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Year : 2021  |  Volume : 5  |  Issue : 3  |  Page : 123-125

Ifosfamide induced encephalopathy: A rare case presentation and management with review of the literature

1 Department of Medical Oncology, Omega Hospitals, Hyderabad, Telangana, India
2 Department of Surgical Oncology, Omega Hospitals, Hyderabad, Telangana, India

Date of Submission27-Jul-2021
Date of Decision09-Sep-2021
Date of Acceptance21-Sep-2021
Date of Web Publication14-Dec-2021

Correspondence Address:
Namratha Sai Reddy Bijivemula
MLA Colony, Banjara Hills-12, Hyderabad - 500 034, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/oji.oji_32_21

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Ifosfamide-induced encephalopathy (IIE) is a rare adverse event and is usually transient and reversible. However, it may cause permanent neurological dysfunction and even death if not addressed early. The use of aprepitant and presence of acute kidney injury may precipitate IIE. In this report, a 55-year-old female presented with a 3-month history of abdominal mass and bleeding per vagina and was diagnosed as locally advanced high-grade uterine leiomyosarcoma. She underwent surgery followed by adjuvant radiotherapy and combination chemotherapy with doxorubicin plus ifosfamide regimen. During her third cycle chemotherapy, despite dose adjustment of ifosfamide according to patient's creatinine clearance, the patient became aphasic, disoriented, and landed in a stuporous state. After complete evaluation and ruling out other causes, she was diagnosed with IIE for which she was treated with methylene blue and thiamine. This patient showed dramatic response within 8 h of methylene blue administration and complete recovery within 24 h. Our report focuses on the risk factors for the development of IIE and the persistent risk despite ifosfamide dose adjustment according to creatinine clearance.

Keywords: Aprepitant, encephalopathy, ifosfamide, methylene blue, thiamine

How to cite this article:
Bijivemula NS, Vaddeboina N, Dattatreya P S, Suresh A V, Vamsy CM. Ifosfamide induced encephalopathy: A rare case presentation and management with review of the literature. Oncol J India 2021;5:123-5

How to cite this URL:
Bijivemula NS, Vaddeboina N, Dattatreya P S, Suresh A V, Vamsy CM. Ifosfamide induced encephalopathy: A rare case presentation and management with review of the literature. Oncol J India [serial online] 2021 [cited 2022 Aug 18];5:123-5. Available from: https://www.ojionline.org/text.asp?2021/5/3/123/332508

  Introduction Top

Ifosfamide belongs to the group of alkylating agents with efficacy in various hematological and solid malignancies. Ifosfamide, similar to its parent compound, cyclophosphamide, causes myelosuppression and urological toxicity. However, differently from cyclophosphamide, ifosfamide exhibits nonnegligible toxic effects on the central nervous system (CNS) with reported incidence of 5%–30% of all patients treated with ifosfamide.[1]

Ifosfamide-induced encephalopathy (IIE) is an acute neurological condition occurring during or shortly after ifosfamide infusion. Although it is usually reversible, it is a serious and potentially fatal complication and prompt treatment should be initiated. Neurotoxicity can manifest in several ways, including lethargy, agitation, disorientation, confusion, hallucinations, extrapyramidal signs, and seizures.[2] In rare cases, the symptoms can progress to coma, irreversible brain damage, and death.[2]

IIE is a clinical diagnosis with the onset of symptoms between 2 h and 146 h after start of the infusion and is generally treated by discontinuing the agent, adequate hydration, and administration of methylene blue.[2] Early resolution of symptoms has been observed with the administration of methylene blue. Thiamine has also been used in the management of IIE, specifically because of the similar clinical syndrome of Wernicke's encephalopathy, and has been found to be effective.[3] Herein, we report a dramatic response of IIE to methylene blue and thiamine administration along with literature review.

