIc and cy- toreductive surgery was suboptimal. Following the surgery, she received 6 cycles of adjuvant chemotherapy with paclitaxel/carboplatin. However, because there was disease progression in this patient, she was further treated with 3 cycles of topotecan, followed by 3 cycles of docetaxel. An abdomino-pelvic computed tomography (CT) scan showed aggravation of disease and her serum carbohydrate antigen 125 (CA-125) concentra- tion was elevated from 534 to 1,270 U/mL. We decided to change her chemotherapy regimen to ifosfamide monotherapy. She was started on ifosfamide 1,200 mg/m2/day, administered via con- tinuous infusion on days 1-3 of each 4 week cycle, along with mesna 300 mg/m2/day. On the third day she received ifosfamide, her mental status worsened, with a change from drowsiness to stupor, followed by disori- entation, stereotyped movements, and emotional instability. She had no lateralizing neurologic signs. Her blood test results, including measure- ments of serum glucose, brain natriuretic peptide, and electrolytes, were normal, and her cerebrospinal fluid was negative for malignant cells. In addition, brain magnetic resonance imaging (MRI) findings were normal. An electroencephalogram showed frequent 1-1.5 Hz periodic or single triphasic waves on both hemispheres (Fig. 1). She was diagnosed with ifosfamide-induced encephalopathy, and her chemotherapy was discon- tinued immediately. Her neurologic symptoms and signs did not improve. Despite the supportive care, her encephalopathy became aggravated, and she developed ifosfamide-induced acute tubular necrosis. She was dis- charged without any hope for recovery and died within 1 month. 2. Case 2 A 46-year-old, gravida 2, para 2, married woman with recurrent ep- You-Jung Shin, Ifosfamide-Induced Encephalopathy ithelial ovarian cancer (serous adenocarcinoma) was referred to our insti- tution for further management. She had no specific medical history. At initial diagnosis of epithelial ovarian cancer, she underwent bilateral salpingo-oophorectomy, partial omentectomy and incidental appendec- tomy at another hospital, and cytoreductive surgery was suboptimal. She received 12 cycles of adjuvant chemotherapy with paclitaxel and carbo- platin. However, an abdomino-pelvic CT scan showed residual peritoneal carcinomatosis and her serum CA-125 concentration was elevated, from 517 to 1,020 U/mL. After referral to our center, she underwent optimal cytoreductive surgery, including total abdominal hysterectomy, pelvic and paraaortic lymph node dissection, low anterior resection, and right di- aphragmatic stripping. After surgery, she received 3 cycles of adjuvant chemotherapy with topotecan and cisplatin. Due to disease progression, her regimen was switched to 3 cycles of docetaxel and carboplatin. Due to the disease progression on this regimen, we changed her chemotherapy regimen to a combination of ifosfamide and etoposide. She received the first cycle of etoposide (75 mg/m2/day in 3-hour infusions on days 1-5) and ifosfamide (1,200 mg/m2/day in 3-hour infusions on days 1-5), along with 300 mg/m2/day mesna, without any complications. On day 6, her speech became unintelligible but her orientation was intact. On day 7, she developed delirium, disorientation, visual and auditory hallucinations, stereotyped movements, and emotional instability. At that time, her esti- mated glomerular filtration rate, serum creatinine and blood urea nitrogen were 27 mL/min (normal, ＞60 mL/min), 2.3 mg/dL (normal, 0.7 to 1.4 mg/dL) and 33 mg/dL (normal, 10 to 26 mg/dL), respectively, and her renal function decreased gradually. Brain MRI was normal. After referral to a nephrologist, her electrolyte imbalance was corrected and her uremia was improved by hemodialysis. However, her mental impairments showed no improvement. She was diagnosed as having severe ifosfamide- induced encephalopathy. She never recovered and was discharged in a hopeless condition on day 10 and died within 1 month. D i s c u s s i o n Ifosfamide is an oxazaphosphorine antineoplastic agent (a nitrogen mustard derivative) and is a structural analog of cyclophosphamide [3,7]. Ifosfamide is a prodrug that requires hepatic activation to its cytotoxic metabolite, ifosfamide mustard [7,8]. The latter is metabolized by cy- tochrome p450 to generate the active alkylating agents, 4-hydroxy-ifos- famide and isophosphoramide mustard [8]. Ifosfamide and its metabolites can penetrate the blood brain barrier (BBB), with CNS toxicity occurring in 10-40% of patients receiving high doses of the drug [2-6]. The exact pathophysiological mechanisms responsible for the devel- opment of ifosfamide-induced encephalopathy are unclear, but one of the causes is thought to be the dechloroethylation of Ifosfamide to form chloroacetaldehyde (CAA) [8-10]. Hypotheses for the possible patho- physiological pathways leading to the development of ifosfamide-induced encephalopathy [2,11,12] were based on the finding of glutaric acid and sarcosine in the urine of a patient with ifosfamide-induced encephalopathy VOLUME 43 NUMBER 4 DECEMBER 2011 261