  Case Report Top

A 55-year-old postmenopausal female patient presented with the complaints of abdominal mass and bleeding per vagina for 3 months. Magnetic resonance imaging (MRI) of abdomen was suggestive of a uterine mass with zones of necrosis which was highly suspicious of malignancy. Preoperative biopsy was suggestive of high-grade uterine leiomyosarcoma. Further metastatic work-up was negative for disease elsewhere. The patient underwent total abdominal hysterectomy plus bilateral salpingo-ophorectomy along with pelvic lymph node sampling and omental biopsy. Histopathological examination of the operated specimen was suggestive of high-grade leiomyosarcoma of uterus, pT3aN0M0 (Stage III), and the patient was further treated with adjuvant radiotherapy followed by adjuvant chemotherapy. Adjuvant radiotherapy was given with a total dose of 50 Gray in 25 fractions at 2 Gray per fraction, five fractions per week. Adjuvant chemotherapy was given as adriamycin plus ifosfamide (AI)-based regimen along with antiemetic prophylaxis. AI regimen consists of intravenous infusion of adriamycin 20 mg/m2 body surface area from day 1 to day 3, and ifosfamide 2500 mg/m2 body surface area from day 1 to day 3 along with mesna 2500 mg/m2 body surface area from day 1 to day 3 and the cycle was repeated at 3-weekly intervals. The antiemetic prophylaxis consisted of intravenous administration of ondansetron 12 mg on days 1–3 and dexamethasone 8 mg PO day 1–3 along with intravenous administration of fosaprepitant 150 mg on day 1. During the third cycle of chemotherapy, her serum creatinine was 2.7 mg/dl which was due to prerenal acute kidney injury (AKI) due to the diarrheal episodes she had for the last few days. Following adequate hydration, her serum creatinine reduced to 1.9 mg/dl and hence during the third cycle, ifosfamide dose was reduced by 50% based on the creatinine clearance. On the 2nd day of third cycle, the patient developed aphasia, altered sensorium and gradually became stuporous. Serum electrolytes along with biochemical tests were within normal limits. MRI brain was done which showed lacunar infarcts in left parietal lobe. Electroencephalogram (EEG) and cerebrospinal fluid (CSF) analysis were normal. After ruling out other possibilities, the patient was diagnosed with IIE and she was immediately started on intravenous administration of methylene blue 50 mg every 6th hourly along with thiamine 100 mg administered intravenous every 8th hourly. Within 8 h of initiation of methylene blue and thiamine, the patient showed signs of improvement with regaining of consciousness and within 24 h, the patient showed complete recovery with normal speech, consciousness, and orientation to time place and person.

  Discussion Top

Ifosfamide is a prodrug that undergoes hepatic activation by cytochrome P450 to its cytotoxic metabolites. The neurotoxicity of ifosfamide is dose dependent and is caused by its metabolites, mainly chloroacetaldehyde (CAA), which can cross the blood–brain barrier and cause neurotoxic effects by inhibition of mitochondrial oxidative phosphorylation and depletion of glutathione from CNS.[4] Various studies have suggested that female gender, low serum albumin, hepatic or renal dysfunction, previous cisplatin use, and interactions with drugs that increase ifosfamide metabolism in the liver increased the risk of toxicity.[5] Through CYP3A4 ifosfamide is hydroxylated to ifosforamide mustard, an active alkylating agent and is also converted to inactive, neurotoxic metabolites: the 2-and 3-dechloroethylifosfamide. Concomitant use of aprepitant a neurokinin-1 inhibitor has been shown to increase the risk of IIE due to inhibition of CYP3A4 by aprepitant which may increase the levels of active ifosfamide metabolites.[6]

The manifestations of IIE include lethargy, agitation, disorientation, confusion, hallucinations, extrapyramidal signs, seizures and can progress to coma, irreversible brain damage, and death.[2] IIE is a clinical diagnosis and diagnosis of exclusion with differential diagnosis of electrolyte imbalance, infections, cerebrovascular accidents, or other drug-induced syndromes. MRI brain, CSF, and EEG analysis aid in ruling out other causes of encephalopathy.

The management of IIE includes immediate cessation of the drug, adequate hydration, and administration of methylene blue.[7] Methylene blue acts as an electron acceptor and the mechanism of action of methylene blue is that it inhibits the extrahepatic monoamine oxidation of chloroethylamine to CAA, thereby preventing the formation of CAA.[8] Evidence is inconclusive about the role of methylene blue in the management as well as in prophylaxis of IIE as all the literature available is only of case reports and retrospective studies.[9] A retrospective study done by Richards et al. suggested that prophylaxis was not associated with a reduced incidence of IIE.[2] Buesa et al. published a case series in which treatment with thiamine in 10 patients with IIE showed complete recovery after a median time of 36 h with few patients showing clinical improvement as early as 8 h.[10]

The present case was premedicated with fosaprepitant and due to elevated creatinine, the ifosfamide dose was adjusted for creatinine clearance. We thought that the administration of fosaprepitant and the preexisting AKI together might have precipitated the development of IIE. As soon as, other causes were ruled out, we promptly administered intravenous methylene blue and thiamine. The patient started to show dramatic clinical improvement within 8 h and regained normal consciousness within 24 h.

In conclusion, this case report suggests that despite ifosfamide dose adjustment for creatinine clearance, the risk of IIE still exists. Aprepitant use and presence of AKI may precipitate the development of IIE. It also emphasizes on the importance of the timely administration of methylene blue which causes early clinical recovery from IIE. The case report raises an important question whether to add methylene blue as prophylaxis in individuals at high risk of developing IIE.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Nicolao P, Giometto B. Neurological toxicity of ifosfamide. Oncology 2003;65 Suppl 2:11-6.  Back to cited text no. 1
Richards A, Marshall H, McQuary A. Evaluation of methylene blue, thiamine, and/or albumin in the prevention of ifosfamide-related neurotoxicity. J Oncol Pharm Pract 2011;17:372-80.  Back to cited text no. 2
Kataria PS, Kendre PP, Patel AA. Ifosfamide-induced encephalopathy precipitated by aprepitant: A rarely manifested side effect of drug interaction. J Pharmacol Pharmacother 2017;8:38-40.  Back to cited text no. 3
[PUBMED]  [Full text]  
Sood C, O'Brien PJ. 2-Chloroacetaldehyde-induced cerebral glutathione depletion and neurotoxicity. Br J Cancer Suppl 1996;27:S287-93.  Back to cited text no. 4
Lo Y, Shen LJ, Chen WH, Dong YH, Wu FL. Risk factors of ifosfamide-related encephalopathy in adult patients with cancer: A retrospective analysis. J Formos Med Assoc 2016;115:744-51.  Back to cited text no. 5
Howell JE, Szabatura AH, Hatfield Seung A, Nesbit SA. Characterization of the occurrence of ifosfamide-induced neurotoxicity with concomitant aprepitant. J Oncol Pharm Pract 2008;14:157-62.  Back to cited text no. 6
Barthelemi L, Bara E, Descoeur J, Sirvent N. Ifosfamide induced encephalopathy: Symptoms and ĞκcĂcy of methylene blue (MB) in the treatment and prevention of this adverse effect. J Fundam Clin Pharmacol 2015;29:24.  Back to cited text no. 7
Patel PN. Methylene blue for management of Ifosfamide-induced encephalopathy. Ann Pharmacother 2006;40:299-303.  Back to cited text no. 8
Sweiss KI, Beri R, Shord SS. Encephalopathy after high-dose Ifosfamide: A retrospective cohort study and review of the literature. Drug Saf 2008;31:989-96.  Back to cited text no. 9
Buesa JM, García-Teijido P, Losa R, Fra J. Treatment of ifosfamide encephalopathy with intravenous thiamine. Clin Cancer Res 2003;9:4636-7.  Back to cited text no. 10


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